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Badar Khan Suri's only “crimes” were his marriage to a US citizen of Palestinian origin and support for Palestine.
Badar Khan Suri's only “crimes” were his marriage to a US citizen of Palestinian origin and support for Palestine.
This piece was handwritten by Badar Khan Suri, who read it to one of his attorneys while he was imprisoned in Texas. It has been lightly edited for clarity. Update: A federal district court judge ordered Khan Suri's immediate release in a hearing on May 14. Read more about that ruling here.
On December 10, 2022, I arrived in the United States to start a post-doc fellowship at Georgetown University in Washington, D.C. I was excited to begin a new phase of my academic career.
Three years later, I am a political prisoner, held unlawfully at a detention center in Texas, more than a thousand miles away from my wife and children. Theoretically I am “detained,” but in practice I am incarcerated, classified as high-risk with extreme restrictions.
On March 17, as I was returning home from Iftar [the sunset fast-breaking meal during Ramadan], a convoy of black unmarked cars blocked my path, and masked agents abducted me, without giving me any explanation. Later, after putting me in a car, they told me my visa was revoked by someone high up at the Secretary of State's office for my social media posts. I would be deported to my home country of India that day, they told me.
The first night was like a walk with death. I feared they were disappearing me. On my flight to Louisiana, I was put in chains with hundreds of other chained people. We experienced such extreme turbulence that I was afraid the plane would be crashed deliberately. Between that night and the next evening, I was moved four times to different locations. I was never informed where I was going and not allowed to call my wife (aside from the first night) or attorneys until March 21, when I was transported to my present location in Alvarado, Texas.
The whole process was started by dangerous pro-Israeli groups that are infamous for witch-hunting. Rather than protect me from this vicious campaign, the Trump administration came after me under the pretense of protecting national security and foreign policy. My only “crimes” making me a “national security threat” are my marriage to a United States citizen of Palestinian origin and my support for the Palestinian cause.
As a student of peace and conflict studies, I was introduced to many conflicts, and the Palestinian cause in particular stuck with me. I unapologetically support Palestinians, and their inalienable rights guaranteed by international law. Where are the Geneva Conventions? Or is it true that elites are protected by laws, but not bound by them, while the unprivileged are bound, but never protected?
To say it all started on October 7, 2023, is a cynical lie. Palestinians have suffered ethnic cleansing for more than a century. The international community has abdicated its responsibility to fellow humans in the Holy Land. The ongoing genocide of Palestinians would not have been possible without billions of dollars of funding, particularly from the U.S., but also from many European and other prominent states. The United Nations is made dysfunctional through vetoes; even when the Security Council or General Assembly passes resolutions sanctioning Israel, they are ignored. This dysfunction has allowed Israel to commit crimes against humanity with impunity as it destroys hospitals, schools, universities and all life-supporting infrastructures. The impunity has also led to unspeakable sadism. Those of us who have cared to look have seen videos of Israeli soldiers destroying kids' toys, raping Palestinian detainees in notorious prisons and killing medical staff.
Nonetheless, the attack of October 7 was a crime against humanity, as many innocent Israelis lost their lives. It was inhumane and against Islamic principles: if you kill an innocent human, it is as if you have killed the entirety of humanity. It also defies Mahatma Gandhi's principle that means should justify the ends, and not vice versa. Gandhi's principle of nonviolent resistance to misery or tyranny is what I believe and practice.
We can neither forget the Holocaust of Jews in Europe nor that Palestinians were not responsible for it.
We must remember that Palestinian resistance has often taken nonviolent forms, such as the Great March of Return in 2018 and 2019. Unfortunately, their demands for justice were ignored by the world, and Israeli snipers killed more than 200 Palestinian nonviolent protesters, medics, and journalists, including forty-six children. As a matter of fact, Marwan Barghouti – the Palestinian Gandhi — has been in jail for more than two decades.
Still, Gandhian nonviolent resistance is the best means to an inalienable free Palestine: a single state with unshakable guarantees of rights to Jews, Muslims, Christians, and others, which any factor — including a majoritarian electoral democracy — can never disturb.
We can neither forget the Holocaust of Jews in Europe nor that Palestinians were not responsible for it. Let us fulfill Pope Francis's last wish to end bloodshed in the Middle East and end wars of retribution.
My Indian upbringing and education have shaped my stance on Palestine, as it comes from the great teachers, not only Gandhi but also Ashoka and Siddhartha (Gautama Buddha). Siddhartha was a royal prince, but he was not indifferent to the suffering that he encountered as he came out of his palace. My beliefs do not allow me to ignore the pain of Palestinians. As a political prisoner, I face deprivation — of sleep, food, hygiene, and, worst of all, contact with my loved ones — but I take solace in knowing that I endure this ordeal for the children of Palestine, and I see my suffering as nothing compared to theirs.
The time-honored principles I have adopted as my own also empower me to leave no avenue unexplored in defying the witch hunt unleashed upon me and others who believe in freedom for Palestinians. We will reject authoritarianism and oppose this travesty of justice. Be courageous, because courage is contagious. Together, we can stand against the tide of totalitarianism, because, as the Mundaka Upanishad states, “satyameva jayate” — ultimately truth triumphs over falsehood.
The Trump administration is cracking down on political dissent. Under pressure from an array of McCarthy-style tactics, academics, activists and nonprofits face significant threats for speaking out or organizing in resistance.
Truthout is appealing for your support to weather this storm of censorship. We've launched a fundraising campaign to find 500 new monthly donors in the next 10 days. Will you be one?
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Dr. Badar Khan Suri is a visiting scholar and postdoctoral fellow at Georgetown University, and an Indian national. He is married to a United States citizen of Palestinian origin whose family is from Gaza. They live with their three young children in Virginia.
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The jury in Sean “Diddy” Combs' sex trafficking trial is being shown images of “freak-off” sex parties involving his ex-girlfriend Cassie Ventura.
Ventura, whose 10-year relationship with the music mogul ended in 2018, claims she was forced to have sex with male escorts in the drug-fuelled sessions, that could last as long as four days.
Privacy screens have been erected in the courtroom while the pictures are displayed.
Ventura told the court on Wednesday that Combs had used the footage of the “freak-offs” to “blackmail” her and was scared he would use it to destroy her career.
“I'm going to put out two embarrassing videos of you,'” he is alleged to have told her when she began dating someone else.
Ventura said: “I feared for my career, I feared for my family. It's horrible, it's disgusting – no one should do that to anyone… It could ruin everything I worked for, make me look like a sl-t.”
On a flight, coming back from the Cannes Film Festival, she said Combs played videos of the “freak-offs” while there were other passengers around.
“I was scared, I felt trapped” she told the court, believing the record producer was going to release the footage.
Combs' teenage daughters, Chance, D'Lila and Jessie, were not present for the third day of their father's trial, having left partway through proceedings on Tuesday.
Combs is charged with racketeering conspiracy, sex-trafficking and transportation to engage in prostitution. If convicted on all counts, he faces a mandatory minimum sentence of 15 years, and could face life in prison.
He has pleaded not guilty on all counts.
Sean “Diddy” Combs's security guard cried when he saw Cassie Ventura's injuries, the R&B singer said.
The rapper beat up his ex-girlfriend in a Las Vegas hotel in 2015 while he was hosting a party in the adjoining wall, she said.
“He punched me, kicked me, I was trying to run away and I made it into the bathroom,” she said, adding that she tried to hide underneath a toilet to get away from him.
When members of Combs's security team finally came into break things up, she had “black eyes” and “golf ball-sized knots” on her forehead, causing one of the guards to burst into tears.
Ventura said she had to stay at Combs' home for nearly a week to recover from the injuries, where she was staying with the rapper's son.
When she spoke to Combs on FaceTime, he allegedly told her to put on more makeup to hide her injuries from his son.
Sean Combs threatened to blow up Kid Cudi's car when he realised the rapper was dating his ex-girlfriend.
Ventura said she broke things off with Kid Cudi, real name Scott Mescudi, in 2011, stating there was “too much danger, too much uncertainty of what could happen if we continued to see each other”.
Combs had said he would blow up Mescudi's car, Ventura said, and that Combs wanted the rival rapper's friends to be present when it happened.
At some point, Mescudi's car blew up, after which he, Ventura and Combs had a meeting at Soho House about their relationship.
When Mescudi asked, “What about my vehicle?” Combs responded, “What vehicle?”
“And that was the end of the meeting,” Ventura said.
Cassie Ventura says Sean Combs lunged at her with a wine bottle-opener when he realised she was dating Kid Cudi, the rapper.
He made the discovery by looking through her phone during a “freak-off” in 2011, she tells the court.
Combs is said to have been enraged and threatened to release two “explicit sex tapes” of her.
Ventura then reads from an email she sent to her mother about Combs, in which she said the music mogul said he would “hurt” her and Cudi, and would be out of the country when it happened.
Cassie Ventura says she did not have the “resources” to leave Sean Combs after he allegedly beat her at a party in Los Angeles.
“I didn't have the resources I needed to get out and move, to get out and not have anybody stop me,” she testifies.
“I understood Sean's capabilities, his access to guns, and the threats that he made prior to that.”
Ventura says her mother saw a story about the incident online which did not mention her name. She denied she was the woman in the story because she was “ashamed”, she tells the court.
“I didn't want to put my mother in danger of knowing anything of that magnitude,” Ventura says.
Cassie Ventura says she ran away from Sean Combs after a drunken fight, but was brought back by his security team.
She had drunkenly punched him in the face, prompting him to beat her and stomp on her, she says.
When she was back at his Los Angeles house, she says she did not recognise herself, telling the court her face was “bleeding”, “swollen” and “horrible”.
Cassie Ventura says she was “shocked” the first time Sean Combs hit her.
She tells the court that, in 2007 or 2008, she was at dinner when she saw Combs flirting with somebody else. When another person noticed her watching, she apparently shrugged her shoulders.
When they returned to the car after dinner, she says he “hit me in the side of my head and I fell to the floor”.
“I was just shocked, and I didn't necessarily understand what happened and why he was so angry except for the little bit he said as he was hitting me in the car,” she testifies.
“And I just went home and kind of hid out after that.”
A photo of the Los Angeles hotel room where Sean Combs allegedly attacked Cassie Ventura has been entered into evidence at the court.
Ventura claimed earlier today that the record producer threw a vase at her head, which missed her and shattered on a wall instead.
Cassie Ventura is identifying the various “freak-offs” participants from the images being shown to the jury.
Three of them are escorts whom she has previously mentioned in her testimony: Dave, Greg and Jules.
Of one image, she says: “There is baby oil on me and I am standing there during a freak off with a candle and lubricant on the table.”
One female member of the jury exhaled sharply when they were shown sexually explicit images from the Sean Combs' “freak-offs”, CNN reported.
A male juror is said to have glanced at one of the pictures before looking away quickly.
Cassie Ventura texted Sean Combs in 2017 saying: “You treat me like you're Ike Turner”, referring to Tina Turner's abusive former husband.
Asked to clarify what she meant, she says her then-boyfriend was “physically abusive” and controlling.
“He put me down a lot. As much as I was built up, I was put down quite a bit,” she tells the court.
“It's also the just sheer embarrassment, like how he treated me in front of other people.”
The air raid was announced at around 2:30 p.m. local time, while the explosion sounded around 2:50 p.m. The number of victims killed rose to three, Sumy Oblast Governor Oleh Hryhorov reported at 8:42 p.m.
If confirmed, the decision would mark the first time since Russia's full-scale invasion that President Volodymyr Zelensky is absent, either physically or virtually, from a NATO summit.
The disclosure follows a warning from Digital Affairs Minister Krzysztof Gawkowski, who on May 6 said Moscow was carrying out an "unprecedented" interference campaign.
Brazilian President Lula da Silva claimed that Ukrainian Foreign Minister Andrii Sybiha had appealed to his Brazilian counterpart, Mauro Vieira, to ask Putin if he was willing to conclude a peace agreement.
Earlier reporting from the Washington Post cited a former Russian official who claimed Russian Foreign Minister Sergey Lavrov and Putin's foreign policy aide, Yuri Ushakov, would represent Moscow in the talks.
Vyshyvanka, a traditionally styled embroidered shirt or dress, is the central feature of Ukraine's national clothing.
The Council of Europe on May 14 approved the creation of a special tribunal to prosecute Russia's top leadership for the crime of aggression against Ukraine, Ukrainian lawmaker Maria Mezentseva reported.
Viktoria Roshchyna, 27, disappeared in August 2023 while reporting from Ukraine's Russian-occupied territories. Moscow admitted she was in Russian detention the following year.
Dutch Justice Minister David van Weel speaks about the future of the EU-led special tribunal for the crime of aggression against Ukraine and its role in bringing Russia to justice.
Turkish officials told Bloomberg that while they don't expect Trump to visit Istanbul, they are not ruling it out, and preparations for any scenario are underway.
Melkonyants was arrested in August 2023 in connection with the activities of the European Network of Election Monitoring Organizations (ENEMO), which was co-founded by Golos's legal predecessor, the Golos association.
Editor's note: This story has been updated with the reaction of Kremlin spokesperson Dmitry Peskov.
Germany gave Russia until the end of May 12 to agree to a ceasefire in Ukraine, warning that failure to do so would trigger preparations for new sanctions, government spokesperson Stefan Kornelius said during a briefing, Tagesschau reported on May 12.
"The clock is ticking — we still have 12 hours until the end of this day," Kornelius reportedly said, adding that Berlin is coordinating with European partners on additional sanctions.
The ultimatum follows Russia's refusal of a 30-day unconditional ceasefire starting May 12, proposed by Ukraine and its allies last week when European leaders visited Kyiv.
The demand for the unconditional 30-day ceasefire was the main outcome of talks between Ukraine, France, the U.K., Germany, and Poland, according to President Volodymyr Zelensky.
Kremlin spokesperson Dmitry Peskov reacted to the remarks, saying that "ultimatum language" in talks with Russia is "unacceptable."
"This kind of ultimatum language is unacceptable for Russia. It's not appropriate. You cannot talk to Russia in this language," Peskov told a pool of Russian journalists on May 12.
Over the past 24 hours, Russian attacks injured at least 22 people in Ukraine. This includes at least seven people injured in drone attacks overnight on May 12, a date from which the 30-day unconditional truce should have started.
The Kremlin continues insisting on negotiations without an unconditional ceasefire. In a press conference in the early hours of May 11, Russian President Vladimir Putin invited Ukraine to resume talks, which, according to Kremlin aide Yuri Ushakov, Russia wishes to be based on the terms of the 2022 Istanbul discussions and the "current situation on the battlefield."
Zelensky announced his readiness to meet Putin in Turkey on May 15, reiterating Ukraine's proposal for a complete and unconditional ceasefire starting May 12. The Kremlin has not responded to Zelensky's proposal for a face-to-face meeting of the two leaders.
News Editor
Anna Fratsyvir is a news editor at the Kyiv Independent, with a background in broadcast journalism and international affairs. Previously, she worked as a TV journalist at Ukraine's public broadcaster Suspilne, covering global politics and international developments. Anna holds a Bachelor's degree in International Communications from Taras Shevchenko National University and is currently an MA candidate in International Relations at the Johns Hopkins School of Advanced International Studies (SAIS).
The law is an “egregiously unconstitutional attempt to censor” free speech, the lawyer for the plaintiffs said.
On Tuesday, a federal appellate court ruled that an injunction barring the enforcement of Florida's drag show ban could remain in place pending the outcome of the case in lower courts, finding that the ban is likely in violation of First Amendment speech freedoms.
The Florida law, passed by a Republican state legislature and signed by GOP Gov. Ron DeSantis, doesn't explicitly mention drag shows in its text. But the regulation of “adult live performances” in front of audiences with children present — including shows that use “prosthetic or imitation genitals or breasts” — undoubtedly targets drag shows. Venues that violate the statute face fines and the possibility of having their liquor license suspended or revoked, while individuals could be charged with a misdemeanor.
The law was challenged by Hamburger Mary's restaurant in Orlando, Florida, which regularly hosts family-friendly drag shows for its patrons.
In a 2-1 decision before the 11th Circuit Court of Appeals, the court's majority ruling, authored by Judge Robin Rosenbaum, found that the law was not specific enough in detailing what should be regulated, adding that the plaintiffs had a very high likelihood of success in showing their First Amendment speech rights would be violated by enforcement of the law.
“By providing only vague guidance as to which performances it prohibits, the Act wields a shotgun when the First Amendment allows a scalpel at most,” Rosenbaum wrote in the court's opinion.
The provisions of the law “turn the Act into an ‘I know it when I see it' law,” Rosenbaum added. “But the Constitution requires more clarity.”
Although the law itself never mentions drag show performances, those involved in its passage — including DeSantis and one of the bill's legislative cosponsors — directly alluded to targeting drag shows.
The court recognized this fact in its opinion.
“Though the Act applies to a range of ‘adult live performances, its enactors focused on how it would restrict one particular type of performance: drag shows,” Rosenbaum wrote.
The court upheld the injunction placed on the law by a judge in a lower court, where the case will now move forward for an eventual final judgment.
Brian Wright, a spokesperson within DeSantis's office, decried the ruling.
“No one has a constitutional right to perform sexual routines in front of little kids. We will do everything possible to have this lawless decision overturned,” Wright said.
But Hamburger Mary's co-owner John Paonessa noted that the governor's definition of what is “sexual” is far too ambiguous.
“For them, lewd and inappropriate is just a drag queen dressed in clothes not exposing anything. That, to them, is too much,” Paonessa said.
“The Court's opinion recognizes this law for what it is — an egregiously unconstitutional attempt to censor the speech and expression of citizens,” said Melissa Stewart, the attorney representing Hamburger Mary's in the lawsuit.
The Trump administration is cracking down on political dissent. Under pressure from an array of McCarthy-style tactics, academics, activists and nonprofits face significant threats for speaking out or organizing in resistance.
Truthout is appealing for your support to weather this storm of censorship. We've launched a fundraising campaign to find 500 new monthly donors in the next 10 days. Will you be one?
As independent media with no corporate backing or billionaire ownership, Truthout is uniquely able to push back against the right-wing narrative and expose the shocking extent of political repression under the new McCarthyism. We're committed to doing this work, but we're also deeply vulnerable to Trump's attacks.
Your support during our fundraiser (8 days left) will help us continue our nonprofit movement journalism in the face of right-wing authoritarianism. Please make a tax-deductible donation today.
Chris Walker is a news writer at Truthout, and is based out of Madison, Wisconsin. Focusing on both national and local topics since the early 2000s, he has produced thousands of articles analyzing the issues of the day and their impact on the American people. He can be found on most social media platforms under the handle @thatchriswalker.
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Georgetown postdoctoral fellow Badar Khan Suri had visa revoked and was arrested by immigration officials in March
A Virginia federal judge has ordered the immediate release of Georgetown academic Badar Khan Suri from Ice detention during a hearing on Wednesday.
Khan Suri was among several individuals legally studying in the US who have been targeted by the Trump administration for their pro-Palestinian activism. He has spent two months in detention.
US district judge Patricia Giles in Alexandria, Virginia, said that the ruling was effective immediately with no conditions and no bond. She added that Khan Suri's release was “in the public interest to disrupt the chilling effect on protected speech” during the hearing. The judge explained in her ruling how the government did not submit sufficient evidence on several of its claims.
A large crowd of demonstrators outside the courthouse reportedly cheered upon hearing the news of the ruling.
The Trump administration had ordered the detention of Khan Suri, a citizen of India, on 17 March. He was previously being held at an immigration prison in Alvarado, Texas.
Immigration officials revoked his J-1 student visa, alleging his father-in-law, Ahmed Yousef, was an adviser to Hamas officials more than a decade ago in addition to claims that he was “deportable” because of his posts on social media in support of Palestine. Yousef, who has not been an adviser to Hamas in over a decade, has said Khan Suri was not involved in “political activism” on behalf of Hamas.
On March 15, the US secretary of state, Marco Rubio, issued a determination that Khan Suri's presence in the US “would have potentially serious foreign policy consequences”, according to a statement filed in the case by a Virginia immigration office.
Khan Suri, who is married to a Palestinian American US citizen, Mapheze Saleh, is a senior postdoctoral fellow at the institution's Alwaleed Bin Talal Center for Muslim-Christian Understanding (ACMCU). Many students and alumni of the institution signed a letter opposing his detention by Ice.
Giles prohibited federal officials in March from deporting the postdoctoral fellow after his wife filed an emergency court request to prevent deportation.
Communities are learning digital security and building autonomous servers to take control of their own data.
In Mexico, the tech oligarchy is thriving.
Amazon is increasing its spending and plans to lavish $6 billion in U.S. currency in Mexico during this year and next. Meanwhile, the multinational technology company Nvidia is manufacturing AI servers (exempted from tariffs) at factories in Mexico.
Roughly 60 percent of the U.S.'s AI servers are made in Mexico, and Foxconn and Nvidia have recently begun production of a $900 million assembly plant in Mexico for AI servers using Nvidia's GB200 Superchips for Project Stargate, the OpenAI and U.S. government program aimed at consolidating U.S. AI dominance.
Mexico recently announced that Netflix will spend $1 billion in U.S. currency over four years producing content within its borders. Beyond entertainment, Netflix is a tech company using sophisticated software and big data analytics to provide personalized content delivery and streaming media. Netflix CEO Ted Sarandos talked about a vision for Mexico of “prosperity … and growth.” The move is strategic, allowing Netflix to increase its exclusive content at a lower cost without considering the vision or needs of locals. Meanwhile Mexico has decreased its culture budget by 31 percent to focus on this collaboration with Hollywood.
Google, DiDi, and others are creeping into Mexico's banking sector by offering loans and digital wallets. Google and Meta took up 82.5 percent of digital advertising in 2022 in Mexico, while Amazon, Walmart, Airbnb, and others displace traditional and local initiatives.
Meanwhile, Google search results are dominated by U.S. companies, funneling money and resources out of Mexico. Platforms like Facebook tolerate and promote sexism, with serious consequences in a nation with high rates of femicide.
In response, Mexican activists are standing up to Big Tech — promoting the use of feminist servers where people can put their safety first, autonomous servers that can help protect communities and activists in danger, and other tools for greater digital agency.
Facebook feeds and Google results certainly won't be highlighting the growing resistance to the Big Tech empire in countries like Mexico. But for many in the Global South, such digital activism can be a question of life and death.
Of the ten richest people in the world, seven are founders of tech companies, including Elon Musk ($342 billion) and Mark Zuckerberg ($216 billion). These companies have monopolistic control of search engines (Google has 90 percent of the market), mobile operating systems, cloud storage, digital advertising and social media. This gives them gatekeeper power to decide who can be heard both online and in the broader public sphere.
Meta's revenue has grown from $1.87 billion in 2010 to $160 billion in 2024 — in part by exploiting big data, generating dependence through agreements with telecommunications companies, and preloading the app on new devices. Big Tech has then exploited network effects to keep users locked in, and bought out any competitors, generating dependence through monopolization. Meta bought at least 28 companies between 2007 and 2022.
Further, Big Tech has taken advantage of economically weaker countries to pitch themselves as “supporting” their education systems by embedding their programs into schools and creating dependency from a young age. Mexico's education department has a deal with Microsoft to provide students with Office for free even though LibreOffice is already free. Meta is also “supporting” Mexico City's coding school by providing courses and certifications.
Big Tech further exploits vulnerable populations by positioning themselves in the nonprofit sector. “They provide services for a low cost or for free. … They can be quite aggressive, creating legitimacy and dependency as they do,” Mayeli Sanchez, a Mexican digital activist and executive director of Técnicas Rudas, told Truthout. For example, Google says it “supports” media organizations in Mexico through its Google News Initiative to provide them (many of which are nonprofit and likely struggling financially) with digital transformation and training. In that way, Google continues to ensure its dominance.
While U.S. companies profit, Global South workers do much of the traumatic and tedious work. Kenyan, Indian and Filipino workers, who make up the majority of low-paid tech laborers, are paid between $1.32 and $2 an hour to train AI algorithms and sift through and flag violent and disturbing content. Moreover, minerals like cobalt, nickel and lithium used for manufacturing AI hardware are looted from Global South countries like the Democratic Republic of the Congo, at the expense of the environment and labor conditions.
Through monopolies, the Big Tech companies can also control the dominant narrative to suit their interests. Those interests revolve around “free” trade (as Amazon and Washington Post owner, Jeff Bezos stated recently) and U.S. empire, in stark opposition to the Global South preserving or developing its own systems of information, culture, news and research.
“Mexico is one of the countries that provides the most users to Facebook … but we don't receive any kind of benefit … because that platform isn't a benefit in of itself. It fosters a damaging culture,” Sanchez said, describing social media's impact on attention spans.
Some 90 percent of data used to train AI comes from the Global North. On the other hand, the data companies gather through social media and use for marketing largely comes from the Global South — given its larger population.
AI projects “a single worldview,” noted Sasha Luccioni, a scientist who studied text-to-image AI bias and found prejudice in the gender and skin attributes prescribed. For example, when looking up “mujer inteligente” (intelligent woman) in Google Images, all of the first page results are young women of white and upper-class appearance. This bias is not limited to AI — Instagram influencers are more likely to be white and young, and a Dutch human rights institute recently found Facebook's algorithm to have clear gender bias.
“Facebook doesn't promote Indigenous rights or culture, but rather Western values,” Armando Gómez, a Mexican-Otomí cybersecurity specialist and activist with Laboratorio Popular de Medios Libres, told Truthout.
Google privileges sites with the most resources. “Now, search engines are like market lists of sellers … the first page of Google is at least a third sponsored spots, and after them, it's private companies that have used marketing tools. It's unequal, unfair, and a small hostel or town in Mexico can't compete,” said Gómez.
Countries like Mexico struggle to access independent and quality content, because internet access is dependent on phones with preloaded apps like Facebook. In Mexico, 81 percent of people have access to smartphones, and just 44 percent of homes have a computer (including laptops or tablets), while in the U.S., 95 percent of homes have at least one computer, often more.
“We use these companies (like WhatsApp) to talk with our family, work, institutions. They are molding our minds, affecting our perception of the world,” Gómez noted.
Domingo, a founder of the Chiapas-based digital activist group, Sursiendo, who used only his first name for fear of reprisal, argued that Big Tech in Mexico is having a “cultural standardization effect, because everyone has Netflix, everyone orders through Amazon … these monopolies are promoting the American dream … people are dressing and behaving like the U.S., because what you see and consume through screens is what is cool. And that is a way of colonizing us, homogenizing cultures here in order to maximize profit.”
He said Uber and Didi were replacing local taxi businesses, and other U.S. companies like Airbnb and Booking are managing tourism. “Before, there was a tourism that was more local,” he said, adding that tourism in Chiapas “has adapted to Instagram, and the local government and companies install displays for Instagram photos, so the character of these places is lost in these photos, and tourism is now about consuming places very quickly.”
At Mexico's northern border, Google is participating in a Customs and Border Patrol plan to use machine learning for surveillance. Meanwhile, at the southern border, Domingo said his group has been working with immigrant-rights coalition Migrar sin Vigilancia and found that Big Tech companies are “trying out new technologies for social control on migrants … and this is only going to get worse under Trump.”
Technology is being used “constantly to violate human rights” at Mexico's southern border, he said. “No one notices what is happening there, and migrants are very vulnerable, so it is easy to use them as a testing ground for digital tools that are then employed elsewhere. … We are seeing more drones flying over (migrant) shelters or transit areas,” he said, noting it wasn't clear if security forces or organized crime were using the drones.
Further, traffickers “use Facebook and Instagram to reach migrants,” he said, noting that because those companies are based in the U.S., it is difficult for the Mexican government to do anything.
While the European Commission recently fined Apple €500 million and Meta €200million for breaking rules on fair competition and user choice, it can be harder for Global South governments to stand up to Big Tech. IMF-imposed structural changes that weaken state institutions, a lack of resources to dedicate to creating and enforcing regulations, trade agreements that weaken state bodies, and other factors can make it harder for Global South countries to develop enforceable regulations. Gómez described how regulation is so weak in Latin America that they often depend on European regulations, “but while those are enforced or obligatory in Europe, here they are just a guide.”
With the state increasingly unable to restrain Big Tech, digital activism becomes a necessity. And in Mexico, where land defenders are often threatened or disappeared, educating activists about digital security is vital. Gómez's group is providing training in open source software and digital security, and using autonomous servers as a means for communities to be independent of Big Tech and control their data. He says his group has been working with “liberated technology for nine years now, and the impact has been very strong … we have 17 autonomous servers in a Latin American network, and we hope to bring in others and have 30 or 40 in the network within a year, providing our own services.”
In March, Gómez and his group visited and supported Indigenous Amazonian communities in Ecuador, “They have internet that they control, and in assemblies they filter it and decide which websites are allowed. They can prohibit Airbnb, pornography, violence. …It's about being able to decide what the Internet is used for. There are also feminist, queer and ecologist servers for example, and they can decide their own rules about respect and collective care … so there are communities that are free of abuse.”
This week, the bodies of Mixe activist and lawyer Sandra Domínguez and her husband were found in Veracruz. Domínguez had denounced a WhatsApp group chat called Sierra XXX, where over 100 men, including Oaxacan politicians, shared intimate photos of Mixe women without their consent.
Mexico's Olimpia law punishes such digital violence, but it's not enough to prevent violations. For example, the First Latin American Summit of Women Digital Defenders held in Mexico this February was hit by a cyberattack mid-livestream, while presenters were critiquing the policies of Big Tech and discussing the Olimpia law. The hackers projected sexually explicit images.
Sanchez´s group is involved in the feminist server movement, “where a ton of women and dissidents, we work together to learn to create the types of services that Google offers (such as email, storage) and to agree on how we are going to manage our Internet.” That way, women and gender nonconforming people can set content and behavior rules that protect them from abuse or objectification, for example. Her group is also promoting open-source software, which she stresses should never be used to exploit anyone, and promoting “social technology … that involves good practices and better conditions for the users.”
Apart from working with migrant organizations, Domingo's group also participates in various national and international digital activism networks, bringing to Chiapas their social issues and needs, while also bringing information about digital safety and technology to local spaces. “We work with organizations or collectives that want another type of Internet, without corporations, for the citizens, communities, the people,” he said.
Sursiendo, he explains, conducts research, provides training, helps groups “take care of themselves in the digital world” and promotes alternative technologies “so the Internet can be created collectively, rather than with an individualist vision.”
“How can technology be managed in such a way that the so-called sacrifice zones aren't facing such dire consequences?” Sanchez asked. “It's worth asking if there is a way of creating AI that is focused on social benefits, or, if, given the environmental and labor costs, AI is even necessary.”
The Big Tech billionaires are benefiting, “and the rest of the world isn't, but ultimately, it's about if these companies or platforms should exist at all,” she said.
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Tamara Pearson is an Australian-Mexican journalist, editor, activist and literary fiction author. Her latest novel is, The Eyes of the Earth, and she writes the Global South newsletter, Excluded Headlines.
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Christopher Young earns up to $1 million annually as he guts the agency that regulates two of Musk's biggest companies.
This story was originally published by ProPublica. ProPublica is a Pulitzer Prize-winning investigative newsroom. Sign up for The Big Story newsletter to receive stories like this one in your inbox.
One of Elon Musk's employees is earning between $100,001 and $1 million annually as a political adviser to his billionaire boss while simultaneously helping to dismantle the federal agency that regulates two of Musk's biggest companies, according to court records and a financial disclosure report obtained by ProPublica.
Ethics experts said Christopher Young's dual role — working for a Musk company as well as the Department of Government Efficiency — likely violates federal conflict-of-interest regulations. Musk has publicly called for the elimination of the agency, the Consumer Financial Protection Bureau, arguing that it is “duplicative.''
Government ethics rules bar employees from doing anything that “would cause a reasonable person to question their impartiality” and are designed to prevent even the appearance of using public office for private gain.
Court records show Young, who works for a Musk company called Europa 100 LLC, was involved in the Trump administration's efforts to unwind the consumer agency's operations and fire most of its staff in early February.
Young's arrangement raises questions of where his loyalty lies, experts said. The dynamic is especially concerning, they said, given that the CFPB — which regulates companies that provide financial services — has jurisdiction over Musk's electric car company, Tesla, which makes auto loans, and his social media site, X, which announced in January that it was partnering with Visa on mobile payments.
The world's richest man has in turn made no secret of his desire to do away with the bureau, posting just weeks after Donald Trump's election victory, “Delete CFPB. There are too many duplicative regulatory agencies.”
“Musk clearly has a conflict of interest and should recuse,” said Claire Finkelstein, who directs the Center for Ethics and the Rule of Law at the University of Pennsylvania. “And therefore an employee of his, who is answerable to him on the personal side, outside of government, and who stands to keep his job only if he supports Musk's personal interests, should not be working for DOGE.”
Young, a 36-year-old Republican consultant, has been active in political circles for years, most recently serving as the campaign treasurer of Musk's political action committee, helping the tech titan spend more than a quarter billion dollars to help elect Trump.
Before joining Musk's payroll, he worked as a vice president for the Pharmaceutical Research and Manufacturers of America, the trade association representing the pharmaceutical industry's interests, his disclosure shows. He also worked as a field organizer for the Republican National Committee and for former Louisiana Gov. Bobby Jindal, the New York Times reported.
Young was appointed a special governmental employee in the U.S. Office of Personnel Management on Jan. 30 and dispatched to work in the CFPB in early February, according to court records and his disclosure form. Someone with his position could be making as much as $190,000 a year in government salary, documents obtained by Bloomberg show. At the same time, Young collects a salary as an employee of Musk's Texas-based Europa 100 LLC, where, according to his disclosure report, his duties are to “advise political and public policy.”
Beyond that description, it's not clear what, exactly, Young does at Europa 100 or what the company's activities are.
It was created in July 2020 by Jared Birchall, a former banker who runs Musk's family office, Excession LLC, according to state records. The company has been used to pay nannies to at least some of Musk's children, according to a 2023 tabloid report, and, along with two other Musk entities, to facilitate tens of millions of dollars in campaign transactions, campaign finance reports show.
As a special government employee, Young can maintain outside employment while serving for a limited amount of time. But such government workers are still required to abide by laws and rules governing conflicts of interest and personal and business relationships.
Cynthia Brown, the senior ethics counsel at Citizens for Responsibility and Ethics in Washington, which has sued the administration to produce a range of public records documenting DOGE's activities, said that Young's government work appears to benefit his private sector employer.
“Which hat are you wearing while you're serving the American people? Are you doing it for the interests of your outside job?” she asked.
In addition to his role at Europa 100, Young reported other ties to Musk's private businesses. He affirmed in his disclosure form that he will “continue to participate” in a “defined contribution plan” sponsored by Excession, the Musk home office, and that he has served since February as a “vice president” of United States of America Inc., another Musk entity organized by Birchall, where he also advises on “political and public policy,” the records show. While he lists the latter among “sources of compensation exceeding $5,000 in a year,” the exact figure is not disclosed.
Young did not return a call and emails seeking comment. The CFPB, DOGE and the White House did not respond to requests for comment.
Musk didn't respond to an email seeking comment, and Birchall didn't return a call left at a number he lists in public formation records. A lawyer who helped form United States of America Inc. hung up when reached for comment and hasn't responded to a subsequent message. Asked about how his business interests and government work may intersect, Musk said in a February interview that, “I'll recuse myself if it is a conflict.”
The revelation of Young's apparent violation of federal standards of conduct follows a series of ProPublica stories documenting how another DOGE aide helped carry out the administration's attempts to implement mass layoffs at the CFPB while holding as much as $715,000 in stock that bureau employees are prohibited from owning — actions one expert called a “pretty clear-cut violation” of the federal criminal conflict-of-interest statute. The White House has defended the aide, saying he “did not even manage” the layoffs, “making this entire narrative an outright lie.” A spokesperson also said the aide had until May 8 to divest, though it isn't clear whether he did and the White House hasn't answered questions about that. “These allegations are another attempt to diminish DOGE's critical mission,” the White House said. Following ProPublica's reporting, the aide's work at the CFPB ended.
On Monday, a group of 10 good government and consumer advocacy groups, citing ProPublica's coverage, sent a letter to the acting inspector general of the CFPB, asking him to “swiftly investigate these clear conflicts of interest violations of Trump Administration officials acting in their own personal financial interest.”
ProPublica has identified nearly 90 officials assigned to DOGE, though it's unclear how many, if any, have potential conflicts. Government agencies have been slow to release financial disclosure forms. But Finkelstein said the cases reported by ProPublica call into question the motivation behind DOGE's efforts to undo the consumer watchdog agency.
“It matters because it means that the officials who work for the government, who are supposed to be dedicated to the interests of the American people, are not necessarily focused on the good of the country but instead may be focused on the good of themselves, self enrichment, or trying to please their boss by focusing on enriching their bosses and growing their portfolios,” she said.
Unionized CFPB workers have sued the CFPB's acting director, Russell Vought, to stop his attempts to drastically scale down the bureau's staff and its operations. Since taking office, the Trump administration has twice attempted to fire nearly all of the agency's employees, tried canceling nearly all of its contracts and instituted stop-work mandates that have stifled virtually all agency work, including investigations into companies, ProPublica previously reported.
The parties will appear before an appeals court this Friday for oral arguments in a case that will determine just how deeply Vought can cut the agency while still ensuring that it carries out dozens of mandates Congress tasked it with when lawmakers established the bureau in the wake of the 2008 financial crisis.
The court records produced in the litigation offer a window into the role Young played in gutting the CFPB during the administration's first attempt to unwind the bureau beginning in early February.
He was dispatched to the CFPB's headquarters on Feb. 6, just two days after Treasury Secretary Scott Bessent, then the agency's acting director, told the staff and contractors to stop working. The following day, Young and other DOGE aides were given access to nonclassified CFPB systems, court records show. That same day, Musk posted “CFPB RIP” with a gravestone emoji.
On Feb. 11 and 12, Young was included on emails with top agency officials. One of those messages discussed the cancellation of more than 100 contracts, an act that a contracting officer described in a sworn affidavit as including “all contracts related to enforcement, supervision, external affairs, and consumer response.” Another message involved how to transfer to the Treasury Department some of the more than $3 billion in civil penalties that the bureau has collected from companies to settle consumer protection cases, a move that could deny harmed consumers compensation. A third discussed the terms of an agreement that would allow for the mass layoff of staffers, court records show.
In his financial disclosure form, which he signed on Feb. 15, Young listed his employment by Musk's Europa 100 as active, beginning in August 2024 through the “present.”
Then, in early March, as the legal fight over the administration's cuts played out before a federal judge, Young sent the CFPB's chief operating officer a message about forthcoming firings, known as a “reduction in force,” or RIF, in government parlance. In the email, he asked whether officials were “prepared to implement the RIF” if the judge lifted a temporary stay, according to a March district court opinion that has for the moment stopped most of the administration's proposed cuts.
In addition to his employment, Young's disclosure presents another potential conflict.
He also lists owning as much as $15,000 in Amazon stock, a company that is on the bureau's “Prohibited Holdings” list. Agency employees are forbidden from having such investments, and ethics experts have said that participating in an agency action that could boost the stock's value — such as stripping the CFPB of its staff — constitutes a violation of the criminal conflict-of-interest statute.
Young hasn't responded to questions about that either.
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Jake Pearson is a reporter at ProPublica covering the business interests of Trump administration officials, including post-election business ventures pursued by the president's children and family company. His past investigative work has ranged from uncovering fraudulent business practices of a prominent political donor to exposing abuse and mismanagement inside New York City's jails. He previously worked for the New York Daily News, NBC News and The Associated Press.
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Chinese President Xi Jinping in Hanoi, Vietnam, on April 14, 2025. (Nhac Nguyen / Pool / AFP via Getty Images)
Ukraine faces a difficult balancing act — sanction more Chinese firms for aiding Russia's war machine without alienating Beijing, which could be key to ending Russia's invasion.
Kyiv is currently considering imposing new sanctions against Chinese firms providing raw materials to Russia's defense sector, a source close to the matter told the Kyiv Independent on condition of anonymity.
But doing so could risk pushing Beijing — an important economic partner for Kyiv — further from Ukraine and closer to Russia, the source said.
As momentum builds around peace talks, with President Volodymyr Zelensky heading to Istanbul on May 15, Kyiv is hoping China can nudge its Russian ally toward negotiating a ceasefire and bringing end to the invasion, Ukrainian officials said.
China could be a key country in ending Russia's war and ushering in a “sustainable” peace, the press service of Ukraine's Foreign Ministry told the Kyiv Independent.
Ukraine has largely abstained from publicly bad-mouthing China, but the relationship has taken a hit in recent weeks as Kyiv grows more vocal against Beijing's support for Russia.
Days after Chinese troops were captured in Donetsk Oblast fighting alongside Russians, President Volodymyr Zelensky on April 18 slapped sanctions on three Chinese companies. In an speech, he accused Beijing of supplying Moscow with gunpowder and weapons.
While claiming to be neutral in the full-scale invasion, China provided 76% of Russia's battlefield goods in 2023, according to the Kyiv School of Economics (KSE).Top Ukrainian sanctions official Vladyslav Vlasiuk told the Kyiv Independent that Ukraine is “concerned about some apparently Chinese-made components found in weapons used to attack civilians and count on our partners to take some serious action to stop it.”Ukraine sanctioned two Chinese firms — Beijing Aviation and Aerospace Xianghui Technology Co. Ltd — as well as Zhongfu Shenying Carbon Fiber Xining Co. Ltd, for supplying carbon fiber to Russia used in Iskander ballistic missiles that frequently target cities across Ukraine, according to an official document seen by the Kyiv Independent.Days later, Zelensky said Chinese citizens were working in Russian drone production factories, even claiming Russia could have “stolen” drone technology from China, during a news conference in Kyiv.
On May 9, as Xi Jinping watched Russian soldiers march through Moscow during the WWII Victory Day parade, Ukraine followed up with sanctions on the Hong Kong-based firm Smart Kit Technology. The company was already subject to U.S. sanctions for shipping raw materials and technology like chip-making machines to Russian enterprises.Meanwhile, Ukrainian media reported in February that Chinese companies were also investing in occupied territories and working with the occupying authorities. Kyiv notifies Beijing when Russia attempts to lure a Chinese company to the occupied territories, Ukraine's Foreign Affairs Ministry press service said. “The government bodies of China respond to such appeals of the Ukrainian side and, after confirming the relevant information, take measures to prevent interaction of Chinese business circles with representatives of the temporarily occupied territories of Ukraine,” the ministry said. The recent sanctions are Ukraine's first proper slap on China's wrist. Zelensky previously accused Beijing of “disrupting” the peace process and supplying “elements of Russia's weaponry” during a conference in Singapore in June 2024, but took no tangible action.
Prior to the crackdown on the Chinese companies, Zelensky's administration turned a blind eye to Beijing's “no limits” partnership with Moscow, despite China helping Russia, including by skirting Western sanctions and supplying dual-use goods for military purposes. There is little anti-China rhetoric from the Ukrainian government, and unlike other countries that support Russia, Kyiv hasn't cut ties with Beijing. In July 2024, Ukraine's Foreign Minister at the time, Dmytro Kuleba, even visited Guangdong Province to convince local businesses and authorities to invest in Ukrainian regions, specifically in Mykolaiv Oblast. “At this moment, we cannot see a strong will from the side of the government to move away from China,” Arthur Khartyonov, President of the Liberal Democratic League of Ukraine, an NGO, and founder of the Free Hong Kong Center, a pro-democracy initiative , told the Kyiv Independent.
Ukraine is unlikely to divest from China, as Beijing remains the top producer for goods that it needs, including radio equipment for military use, drones, generators, and equipment that props up the energy grid after attacks.
Chinese exports to Ukraine reached a record high last year. The value of Chinese goods increased to $14.5 billion from $10.44 billion in 2023, outgunning Polish, German, and Turkish imports for the top spot, according to the Center for Economic Strategy (CES) in Kyiv. While Ukrainian exports to China dipped from $8 billion in 2021 to $2.4 billion last year, this is largely due to blocked trade routes and war-time complications rather than any political decision, Dmytro Goriunov, an expert at the KSE Institute and Head of the “Russia Will Pay” project, told the Kyiv Independent.
Ukraine is unlikely to divest from China, as Beijing remains the top producer for goods that it needs, including radio equipment for military use, drones, generators, and equipment that props up the energy grid after attacks, he added. Kyiv's budgetary constraints mean it is stuck with China, for now.
Issues began piling up when Kyiv failed to woo Beijing with its 10-point peace plan presented in 2022. Instead, Xi presented his own peace formula in February 2023 that received a lukewarm response in Ukraine. Zelensky said he agreed with only some of China's points. In the West, the plan was largely criticized for being too much in Moscow's favor, while Russia celebrated it. The points were general and included conditions like a cease-fire, the lifting of sanctions on Russia, and respect for territorial sovereignty. Beijing hasn't recognized Russia's 2-14 annexation of Crimea nor the occupied Ukrainian territories Moscow claims to have annexed in 2022.A year later, China snubbed Kyiv's invitation to the Global Peace Summit in Switzerland that gathered nations supportive of Ukraine's peace formula. To add insult to injury, Beijing then announced that over two dozen countries backed the Chinese peace plan. By June, Zelensky's frustrations reached a tipping point, and he accused China of “working hard… to prevent countries from coming to the peace summit.” Beijing maintained its neutrality and refuted “fanning fire or fueling the flames.”
On China's end, it wants to make sure the status quo within Russia remains steadfast, Dr. Marina Rudyak, an international development consultant and a lecturer at Heidelberg University's Center for Asian and Transcultural Studies, told the Kyiv Independent.“It's in China's interest to keep its border (with Russia) stable and secure and keep Russia stable. Anything that is not (Russian President Vladimir) Putin is more unpredictable than Putin,” she said.
After several attempts to engage with Chinese officials in Ukraine failed, Kyiv realized it needed a different approach. When Ukraine captured several Chinese soldiers on April 8 and Beijing denied any involvement, Kyiv saw its opportunity to put its foot down. While Ukraine can't simply cut trade with China, it knew it had scope to go after Chinese companies involved in Russian weapons production, as well as two Chinese captains sailing sanctioned Shadow Fleet vessels. It's not clear how informed the CCP is about the involvement of Chinese citizens and companies in the war. The central leadership is unlikely to have full knowledge or responsibility for all the Chinese support for Russia, said Rudyak. The testimonies of the captured Chinese troops suggest there is a “significant number” of Chinese citizens fighting with Russia, the Foreign Ministry's press service said. “This may indicate a systemic problem and insufficient effectiveness of the Chinese authorities' measures to prevent this phenomenon,” the ministry added. For now, China has not publicly responded to the sanctions aside from calling the accusations “groundless.” Tensions then escalated when Kyiv presented evidence of Chinese citizens and companies to the Chinese Ambassador to Ukraine Ma Shengkun.
“China is first pro-China, not exactly pro-Russia, so there are hopes that China may persuade Russia to stop the war.”
“We have clarified China's position on the relevant issues. China strongly opposes groundless accusations and political manipulations,” Guo Jiakun, a spokesperson of the Chinese Foreign Ministry, said during a press briefing on April 22. Ukraine wants to open up dialogue with China so that tensions don't boil over. The country is powerful and, like Turkey, a possible mediator between Ukraine and Russia if Kyiv can win it over. “China is first pro-China, not exactly pro-Russia, so there are hopes that China may persuade Russia to stop the war,” Goriunov said. Ukrainian Deputy Foreign Minister Yevhen Perebyinis cautiously assured Ambassador Shengkun on April 22 that Ukraine “values its strategic partnership with China” while urging Beijing to “stop supporting Russia.”
President Xi didn't seem to get the message as he sat next to President Putin during Moscow's Victory Day Parade. The day before, the two “friends of steel” reiterated their partnership in a joint statement and announced deeper cooperation, including in military ties to counter the U.S. Conceringly for Ukraine, the statement included a line about China helping establish peace in Ukraine with Russia and addressing the “root causes” of the war– a thinly veiled reference to Russia's narrative about NATO expansion. While Ukraine is eager for a diplomatic meeting to iron out the tensions, the Chinese side is taking a long time to consider Kyiv's proposals, the Ukrainian Foreign Ministry said. This does not bode well for their bilateral relations.“Further delaying or avoiding such contacts could lead to a crisis of confidence, which is highly undesirable,” the ministry added.
Reporter
Dominic is the business reporter for the Kyiv Independent. He has written for a number of publications including the Financial Times, bne IntelliNews, Radio Free Europe/Liberty, Euronews and New Eastern Europe. Previously, Dominic worked with StopFake as a disinformation expert, debunking Russian fake news in Europe.
Canada Post says it's pressing pause on negotiations with the union representing postal workers with a little over a week before the deadline to get a deal.
The Crown corporation says the past few days of negotiations with the Canadian Union of Postal Workers have been fruitless, and this temporary pause will allow the postal service to come back to the table with “comprehensive proposals” that it hopes can move discussions forward.
The union calls the pause “reprehensible,” in part because there's no clear date for when these new proposals will arrive.
Ottawa asked the federal labour board to send workers back to the job in December when talks were at an impasse and a strike was disrupting holiday mail deliveries.
That reprieve expires on May 22, at which point a labour dispute could again grind Canadians' mail service to a halt.
Canada Post says any proposals will reflect the significant financial challenges that put the postal service's future in jeopardy.
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A Venezuelan toddler who had been kept in US government custody after her parents were deported has been returned to Venezuela.
Maikelys Antonella Espinoza Bernal arrived at the Simón Bolívar International Airport on Wednesday on a repatriation flight from the US.
Venezuelan First Lady Cilia Flores carried the 2-year-old in her arms as officials announced the girl's return to reporters gathered at the airport.
“Today we have a great victory,” Interior Minister Diosdado Cabello said.
Venezuela had been demanding that the United States return the girl for weeks, accusing US officials of kidnapping her.
The US Department of Homeland Security (DHS) previously denied the allegation, arguing the family was separated in an attempt to protect Maikelys from her parents, whom they accused without evidence of being part of criminal group Tren de Aragua (TDA).
Maikelys' mother has rejected that claim.
Related article
Trump administration asks Supreme Court to resume deportation of nearly 200 Venezuelan migrants
In March, the US deported the father Maiker Espinoza-Escalona to a notorious prison in El Salvador, according to the Venezuelan government. The mother Yorelys Bernal was later deported on a flight to Venezuela without her daughter.
On Wednesday, the girl was reunited with her mother and grandmother at the presidential palace in Caracas. State TV showed Bernal crying tears of joy as she held her daughter tightly in her arms.
President Nicolás Maduro said Venezuelan officials had coordinated with lawyers and rights groups in the US to secure the girl's return.
“I have to thank in fairness Ambassador Richard Grenell, special envoy of (US) President Donald Trump, for his efforts. And with Ambassador Richard Grenell, thank President Donald Trump, as well,” he said.
“There have been and there will be differences, but it's possible with God's blessing to move forward.”
CNN has reached out to DHS and the US State Department's Venezuela Affairs Unit for more information.
The toddler and her parents entered the US in May 2024 to seek asylum, according to a court document filed by legal advocacy groups.
After their arrival, the couple were put in immigration detention while their daughter was placed in the custody of the Office of Refugee Resettlement (ORR), the father had said in a sworn declaration.
In July, he received a deportation order under the Biden administration. Between October and March, the couple had weekly, in-person visits with their daughter, Espinoza stated.
On March 29, Espinoza was sent to a naval base in Guantanamo Bay, Cuba, where DHS has transferred migrants, according to court documents filed by his lawyers.
They said he was flown the following day to El Salvador's notorious Cecot mega-prison, which the US is using to detain hundreds of Venezuelan migrants it accuses of being violent gang members, though it hasn't provided strong evidence to back that claim.
The toddler's mother was deported soon after her father was sent to El Salvador. She was forced to return to her country on a flight without her 2-year-old child, Venezuela said.
The girl was kept in ORR custody, with DHS saying, “We will not allow this child to be abused and continue to be exposed to criminal activity that endangers her safety.”
Bernal previously said she suspects US authorities linked her to Tren de Aragua because of her tattoos, which she says only record her family's birth dates.
This is a developing story and will be updated.
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Commerce chief Howard Lutnick's firm backed controversial crypto giant Tether as Bukele ties deepened
Trump administration's commerce secretary, Howard Lutnick, and his family have had extensive business interests linked to El Salvador, whose authoritarian leader Nayib Bukele has grown close to the White House and who has courted controversy by imprisoning people deported from the US in an immigration crackdown.
El Salvador also plays host to a booming cryptocurrency and new media industry, which has numerous ties to Donald Trump allies who are seeking to make money from various ventures which have sometimes drawn the attention of authorities or ethics watchdogs.
Securities and Exchange Commission and Office of Government Ethics (OGE) filings, along with public records in the US and El Salvador, indicate that Cantor Fitzgerald, the firm Lutnick headed until weeks ago before handing off to a management team including two of his sons, holds an effective 5% stake in the cryptocurrency firm Tether, has negotiated several investments on behalf of the highly profitable company, and is custodian of the US treasury holdings from which those profits arise.
The Guardian contacted the commerce department's public affairs office seeking comment from Lutnick on this reporting and received no response.
One of Cantor's investments was a $775m purchase of shares in Rumble, a Trump-aligned video platform, in a deal that closed in February. Just ahead of that deal closing, Rumble inked another deal to provide cloud services to El Salvador's government, with Bukele's regime saying the arrangement rested on shared values of “freedom, innovation and prosperity”.
As well as facilitating the buy – which allowed Rumble insiders to cash out with nine- and 10-figure windfalls – Cantor has been a longterm investor in Rumble since it sponsored the special purpose acquisition company (Spac) that took the platform public.
Tether relocated to El Salvador in January, where the regime allows crypto firms to operate tax- and regulation-free – and has taken advantage of further tax breaks to accumulate real estate in downtown San Salvador alongside transplanted US crypto influencers and members of Bukele's family.
New York Times reporting this week revealed some of the relationships previously scandal-plagued for Tether have become more palatable in Washington during the Trump administration, but not the extent of the company's ties to El Salvador.
Cantor and Lutnick's El Salvador deals raise further questions about the Trump administration's deepening involvement with Bukele's authoritarian regime, which has imprisoned 2% of its population during a two-year “state of exception”, which has consolidated Bukele's power during a harsh crackdown on criminal gangs.
They also raise questions about the direction of cryptocurrency regulations after Tether's founder, Giancarlo Devasini, reportedly told associates in November that Lutnick would “use his political clout” to lift the regulatory scrutiny that has plagued the troubled firm for almost a decade.
Tether – which reportedly mints the world's most traded cryptocurrency – has attracted controversy since it was founded in 2014 alongside sister company Bitfinex, a cryptocurrency exchange by Devasini, an Italian former cosmetic surgeon who has relocated to El Salvador.
Increasingly, it also attracted hostile attention from US regulators. As recently as October, the Wall Street Journal reported that the Manhattan US attorney's office was investigating Tether for its use in sanctions busting, money laundering, and “to fund illegal activities such as the drug trade, terrorism and hacking”.
That was the 19th time that Tether had attracted US government action, according to reporting at Protos, a cryptocurrency watchdog outlet. Many previous investigations and prosecutions alleged a fundamental fraud at the heart of Tether's business.
The main product, USDT, is a stablecoin, a cryptocurrency whose value is exactly equivalent to that of the US dollar.
As the name implies, stablecoins are intended to offer a stable reservoir of value amid the volatility of crypto markets, allowing investors to trade, invest and transfer funds in dollar-equivalent values.
Its dollar equivalence is purportedly secured by an amount of US dollars, or easily converted equivalent assets, so that any holder can convert their USDT into dollars at any time. In theory, the company derives its profits from interest on the holdings that back its cryptocurrency.
But cryptocurrency traders, critics, government agencies and law enforcement have persistently questioned whether Tether holds reserves equivalent to the USDTs it has issued.
In 2021, Tether and Bitfinex agreed to jointly settle a Commodity Futures Trading Commission (CFTC) suit with a payment of $42.5m, with $41m of that coming from Tether.
In their statement on the fines, CFTC said: “From at least June 1, 2016 to February 25, 2019, Tether misrepresented to customers and the market that Tether maintained sufficient U.S. dollar reserves to back every USDT in circulation.”
Instead, the statement said: Tether had “relied upon unregulated entities and certain third-parties to hold funds comprising the reserves; co-mingled reserve funds with Bitfinex's operational and customer funds; and held reserves in non-fiat financial products”.
The same year, they had paid $18.5m to the New York attorney general's office to settle a suit that foreshadowed the circumstances surrounding the collapse of cryptocurrency exchange FTX. The attorney general's office alleged that Tether had commingled client and corporate funds to cover up an $850m shortfall in their reserves.
As part of the settlement, Tether and Bitfinex were not required to admit wrongdoing.
In January, Protos reported in summary that the company had “lied repeatedly about the quality and quantity of its backing”.
The company has also resisted compliance with regulations designed to ensure that stablecoins including USDT have sufficient backing.
Tether is not currently listed on European exchanges because of the company's refusal to comply with the European Union's Markets in Crypto-Assets (Mica) framework, effective from 1 January. It requires stable issuers operating in Europe to obtain authorization as an electronic money institution, and to hold at least 60% of their reserve assets in European banks.
Other allegations have probed Tether's knowledge and involvement in the use of the token in illicit activities like sanctions busting and trafficking.
Ricardo Valencia, an assistant professor at California State University, Fullerton, and a former staffer at the Salvadorian US embassy under a previous administration, said that the growing relationship between Tether and the Bukele regime was unsurprising.
While the Trump regime was exploiting the “crypto gulag horror movie” of Cecot, a destination of summarily deported immigrants under Trump, both the US administration and Tether were exploiting the fact that “you can pay the Salvadoran government to do shady deals for a fee,” Valencia said.
The extent of Lutnick's relationship with Tether only fully came to light during his confirmation hearings in January, when US senators including Democrat Elizabeth Warren sought to shed light on how entwined Lutnick's business affairs were with the cryptocurrency firm.
On 27 January, just ahead of those hearings, Warren sent a letter to Lutnick that in part said: “Your deep involvement with and support for Tether, a known facilitator of criminal activity that has been described as ‘outlaws' favorite cryptocurrency,' raises concerns about your judgment and ability to put the interests of the American people ahead of your own financial interests.”
In the hearings, Lutnick disclosed that a 2024 deal gave Cantor a convertible bond equivalent to a 5% stake in Tether, whose value he put at $600m. Meanwhile, according to the Wall Street Journal, Cantor “holds most of Tether's $134 billion in assets, largely US Treasury bills, in exchange for tens of millions of dollars in fees each year”.
The relationship began at a time when Tether was in perhaps its deepest crisis. After they had paid the combined $61m in settlement funds to the New York attorney general and CFTC, Tether's Bahamian bankers lost their ability to process international payments, cutting them off from customers. Reportedly, an investment adviser from their original bank connected them to Lutnick.
According to the Wall Street Journal, Lutnick personally traveled to meet Devasini, the Tether founder, in the Bahamas in late 2021 to determine whether the company had the assets it claimed to have.
Last July, he told a crypto conference that at that time, “I said: ‘Show me the money'”, and that “we found every penny, and they had every penny, but they had it in what I would call some pretty godforsaken places.”
Previous reports have suggested that at times, Tether's backing has carried significant proportions of so-called “commercial paper”: undertakings from other companies to repay loans at a future date.
Cantor later became Tether's asset manager, and its position as a so-called primary dealer in the treasury market meant that it could liquidate assets with relative ease. The firm also reportedly won the business of some crypto-trading firms who are Tether customers.
Even before relocating and re-incorporating in El Salvador, Tether's managers apparently exercised significant influence in Bukele's crypto-happy regime.
Salvadoran media reports show that Max Keiser and Stacy Herbert, US crypto advocates who head El Salvador's national bitcoin office, are also investors in Bitfinex, the cryptocurrency exchange that was founded by Tether's Devasini and whose management overlaps with the stablecoin firm.
In 2023, Salvadoran newspaper El Faro called the office they run “Bitfinex's puppet embedded in the Salvadoran state”.
That year, Tether announced a $250m investment in Bukele's project that sought to harness geothermal energy to fuel bitcoin mining at a so-called “Volcano Energy” park.
The company also planned to collaborate in the issuance of bonds to finance the construction of a planned bitcoin city in the country, though that project never came to fruition.
More recently, Tether identities have been on a real estate spending spree in the country.
According to reports, Devasini bought a house in San Salvador for $2m.
He also reportedly bought a historic hotel building in downtown San Salvador in a joint venture with Keiser. This purchase of “a prime location in the historic center”, according to El Faro, came into force after the regime exempted investors in that part of town from income tax.
Tether's CEO, Paolo Ardoino, bought two plots of land in the port city of La Libertad, in a deal that revealed he had been naturalized as a Salvadorian citizen.
Tether is also set to receive tax concessions for a planned 70-storey headquarters tower in San Salvador.
In the Rumble deal, concluded on 7 February, Tether Holdings handed $775m to Rumble, with $525m earmarked for a “self-tender offer” for a share buyback, and another $250m hitting Rumble's balance sheet for “growth initiatives”, according to the announcement.
Weeks after the announcement, Rumble and El Salvador announced their partnership on cloud services infrastructure, despite the country announcing a separate deal with cloud titans Google in 2023.
Market analysts say this makes Tether the single largest shareholder in the company, with just more than 20% of all outstanding shares.
But the deal also put constraints on Tether's influence over Rumble. According to Rumble's 20 December press release and the SEC filing announcing the deal, “Rumble's existing Board and governance structure, including Chris Pavlovski's super-majority voting control, will remain unchanged”, and “Tether will own a minority position in our outstanding common stock but will not have the right to designate any members of the Board”.
This lack of say in Rumble's operations is not offset by the likelihood of near-term profits.
Writing on the Tether-Rumble deal when it was announced in December, financial news site Sherwood reported that “by any conventional metric, Rumble is just a really, really bad business”, noting that “in Q3 2023, it lost $29m on $18m in revenue, and in Q3 2024 it lost $32m on $25m in revenue”.
Sherwood also noted that “the company's cash and cash equivalents shrank from $218m at the beginning of the year to $131m at the end of September” and that “at its current pace the company would be running low on cash within the next 12 months”, since “despite its revenue growth, Rumble's losses have grown even faster”.
Tether's interest in buying into Rumble – even without any significant say over its operations – may be explained by its alignment with the Trump administration.
The company's central offering is an “anti-woke” video platform that won favor among Maga influencers beginning in 2020, amid crackdowns on pandemic and election disinformation on leading platforms such as YouTube.
At that time, Rumble leaned into an anti-“cancel culture” pitch, offered signing deals to rightwing, conspiracy-minded and contrarian creators such as Andrew Tate, Tulsi Gabbard and Glenn Greenwald, and positioned itself as a pillar of a rightwing “parallel economy” of explicitly ideological, Maga-forward companies advocating for an ideologically inflected vision of “free speech”.
In its first round of venture capital funding in 2021, lead investors were rightwing billionaire Peter Thiel and JD Vance's venture fund, Narya Capital. Vance and Thiel reportedly exited their investments after Rumble went public in September 2022.
In 2022, Trump's Truth Social platform, operated by Trump Media and Technology Group, became the first outside publisher to adopt Rumble's ad network, an alternative to dominant players such as Google's AdSense. At that time, Rumble's CEO said the ad network's mission was to “fight back against cancel culture”.
At the beginning of 2023, the company inked a “seven-figure” deal with Donald Trump Jr to exclusively carry his biweekly livestream show, Triggered.
Rumble sued the government of Brazil, alongside Trump Media, over a Brazilian judge's order that the platforms remove accounts of a supporter of Brazil's former president, Jair Bolsonaro.
On 12 February, Pavlovski was given a “new media” seat at the White House's daily press conference, where he told spokesperson Karoline Leavitt “Rumble was a victim of censorship at the hands of multiple foreign governments” and asked: “Can you describe what the administration will do to protect US interests and values worldwide?”
Via Cantor, Lutnick was also deeply involved with Rumble.
Under Lutnick, Cantor “made a fortune, thanks to a favorable deal structure”, according to Forbes when it sponsored the special purpose acquisition company that took Rumble public in 2022.
Spacs allow private companies to go public by merging with a shell company set up to explore such merger opportunities. They have been popular in the last half-decade because they enable companies to avoid the investor and regulatory scrutiny that comes ahead of a more conventional initial public offering.
Spac sponsors, such as Cantor, are generally issued with stocks and warrants in the eventual public company with little downside risk. In the Rumble Spac, 12m shares, or 4.6% of the total, were issued to “Sponsor Related Parties” according to Securities and Exchange Commission filings.
Prospectuses filed by Rumble show that at the time the company went public, several people and entities related to Lutnick and his family had also been dealt in. Lutnick 2020 Descendants Trust UA had 375,000 shares; his wife, Allison Lutnick, had 50,000 shares; and his sister, Edith Lutnick, had 35,000 shares.
This may be the source of the holdings disclosed in Cantor's most recent holdings report, filed on 14 February, which indicates that the company he led holds 9.3m Rumble shares, which at that time they valued at over $120m.
Lutnick personally owned between $1m and $5m worth of Rumble stock according to his Office of Government Ethics filings.
Finally, Cantor was the placement agent for Tether's buy-in to Rumble. Normally such a role attracts fees, but Lutnick said at his confirmation hearing that on this occasion Cantor waived them.
Rumble had several officers and shareholders besides Lutnick who have since gone on to serve in the Trump administration.
Tech-right ideologue and venture capitalist David Sacks resigned from Rumble's board in December “to pursue a position in government”, according to a 13 December SEC filing. He now serves as the Trump administration's “crypto czar”.
Sacks joined the board in 2023 after Rumble acquired Callin, the podcasting and livestreaming platform he founded, and Locals, a crowdfunding platform fronted by rightwing comedian Dave Rubin that Sacks had backed.
Any share sales he made in the February deal were not subject to insider trading disclosures. However, the most recent filing detailing Sacks interest in the company from last July shows him increasing his shareholding to just over 571,000 shares, a position being worth over $4.2m in the Tether deal.
Ethan Fallang, formerly a board member of Rumble and Narya Capital – the Vance-founded venture firm – resigned in January to work in government, according to SEC filings. The most recent documentation of his holdings while he was still on the board show him owning some 27,000 shares.
Although he is not subject to insider trading disclosures, filings show that Trump's deputy FBI director, Dan Bongino, has maintained his 5.72% share in Rumble since it went public. No OGE agreements or disclosures for Bongino have been made public to date.
OGE disclosures do indicate that on the way into their jobs, Bongino's new boss, Kash Patel, held between $1,001 and $15,000 worth of stock; transportation secretary Sean Duffy held between $1,000 and $15,000; and the director of national intelligence, Gabbard, held between $100,001 and $250,000 of the stock.
Patel, Gabbard and Lutnick all undertook to divest themselves of holdings including their interest in Rumble within 90 days of taking office, according to their OGE agreements.
Schumer said the slowdown of the nomination process would remain in place “until we get more answers” on the gift.
Senate Minority Leader Chuck Schumer (D-New York) announced on Tuesday that he was placing a hold on all of President Donald Trump's remaining nominees at the Department of Justice (DOJ), in light of the president reportedly accepting a $400 million luxury jet as a gift from the government of Qatar.
The jet is set to be used by Trump to act as Air Force One, after which it will be a featured part of his presidential library. The gift likely runs afoul of the Constitution's Emoluments Clause, which states:
No Person holding any Office of Profit or Trust under them, shall, without the Consent of the Congress, accept of any present, Emolument, Office, or Title, of any kind whatever, from any King, Prince, or foreign State.
In an appearance on the Senate floor on Tuesday, Schumer said he would slow down the process of DOJ nomination, citing the “naked corruption” of the Trump administration accepting the gift and the “grave national security threat” it presents.
“In light of the deeply troubling news of a possible Qatari-funded Air Force One, and the reports that the Attorney General personally signed off on this clearly unethical deal, I am announcing a hold on all DOJ political nominees, until we get more answers,” Schumer said, according to his prepared remarks.
Schumer, who doubted the president's insistence that the gift was “free,” listed a number of questions that required answers before the hold could be lifted, including whether the jet would be ready on “day one” with security measures in place, whether taxpayers would have to pay for updates to the jet (including those security measures), whether a government contract would be voided with Boeing to build a new Air Force One (and how much that would cost to invalidate), and what the government of Qatar may get in return for the gift.
Schumer also demanded that Attorney General Pam Bondi, who indicated she found no problems with the gift, “testify before both the House and Senate to explain why gifting Donald Trump a private jet does not violate the Emoluments Clause — which requires congressional approval — or any other ethics laws.”
“Until the Attorney General explains her blatantly inept decision and we get complete and comprehensive answers to these and other questions, I will place a hold on all political nominees to the Department of Justice,” Schumer said.
Democrats cannot put an indefinite block on nominees from Trump, but they can slow the process down considerably — indeed, a majority of Trump's nominees have already been slowed down through the same process Schumer is now using.
A DOJ spokesperson tried to justify moving forward with nominees, unimpeded, by citing Trump's election win last fall.
“The American people overwhelmingly elected President Trump to nominate highly qualified candidates at the Department of Justice who will Make America Safe Again, and the Senate should do its part by confirming these nominees,” that spokesperson said.
While some Republicans have expressed concern over Trump's gift of a multimillion-dollar jet from Qatar, others, like Senate Republican Whip John Barrasso (Wyoming), are downplaying his action.
“Schumer has held every nominee of President Trump. So, he's not done anything new today at all,” Barrasso said, calling the Democratic leader's speech on the Senate floor a grandstanding display.
Some voices on the left praised Schumer's action, but said that he should have placed a hold on this set of nominees much sooner.
“It's good that Schumer is taking action, but it's coming after many other ethical issues in the Trump administration that apparently didn't warrant a hold on nominees,” The New Republic's Hafiz Rashid wrote.
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MOSCOW, May 14. /TASS/. The Brazilian embassy in Russia has confirmed that the plane of President Luiz Inacio Lula da Silva will make a stopover in Moscow.
"The Brazilian embassy is aware that Brazilian President Luiz Inacio Lula da Silva will make a technical stop in Moscow. The embassy does not have any additional information on this issue," an official at the Brazilian diplomatic mission told TASS.
Earlier, Lula da Silva said that he intends to return to Moscow after his visit to China to talk with Russian President Vladimir Putin about the upcoming Russian-Ukrainian talks in Istanbul.
Russian Presidential Spokesman Dmitry Peskov said that the Kremlin will inform the press if Putin holds a meeting with the Brazilian leader today.
State was among the first in the US to extend free healthcare benefits to all poor adults regardless of immigration status
The California governor, Gavin Newsom, wants his state to stop enrolling more low-income immigrants without legal status in a state-funded healthcare program starting in 2026 and begin charging a monthly premium the following year to those already enrolled.
The decision is driven by a higher-than-expected price tag on the program and economic uncertainty from federal tariff policies, Newsom said in a Wednesday announcement. The Democratic governor's move highlights his struggle to protect his liberal policy priorities amid budget challenges in his final years on the job.
California was among one of the first states to extend free healthcare benefits to all poor adults regardless of their immigration status last year, an ambitious plan touted by Newsom to help the nation's most populous state inch closer to a goal of universal healthcare. But the cost for such expansion ran $2.7bn more than the administration had anticipated.
Newsom in March suggested to reporters he was not considering rolling back health benefits for low-income people living in the country illegally as the state was grappling with a $6.2bn Medicaid shortfall. He also repeatedly defended the expansion, saying it saves the state money in the long run. The program is state-funded and does not use federal dollars.
Under Newsom's plan, low-income adults without legal status will no longer be eligible to apply for Medi-Cal, the state's Medicaid program, starting in 2026. Those who are already enrolled won't be kicked off their plans because of the enrollment freeze, and the changes won't impact children. Newsom's office didn't say how long the freeze would last.
Starting in 2027, adults with “unsatisfactory immigration status” on Medi-Cal, including those without legal status and those who have legal status but aren't eligible for federally funded Medicaid, will also have to pay a $100 monthly premium. The governor's office said that is in line with the average cost paid by those who are on subsidized heath plans through California's own marketplace. There's no premium for most people currently on Medi-Cal.
In total, Newsom's office estimated the changes will save the state $5.4bn by 2028-2029.
The Medi-Cal expansion, combined with other factors such as rising pharmacy costs and larger enrollment by older people, has forced California to borrow and authorize new funding to plug the multibillion dollar hole earlier this year. California provides free healthcare to more than a third of its 39 million people.
Newsom's proposal come ahead of his scheduled presentation on the updated budget. Recovery from the Los Angeles wildfires, changing federal tariff policies and the expensive healthcare expansion are putting a strain on California's massive state budget. Lawmakers are expecting a multibillion dollar shortfall this year and more deficits projected for several years ahead.
Newsom is expected to blame Donald Trump's tariff policies for the shortfalls, estimating that the polices have cost the state $16bn in tax revenues. California is also bracing for major budget hits if Republicans in Congress follow through with a plan to slash billions of dollars in Medicaid and penalize states for providing healthcare to immigrants without legal status.
Newsom now opens budget negotiations with lawmakers and it is unclear how Democrats who control the legislature will react to his plan to freeze new Medi-Cal enrollment for some immigrants. A final budget proposal must be signed by June. California's budget is by far the largest among states.
The budget proposals presented this week will build in some of the impacts from federal policies, but many unknowns remain.
The governor already said he's planning to scale back on baseline spending this year. Analysts and economists also warn that California will face bigger deficits in the tens of billions of dollars in coming years due to economic sluggishness and stock market volatility brought on by the tariff war.
The disclosure follows a warning from Digital Affairs Minister Krzysztof Gawkowski, who on May 6 said Moscow was carrying out an "unprecedented" interference campaign.
Brazilian President Lula da Silva claimed that Ukrainian Foreign Minister Andrii Sybiha had appealed to his Brazilian counterpart, Mauro Vieira, to ask Putin if he was willing to conclude a peace agreement.
Earlier reporting from the Washington Post cited a former Russian official who claimed Russian Foreign Minister Sergey Lavrov and Putin's foreign policy aide, Yuri Ushakov, would represent Moscow in the talks.
Vyshyvanka, a traditionally styled embroidered shirt or dress, is the central feature of Ukraine's national clothing.
The Council of Europe on May 14 approved the creation of a special tribunal to prosecute Russia's top leadership for the crime of aggression against Ukraine, Ukrainian lawmaker Maria Mezentseva reported.
Viktoria Roshchyna, 27, disappeared in August 2023 while reporting from Ukraine's Russian-occupied territories. Moscow admitted she was in Russian detention the following year.
Dutch Justice Minister David van Weel speaks about the future of the EU-led special tribunal for the crime of aggression against Ukraine and its role in bringing Russia to justice.
Turkish officials told Bloomberg that while they don't expect Trump to visit Istanbul, they are not ruling it out, and preparations for any scenario are underway.
The air raid was announced at around 2:30 p.m. local time, while the explosion sounded around 2:50 p.m.
Melkonyants was arrested in August 2023 in connection with the activities of the European Network of Election Monitoring Organizations (ENEMO), which was co-founded by Golos's legal predecessor, the Golos association.
Ukraine's underground storage facilities are currently using 19.4% of their capacity. Almost 32%, or 2.79 bcm, less gas is available in the storages than in the previous year, according to the estimates.
The majority of Ukrainians, 71%, do not support holding elections before a full peace deal, even in the case of a ceasefire and security guarantees, according to a poll published by the Kyiv International Institute of Sociology (KIIS) on May 14.
"He'd like me to be there, and that's a possibility. ... I don't know that he would be there if I'm not there. We're going to find out," U.S. President Donald Trump told reporters aboard Air Force One while traveling to Qatar, Reuters reported.
Trump has long demanded that NATO allies increase their military spending, previously calling for the alliance to raise its benchmark from 2% to 5% of GDP.
U.S. President Donald Trump said on May 14 that he is unsure whether Russian President Vladimir Putin will attend peace talks with Ukraine in Turkey on May 15.
"He'd like me to be there, and that's a possibility... I don't know that he would be there if I'm not there. We're going to find out," Trump told reporters aboard Air Force One while traveling to Qatar, Reuters reported.
President Volodymyr Zelensky has invited Putin to hold ceasefire talks in Turkey this week in what would be the first direct negotiations between Moscow and Kyiv since 2022.
Russia has confirmed that it will dispatch a delegation but declined to confirm Putin's participation. Russian lawmaker Leonid Slutsky hinted that the delegation's composition would be announced on the evening of May 14.
According to a former Russian official who spoke to the Washington Post, Moscow will be represented by Foreign Minister Sergey Lavrov and Putin's foreign policy aide, Yuri Ushakov.
Without confirming his attendance, Ushakov told journalists that the Russian delegation's composition will be based on the range of political and technical issues that should be discussed.
Trump has voiced optimism about the possible meeting of the two leaders and suggested he might attend as well.
"Thursday's meeting between Russia and Ukraine is very important. I strongly pushed for it to happen. I think good things can come from it," the U.S. president said earlier this week.
Zelensky welcomed Trump's potential participation while calling upon the U.S. leader to realize that Putin continues to manipulate and obstruct peace efforts. Ukraine and its allies have called for an unconditional 30-day ceasefire starting on May 12 as the first step toward peace – a proposal ignored by Russia.
"If Putin does not arrive and plays games, it is the final point that he does not want to end the war," Zelensky said in Kyiv on May 13.
The White House has grown increasingly frustrated with the stalled peace efforts as the self-imposed 100-day deadline to broker a deal has passed. The U.S. president has been critical of both Ukraine and Russia, blaming them for the deadlock in the negotiations.
Senior News Editor
Martin Fornusek is a news editor at the Kyiv Independent. He has previously worked as a news content editor at the media company Newsmatics and is a contributor to Euromaidan Press. He was also volunteering as an editor and translator at the Czech-language version of Ukraïner. Martin studied at Masaryk University in Brno, Czechia, holding a bachelor's degree in security studies and history and a master's degree in conflict and democracy studies.
Rescue workers clear the rubble after a Russian strike in a residential neighbourhood in Kyiv, on April 24.Alex Babenko/The Associated Press
U.S. President Donald Trump and his Russian counterpart Vladimir Putin were still “maybes” for what could be the first direct peace talks between Moscow and Kyiv in years after the Kremlin on Wednesday held off disclosing who would represent Russia.
Putin on Sunday proposed direct negotiations with Ukraine, in Istanbul on Thursday “without any preconditions”. But he did not say who would be attending from Moscow's side and his spokesman was unable to give further details on the matter on Wednesday.
Trump earlier this week urged Ukraine to attend the talks and Ukrainian President Volodymyr Zelensky quickly said he would be there, but only if Putin showed up, setting up a diplomatic standoff as part of an apparent contest to show Trump who wants peace more.
Trump said on Wednesday he himself was still considering whether to attend the talks in Turkey but did not know whether Putin would go, something that Zelensky has challenged the Kremlin leader to do “if he's not afraid”.
“(Putin) would like me to be there, and that's a possibility … I don't know that he would be there if I'm not there. We're going to find out,” Trump told reporters aboard Air Force One en route to Qatar.
Trump wants the two sides to sign up to a 30-day ceasefire in what is Europe's biggest land war since World War Two, and a Russian lawmaker said on Wednesday there could also be discussions about a huge prisoner of war exchange.
Zelensky backs an immediate 30-day ceasefire, but Putin has said he first wants to start talks at which the details of such a ceasefire could be discussed.
Trump, who is growing increasingly frustrated with both Russia and Ukraine as he tries to push them towards a peace settlement, said he was “always considering” secondary sanctions against Moscow if he thought it was blocking the process.
U.S. officials have spoken about possible financial sanctions as well as potential secondary sanctions on buyers of Russian oil.
A Ukrainian diplomatic source told Reuters on Wednesday that Ukraine's leadership would decide on its next steps for peace talks in Turkey once there was clarity on Putin's participation.
“Everything will depend on whether Putin is scared of coming to Istanbul or not. Based on his response, the Ukrainian leadership will decide on the next steps,” the source said,
If Putin agrees to join, it would be the first meeting between the leaders of the two warring countries since December 2019. Direct talks between negotiators from Ukraine and Russia last took place in Istanbul in March 2022, a month after Putin sent tens of thousands of troops into Ukraine.
Some unconfirmed Russian and U.S. media reports had said that Russian Foreign Minister Sergei Lavrov and Yuri Ushakov, Putin's foreign policy aide, would be in Istanbul and ready to meet their Ukrainian counterparts.
But Russia's Kommersant newspaper, which is regarded as having good sources in the Russian Foreign Ministry and the Kremlin, said on Wednesday evening that Lavrov would not attend.
Asked earlier by reporters during a daily briefing if the Kremlin could reveal the make-up of the Russian delegation, spokesman Dmitry Peskov said: “We will do that when we get an instruction to do so from the president.”
“The Russian delegation will be waiting for the Ukrainian delegation in Istanbul on May 15,” he added.
Trump has said he will send Secretary of State Marco Rubio and senior envoys Steve Witkoff and Keith Kellogg to Turkey, while also offering to attend himself.
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President Donald Trump's newly tabbed pardon attorney said on May 13 that his work will include scrutinizing pardons that former President Joe Biden issued just before leaving office in January.
“I do think that the Biden pardons need some scrutiny. And they need scrutiny because we want pardons to matter and to be accepted and to be something that's used correctly,” Ed Martin, the pardon attorney, told reporters during a press briefing in Washington.
“So I do think we're going to take a hard look at how they went and what they did and if they're, I don't know, but null and void, I'm not sure how that operates,” he added.
Biden's pardons, issued in his final hours in office, went to multiple individuals, including former Rep. Liz Cheney (R-Wyo.). The pardons were for conduct for which the individuals had not been charged.
Biden said at the time that the people “do not deserve to be the targets of unjustified and politically motivated prosecutions.”
Martin said on Tuesday that the pardons were not particularly reasonable but that he did not necessarily think the use of an autopen would nullify them.
That kind of conduct “does make you pause,” Martin said. “That's what you're supposed to do, is pause, just like if the Biden pardons are unprecedented in their extent. Right back to when Hunter Biden was whatever age you say, 'that's uncommon, we ought to take a look at that.'”
Martin also said that the weaponization working group has been looking at various actions taken during the Biden administration, including the prosecution of people who participated in the Jan. 6, 2021, breach of the U.S. Capitol. He said that under him, the group will be giving more updates on its work and is exploring the launch of a portal that will enable people to provide them tips.
MOSCOW, May 14. /TASS/. The composition of the Russian delegation will depend on the agenda to be discussed at the Istanbul talks with Ukraine, which are expected to address political and technical issues, Kremlin aide Yury Ushakov told VGTRK reporter Pavel Zarubin.
"The delegation needs to address both political and, I'd say, a billion of technical issues," the official said. "So the composition of the delegation will be determined based on that," he pointed out.
Ushakov did not answer whether he himself is part of the Russian delegation. "I work here," he said as he headed to the Russia-Malaysia talks in the Kremlin.
When asked whether the Istanbul talks could begin at 12:00 a.m. on May 15, the Kremlin aide said with a smile: "I've been thinking about it since early morning." Ushakov recalled that Moscow's proposal is to resume the 2022 talks "that were suspended by the Ukrainian side at the urging of Western colleagues and partners."
On May 11, Vladimir Putin, speaking to reporters in the Kremlin, suggested that the Kiev authorities resume without preconditions the direct talks Ukraine broke off in 2022. The Russian delegation will wait for the Kiev representatives on May 15 in Istanbul.
In turn, Vladimir Zelensky said that he himself would arrive in Turkey. At the same time, he, supported by EU countries, started putting forward demands regarding the composition of the Russian delegation.
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“Labès?” (‘OK?”) asks Baba Atanof as a tourist struggles to get her leg over a large rock on a steep ascent in the Algerian Sahara Desert. Fighting jelly legs and vertigo, she can barely answer.
This desert makes up 83% of Africa's largest country. It's the focus of a government master plan for tourism development by 2030 that aims to make Algeria a major tourist destination after decades of self-reliance post-French colonialism, which ended in 1962.
Atanof takes the woman's camera bag — he's already carrying her small backpack. With nothing weighing her down, plus a push upwards, she becomes sure-footed again.
Meanwhile, 20 donkeys carry extensive camping gear and supplies for a dozen people without faltering. There are four tourists and eight staff, including guides, cooks and shepherds.
In worn-out sneakers, a chèche (head-and-face scarf for Touareg men) and daraa (long, loose gown), topped with his own backpack and a large solar power bank, Atanof stabilizes the tourist.
The 57-year-old father (“baba” in Arabic) of seven has made this challenging climb many times as a guide for 30 years. As a Touareg — a person of Berber origin, traditionally a nomadic pastoralist, who principally lives in the Sahara Desert — he can navigate the challenging, vast terrain.
Atanof works for Touareg Voyages, an accredited travel agency that facilitates visas for international visitors to the Algerian desert.
In January 2023, the government introduced a visa-on-arrival program for all non-exempt foreign tourists traveling to the Sahara — essentially everyone except citizens of Mahgreb countries (five neighboring states), Malaysia and Seychelles.
That December saw the launch of an Air Algerie flight between Paris and the oasis town of Djanet.
Once challenging to obtain, visas of up to 30 days are now practically guaranteed and visitors pay the relevant fees ($38 to $376, depending on length of stay) upon arrival.
Tourism is increasing significantly as a result. In 2023, Algeria had an all-time record of nearly 3.3 million tourists, including almost 2.2 million foreigners — a year-on-year increase of 44% and 65% respectively, according to the Algerian Ministry of Tourism and Handicrafts.
The government wants to increase the number of international visitors to 12 million by 2030, according to Reuters. It's produced a roadmap that includes a Tourism Development Master Plan 2030 aimed at enhancing the quality of tourism services and infrastructure and significantly increasing investment and hotel capacity.
There are reportedly also plans to strengthen connections with various European capitals, particularly for visiting the desert.
Atanof leads the tourists to the top of Tassili n'Ajjer National Park, a UNESCO World Heritage Site filled with giant, sandstone “sculptures” by Mother Nature — “forests of rock” eroded over seven million years.
Located near Djanet in the southeast of the country, the nearly 50,000-square-mile park is like a moonscape on a high plateau at altitudes of 4,600 to 6,600 feet.
Among these rock formations are an estimated 15,000 prehistoric paintings and engravings dating from 10,000-750 BCE. Atanof is one of the few people who knows where they are.
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The Algerian Ministry of Tourism and Handicrafts reckons this might be the world's largest open-air museum — a place where concave rock bases were “canvases” for paintings made of natural pigments like red and yellow ocher.
They depict humans in everyday life and ceremonies such as hunting and dancing, as well as animals, including cattle, giraffes and camels, represented over five stylistic and chronological periods.
Those are Kel Essuf (over 9,875 years old, the oldest form of engraved anthropomorphic rock art in the area), Round Head (7,575-4,575 years ago), Bovidian (6,575-4,575 years ago, depicting cattle and herdsmen), Caballine (3,575-2,075 years ago, known for its representations of horses) and Cameline (from 750 BCE, famous for its depictions of camels).
In the abundant rock sculptures, the visitors see all kinds of objects. Atanof jumps on a rock shaped like a gymnastic vault and pretends to ride a motorcycle, beckoning someone to jump on the back.
Later he points out black fossils estimated to be a million years old on shards of red rock, and shows how colored stones can be pulverized into pigments. “Make-up,” he jokes, streaking some on the tourists' cheeks.
The quest to see this prehistoric art involves an extraordinary adventure: a trek of about 75 miles across the craggy plateau where there is nothing but nature.
In other words, it's a week without a shower, toilet, electricity, phone reception (though the guides carry a satellite phone for emergencies), Wi-Fi, media and most 21st-century comforts.
These tourists think of it as a “desert spa,” they say, with daily exercise, healthy food, no alcohol, pure air, serenity and plenty of sleep. They aptly don custom T-shirts with the phrase: “It's all about the journey.”
“The people who live in the desert have good health,” notes their other guide Sidi Baika, who grew up in a tent as a Touareg but now lives in a house in a desert town, working as a meteorological engineer at a global atmospheric watch station.
“The life of nomads is very simple and healthy — better than the town,” he says. On this trip “I am returning to my primitive life … It's a very beautiful feeling.”
Wholesome meals are prepared by a professional cook with the help of a gas stovetop in a cardboard box. There are campfires and, at night, flashlights and headlamps.
Fresh breads are even baked with hot coals. Every lunch and dinner ends with three cups of tea per person: the first “hard like life,” the second “sweet like love” and the third “light like death,” as the Touaregs say.
A dedicated tea-maker ceremoniously mixes green tea with powdered sugar, pouring it back and forth from the teapot to a metal cylinder until it's well blended and frothy (the froth makes it easy to remove any wayward sand).
“No tea, big problem,” says Baika, who explains that teatime is for storytelling — part of the Touareg oral culture. “Tea is very important in the desert. News is spread from person to person over tea around a fire,” he says.
Baika shares several stories, including about “jinn” (Arabic for “genies”), invisible spirits believed to do bad or good.
The tourists move close to the fire to try to keep warm — it's February, and winter desert temperatures drop from an average of 60 F (15.5 C) by day to freezing at night.
They pull wool blankets over themselves as he opens an offline stargazing app on his phone to show constellations in the clear starscape.
Touaregs traditionally use the stars and sun to navigate, and time to measure distance.Based on the hours of walking, Baika estimates they've gotten as close as 30 miles from the Libyan border on this trip.
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Security and operations along this border are being augmented by new customs agreements between Algeria and Libya.
The Algerian government has also made recent efforts to secure borders with other neighbors: Tunisia, Niger, Mali, Mauritania, Morocco and Western Sahara territory. These are among several actions that have positioned Algeria — which now views tourism as an imperative for sustainable development — to slowly open up to the world.
“In the desert, you have more time… with yourself, with your mind,” Baika says. “In one week, you can review all of your life.”
The Touaregs on the journey have an inherent sense of peace. They are never annoyed or stressed and speak softly, philosophically and humorously. The visitors are completely unplugged in another world. There is not a car, building or sign of modern civilization in sight except for the brief passing of a few other tourists.
Tassili n'Ajjer has spiritual and cultural significance for Touaregs. It contains endangered Saharan cypress trees that are more than 4,000 years old, says Baika, as well as medicinal plants and other organic materials used to treat a variety of ailments. (Who knew that steam from dried camel poop helps a cold?!) Sefar, a stunning part of Tassili that the group visits, even means “medicine” in the Touareg language Tamahaq.
To the visitors' surprise, there is a virtual pharmacy in plants, plus a few freshwater ponds and even rain one night in the dry winter. “It's a myth that the desert has no water,” Baika says. “If that were the case, nothing could live here. But it only rains a total of five days a year.”
The Algerian Sahara is also home to several animals like the desert fox, wild sheep, jackal and gazelle. Their footprints prove it. But the group only sees donkeys and birds, whose sounds are amplified by the otherwise silent terrain.
Every sunrise, the tourists hear the donkeys slowly return to the campsite from overnight in a pasture as well as the beautiful singing of Muslim prayers by the Touaregs.
They become acutely aware of sounds: the sides of tents flapping in the wind, popping of steaming vegetables, crackling of fires and the whistling of air running through holes in their aluminum walking sticks. They also become attuned to silence and the power of non-verbal communication.
“If you look for peace and want to take rest for your mind, from your stress, you go to the desert,” Baika says. “It's a really magical place. Every time you travel there, you discover something new.”
That's true throughout Algeria, which has remnants from several civilizations over the centuries from Neolithic, Numidian (Berber) and Roman to Arab, Ottoman and French.
Its northern coastal strip, the Tell, includes the port capital Algiers, Mediterranean beaches, vineyards, mountains — and abundant Roman ruins, including the UNESCO-listed archeological sites Djémila, Timgad and Tipasa, which have spectacularly well preserved ancient Roman cities.
South of the Tell lies the Saharan Atlas mountain range and oases. The rest of the country is the Sahara Desert with lunar and volcanic landscapes, stony plains and ergs (“fields” of sand dunes).
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After descending a steep gorge leaving Tassili, monster trucks drive the tourists to the sand “sea” of Erg Admer, where they walk upon golden dunes of epic proportions. Three sandstone inselbergs (isolated mountains) rise high on flat sand — one has prehistoric etchings of cows. The various shades of chèches in the group and Baika's bright blue daraa contrast against the beige rocks and sand.
The visitors see each other on top of dunes — mere dots among infinite grains of sand rippled by wind — and realize how small they are in the magnificence of nature.As streaks of sunlight diffuse over the ethereal landscape, from the top of the highest dune at least 300 feet up, one says, “Salam alaikum” (“peace be upon you” in Arabic).
Beyond its majestic sights, the desert's magic comes from living simply and simply being. In fact, it is all about the journey.
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European court of justice says no ‘plausible explanation' given for denying New York Times access to texts from pandemic
The EU's highest court has cancelled a decision to withhold Ursula von der Leyen's text messages with a pharmaceutical executive during the pandemic, in a significant defeat for the commission president.
The European court of justice on Wednesday annulled a decision taken by the European Commission in November 2022 to deny the New York Times access to the messages, after a freedom of information request by the paper.
The court said that, in its refusal, the commission did not respect the EU's access to documents law. In a withering assessment it said the commission had “not given a plausible explanation to justify the non-possession of the requested documents”.
It was not immediately clear if the commission, which still has the right to appeal, would release the messages. In a statement that it would “closely study” the ruling, the EU executive suggested it still intended to block access to the texts, saying it would “adopt a new decision [on the FoI request] providing a more detailed explanation”.
Despite those questions, the decision is a defining moment for von der Leyen, who is a few months into a second five-year term as head of the EU executive. While praised as a crisis manager, von der Leyen has also faced frequent criticism for her top-down management style and been accused of lacking transparency.
In January 2023, the New York Times and its then Brussels bureau chief, Matina Stevis-Gridneff, started the case to challenge a commission decision not to release the text messages.
The paper had reported the existence of the text messages exchanged between von der Leyen and the Pfizer chief executive, Albert Bourla, in an article that included interviews with both.
Von der Leyen's personal diplomacy was said to have unlocked 1.8bn doses of the Pfizer/BioNTech vaccine at a moment when the EU was falling behind the UK and Israel in the race to secure jabs. Critics later alleged the commission had overpaid for the vaccines after it emerged that Pfizer had increased its prices to €19.50 a shot, compared with €15.50.
An investigative journalist, Alexander Fanta, asked the commission in May 2021 to release the text messages under the EU's freedom of information rules. After the commission refused, he took the case to the European Ombudsman, who found the commission guilty of maladministration.
Von der Leyen's texts, Fanta wrotein the Guardian, might “help to answer questions such as why the EU became Pfizer's single biggest customer but reportedly paid a much steeper price”.
The New York Times applied to see the text messages in May 2022 and went to court to challenge the commission's refusal. The court's negative verdict was not unexpected, as judges had criticised commission lawyers' responses during hearings last year.
The commission had claimed the texts were sent only to coordinate meetings, but its lawyers admitted they had not seen the messages and could not say whether they still existed.
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On Wednesday, the court said the commission had “not sufficiently clarified” whether the messages had been deleted and, if so, whether that “was done deliberately or automatically”, or whether the president's phone had been replaced in the meantime.
Alberto Alemanno, an EU law professor at HEC Paris Business School, said the result would promote greater accountability of EU leaders. “This judgment provides a fresh reminder that the EU is governed by the rule of law, with its leaders subject to the constant scrutiny of free media and of an independent court.”
Transparency International said it was a landmark ruling that “makes clear that the commission's contradictory approach to transparency cannot stand”.
A New York Times spokesperson said: “Today's decision is a victory for transparency and accountability in the European Union, and it sends a powerful message that ephemeral communications are not beyond the reach of public scrutiny.”
Prosecutors say men intended to attack German cargo transport by sending packages that would explode in transit
Three Ukrainian nationals have been arrested on suspicion of plotting parcel bomb attacks in Germany on behalf of the Russian state, according to prosecutors, reviving fears about an alleged Moscow-engineered sabotage campaign in Europe.
After the detonation of several parcels at European cargo centres last year, the German investigation drew comparisons with incidents believed to be part of a wave of hybrid attacks against western countries since Russia's full-scale invasion of Ukraine.
The German federal prosecutor's office said on Wednesday that the men, identified only as Vladyslav T, Daniil B and Yevhen B, in line with German privacy rules, had been detained in recent days in Germany and Switzerland.
They are accused of “secret agent activity for sabotage purposes” and of agreeing by, at the latest, March 2025 “with one or several persons presumed to be working for Russian state institutions” to carry out “aggravated arson” and “cause a detonation using explosives”.
The prosecutors alleged the men's intent had been to carry out “explosives attacks on cargo transport in the Federal Republic of Germany” by shipping parcels from Germany to recipients in Ukraine carrying “explosives or incendiary devices” that would “detonate during transport”.
Vladyslav T allegedly sent two test packages containing GPS trackers in late March from Cologne, in western Germany, “to scout out suitable transport routes” on the orders of Yevhen B, who is believed to have provided the package contents via Daniil B.
The federal criminal police have been carrying out the investigation owing to its “special significance”, as is common in suspected terrorism cases. The news magazine Der Spiegel cited sources close to the investigation as saying that the plot had been at an early stage.
Regional officials said it was the test runs that had brought the plans to the attention of security authorities in North Rhine-Westphalia state. Its interior minister, Herbert Reul, said the arrests pointed to the “hybrid threat” posed by “low-level agents” working for Russian services for “little money”.
“We know that Russia is trying to destabilise western democracies by all means – including targeted sabotage and perfidious intelligence methods,” the German justice minister, Stefanie Hubig, said, adding that security authorities were “keeping a close eye on this threat”.
The chancellor, Friedrich Merz, did not mention the arrests during his first speech to parliament since taking office last week. But he condemned murders, cyber-attacks and destruction of undersea data cables across Europe “that are overwhelmingly the work of the Russian state leadership and its helpers”.
Merz called such plots “attempts to sow division” and said Germany and Europe would meet these security threats “with the greatest decisiveness, with unity and above all with defence preparedness”.
Germany is the second-largest national supplier of military aid to Ukraine after the United States and Merz has pledged his government's unwavering support of Kyiv.
Last July, European security agencies were shaken by three separate explosions in packages sent from Lithuania, which detonated in Birmingham in the UK; Leipzig, Germany; and near Warsaw, in Poland.
All the couriers appear to have operated within the same network and transported similar content of sex toys and massage pillows.
Reuters reported that the devices were rigged to ignite using pre-set timers repurposed from inexpensive Chinese electronics typically used for tracking lost items. Their impact was intensified by tubes disguised as cosmetics, which were filled with a flammable gel containing compounds such as nitromethane.
Western security officials were quick to suspect Russian intelligence, with the incidents coming amid a series of other hostile acts.
German authorities said in October that a plane could have been downed if the devices had ignited in flight. Security officials noted the parcels were due to have been in the air when they caught fire and the delayed arrival of the aircraft had prevented a catastrophe.
The logistics firm DHL took measures to protect its network after fires at one of its warehouses in Leipzig.
When the US government became aware of the alleged plot, alarmed officials in Joe Biden's White House reportedly contacted their Russian counterparts to demand the Kremlin put a stop to it.
Russia has denied any involvement.
Richard Moore, the head of the UK's Secret Intelligence Service, commonly known as MI6, warned in November that Russia was waging a “staggeringly reckless campaign” of sabotage in Europe while also increasing its nuclear sabre-rattling to scare off other countries from backing Ukraine.
Airlines will meet with the Federal Aviation Administration Wednesday to address weeks of delays at Newark Liberty International Airport following air traffic control staffing and equipment issues.
The “delay reduction meeting” at the Department of Transportation was announced by Transportation Secretary Sean Duffy.
“The goal is to have a manageable number of flights land at Newark,” he told reporters at a news conference Monday. “Families shouldn't have to wait four or five hours for a flight that never takes off.”
It comes after more than two weeks of delays and cancellations prompted by air traffic control staffing shortages at a Philadelphia facility that handles flights headed to or from the airport, runway construction and congestion.
Thirty-eight certified professional controllers are needed to operate the facility that handles Newark traffic, yet only 24 of the positions – 63% – are currently filled, the FAA notes in the meeting announcement.
Sixteen of those controllers are due to return to a New York FAA facility next year.
Additionally, five controllers took a 45-day trauma leave after an outage on April 28 caused their radar screens to go blank for 90 seconds and their radios to go out for 30 seconds during the busy afternoon.
Since runway construction started on April 15, Newark airport saw an average of 34 cancelations per day and “consistently high” delayed arrivals with an average delay time at 5 p.m. of 137 minutes.
“EWR is unacceptably congested airport due to current circumstances,” the FAA said in the meeting notice. “The airport clearly is unable to handle the current level of scheduled operations.”
Each airline will be asked to offer “specific flight reductions or schedule modifications” that are not contingent on what other airlines do, the notice said. The FAA will then consider an order which could limit schedules at the airport.
Chicago-based United Airlines, which operates a hub at Newark, recently called for assigned “slots” at the airport, which would require government approval for flights.
In the meeting notice, the FAA proposed limiting flights to only 28 domestic airline arrivals and 28 departures per hour until runway construction is complete on June 15, and during weekends in the fall. During other times, 34 domestic airline arrivals and 34 departures would be allowed each hour at the airport.
International air operations will be managed through a different process.
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NEW DELHI, May 14. /TASS/. India's Operation Sindoor, conducted amid escalating tensions with Pakistan, has become a litmus test for New Delhi's relations with the other QUAD members (Australia, Japan, and the United States), who did not support it, the India Today magazine reported.
"India's recent military strikes on Pakistan-based terror camps, a response to the Pahalgam terrorist attack, received no support from the Quad - the US, Japan, Australia, and India - united to counter China. No endorsements, no tweets, not even a nod," the magazine pointed out.
"While India waged a war on Pakistan-sponsored terror through Operation Sindoor, her so-called Quad allies ghosted her in real time. US President Donald Trump's diplomacy visibly turned the Quad from a strategic alliance into a WhatsApp group chat, leaving messages unread," India Today noted.
In addition, the magazine stressed that "in his attempt to claim credit for the fragile de-escalation after days of hot battle between Indian and Pakistani armed forces, Donald Trump <…> declared that India and Pakistan would negotiate at a neutral venue and offered to mediate on Kashmir, a proposal, even from friends, India firmly rejects."
India-Pakistan relations soured after the April 22 terrorist attack in Pahalgam, in the Indian union territory of Jammu and Kashmir, that killed 25 Indian citizens and a Nepali national. In the early hours of May 7, Indian forces began attacking terrorist bases in Pakistan. In response, the Pakistani government launched a large-scale military operation codenamed Bunyan-um Marsoos.
On May 10, New Delhi and Islamabad agreed to a ceasefire. Prior to the announcement of the agreement, US President Donald Trump wrote on his Truth Social page that India and Pakistan had agreed to a complete ceasefire brokered by Washington.
The disclosure follows a warning from Digital Affairs Minister Krzysztof Gawkowski, who on May 6 said Moscow was carrying out an "unprecedented" interference campaign.
Brazilian President Lula da Silva claimed that Ukrainian Foreign Minister Andrii Sybiha had appealed to his Brazilian counterpart, Mauro Vieira, to ask Putin if he was willing to conclude a peace agreement.
Earlier reporting from the Washington Post cited a former Russian official who claimed Russian Foreign Minister Sergey Lavrov and Putin's foreign policy aide, Yuri Ushakov, would represent Moscow in the talks.
Vyshyvanka, a traditionally styled embroidered shirt or dress, is the central feature of Ukraine's national clothing.
The Council of Europe on May 14 approved the creation of a special tribunal to prosecute Russia's top leadership for the crime of aggression against Ukraine, Ukrainian lawmaker Maria Mezentseva reported.
Viktoria Roshchyna, 27, disappeared in August 2023 while reporting from Ukraine's Russian-occupied territories. Moscow admitted she was in Russian detention the following year.
Dutch Justice Minister David van Weel speaks about the future of the EU-led special tribunal for the crime of aggression against Ukraine and its role in bringing Russia to justice.
Turkish officials told Bloomberg that while they don't expect Trump to visit Istanbul, they are not ruling it out, and preparations for any scenario are underway.
The air raid was announced at around 2:30 p.m. local time, while the explosion sounded around 2:50 p.m.
Melkonyants was arrested in August 2023 in connection with the activities of the European Network of Election Monitoring Organizations (ENEMO), which was co-founded by Golos's legal predecessor, the Golos association.
Ukraine's underground storage facilities are currently using 19.4% of their capacity. Almost 32%, or 2.79 bcm, less gas is available in the storages than in the previous year, according to the estimates.
The majority of Ukrainians, 71%, do not support holding elections before a full peace deal, even in the case of a ceasefire and security guarantees, according to a poll published by the Kyiv International Institute of Sociology (KIIS) on May 14.
"He'd like me to be there, and that's a possibility. ... I don't know that he would be there if I'm not there. We're going to find out," U.S. President Donald Trump told reporters aboard Air Force One while traveling to Qatar, Reuters reported.
Trump has long demanded that NATO allies increase their military spending, previously calling for the alliance to raise its benchmark from 2% to 5% of GDP.
Russia seems to be preparing a significant offensive in Ukraine as it is moving troops toward key positions on the front, the Financial Times reported on May 13, citing undisclosed Ukrainian intelligence officials.
These reported preparations indicate Moscow's efforts to escalate the war despite expected ceasefire talks this week and calls by Kyiv and its partners for an unconditional 30-day truce.
Russia has rejected ceasefire proposals unless accompanied by a halt on military aid for Ukraine and continues ground assaults along the front and long-range strikes on Ukrainian infrastructure.
Some 163 clashes were recorded at the front over the past day, the Ukrainian military reported on the morning of May 14. The DeepState monitoring group said that Russian forces recently advanced in Toretsk and near Pokrovsk in Donetsk Oblast.
Kyiv has been warning about a major Russian spring offensive aimed at seizing as much territory as possible to strengthen its position in potential negotiations. Commander-in-Chief Oleksandr Syrskyi said last month this campaign had "effectively already begun" with the intensification of Russian assaults.
President Volodymyr Zelensky is traveling to Turkey this week and has invited Russian President Vladimir Putin to discuss a ceasefire in what would be their first meeting since 2019.
U.S. President Donald Trump, who pledged to broker a peace deal between Moscow and Kyiv, voiced optimism about the potential talks and dispatched Secretary of State Marco Rubio and special envoys Steve Witkoff and Keith Kellogg to attend.
The Kremlin has not confirmed whether Putin will attend the talks himself, but the Washington Post reported that Moscow will be represented by Foreign Minister Sergey Lavrov and Putin's foreign policy aide, Yuri Ushakov.
Andriy Yermak, Zelensky's chief of staff, said on May 13 that if Putin does not come to Turkey, it will be "the last signal" that Russia "does not want to end the war and is not ready for any negotiations."
Senior News Editor
Martin Fornusek is a news editor at the Kyiv Independent. He has previously worked as a news content editor at the media company Newsmatics and is a contributor to Euromaidan Press. He was also volunteering as an editor and translator at the Czech-language version of Ukraïner. Martin studied at Masaryk University in Brno, Czechia, holding a bachelor's degree in security studies and history and a master's degree in conflict and democracy studies.
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ISABELLA M. WEBER is Associate Professor of Economics at the University of Massachusetts, Amherst, a Fellow at the Roosevelt Institute, and the author of How China Escaped Shock Therapy: The Market Reform Debate.
TOM KREBS is Professor of Economics at the University of Mannheim, a member of the German Minimum Wage Commission, and a former Senior Adviser at the German Finance Ministry.
Isabella M. Weber and Tom Krebs
Germany is in a prolonged economic crisis that has bred a subsequent crisis of democracy. The energy shock in the wake of the Russian attack on Ukraine in 2022 stalled the country's recovery from the pandemic. After six years of stagnation, the real GDP has plateaued and is almost ten percent below where it should be according to pre-pandemic trends. The energy crisis also fueled inflation and led to the largest one-year drop in real wages since World War II. Despite some gains in 2024, real wages are still eight percent lower than where they were trending before the pandemic.
This economic malaise has helped the extreme right Alternative for Germany party, or AfD, make startling and troubling gains. It managed a historic second-place finish in February's federal election. With prominent neo-Nazi members and overt hostility to the liberal principles that Germany has sought to enshrine since World War II, the AfD poses a direct threat to the country's democracy. Its success bodes ill not just for Germany but also for Europe writ large.
And yet Germany's leaders have struggled to come to grips with the full dimensions of the crisis. The prior government, a three-party coalition helmed by the center-left Social Democratic Party of Germany (SPD), stuck to strict balanced budget rules even though a deficit-financed economic stimulus program would have been the right medicine for the ailing patient. It applied fiscal austerity in both 2023 and 2024. The result was two more years of economic stagnation and eventually the political deadlock that led to the downfall of Chancellor Olaf Scholz and the fresh federal elections this year. The incoming government, led by the center-right Christian Democratic Union of Germany (CDU), tried to avoid the fate of its predecessor by initiating a change of the constitutionally enshrined fiscal rules (known as the “debt brake”) in March to allow for unlimited deficit spending on the military and limited additional spending on infrastructure. Many analysts praised the change as a breakthrough. The markets soared. The new chancellor, Friedrich Merz, claimed: “Germany is back.”
To be sure, fiscal policy reform was long overdue. But the new exceptions will not be enough to put the German economy on a sustainable growth path that benefits workers. Although Merz wants to spend on the country's rearmament and infrastructure, much of the rest of his economic agenda consists of social spending cuts, privatization, and deregulation. Such an agenda will not solve the problems caused by real wage losses and heightened economic insecurity. It is bound to produce constant tension with the center-left coalition partner. And it is unlikely to restore trust in democratic elites in a country where the frustration with the cost-of-living crisis drives growing support for the AfD.
Germany's economic success in prior decades relied on demand for its exports; reliable energy imports from Russia; affordable housing and food that together helped prop up living standards at competitive wages; and global leadership in the form of major companies of the mechanical and fossil fuel age. All these key planks of German power have been falling away. The war in Ukraine has led to rising energy prices; Chinese manufacturing success has made it more difficult to hold a leadership position in key industries such as clean technology; U.S. President Donald Trump's trade war is threatening export markets; and domestic policy mistakes have made this difficult situation worse. Beyond rearmament and infrastructure investments, Germany would benefit from a comprehensive fiscal reform that gives it greater latitude to advance policies that ensure the affordability of essentials and the creation of good jobs, speed up the green transition, and strengthen safety nets to encourage domestic consumption and less reliance on external demand. Such a program can generate shared prosperity and allow people to regain control of their lives. In so doing, it would weaken the appeal of extremists and help buttress the liberal democracy at the heart of Europe.
Merz and his coalition government, comprising the center-right CDU and center-left SPD, were sworn in on May 7. The fiscal foundation of their agenda, however, was set in March, when the coalition amended the debt brake—with support from the Green party, whose votes were needed for the necessary two-thirds majority in parliament. Since the 2008–9 financial crisis, Germany has maintained strict limits on spending, capping its deficit at 0.35 percent of GDP. That bar remains intact, but the coalition added major exceptions. Most notably, defense spending is no longer subject to deficit limits, a development that the arms manufacturer Rheinmetall hailed in its earnings call in March. To get the SPD and Greens on board, the new fiscal rules also include exemptions for deficit spending on infrastructure investment of 0.8 percent of GDP (about $40 billion) and on climate protection of 0.2 percent (about $10 billion) annually until 2037.
The incoming coalition government decided to hike military spending to strengthen Germany's defense capabilities and boost the economy. Once the German economy is back on track, Merz and his allies reasoned, social problems would presumably solve themselves; Merz is an advocate for free markets and espouses “trickle-down economics.” When it comes to the military sector, however, Merz has pushed Germany into a Keynesian world of industrial policy and unlimited government spending. For everything else, the government is taking a back seat. Public spending on infrastructure and climate change is capped, while spending on social benefits is in danger of being cut.
The prior government's austerity did not do the country any favors. The scrapping, for instance, of electric vehicle subsidies in 2023 has slowed production in a key industry and threatened jobs. Merz is not planning to reverse rollbacks such as that cut. Pressure from his center-left coalition partner SPD will not likely change his mind. This laissez-faire approach could have a devastating effect on Germany's industrial base: Volkswagen, for example, is planning to reduce its workforce in Germany by more than one-fourth until 2030 while freezing workers' wages.
Merz's far more generous approach to military spending will not boost domestic growth in the coming years as much as its advocates suggest. The defense sector is already operating near capacity, and in the short run, increasing government spending on weapons and tanks will have only a limited effect on production. Arms companies such as Rheinmetall have seen soaring profit margins, revealing their market power and the lack of competition they face even amid rising demand. Significant additional public spending may go into boosting their margins further. Rheinmetall's 15-fold stock surge reflects expectations of continued windfall profits.
Of course, the government has insisted that this military spending will create well-paid manufacturing jobs. Yet Merz's cabinet is full of business executives and lacks a strong voice for labor issues, an absence that has drawn criticism from the CDU itself. Moreover, the defense build-out will not likely compensate for the impending loss of jobs in ailing industries such as the automotive sector. Rheinmetall's profits almost doubled between 2020 and 2024, but the number of its employees based in Germany rose just 25 percent in that period. The conversion of civilian plants to military use does not offer much more hope. In the East German town of Görlitz, a former Alstom train factory was taken over by the German-French defense company KNDS and now produces tanks, but the factory's workforce has been slashed in half. The arrival of KNDS was clearly better than nothing, but it is unlikely to turn things around in a place such as Görlitz with a high unemployment rate of 7.7 percent. In this year's federal election, the far-right AfD candidate Tino Chrupalla won nearly 49 percent of the vote in the town.
Given stagnant growth and precarious external demand, the government would be well advised to stimulate consumer spending and inspire greater confidence among consumers. Instead, Merz and his party have advocated for social spending cuts, partly to offset rising defense costs. It is unlikely that large cuts will materialize since no party, so far, wants to touch the two biggest spending pots—public retirement benefits and public health care. But the rhetoric alone can dampen consumer sentiment and affect spending habits. In addition, such messaging amid prolonged economic strain may further alienate voters. If citizens believe that their government is spending freely on defense while forcing them to shoulder the burden of a six-year economic crisis, Germany's mainstream parties may hemorrhage more support to far-right populists.
Public confidence in Merz's leadership is already at stunning lows, even at the outset of his time in office. Only 30 percent of Germans believe the new government will bring positive change. Merz holds the lowest favorability rating of any incoming postwar chancellor and is the first to fail to secure a parliamentary majority in the initial confirmation vote. The AfD now has a narrow lead in some polls. For the first time since World War II, a right-wing extremist party (it was classified as such by German intelligence this year) has a realistic chance of winning federal power.
To escape stagnation—and thus slow the rise of the far right—Germany needs a policy approach that renews the economic model and generates broadly shared economic gains. Instead of the one-sided approach of the Merz government, Germany should be embarking on a real and balanced reform of the debt brake and European fiscal rules. The reform should allow for deficit financing of public investment spending—not just in the military and a few other sectors. The U.S. bond market is currently experiencing historic turbulence. Trump's tariff rollout in April triggered a major bond selloff and shook the trust in what used to be one of the world's most important safe haven assets. This volatility has spooked leaders in Washington, but it presents an enormous opportunity for Europe, Germany in particular. Germany has massive public spending needs, and many countries and financial investors are keen to buy German government debt. Loosening the fiscal rules to allow Germany to sell more of its debt would consequently grant the government greater fiscal firepower.
That firepower should be used efficiently. Investments that create public ownership of critical infrastructure come at a lower cost than investments owned by private equity since public infrastructure does not have to generate profits. Enhanced European coordination can increase the effectiveness of military spending and enable some rebalancing of fiscal resources away from defense spending toward needed areas of investment such as clean technology and elder- and childcare. Investment in these areas has a far greater economic effect than it does in defense; compared with military spending, every euro spent in nonmilitary sectors generates four times as much growth.
Germany urgently needs an ambitious industrial policy that delivers sustainable economic growth and good jobs. Key industries such as the automotive sector must regain competitiveness, in part by pioneering clean production techniques. Merz hopes the free market will facilitate this positive transformation, but the evidence suggests it will not. Leaving German companies to their own devices has led to them lagging in the green transition. Targeted green industrial policy with the right mix of incentives and conditions is needed to steer firms toward catching up with the technological frontier in clean tech. To ensure that workers benefit, firms should receive subsidies only if they pay decent wages and maintain domestic production sites. For large companies coming from China and other countries outside the European Union, joint venture agreements that require strong labor standards can be made a requirement for market access in key sectors—much as China requires joint ventures for foreign firms to access critical areas of the Chinese market. This could help secure jobs and technology transfers where Germany has fallen behind.
The German economy also needs to become more resilient to global demand shocks. To this end, Germany should strengthen domestic demand for goods and services. High labor standards, including minimum-wage laws and broad union coverage of all sectors of the economy, are key to boosting the incomes of the majority of households. The government should raise the minimum wage from its current level of around 13 euros to 15 euros and give preferential treatment in procurement to companies that pay union-level wages. The government must also help keep down the price of essentials, such as housing, food, and energy, so that they do not eat up people's purchasing power. Authorities should craft an ambitious program to address the cost-of-living crisis through effective national rent control, energy price stabilization, and strict antitrust enforcement in the food processing and grocery sectors to reduce food prices.
Both Trump and the AfD have capitalized on economic problems that mainstream politicians have ignored or downplayed for too long. Of course, neither of the so-called populists offers a credible solution, but the problems they identify are real. So far, the new German government has no convincing plan to solve the economic problems tearing society apart. To be sure, its coalition agreement includes several useful ideas for a pro-worker growth model, but it is unlikely that Merz, an unreconstructed free-marketeer, and his conservative ministers will advance these ideas into workable policy programs. If mainstream parties can't offer an alternative playbook for economic policy that really addresses the current crisis, they will end up ceding even more ground to the extreme right—with terrible consequences for Germany's democracy.
An earlier version of this article incorrectly stated that real GDP growth in Germany was almost ten percent below where it should be according to pre-pandemic trends. In fact, it is not real GDP growth but the real GDP itself.
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President Donald Trump may have backed off, for now, from the sweeping tariffs he proposed placing on almost every country in the world. But he is still upending global trade. Trump has established baseline ten percent tariffs on most imports. He has made those levies higher for a variety of specific goods, including steel. And he slapped 145 percent tariffs on imports from China, the world's largest manufacturer, although he has now agreed to cut this rate to 30 percent. The result has been a raft of trade wars between Washington and other governments, Beijing foremost among them.
Trump's disruptions to the global economy are serious, and they may feel novel. But today's situation is hardly without precedent. One does not have to look especially far back to see what the president's tariffs might do to the world. The problems the global economy now faces echo some that existed before the 1995 creation of the World Trade Organization and others that existed even before the WTO's predecessor, the 1947 General Agreement on Tariffs and Trade (GATT). Until those bodies helped standardize commerce, countries frequently used trade to extract concessions from one another. They created and exploited what economists call “hold-up problems”: when one state or firm makes an investment in another in which profits depend on the continuation of the relationship. For example, one country could build oil infrastructure in another country that the supplier alone can service or operate. Once such deals are concluded, powerful countries can coerce their partners simply by threatening to change the terms of the agreement.
In the near term, countries can benefit from wielding trade as a cudgel. But in the long term, trade wars leave almost everyone worse off. When countries frequently use economic leverage to secure concessions from vulnerable partners, investment and economic growth go down. Political instability, meanwhile, goes up. States that chafe at economic coercion sometimes turn to their militaries in order to fight back. Countries that once cooperated because of commercial ties turn into competitors. Even close allies drift apart. Trump may think his tariff regime will make the United States richer, safer, and stronger. But history suggests it will do just the opposite.
In the early nineteenth century, American traders began doing business with U.S. settlers in the kingdom of Hawaii. At the time, the islands' economy revolved around sugar plantations, many of which were owned or controlled by American businessmen who exported sugar to the U.S. market. Eventually, to help the sugar farmers, the two countries struck the Reciprocity Treaty of 1875, which eliminated tariffs on Hawaiian sugar entering the United States. In response, Hawaii's sugar economy boomed.
Initially, this deal worked reasonably well for Hawaii, which grew much richer from the exports. But it made the kingdom ever more dependent on the United States, which was able to exploit this reliance to its advantage. Washington refused, for example, to renew the Reciprocity Treaty unless Hawaii gave it exclusive rights to Pearl Harbor. American officials then eliminated tariffs on all foreign sugar in the 1890s and gave domestic producers a subsidy to shield the U.S. industry from foreign competition and keep prices low. This deprived Hawaii of its cost advantage. Hawaiian planters were crushed, increasing support among the islands' U.S. elite for annexation. The elite's push was successful, despite overwhelming opposition by the native Hawaiian population.
Hawaii was hardly the only country victimized by trade dependence. The United States and European countries had their investments in railroads, mines, and oil infrastructure in Mexico after Mexico expropriated them both outright and through regulator changes. Their banks and railways in China were attacked by the Qing dynasty. Western investments in Cuba were sabotaged under Spanish colonial rule. Perhaps most famously, Germany used its status as one of the largest importers of eastern European agriculture to gain political influence in that region before World War II.
These risks, in turn, suppressed overall economic exchange. No countries wanted to be conquered or coerced, so many of them steered clear of international commerce. The founders of the United States feared that economic dependence on the United Kingdom would give London undue influence even after they won the Revolutionary War, so they curtailed transatlantic trade. Qing China feared that trade dependence was a security vulnerability and likewise held back from global markets. Imperial Russia embraced autarky in the late nineteenth century to avoid vulnerability. In the 1930s, Japan went so far as to seize Manchuria in order to create an autarkic bloc that would supply Tokyo with raw materials without having to negotiate with the West.
In this rough-and-tumble era, trade wars were frequent and destabilizing. Sometimes, they helped produce outright conflict. The Smoot-Hawley Tariff Act of 1930, which raised U.S. tariffs on over 20,000 goods, prompted a global trade war that intensified geopolitical rivalries and helped push Germany, Italy, and Japan toward autarky and expansionism. Most famously, after the United States placed tariffs, embargoes, and export controls on Japanese oil, scrap metal, and aviation fuel, Tokyo struck Pearl Harbor in 1941. Trade tensions have featured in many other military conflicts, as well. Trade pressure and maritime coercion, for example, also helped lead to the War of 1812.
There still were bright moments for trade in the pre-WTO era, especially after World War II ended. In 1979, for instance, China and the United States normalized ties, and in 1980, the latter country granted the former permanent normal trade relations—preferential tariff treatment under U.S. law. But for two decades, the U.S. Congress had to vote yearly to renew China's normal trade status, which legislators conditioned on Beijing making human rights and nonproliferation concessions. Although Congress always granted this status, the recurring uncertainty depressed trade and investment, as firms hesitated to engage deeply with a partner whose access to the American market could be revoked at any time. Economic actors, after all, require stable, predictable frameworks to make long-term investments.
In response, Beijing pushed to join the WTO from the moment it was created, hoping the body could guarantee Chinese manufacturers predictable global access. This effort sparked fierce debate within the United States about whether to permit accession. Advocates of integration argued that tying China's economy to the world's would deter China from launching military conflicts, lest it risk a cutoff, and encourage political liberalization. Opponents feared that economic integration before political liberalization would only strengthen an authoritarian competitor. Ultimately, the optimists prevailed: Washington allowed Beijing to join the WTO in 2001. The organization then alleviated China's hold-up problems by prohibiting the United States from threatening tariff hikes each year. The Chinese economy, already expanding at a healthy rate, began to grow even faster.
For the WTO, Chinese accession was a triumph. The organization was created to increase trade everywhere and stop countries from using commerce as a weapon, and integrating the world's most populous country (and a former U.S. adversary) suggested the body was having its intended effect. And at the time, it was—countries typically obeyed the WTO's common rules, listened to its adjudicators, and played along with its enforcement tribunals. The resulting system was hardly perfect; it failed, for example, to stop China from using industrial policy as a means to promote specific sectors or companies, often at the expense of foreign firms, or from restricting exports to countries that criticized Beijing. But for the most part, the WTO was quite successful. Trade flourished, and the global economy grew more quickly than it otherwise would have.
Then came the 2016 election of Trump. The president, always a critic of free trade, quickly went about abandoning and dismantling the WTO framework—taking opposition to the body to a whole new level. The United States, once the organization's biggest champion, largely stopped listening to WTO guidance. It adopted trade practices that outright violated the body's rules. And it paralyzed the organization's appellate body in order to further weaken the system. Instead, Washington's leaders reembraced a transactional view of trade, deploying tariffs as blunt instruments of punishment and coercion. Hold-up problems, once thought tamed, returned with a vengeance. Long-term investment and cross-border economic planning became riskier as geopolitical considerations reasserted themselves.
During Trump's first term, these policies helped spur a more defensive posture by the United States' trade partners. The EU, for example, devised new geoeconomic policies such as its anti-coercion instrument, which allows the bloc to respond to economic coercion by imposing tariffs, restricting access to EU markets, or suspending international obligations. China and the United States began to separate out investments. Such actions may well have suppressed both trade and foreign direct investment, although the declines in both are difficult to disentangle from the consequences of the COVID-19 pandemic. But even if Trump's policies mattered little the first time around, that does not mean they will have trivial effects now. The first Trump administration featured many advisers who prevented the president from unleashing the kind of broad-based tariffs that he has implemented in 2025. Today, firms face even greater uncertainty. As a result, Chinese companies are already intensifying efforts to eliminate foreign components from their supply chains. So is the EU.
Trump's tariffs are unlikely to help the U.S. economy. They will probably fail at their main stated goal—bringing manufacturing jobs back to the United States—because businesses will be reluctant to invest more at home when Washington keeps making and breaking trade agreements. The White House, after all, could instantly render whatever domestic factories companies build unprofitable by slashing tariffs. Trump also wants to use the leverage from the tariffs to compel countries to sign bilateral agreements with the United States, as was common before the advent of the multilateral trading system, but these deals will not do much to encourage investment, either. Unlike in a multilateral system, bilateral agreements are difficult to enforce and thus difficult for countries and firms to trust. In a bilateral system, trading partners also constantly worry that whatever agreement they sign with the United States will be undercut by a new deal between Washington and a different government. The result is even more uncertainty and thus less investment.
Trump's trade war, in other words, will likely have similar economic effects as trade wars past. It could also have similar political consequences. Alliances may fray as countries look to hedge their bets, diversifying economic ties rather than simply trusting their partners. Governments will use tariffs to try to weaken competitors. Trump has already apparently used tariffs in an effort to annex Canada (in a strange redux of U.S. policy toward Hawaii), saying that Canada could avoid tariffs by becoming an American state and threatening “economic force” if it doesn't. In response, Canadians have pivoted away from the United States, including by boycotting U.S. products. So have people in other countries; for example, overall favorability ratings of the United States have fallen across Western Europe since Trump won.
The United States is unlikely to attack any of these countries outright, although Trump has threatened Danish-controlled Greenland. But by reducing mutual dependency, his tariffs do lower the costs of military confrontation. If the United States reduces its economic reliance on Taiwanese semiconductors, for instance, Beijing might decide that Washington won't respond if China blockades or invades the island. Conversely, in a more transactional world, countries could use whatever dependencies still exist to gain a political advantage—as Berlin did with agriculture in the 1930s. Russia, in particular, has long used such tactics by manipulating the price of oil and gas to extract political concessions from countries in its periphery, contributing to regional conflict.
Moscow's tactics have naturally led many nearby states to diversify away from Russia. Now, similar tactics are also costing the United States. But should Washington lose its economic credibility, the result could be far more destabilizing than is the case for countries that do not trust the Kremlin. Washington's ability to stand by its agreements has been the backbone of many essential global institutions, including NATO. It is a key reason the dollar is the world's reserve currency. Without reliable frameworks, international politics will become more uncertain and volatile, making miscalculation and conflict more likely. The situation could start to resemble the lead-up to World War II, which partially resulted from the collapse of the League of Nations and the failure of European powers to nip German expansionism in the bud.
Trump may ultimately reduce some of his levies, particularly as he negotiates with more and more countries. He has already made a trade deal with the United Kingdom. But the president has abandoned the institutions and norms that once stabilized global trade. In doing so, he is ushering in an era not of renewed American strength but of stagnation, fragmentation, and danger. History, after all, shows that this is what trade wars create.
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Harvard University expanded its lawsuit against the Trump Administration's federal funding cuts on May 13 to include the additional $450 million in grants that administration officials announced were being terminated earlier that same day.
That grant money, which was to come from eight different federal agencies, added to the already $2.2 billion in terminated federal grants. It was announced by the Joint Task Force to Combat Anti-Semitism, which includes representatives from the Departments of Education, Justice, and Health and Human Services, and was designed to “root out anti-Semitic harassment in schools and on college campuses,” according to one of President Donald Trump's executive orders.
“Harvard University has repeatedly failed to confront the pervasive race discrimination and anti-Semitic harassment plaguing its campus,” the task force said in a statement.
“Jewish students were subjected to pervasive insults, physical assault, and intimidation, with no meaningful response from Harvard's leadership.”
The federally-funded Ivy League institution challenged the freezing of funds as a violation of the First Amendment. It asked U.S. District Judge Allison Burroughs to block the grant terminations. Burroughs scheduled the arguments for the case to be heard on July 21.
“The Government has not identified—and cannot identify—any rational connection between antisemitism concerns and the medical, scientific, technological, and other research it has frozen or terminated,” the lawsuit said.
Education Secretary Linda E. McMahon has accused Harvard of “engaging in a systemic pattern of violating federal law,” and alleged other issues such as political bias on campus and upholding an admissions process not based on merit.
“The Administration's priorities have not changed and today's letter marks the end of new grants for the University,” McMahon said in a May 5 letter.
“Harvard should no longer seek GRANTS from the federal government, since none will be provided.”
In one instance, Harvard was criticized when a pro-Hamas protester, who faced criminal charges for allegedly assaulting a Jewish student on campus, was awarded a $65,000 fellowship grant by the Harvard Law Review.
Harvard argued in its complaint that it was committed to combating anti-Semitism and ensuring its campus is safe for Israeli and Jewish students, and called the administration's actions a threat to academic freedom at the institution.
In a letter issued on May 12, Harvard President Alan M. Garber reaffirmed the school's stance and further accused the Trump administration of “overreach into the constitutional freedoms of private universities” and “continuing disregard of Harvard's compliance with the law.”
“Harvard will not surrender its core, legally-protected principles out of fear of unfounded retaliation by the federal government,” he said.
NEW YORK, May 14. /TASS/. Israeli military officers who monitor humanitarian conditions in the Gaza Strip have warned their commanders that the continued blockade of the embattled enclave will lead to a severe lack of food products, sources in Israel told the New York Times (NYT).
Speaking on the condition of anonymity, "the officers said that immediate steps were needed to ensure that the system to supply aid could be reinstated fast enough to prevent starvation." "It takes time to scale up humanitarian deliveries," they explained.
According to the newspaper, "Palestinians in Gaza face widespread starvation unless aid deliveries are restored within weeks."
The Integrated Food Security Phase Classification initiative (IPC) has asserted that about 1.95 million Gazans experience food shortages while 133,000 people are starving. IPC experts insist that "with the announced expansion of military operations throughout the Gaza Strip, the persistent inability of humanitarian agencies to access populations in dire need, an anticipated escalation in hostilities, and the continued mass displacement of people, the risk of Famine in the Gaza Strip is not just possible- It is increasingly likely."
On March 18, the Israel Defense Forces (IDF) resumed fighting in the Gaza Strip, launching massive strikes on the enclave and thus breaking the ceasefire established in January. Israeli Prime Minister Benjamin Netanyahu's office stated that Israel had restarted military operations in the enclave after the Gaza-based Palestinian movement Hamas rejected the US proposals put forward by mediators and US Special Presidential Envoy Steve Witkoff. The office claimed that the Israeli military had resumed strikes on Hamas targets in Gaza to advance the release of hostages and that the army would intensify its campaign in the enclave. The Gaza-based movement has blamed the United States for the renewal of Israeli aggression.
President Donald Trump‘s first foreign trip of his second term is underway. The president is visiting Saudi Arabia, Qatar, and the United Arab Emirates. But Trump will not be visiting Israel. The exclusion of America's historic Middle Eastern ally from Trump's itinerary is a marked example of Trump's declining sympathy for Prime Minister Benjamin Netanyahu's government. In contrast, Trump appears ecstatic at his evolving relationship with Saudi Arabia's de facto leader, Mohammed bin Salman.
Senior members of Trump's administration, including U.S. Ambassador to Israel Mike Huckabee, diplomatic envoy Steve Witkoff, and others, insist that there is no daylight between Trump and Netanyahu. But this rhetoric plainly doesn't stand up to reality. The fact that Trump is not visiting Israel on this first trip is evidence enough of some discord. But there are also more specific examples of Trump and Netanyahu being in disagreement.
For a start, Israel is manifestly opposed to Trump's diplomatic effort to secure a new nuclear agreement with Iran. Instead, Netanyahu, supportive Washington think tanks, and some Republican allies have pushed for immediate joint U.S.-Israeli military action to degrade Iran's nuclear infrastructure. They fear that Trump will negotiate an agreement that fails to end Iranian nuclear enrichment and covert weapons research. They worry that Trump will accept a deal that leaves the door open to future Iranian nuclear enrichment. But Trump appears to believe that an imperfect agreement is preferable to the use of military force. And even if there is little reason to think it possible, Trump seems to believe a nuclear deal will facilitate a broader political rapprochement with Iran.
Israel is similarly concerned about Trump's recent agreement with the Yemen-based Houthi rebels. In return for the Houthis' suspending strikes on U.S. and commercial vessels in the Red Sea, Trump has ended U.S. military action against them. Still, the Houthis are continuing to launch ballistic missile attacks on Israel.
Then, there's Israel's confrontation with Hamas in Gaza. Distant are the February days in which Trump suggested forcibly relocating the Palestinian population of Gaza and turning the Mediterranean Sea-facing territory into an American-run resort city. Today, Trump is increasingly comfortable pursuing negotiations with Hamas independent of Israel. That led to this week's release by Hamas of dual American Israeli citizen Edan Alexander. The Times of Israel reports that the Trump administration told Hamas that it would pressure Israel to agree to a 90-day ceasefire/10 hostage release deal in return for Alexander's freedom. The newspaper also reports that Witkoff has told the families of Israeli hostages that Netanyahu wants to sustain the war even though Trump wants a negotiated settlement.
Trump's recent social media posts also suggest he wants an end to Israel's war against Hamas. And the Sunni Arab monarchies and the vast majority of America's international allies certainly want the war ended. But Netanyahu wants to maintain the offensive. The prime minister has an obvious moral interest in imposing maximal damage on Hamas following its Oct. 7, 2023, atrocity. Perhaps more importantly, however, Netanyahu knows his fragile coalition government will collapse if he agrees to end the war in return for the release of the remaining hostages.
This issue-centric discord is exacerbated by Israel's inability to match the Sunni Arab monarchies in dangling financial investments to earn Trump's favor. And the scale of investments Trump is securing on this Middle Eastern trip is eye-watering.
On Tuesday, Trump and Salman announced a plan for $600 billion in Saudi investments in the United States. The UAE has previously said it will invest $1.4 trillion in the U.S. over a 10-year period. Qatar used Trump's visit to announce $243 billion in new U.S. defense, energy, and technology contracts. The figure includes a vast aircraft purchase from Boeing, following Qatar's earlier offer to Trump of a $250 million jet to replace the aging Air Force One aircraft.
Lubricating these investments is an Arab pageantry of extraordinary scale and opulence. From red carpet ceremonies to mobile McDonald's restaurants, Salman has spared no effort in treating Trump as American royalty. Salman and his fellow monarchs in the UAE, Qatar, Kuwait, and Bahrain recognize that the surest way to win Trump's favor is twofold: by investing heavily in the U.S. and flattering Trump's person. They hope to secure Trump's fundamental commitment to their security. Salman also hopes Trump will then pressure American businesses to support the crown prince's modernization project to turn Saudi Arabia into a world-leading center for entertainment, tourism, and business investment.
Again, Israel cannot match these investments. And far more than other American presidents, Trump tends to view foreign policy through the prism of immediate transactional opportunities rather than that of historic partnerships. Former Presidents Joe Biden, Barack Obama, and George W. Bush would likely all be far more reticent to tolerate Qatar's funding of various jihadist groups were they in power in 2025. But even in terms of Israel's traditionally most prized offering to the U.S., its assurance of stable democratic governance and exceptional intelligence services, Israel has limited means of wooing Trump.
After all, while the relationship between the U.S. and Israeli intelligence services remains very close, Saudi Arabia and Jordan can also point Trump to the critical activities of their own intelligence services in the fight against the Islamic State. This limits Netanyahu's ability to earn Trump's unique favor from acts such as Israel's elimination last year of numerous terrorists responsible for killing Americans. At the same time, Netanyahu has risked Trump's anger by conducting Israeli intelligence operations on U.S. soil and by sharing high-end Israeli technology with China.
PUTIN'S PROBLEM: ZELENSKY HAS LEARNED THE ART OF TRUMP'S FAVOR
Trump may now be more inclined to listen to Salman's advice, or that of Qatar's emir Tamim bin Hamad Al Thani, than he is inclined to listen to Netanyahu's advice. We saw an example of this dynamic in Trump's announcement on Tuesday to drop all sanctions on Syria. Israel wants Syrian President Ahmed al Sharaa's government to yield to a de facto Israeli right of military action against whatever targets inside the country it decides to target. But by Trump's establishing a new relationship with Sharaa, Israel will have to consider U.S. interests before taking future military action. This is a complicating rather than complementary U.S. intervention into Israeli-Syrian relations.
Netanyahu will fear that Trump's Arab agenda may now lead to escalating pressure to end Israel's military action in Gaza. Or perhaps even Trump's unilateral declaration of a Palestinian state, a key ask of Salman in return for his willingness to join the Abraham Accords. But it's clear that the Arabs are getting far more access to and impact on Trump's open ear than Israel would like.
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A federal judge on Wednesday ordered the release of Badar Khan Suri, the Georgetown University postdoctoral researcher detained by immigration officials in March for allegedly spreading propaganda in support of Hamas.
Federal Judge Patricia Tolliver Giles issued her order from the bench during a court hearing in Virginia, saying that the government presented no evidence to refute Suri's claims that he was being punished for his views on the war in Gaza.
Suri, who is married to an American citizen, was being held in federal detention in Texas following his arrest.
Suri, an Indian national in the U.S. on a student visa, was accused of "actively spreading Hamas propaganda and promoting antisemitism on social media," a senior Department of Homeland Security (DHS) official said in a statement in March.
MILWAUKEE JUDGE INDICTED FOR HELPING IMMIGRANT EVADE ICE FACES UP TO 6 YEARS IN PRISON
Badar Khan Suri, an Indian national and postdoctoral researcher at Georgetown University, was arrested by ICE on Monday over allegations claiming that he spread Hamas propaganda on social media. (Georgetown University)
"Suri has close connections to a known or suspected terrorist, who is a senior advisor to Hamas," the DHS statement continued. DHS did not name the suspected terrorist or Hamas advisor.
Secretary of State Marco Rubio determined on March 15 that Suri's activities and presence in the U.S. "rendered him deportable" under the Immigration and Nationality Act, the senior official said. The act is a rarely used legal statute that gives Rubio sweeping power to deport those who pose "potentially serious adverse foreign policy consequences for the United States."
Secretary of State Marco Rubio rendered Badar Khan Suri "deportable" under the Immigration and Nationality Act, a senior DHS official said in March. (AP Photo/Mark Schiefelbein, Pool, File)
Suri was duly granted a visa to enter the U.S. to perform doctoral research on peace building in Iraq and Afghanistan, a Georgetown University spokesperson said in a statement to Fox News following his March arrest.
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U.S. Attorney General Pam Bondi shares some of the Trump administration's key accomplishments in the first 100 days on 'Hannity.'
A former Michigan Army National Guard member was arrested for allegedly planning a mass shooting at a military base on behalf of the Islamic State terrorist group, the Justice Department announced Wednesday.
Ammar Abdulmajid-Mohamed Said, 19, was taken into custody Tuesday after he traveled to an area near the U.S. Army's Tank-Automotive & Armaments Command (TACOM) facility at the Detroit Arsenal in Warren, Michigan, and "launched his drone in support of the attack plan," officials said.
"I recommend everyone have about seven magazines because you don't want to be in there and run out of ammo," Said allegedly told an undercover FBI agent in the leadup to the foiled plot, according to a criminal complaint.
Said is now facing charges of attempting to provide material support to a foreign terrorist organization and distributing information related to a destructive device. He faces a maximum penalty of 20 years per count if convicted.
ABBEY GATE TERROR SUSPECT'S MUGSHOT REVEALED AS HE MAKES FIRST FEDERAL COURT APPEARANCE
Ammar Abdulmajid-Mohamed Said, of Melvinville, Mich., was arrested on Tuesday, May 13, for allegedly plotting an ISIS-inspired attack at the Tank-Army Automotive and Armaments Command (TACOM) in Warren, shown right. (Justice Department/AP)
"This defendant is charged with planning a deadly attack on a U.S. military base here at home for ISIS," Sue J. Bai, head of the Justice Department's National Security Division, said in a statement. "Thanks to the tireless efforts of law enforcement, we foiled the attack before lives were lost. We will not hesitate to bring the full force of the Department to find and prosecute those who seek to harm our men and women in the military and to protect all Americans."
The Justice Department said that in April, "two undercover officers indicated they intended to carry out Said's plan at the direction of ISIS" and "in response, Said provided material assistance to the attack plan, including providing armor-piercing ammunition and magazines for the attack, flying his drone over TACOM to conduct operational reconnaissance, training the undercover employees on firearms and the construction of Molotov cocktails for use during the attack, and planning numerous details of the attack including how to enter TACOM and which building to target."
7 TIMES ISIS HAS INSPIRED TERROR ATTACKS ON US SOIL
Ammar Abdulmajid-Mohamed Said is seen posing in front of an ISIS flag, according to the Justice Department. (Justice Department)
The criminal complaint stated that around June 2024, Said started communicating with an undercover FBI agent whom he had thought was a fellow ISIS supporter.
"During the course of their interactions, which were audio- and/or video-recorded, Said described his longstanding desire to engage in violent jihad, either by traveling to ISIS-held territory abroad or by carrying out an attack in the United States," the complaint said.
"On July 18, 2024, FBI agents executed a search warrant for Said's iPhone by performing a covert search of that device... when SAID provided it to personnel with the Michigan Army National Guard prior to boarding a military aircraft. During that search, FBI agents identified a Facebook message exchange (in Arabic) that took place on or about October 5, 2023, between Said and another Facebook user located in the Palestinian territories," the complaint continued.
Said is pictured showing an undercover FBI agent the planned site of the attack, according to the Justice Department. (Justice Department)
"In that Facebook message exchange, Said stated, ‘I want to go for Jihad,' and the other Facebook user replied, ‘Talk to me on Telegram.' Agents also determined during the search that Said was a member of multiple channels in the encrypted messaging application Telegram, one of which contained videos and images with ISIS flags," it also said.
The complaint noted that Said enlisted in the Michigan Army National Guard in September 2022 and attended basic training at Fort Moore in Georgia. He later reported to the Michigan Army National Guard Taylor Armory before being discharged around December 2024.
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The FBI's Joint Terrorism Task Force is leading the investigation into the case.
Greg Norman is a reporter at Fox News Digital.
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Logan Feeney pours a water sample with forever chemicals, known as PFAS, into a container for research, April 10, 2024, at a U.S. Environmental Protection Agency lab in Cincinnati. (AP Photo/Joshua A. Bickel, File)
Equipment sits inside the Sweeney Water Treatment Plant, which processes water for much of New Hanover County in Wilmington, N.C., Monday, April 28, 2025. (AP Photo/Ben McKeown)
Water is processed through carbon filters inside large reservoirs designed to remove a forever chemical, known as PFAS at the Sweeney Water Treatment Plant in Wilmington, N.C., Monday, April 28, 2025. (AP Photo/Ben McKeown)
Vials containing samples of forever chemicals, known as PFAS, sit in a tray, April 10, 2024, at a U.S. Environmental Protection Agency lab in Cincinnati. (AP Photo/Joshua A. Bickel, File)
The Environmental Protection Agency said Wednesday that it plans to weaken limits on some “forever chemicals” in drinking water that were finalized last year, while maintaining standards for two common ones.
The Biden administration set the first federal drinking water limits for PFAS, or perfluoroalkyl and polyfluoroalkyl substances, finding they increased the risk of cardiovascular disease, certain cancers and babies being born with low birth weight. Those limits on PFAS, which are human-made and don't easily break down in nature, were expected to reduce their levels for millions of people.
Limits on three types of PFAS, including what are known as GenX substances found in North Carolina, will be scrapped and reconsidered by the agency, as will a limit on a mixture of several types of PFAS.
The Biden administration's rule also set standards for the two common types of PFAS, referred to as PFOA and PFOS, at 4 parts per trillion, effectively the lowest level at which they can be reliably detected. The EPA will keep those standards, but give utilities two extra years — until 2031 — to comply.
“We are on a path to uphold the agency's nationwide standards to protect Americans from PFOA and PFOS in their water. At the same time, we will work to provide common-sense flexibility in the form of additional time for compliance,” said EPA Administrator Lee Zeldin.
The development was first reported by The Washington Post.
Vials containing samples of forever chemicals, known as PFAS, sit in a tray, April 10, 2024, at a U.S. Environmental Protection Agency lab in Cincinnati. (AP Photo/Joshua A. Bickel, File)
It appears few utilities will be impacted by the withdrawal of limits for certain, newer types of PFAS. So far, sampling has found nearly 12% of U.S. water utilities are above the Biden administration's limits. But most utilities face problems with PFOA or PFOS.
Health advocates praised Biden's administration for the limits. But water utilities complained, saying treatment systems are expensive and that customers will end up paying more. The utilities sued the EPA.
The EPA's actions align with some arguments in the utilities' lawsuit. They argued the EPA lacked authority to regulate a mixture of PFAS and said the agency didn't properly support limits on several newer types of PFAS that the EPA now plans to rescind. They also sought the two-year extension.
Erik Olson, a senior strategist at the nonprofit Natural Resources Defense Council, said the move is illegal. The Safe Water Drinking Act gives the EPA authority to limit water contaminants, and it includes a provision meant to prevent new rules from being looser than previous ones.
“With a stroke of the pen, EPA is making a mockery of the Trump administration's promise to deliver clean water for Americans,” Olson said.
President Donald Trump has sought fewer environmental rules and more oil and gas development. EPA Administrator Lee Zeldin has carried out that agenda by announcing massive regulatory rollbacks. The EPA plans to loosen regulations for greenhouse gas emissions, cleanup standards for coal plant waste and car emission limits, among many other clean air and water rules.
Zeldin's history with PFAS is more nuanced; during his time as a New York congressman, he supported legislation to regulate forever chemicals.
Water is processed through carbon filters inside large reservoirs designed to remove a forever chemical, known as PFAS at the Sweeney Water Treatment Plant in Wilmington, N.C., Monday, April 28, 2025. (AP Photo/Ben McKeown)
Manufactured by companies like Chemours and 3M, PFAS were incredibly useful in many applications -– among them, helping clothes to withstand rain and ensuring that firefighting foam snuffed out flames. But the chemicals also accumulate in the body. As science advanced in recent years, evidence of harm at far lower levels became clearer.
The Biden-era EPA estimated the rule will cost about $1.5 billion to implement each year. Water utility associations say the costs, combined with recent mandates to replace lead pipes, will raise residents' bills and fall hardest on small communities with few resources.
The Biden administration did work to address cost concerns. The Bipartisan Infrastructure Law provided $9 billion for chemicals like PFAS, utilities have won multibillion-dollar settlements against PFAS polluters.
Some utilities have been surprised to find out they are over limits. And small water providers might struggle with compliance costs and expertise.
“This gives water pros more time to deal with the ones we know are bad, and we are going to need more time. Some utilities are just finding out now where they stand,” said Mike McGill, president of WaterPIO, a water industry communications firm.
Some utilities wanted a higher limit on PFOA and PFOS, according to Mark White, drinking water leader at the engineering firm CDM Smith. He suspects the utility industry will continue to sue over those limits. Environmental groups will likely file challenges, too.
Melanie Benesh, vice president of government affairs at the nonprofit Environmental Working Group, said utilities may not have to install treatment that's as broadly effective if they just have to focus on two types of older PFAS.
“You really reduce what utilities have to do to make sure that the other, newer generation PFAS are captured” she said.
When the Biden administration announced its rule, the head of the EPA traveled to North Carolina and was introduced by activist Emily Donovan, who said she was grateful for the first federal standards. She had long campaigned for tougher rules for GenX substances that had contaminated a local river.
Now the EPA says it will roll back those GenX limits.
“This current administration promised voters it would ‘Make America Healthy Again' but rescinding part of the PFAS drinking water standards does no such thing,” she said.
___
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Hearing aids are cool now.
by Adam Clark Estes
Hearing aids, like canes or orthopedic shoes, are something you don't think about a lot when you're young. But maybe you should.
You probably either know someone who needs hearing aids, or you'll need them some day yourself. About 30 million people in the United States, aged 12 and older, have hearing loss in both ears, and about two-thirds of people end up with hearing loss, which can range from mild to severe, by their 70s.
But talking to your parents or grandparents about getting hearing aids can be tough — I've done it. They might not like the idea of sticking things in their ear canals or confronting the difficult realities of aging and health. They surely shy away from the price tag of hearing aids, which can cost thousands of dollars and are not covered by insurance or Medicare.
But plugging tiny and exorbitantly expensive speakers into your ears isn't the only way. Your mom might already own hearing aids without even knowing it.
A weekly dispatch to make sure tech is working for you, instead of overwhelming you. From senior technology correspondent Adam Clark Estes.
Hearing aids have never been more accessible — or futuristic. In April, a company called Nuance started selling glasses that double as hearing aids thanks to microphones and beam-forming speakers built into the frame. Although at $1,200, they're not cheap, they cost far less than a pair of prescription hearing aids, which tend to range from $2,000 to $7,000.
The Nuance glasses joined an increasingly crowded market of FDA-regulated over-the-counter hearing aids that includes everything from the latest Apple AirPods Pro, which gained the capability through a software update, to bean-sized buds from Sony. Prices for these devices start as low as $100, and you don't need an audiologist to help set them up.
Hearing aids have never been more accessible — or futuristic.
You can also buy something that's legally considered a personal sound amplification product (PSAP), which is not designed to treat hearing loss but does make things louder. Some of them can play music and handle phone calls too. In the age when earbuds are ubiquitous, these devices appeal to all ages.
“It's good that we're seeing people in their 30s, 40s, and 50s, talking about it, because it's totally changing the paradigm for them of engaging in hearing care earlier,” Nicholas Reed, a faculty member at the NYU Grossman School of Medicine, told me.
I'm a millennial, but I've also dealt with hearing loss my entire life. A bad stretch of childhood ear infections left me mostly deaf in one ear and pretty spotty in the other. I learned to read lips as a teenager and avoid conversations at loud parties in college. Some surgery in my 20s brought me closer to normal, but I could still use a little help.
I've spent the past few weeks trying out the Nuance glasses in various settings. They're remarkable, not only because they feel almost indistinguishable from my regular glasses but also because I forget they're hearing aids. Made by EssilorLuxottica, the company behind Ray-Ban and dozens of other glasses brands, the Nuance glasses employ some of the same technology that the Ray-Ban Meta glasses use to play music and help you talk to AI. And while the Nuance glasses don't currently offer the option to stream audio, they do help you hear what your friend is saying in a loud bar.
The AirPods Pro 2, which retail for $250, work equally as well. After Apple announced last fall that a software update would unlock an accessibility setting — it's appropriately called Hearing Aid — I started using it all the time, toggling between listening to podcasts to ordering cold brew in a crowded coffee shop. In instances where I may have needed to ask people to repeat themselves in the past, I hear them fine the first time. I just have to wear AirPods all the time, which makes the glasses solution even more appealing.
For most people, hearing loss typically starts in your 50s and gains momentum in your early retirement years. If you've ever been to a busy restaurant with your parents or grandparents, you know this can be alienating for the person left out and frustrating for the hearing person, too. The social isolation can lead to loneliness and anxiety, which can hasten cognitive decline and lower life expectancy.
Nevertheless, neither traditional clinical hearing aids or the newer category of devices are easy fixes. Once you start wearing any sort of hearing aid, it takes time to adjust, and you might need help tweaking the sound as you get used to it. That's one reason why so many people avoid it — only one in five who need hearing aids actually have them. You can't put them in your ears and immediately have perfect hearing. Your brain adjusts over time, and so it may take weeks or months to adapt to the new frequencies hearing aids help you hear.
Still, it's a worthwhile project.
“Sensory input is so key to our existence, but we just sort of overlooked it for so long,” Reed said. “It's something that's vital to your existence and how you connect with other people.”
It's not clear how the latest hearing aid innovation will move the needle on adoption. Even though over-the-counter hearing aids have been available since 2022, when the FDA implemented new regulations for the devices, it's still an uphill battle to get people to wear them.
“Sensory input is so key to our existence, but we just sort of overlooked it for so long.”
“We are not seeing large increases in hearing aid uptake since over-the-counter hearing aids have become available,” said Tricia Ashby, senior director of audiology practices at the American Speech-Language-Hearing Association (ASHA). “And I have to say that mimics other countries who had over-the-counter hearing aids before the US did.”
Given the fact that the older people who need them most are potentially less likely to try the latest technology, it might still take a few years for over-the-counter hearing aids to go mainstream. Given the precedent set by companies like Apple and Nuance, though, it's possible that more devices will add hearing assistive features to existing products.
You can imagine a future where you wear earbuds that are the interface for your voice assistant as well as your lifeline on a loud plane. You might have glasses that project walking directions onto your field of view and help you hear which direction traffic's coming from when you have to cross the street. These kinds of features together only get more important as you get older and need a little more help.
“We are in an age now where you're thinking about optimizing aging, and how do you do it?” Reed said. “And it's things like this.”
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U.S. President Donald Trump met Wednesday with Syria's interim President Ahmad al-Sharaa, the first such encounter between the two nations' leaders in 25 years. The meeting, on the sidelines of Trump get-together with the leaders of the Gulf Cooperation Council, marks a major turn of events for a Syria still adjusting to life after the over 50-year, iron-gripped rule of the Assad family.
US President Donald Trump said on Wednesday that he will order the “cessation of sanctions against Syria to give them a fresh start,” and move to normalize relations with its new government.
US President Donald Trump on Wednesday said there is a “possibility” he will attend the Russia-Ukraine peace talks in Turkey on Thursday. Trump told reporters on Air Force 1 on his way to Doha that he does not know if Russia President Vladimir Putin will show up to the talks.
President Donald Trump's announcement that the U.S. will ease sanctions on Syria could eventually facilitate the country's recovery from years of civil war and transform the lives of everyday Syrians.
US President Donald Trump opened his four-day Middle East trip on Tuesday by paying a visit to Saudi Arabia's de facto ruler, Crown Prince Mohammed bin Salman, for talks on U.S. efforts to dismantle Iran's nuclear program, end the war in Gaza, hold down oil prices and more.
Syrians took to the streets in cities across the country to celebrate following U.S. President Donald Trump's announcement that he will ease sanctions and move to normalize relations with the new government to give the country “a chance at peace.” (AP video shot by Ghaith Alsayed and Omar Al Bam /Production by Malak Harb)
President Donald Trump arrived in Qatar on Wednesday, where he was greeted by the country's ruling emir, Sheikh Tamim Al Thani, as he kicked off the second leg of his three-nation Middle East tour this week.
President Donald Trump and Qatar's Emir Sheikh Tamim bin Hamad Al Thani meet at the Amiri Diwan in Doha, Qatar, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
In this photo released by the Saudi Royal Palace, Syria's interim President Ahmad al-Sharaa, left, shakes hands with President Donald Trump, centre, in Riyadh, Saudi Arabia, Wednesday, May 14, 2025. At right is Saudi Crown Prince Mohammed bin Salman.(Bandar Aljaloud/Saudi Royal Palace via AP)
President Donald Trump arrives with Saudi Crown Prince Mohammed bin Salman for the group photo with Gulf Cooperation Council leaders during the GCC Summit in Riyadh, Saudi Arabia, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
Qatar Emiri Air Force F-15s provide an honorary escort for Air Force One, carrying President Donald Trump, as it arrives in Doha, Qatar, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
President Donald Trump speaks to reporters aboard Air Force One en route from Riyadh, Saudi Arabia to Doha, Qatar, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
President Donald Trump holds up a pen given by Qatar's Emir Sheikh Tamim bin Hamad Al Thani as they exchange documents during a signing ceremony at the Amiri Diwan in Doha, Qatar, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
President Donald Trump and Qatar's Emir Sheikh Tamim bin Hamad Al Thani reviews Qatari honor guard during an official welcoming ceremony at the Amiri Diwan in Doha, Qatar, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
Qatar Emiri Air Force F-15s provide an honorary escort for Air Force One, carrying President Donald Trump, as it arrives in Doha, Qatar, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
DOHA, Qatar (AP) — President Donald Trump said Wednesday he urgently wants “to make a deal” with Iran to wind down its nuclear program but Tehran must end its support of proxy groups throughout the Mideast as part of any potential agreement.
Trump, who is in the midst of a three-country visit to the region, also discussed Iran's rapidly advancing nuclear program in one-on-one talks with Qatar's emir, Sheikh Tamim bin Hamad Al Thani. The American president expressed measured confidence that the U.S. effort with Tehran would “work out one way or another.”
But in comments earlier in the day, at a Gulf Cooperation Council meeting hosted by Saudi Arabia's Crown Prince Mohammed bin Salman in Riyadh, Saudi Arabia, Trump made clear he expected Tehran to end its role as the chief financial backer of the militant groups.
Iran “must stop sponsoring terror, halt its bloody proxy wars and permanently and verifiably cease pursuit of nuclear weapons,” Trump told the GCC leaders. “They cannot have a nuclear weapon.”
Al Thani did not directly address the Iran issue after his session with Trump in Doha. But the emir said U.S.-Qatar cooperation on a broad range of issues was lifting their partnership to “another level of relations.”
The two leaders, and others from their respective delegations, signed a series of agreements, including one between U.S. aircraft company Boeing and Qatar Airways. The White House said the deal was worth $96 billion.
The U.S. and Iran have engaged in four rounds of talks since early last month, and Trump has said he believes brokering a nuclear deal is possible but that the window is closing.
The Republican president's latest push on Iran to cease support of Hamas in Gaza, Hezbollah in Lebanon and the Houthis in Yemen come as that proxy network has faced significant setbacks in the 19 months since Hamas launched its Oct. 7, 2023, attack on Israel.
In Iran, Foreign Minister Abbas Araghchi called Trump's remarks “deceitful” but did not directly address Trump's demand.
Trump said that he also believed the moment was ripe “for a future free from the grip of Hezbollah terrorists.” Hezbollah is severely weakened after its war last year with Israel in which much of its top leadership was killed, and after losing a key ally with the fall of former Syrian President Bashar Assad, a conduit for Iran to send arms.
Trump met with Syrian President Ahmad al-Sharaa, a face-to-face engagement with the onetime insurgent leader who spent years imprisoned by U.S. forces after being captured in Iraq. Trump agreed to meet al-Sharaa at the end of his stay in Saudi Arabia.
Al-Sharaa was named president of Syria in January, a month after a stunning offensive by insurgent groups led by al-Sharaa's Hayat Tahrir al-Sham, or HTS, stormed Damascus and ended the 54-year rule of the Assad family.
Trump said he decided to meet with al-Sharaa after being encouraged to do so by Saudi Arabia's Prince Mohammed and Turkish President Recep Tayyip Erdogan. He also pledged to lift yearslong sanctions on Syria.
Trump told reporters that the meeting with al-Sharaa went “great” and described him as a “young, attractive guy” with a “very strong past.”
“He's got a real shot at holding it together,” Trump said.
Prince Mohammed joined Trump and al-Sharaa for the meeting, which lasted 33 minutes. Erdogan took part via video conference.
Formerly known by the nom de guerre Abu Mohammed al-Golani, al-Sharaa joined the ranks of al-Qaida insurgents battling U.S. forces in Iraq after the U.S.-led invasion. He still faces a warrant for his arrest on terrorism charges in Iraq. The U.S. once offered $10 million for information about his whereabouts because of his links to al-Qaida.
Al-Sharaa returned to his home country of Syria after the conflict began in 2011 and led al-Qaida's branch called the Nusra Front. He changed the name of his group to Hayat Tahrir al-Sham and cut links with al-Qaida.
The sanctions go back to the rule of Bashar Assad, who was ousted in December, and were intended to inflict major pain on his economy.
In Qatar, Trump was greeted at the airport by Al Thani. Air Force One was escorted by Qatari F-15 jets as it neared Doha, the capital city.
As he sat down for talks at Amiri Diwan, the administrative office of the emir, Trump told the Qatari leader he was impressed with the “perfecto” marble as well as the camels that took part in the arrival ceremony.
Al Thani said he had high hopes for Trump's efforts with Iran and at ending the war in Gaza.
“I know that you are a man of peace,” said Al Thani, who later on Wednesday was to honor Trump with a state dinner. “I know that you want to bring peace to this region.”
Trump will head to the United Arab Emirates on Thursday for the final stop of his Mideast tour.
Qatar, like the other Gulf Arab states, is an autocratic nation where political parties are banned and speech is tightly controlled. The country has also played a central role in pay-to-play-style scandals around the globe.
In Israel, authorities are investigating allegations that Qatar hired close advisers to Israeli Prime Minister Benjamin Netanyahu to launch public relations campaigns to improve the Gulf nation's image among Israelis.
Two European Union lawmakers were accused of taking money from Doha in a scandal known as “Qatar-gate.” U.S. prosecutors in 2020 accused Qatar of bribing FIFA executive committee members to secure the tournament in the country in 2022.
In 2024, RTX Corp., the defense contractor formerly known as Raytheon, agreed to pay more than $950 million to resolve allegations that it defrauded the U.S. government and paid bribes to secure business with Qatar. Doha always has denied wrongdoing.
But Qatar has also served as valuable partner to the U.S. Qatar is also home to Al-Udeid Air Base, a sprawling facility that hosts the forward headquarters of the U.S. military's Central Command.
It's a key mediator, particularly with Hamas.
The oil-and-gas rich country is also in the center of a controversy over its offer to provide Trump with the gift of a luxury Boeing 747-8 that the U.S. could use as Air Force One while new versions of the plane are under construction by Boeing.
The Qatari government has said a final decision hasn't been made. Trump has defended the idea even as critics argue it would amount to a president accepting an astonishingly valuable gift from a foreign government.
Trump has indicated he would refurbish the aircraft and it would later be donated to his post-White House presidential library. He says he would not use the plane once he leaves office.
___
Associated Press writers Suzan Fraser in Ankara, Turkey, Tia Goldenberg in Tel Aviv, Israel, and Nasser Karimi in Tehran, Iran, contributed to this report.
Copyright 2025 The Associated Press. All Rights Reserved.
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One company dominated the competition: Impossible Foods.
by Kenny Torrella
Over the last decade, plant-based meat has gotten a lot more meaty.
Dozens of startups have launched in recent years to develop more realistic-tasting burgers, nuggets, and sausages as an alternative to factory farmed meat, which causes billions of animals to suffer terribly, pollutes our air and water, and accelerates climate change.
For a time, the plant-based meat sector was on a major upswing: Retail sales doubled from 2017 to 2020. But since then, sales have continually declined. Recently published data found a seven percent drop in plant-based meat retail dollar sales from 2023 to 2024 and an 11 percent drop in the number of products sold.
To better understand what consumers really think about plant-based meat, a few months ago one organization conducted a huge blind taste test, which I recently covered:
In December and January, Nectar — a nonprofit that conducts research on “alternative protein,” such as plant-based meat — brought together nearly 2,700 people in a first- and largest-of-its-kind blind taste test. Without knowing which version they were tasting, the participants tried 122 plant-based meat products across 14 categories, like burgers, hot dogs, and bacon, alongside one animal meat “benchmark” product per category. Each product was tested by at least 100 participants, who then rated them on texture, flavor, appearance, and overall enjoyment on a 7-point scale from “dislike very much” to “like very much.”
Twenty of the plant-based products won Nectar's “Tasty award” — meaning that half or more of the participants rated them better than or equal to the animal-based counterpart (six of the 20 came from just one company: Impossible Foods). This suggests that some of consumers' preference for animal meat — or dislike of plant-based meat — is just in their head, an idea I explored in depth in April.
The products were all served as part of a dish, like they'd be eaten in regular life — vegan meatballs were served with spaghetti, for example, and deli slices in a sandwich with fixings. While some of these products don't taste identical to meat when eaten on their own, when prepared in a meal, differences in taste become much less important.
If you want to give the top-performing products a try, continue on to learn where to find the 14 that are available in the US, what I think of them (at least, the ones I've tried), and a bit about the companies behind these standout plant-based meats. (The six award-winning plant-based meat products that are only available in Europe can be found at the end of the article.)
US plant-based meat companies have reliably churned out meat-free burgers for decades, in part because they're a beloved American staple, but also because ground beef is easier for food scientists to replicate than, say, a steak's complex fibrous structure. You can now find plant-based burgers at the vast majority of US grocery stores, and even at a lot of restaurants. Here are the companies that made the best burgers in Nectar's blind taste test:
I'll be honest: I've tried a lot of plant-based chicken nuggets, and I can't tell much of a difference between them (they all taste like, well, chicken). They're among the easiest foods to make plant-based because chicken nuggets are already highly processed and bear little resemblance to whole chicken meat.
You can't go wrong with meat-free nuggs from the two Tasty award winners — Impossible Foods and MorningStar Farms — but I also recommend chicken nuggets from Beyond Meat and chicken tenders from Gardein.
A newsletter analyzing how the meat and dairy industries impact everything around us.
Plant-based breakfast sausage patties, like plant-based nuggets, all kind of taste the same to me. But blind taste testers have a preference for two companies' products: Impossible Foods and Gardein, a Canadian company that's launched a number of delicious plant-based meat products over the years, which are widely available in the US.
I also like Impossible's ground sausage, which comes in a roll, giving you flexibility in how to use it.
The only plant-based meatballs and hot dogs to win a Tasty award are made by — you guessed it — Impossible Foods. Its hot dogs are even good enough for Joey Chestnut, the world's top-ranking competitive eater, who signed an endorsement deal with the company in 2024.
The list above only includes products available in the US, but a number of Nectar's winners appear to only be available in Europe:
While a blind taste test is the best measurement of a plant-based meat's quality, I also want to share some of my personal favorites — and those from friends and fellow Vox colleagues — that didn't win a Tasty award but deserve the limelight just as much:
If you can't find a product near you, or want to try something not widely available in the US, there are a number of online food retailers, like Vegan Essentials and Thrive Market, that carry specialty plant-based products.
Nectar's blind taste test demonstrated that, overall, plant-based meat still has a long way to go to compete with animal meat on flavor, texture, price, and other attributes. But that so many of the plant-based products were rated just as good or better than their animal meat equivalents shows how far the industry has come in recent decades.
In the years ahead, as the problems of our food system — animal cruelty, climate emissions, water pollution, and more — grow and worsen, its alternatives will improve. If we're lucky, they'll come to be seen less as substitutes and more as ethical, and tasty, options to satisfy humanity's desire for meat.
Clarification, May 14, 12:10pm ET: A previous version of this story was unclear where Swap Food's chicken fillet is available at North American restaurants.
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Collin County, Texas, DA Greg Willis discusses a judge reducing 17-year-old Karmelo Anthony's bond in the stabbing death case of Austin Metcalf on 'The Will Cain Show.'
The teenager suspected of killing high school track star Austin Metcalf will be allowed to graduate from his Frisco, Texas, high school despite being charged with first-degree murder, according to a report.
Karmelo Anthony will graduate from Centennial High School, part of the Frisco Independent School District, according to WFAA. Students from that high school are set to graduate on May 22.
Anthony will not be part of the graduation ceremony, according to the report.
"We are proud to share that Karmelo Anthony will graduate and receive his high school diploma, and that his academic achievements will not be disrupted," Next Generation Action Network (NGAN) President Dominique Alexander, a spokesman for Anthony's family, reportedly said.
Karmelo Anthony, left, is charged with murdering Austin Metcalf, right. (FOX 4/Jeff Metcalf)
"NGAN has worked diligently alongside the Anthony family's legal team to bring about this fair and student-focused resolution," he said. "This is a moment of dignity for Karmelo and a reminder of the power of advocacy done right."
SUSPECT IN AUSTIN METCALF KILLING MOVED TO ‘UNDISCLOSED LOCATION' FOR PROTECTION: FAMILY SPOKESMAN
Frisco ISD Superintendent Mike Waldrip addressed what he said were false rumors that Anthony would be able to attend the graduation ceremony.
"Frisco ISD has learned that misinformation is being shared regarding Centennial High School's graduation via several media outlets and perpetuated through social media," he told WFAA. "It is disheartening that the incredible accomplishments and achievements of our Centennial seniors may be dampened by needless fearmongering, attention-seeking and media vitriol. Our students, staff and community deserve better.
"I want to be clear. No student who commits a serious criminal offense (Title V felony) is permitted to participate in the graduation ceremony. Additionally, anyone who trespasses on Frisco ISD property or at a District event will be subject to immediate removal and possible arrest by law enforcement," he said, adding that the school district does not condone violence.
File photo of Austin Metcalf, a junior at Memorial High School in Frisco, who was stabbed in the chest, allegedly by 17-year-old Karmelo Anthony, a student-athlete from Frisco Centennial High School. (Courtesy Jeff Metcalf)
"We work to ensure every student is safe to learn and feels part of our culture of respect, honor and integrity," he said.
"Let's come together as a community to honor and support our students and staff. This moment is about their success, and they deserve our full attention and encouragement. Congratulations to the Centennial Class of 2025!"
Anthony, now 18, is accused of stabbing and killing Metcalf over a dispute regarding Anthony's presence in the Memorial High School tent at the April 2 track meet.
ACCUSED AUSTIN METCALF KILLER WON'T FACE DEATH PENALTY OR LIFE WITHOUT PAROLE: DA
He and his supporters claim that he acted in self-defense, and that Metcalf pushed him out of the tent.
That claim is tenuous, according to Julie Rendelman, a former homicide prosecutor from New York who now runs a private criminal defense firm.
File photo of Jeff Metcalf with his son, Austin Metcalf, a junior at Memorial High School in Frisco, who was stabbed in the chest allegedly by 17-year-old Karmelo Anthony, a student-athlete from Frisco Centennial High School. (Courtesy Jeff Metcalf)
"If the evidence is what it is right now, I think he's going to have an uphill battle claiming self-defense," she previously told Fox News Digital. "If the scenario is… that the victim told [Anthony] to leave, and then in some way physically touched him without more, then I'm not comfortable – I don't believe that a self-defense claim will work."
Meanwhile, Alexander has compared Anthony to figures like Kyle Rittenhouse and Daniel Penny, who have won self-defense cases in criminal court.
"Nobody in the public media has one video, but we got the video of Kyle Rittenhouse with an AK-47 shooting three people in the back," he said in a chaotic April 17 news conference before which Jeff Metcalf, Austin's father, was escorted off the property. "We got that, and he raised more than $2 million publicly, and nobody said anything about that."
TEXAS TRACK MEET STABBING SUSPECT TOLD RESPONDING OFFICER HE 'DID IT': DOCS
He also called Anthony's detractors bigots, in what has become a racially charged public discussion.
Dominique Alexander of the Next Generation Action Network hosted a news conference on behalf of Karmelo Anthony's family on April 17. (Next Generation Action Network via Facebook)
"Because these racist bigots try to prevent us from standing up for our baby, our boy, he should be afforded the same rights that Kyle Rittenhouse had, Daniel Penny and all the people who have claimed whatever their defense was. He should be afforded the same right," Alexander said.
"What [Jeff Metcalf] has felled [sic] into is the political operatives that want to make this thing a political thing of hate and yet bigotry and yet racism," he said of Austin's father. "We have conservative operatives that have been posting nonstop about this case."
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NGAN and Frisco ISD declined to comment.
Anthony's attorney, Mike Howard, did not return a comment request.
Jeff Metcalf did not return a comment request.
Peter D'Abrosca joined Fox News Digital in 2025 after four years as a politics reporter at The Tennessee Star.
He grew up in Rhode Island and is a graduate of Elon University.
Follow Peter on X at @pmd_reports. Send story tips to peter.dabrosca@fox.com.
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Tom Cruise spotted at the Cannes Film Festival, before holding a photocall for ‘Mission: Impossible - The Final Reckoning' photocall. (May 14)
Tom Cruise poses for photographers during the photo call for the film ‘Mission: Impossible – The Final Reckoning' at the 78th international film festival, Cannes, southern France, Wednesday, May 14, 2025. (Photo by Scott A Garfitt/Invision/AP)
Greg Tarzan Davis, from left, Hayley Atwell, Tom Cruise, and Pom Klementieff pose for photographers upon arrival at the premiere of the film ‘Mission: Impossible - The Final Reckoning' at the 78th international film festival, Cannes, southern France, Wednesday, May 14, 2025. (Photo by Scott A Garfitt/Invision/AP)
Tom Cruise, bottom right, signs autographs upon arrival for the premiere of the film ‘Mission: Impossible - The Final Reckoning' at the 78th international film festival, Cannes, southern France, Wednesday, May 14, 2025. (Photo by Lewis Joly/Invision/AP)
Hayley Atwell, left, and Tom Cruise pose for photographers upon arrival at the premiere of the film ‘Mission: Impossible - The Final Reckoning' at the 78th international film festival, Cannes, southern France, Wednesday, May 14, 2025. (Photo by Scott A Garfitt/Invision/AP)
Greg Tarzan Davis, from left, editor Eddie Hamilton, Angela Bassett, Tramell Tillman, Tom Cruise, director Christopher McQuarrie, Hannah Waddingham, Simon Pegg, Esai Morales, and Pom Klementieff take a selfie upon arrival at the premiere of the film ‘Mission: Impossible - The Final Reckoning' at the 78th international film festival, Cannes, southern France, Wednesday, May 14, 2025. (Photo by Scott A Garfitt/Invision/AP)
Angela Bassett, from left, writer Erik Jendresen, Pom Klementieff, Tom Cruise, Hayley Atwell, and Greg Tarzan Davis pose for photographers upon arrival at the premiere of the film ‘Mission: Impossible - The Final Reckoning' at the 78th international film festival, Cannes, southern France, Wednesday, May 14, 2025. (AP Photo/Natacha Pisarenko)
Tramell Tillman, from left, director Christopher McQuarrie, Hannah Waddingham, and Angela Bassett take a selfie upon arrival for the premiere of the film ‘Mission: Impossible - The Final Reckoning' at the 78th international film festival, Cannes, southern France, Wednesday, May 14, 2025. (Photo by Joel C Ryan/Invision/AP)
Tom Cruise poses for photographers upon arrival at the premiere of the film ‘Mission: Impossible - The Final Reckoning' at the 78th international film festival, Cannes, southern France, Wednesday, May 14, 2025. (Photo by Lewis Joly/Invision/AP)
CANNES, France (AP) — Three years after flying into the Cannes Film Festival with “Top Gun: Maverick,” Tom Cruise returned to the Croisette on Wednesday with “Mission: Impossible — Final Reckoning.”
Christopher McQuarrie's latest “Mission: Impossible” installment is the biggest Hollywood tentpole wading ashore in Cannes this year. And its sizable impact at the French Riviera festival prompted shouts of “Tom! Tom!” up and down the Croisette.
Just his arrival outside the premiere, beamed onto the screen in the Grand Théâtre Lumière drew a response. When Cruise stepped out his car, oohs and applause reverberated through the theater. Cruise spent several minutes signing autographs for fans lined up on the Croisette.
Some had wondered whether Crusie might make a more daring arrival. Instead, he and the film's cast walked the red carpet accompanied by an orchestra performing the “Mission Impossible” theme on the Palais steps. “Bravo!” cheered Cruise.
Though selfies are frowned upon on the Cannes red carpet, McQuarrie took several of the group, including Hayley Atwell, Simon Pegg, Angela Bassett and Hannah Waddingham.
Earlier in the day, Cruise joined McQuarrie midway through the director's masterclass talk. There was no press conference for the film, which meant Cruise and company faced no questions from reporters. But Cruise's surprise appearance allowed the 62-year-old star a moment to reflect on his 30 years with “Mission: Impossible.” As to whether “Final Reckoning” is a last hurrah for him, he demurred, calling it “the culmination of three decades of work.”
“I'd rather just people see it and enjoy,” Cruise said.
Whether Cruise has any Cannes stunt up his sleeve this time was much anticipated at the festival. On Sunday, he climbed atop the roof of the British Film Institute in London. When Cruise received an honorary Palme d'Or from the festival in 2022, the “Top Gun: Maverick” premiere included an impressively timed jet flyover.
With McQuarrie, Cruise said he relishes the stunt work in “Mission: Impossible.”
“I don't mind encountering the unknown. I like the feeling. It's just an emotion for me. It's something that is not paralyzing,” Cruise said.
Cruise, McQuarrie and Paramount Pictures, which will release “Final Reckoning” in North American theaters on May 23, are hoping the eighth “Mission: Impossible” installment returns the franchise to box-office heights.
Their previous film, “Mission: Impossible — Dead Reckoning Part One ” was considered a box-office disappointment, though it ultimately grossed $571.1 million worldwide. Still, with production budgets close to $300 million for these films, a lot is riding on “Final Reckoning.” Cruise has been traversing the world — with stops in Japan, South Korea and England in the run-up to Cannes — to drum up excitement.
Cruise and McQuarrie, as they did around the release of “Top Gun: Maverick” (which McQuarrie co-wrote and produced), have made themselves passionate pitchmen for the big-screen experience. McQuarrie on Wednesday granted: “I worry for the fate and survival of cinema.”
“Streaming is in danger of driving the industry into extinction,” said McQuarrie. “The advantage a filmmaker has entering the world is that he doesn't have the pressure of an opening weekend.”
___
For more coverage of the 2025 Cannes Film Festival, visit https://apnews.com/hub/cannes-film-festival.
Copyright 2025 The Associated Press. All Rights Reserved.
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A research team in China got creative in its efforts to save a critically endangered species by turning to ancient poems. The scientists pored over more than 700 ancient Chinese poems from the Tang through the Qing dynasties that mention the Yangtze finless porpoise to find out where and when poets described seeing the animal because little is known about its population history.
The Yangtze finless porpoise — the world's only freshwater porpoise — has faced extreme declines in numbers in the past four decades. With fewer than 1,300 individuals left in the wild, scientists in eastern China have made huge efforts to better understand the animal's past habitat range to better inform future conservation initiatives.
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The findings were stark: The data suggests that the historic range of the finless porpoise has shrunk by 65% over the past 1,200 years, with the most extreme reduction happening over the past century. The team published the findings in the journal Current Biology on May 5.
“Some older fishers told me they used to frequently see porpoises in areas where they've now disappeared completely,” study coauthor Zhigang Mei told CNN in an email. “That really sparked my curiosity: Where did these porpoises historically live?”
Yangtze finless porpoises only live in the middle-lower Yangtze River basin in eastern China. From the early 1980s until the 2010s, the population steeply declined an estimated 60%, according to a 2014 study, due to a combination of illegal fishing practices, industrial pollution in waterways, dams and sand mining in the adjoining lakes.
Because hard scientific data for the porpoise only exists for recent decades, scientists have a very narrow understanding of its spatial distribution. This creates a problem known as shifting baseline syndrome, explained Mei, a professor at the Institute of Hydrobiology, Chinese Academy of Sciences, in Wuhan.
“(This research) answers important questions about what constitutes a healthy population,” he said, which will help with setting realistic management goals. “Without historical baselines, there is a risk of shifting expectations downward over generations, accepting an ever-declining status as ‘normal.'”
When Mei and his colleagues started poking around archives for answers, they were surprised. Official records such as local gazettes and county chronicles didn't have any information about the porpoises — only terrestrial megafauna like tigers and elephants, species that have frequent conflict with humans.
Porpoises, in contrast, are less likely to have close encounters with humans. (No drama, no record.) Instead, sightings were typically by local, less-educated anglers or wealthy travelers — who caught glimpses of the elusive porpoises while traveling the Yangtze River by boat — and weren't formally recorded, Mei said.
Facing this dead end, the scientists realized ancient poems could come in handy.
“We were amazed,” Mei said of the researchers efforts to explore written documentation via literature.
The authors sorted through hundreds of poems dating back to AD 830 that referenced porpoises. For each poem, the scientists looked for evidence of locations, such as descriptions of unique geographical features of the Yangtze River basin. Then, the team researched the poem's time period and each poets' personal history to ensure their accuracy. About half of the poems contained precise location information, allowing the team to map sightings for each dynasty.
Ancient Chinese poetry is often nonfiction, including first-person accounts of everyday life and observations of nature, the authors explained. That's why the poems served as a reasonable metric for finless porpoise sightings throughout the river basin.
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“Emerald seals the jade-green tiles as idle dawn clouds drift / Specks of porpoises vanish between the waves' swift lift,” reads one Qing Dynasty poem by Gu Silì 顾嗣立 called “Crossing the River in Rain, Looking at Jinshan,” as translated by lead study author Yaoyao Zhang, an ecologist at the Institute of Hydrobiology, Chinese Academy of Sciences.
“It's beautiful, actually,” said Paulo Corti, a conservation ecologist at Austral University of Chile who was not involved in the research. “They did something great with some very simple information.”
Using historic materials for science isn't uncommon — especially in paleontology or archaeology — but it's less often used for wildlife research, Corti said.
“It's a very useful tool, especially when you refine the analysis, taking those qualitative data into quantitative (data),” he said.
The poetry data only offers an estimate. However, it's the study authors' best source for formulating how the Yangtze finless porpoise population's distribution changed before modern times.
Such studies need to be conducted carefully, adds Corti, who has written journal articles about responsibly using historical records for wildlife studies after noticing that some scientists were using such data inappropriately.
One major limitation of cultural records is human error, he explained. A fisherman or hunter, for example, is a more reliable observer than a foreign explorer likely to misidentify similar-looking animals. That's why the study authors researched each poet's background, such as where they lived and traveled, to verify their observations.
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The Yangtze finless porpoise looks distinct, with a short snout, dark gray color and signature lack of a dorsal fin, which sets it apart from its dolphin relatives.
As mammals, porpoises need to surface for air, making them visible to humans, said study coauthor Jiajia Liu, a professor of biodiversity science at Fudan University in Shanghai. And because finless porpoises did not historically hold cultural importance, it was less likely for poets to write about them without a literal observation, he added.
For these reasons, the researchers trusted the poems for data.
That said, the authors acknowledge that some historical references of the river porpoise could be confused with the now-extinct baiji, a freshwater dolphin that lived in the Yangtze. But this species was much bigger, lighter-colored, and touted a long snout — its most distinguishing feature, Mei said.
Indeed, the baiji serves as a cautionary tale for the finless porpoise. The freshwater dolphin already became functionally extinct in 2006 from many of the same threats.
Extinction of the finless porpoise would throw the ecosystem out of balance, Liu explained. As a top predator, the porpoise eats fish that feed on aquatic grasses. The rare mammal is also an ecosystem engineer by facilitating a process called nutrient cycling. By migrating long distances, the finless porpoise carries nitrogen and phosphorus from the river bottom to its surface, and from downstream to upstream.
Now that there is some evidence that the finless porpoise lived not only in the main river, but also in tributaries and lakes, scientists have a better idea of where the porpoise historically thrived — and whether it might thrive in those locations once again.
With captive breeding — a process in which endangered species are bred in captivity and released back into the wild — underway since 1996, the authors hope their new findings may help inform future conservation efforts, such as identifying areas where they can be released.
But it's important not to jump to conclusions, Corti warned. Using such information for modern-day wildlife management requires a thorough understanding of species behavior, morphology, diet and other factors, he said. “You can make a lot of mistakes” extrapolating historic observational data to inform future management decisions, he added.
“If you are trying to see what happened with the species in the past, you need to know what is going on now,” Corti said.
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Importantly, Mei noted, this study creates a link between endangered species and culture, which could attract public attention. If the Yangtze finless porpoise can be a flagship species, such as the panda, it will help improve their conservation, he said.
Over the past few years, the porpoise population increased for the first time, thanks in part to conservation policies such as fishing bans.
“Conservation is not only (for) scientists,” Mei said. “It's about everyone, it's about our culture.”
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This image provided by Prof. Per Erik Ahlberg shows an artist's illustration of the possible appearance of a reptile-like creature that lived around 350 million years ago in what's now Australia. The animal was around 2 ½ feet long (80 cm) and its feet has long fingers and claws, which are visible in newly discovered fossil footprints. (Marcin Ambrozik/Prof. Per Erik Ahlberg via AP)
This image provided by Prof. Per Erik Ahlberg shows a slab of sandstone found near Melbourne, Australia preserving fossil footprints from a reptile-like animal that lived around 350 million years ago. The footprints are highlighted in yellow (front feet) and blue (back feet) and show the movements of three similar animals, researchers say. (Grzegorz Niedzwiedzki/Prof. Per Erik Ahlberg via AP)
WASHINGTON (AP) — Scientists in Australia have identified the oldest known fossil footprints of a reptile-like animal, dated to around 350 million years ago.
The discovery suggests that after the first animals emerged from the ocean around 400 million years ago, they evolved the ability to live exclusively on land much faster than previously assumed.
“We had thought the transition from fin to limb took much longer,” said California State University paleontologist Stuart Sumida, who was not involved in the new research.
Previously the earliest known reptile footprints, found in Canada, were dated to 318 million years ago.
The ancient footprints from Australia were found on a slab of sandstone recovered near Melbourne and show reptile-like feet with long toes and hooked claws.
This image provided by Prof. Per Erik Ahlberg shows a slab of sandstone found near Melbourne, Australia preserving fossil footprints from a reptile-like animal that lived around 350 million years ago. The footprints are highlighted in yellow (front feet) and blue (back feet) and show the movements of three similar animals, researchers say. (Grzegorz Niedzwiedzki/Prof. Per Erik Ahlberg via AP)
Scientists estimate the animal was about 2 1/2 feet (80 centimeters) long and may have resembled a modern monitor lizard. The findings were published Wednesday in Nature.
The hooked claws are a crucial identification clue, said study co-author and paleontologist Per Ahlberg at Uppsala University in Sweden.
“It's a walking animal,” he said.
Only animals that evolved to live solely on land ever developed claws. The earliest vertebrates -- fish and amphibians – never developed hard nails and remained dependent on watery environments to lay eggs and reproduce.
But the branch of the evolutionary tree that led to modern reptiles, birds and mammals – known as amniotes -- developed feet with nails or claws fit for walking on hard ground.
“This is the earliest evidence we've ever seen of an animal with claws,” said Sumida.
At the time the ancient reptile lived, the region was hot and steamy and vast forests began to cover the planet. Australia was part of the supercontinent Gondwana.
The fossil footprints record a series of events in one day, Ahlberg said. One reptile scampered across the ground before a light rain fell. Some raindrop dimples partially obscured its trackways. Then two more reptiles ran by in the opposite direction before the ground hardened and was covered in sediment.
Fossil “trackways are beautiful because they tell you how something lived, not just what something looked like,” said co-author John Long, a paleontologist at Flinders University in Australia.
___
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Republicans and Democrats grew weary in the early hours of Wednesday morning on Capitol Hill as they slogged through at-times contentious debate over provisions in President Donald Trump's sweeping tax and spending cuts package.
The House Ways and Means and Energy and Commerce panels held marathon sessions overnight, while a third committee, Agriculture, paused late Tuesday night and was set to convene later in the morning.
Each committee is ultimately expected to move elements of the broader bill one step closer to a full floor vote in the chamber. If that goes as planned, House Republicans believe they'll be on track to take up what the president has dubbed his “one big, beautiful bill” in a floor vote by Memorial Day, a target that even some members of the GOP conference once described as overly ambitious.
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House Ways and Means, the GOP's powerful tax-writing panel, clocked nearly 18 hours of debate before advancing the tax portion of Trump's agenda Wednesday morning.
Lawmakers at times shared personal stories as they argued for changes to the measure, which failed amid GOP opposition.
Democratic Rep. Gwen Moore of Wisconsin argued Republicans wanted to pay women to have children but wouldn't “feed the ones we have.” An amendment being offered by a member of her party, Moore said, was “about the 17 million children like me.”
“I was smart, intelligent, but I went to school every day and ate the crumbs and the garbage off of kids' plates until I got brave enough one day to stand in line and demand something to eat. … What's up with this Charles Dickensian attitude that you know you gotta work, somebody's got to have income before we can help kids?” she said.
In one brief bipartisan moment of levity in what was otherwise a deeply partisan hearing, Republican Rep. Blake Moore of Utah dozed off in his seat just before 5 a.m. Wednesday. A colleague on the panel had to gently wake him up to record his vote.
Massachusetts Rep. Richard Neal, the top Democrat on the committee, ended the vote on their portion of the bill by pleading the panel start in the morning next time.
“We should start at 9 a.m. … This is the longest in 33 years I have ever been in this room at any one time for a markup,” he remarked.
The House Energy and Commerce Committee, meanwhile, has shown no sign of slowing as Democrats continue to hit Republicans with emotional stories from their constituents about Medicaid.
In a contentious moment overnight, Rep. Alexandria Ocasio-Cortez charged that she “will not yield to disrespectful men” after Republican Rep. Randy Weber of Texas asked her to yield her time following an exchange over addressing the camera instead of members of the panel.
“There are 13.7 million Americans on the other side of that screen there. Hello, hello, I'm talking to you because I work for you,” Ocasio-Cortez said as she waved to the camera.
“They deserve to see what is happening here because there are plenty of districts, including Republican ones, where 25% of your constituents are on Medicaid, 40% of your constituents are on Medicaid.”
“I will not yield because it was a terribly disrespectful comment, and I will not yield to disrespectful men,” she said.
The exchange came as Ocasio-Cortez posed a question about work requirements and how those having miscarriages might be affected.
The panel's record for a markup – set in 2017 – is 27 hours.
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President Donald Trump commended Qatari Emir Sheikh Tamim bin Hamad Al Thani for their longtime friendship and for his country's purchase of Boeing planes following an agreement signing ceremony in Doha, Qatar.
President Donald Trump signed a series of agreements with Qatar's Emir Sheikh Tamim bin Hamad Al Thani in Doha, Qatar, on Wednesday.
The agreements involved a purchasing agreement by Qatar for Boeing aircraft, as well as letters of intent and "joint cooperation" between Qatar and the U.S. The emir also signed an intent agreement to purchase MQ-9 drone aircraft.
Al Thani said he had a "great" conversation with Trump prior to the signing ceremony on Wednesday, adding that the agreements have elevated the U.S.-Qatar relationship to "another level."
The deepening U.S. relationship with Qatar has drawn fresh scrutiny this week, both due to Trump's visit and amid reports that his administration may accept a free jet from the Qatari royal family to temporarily replace the current Air Force One.
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U.S. President Donald J. Trump attends a meeting with Emir of Qatar Tamim bin Hamad al Thani at the Amiri Diwan, the official workplace of the emir, on May 14, 2025, in Doha, Qatar. (Win McNamee/Getty Images)
The prospect has drawn bipartisan pushback, which Trump has met with indifference.
"Qatar is not, in my opinion, a great ally. I mean, they support Hamas. So what I'm worried about is the safety of the president," Sen. Rick Scott, R-Fla., told reporters on Tuesday.
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U.S. relations with Doha have come a long way since 2017, when Trump accused Qatar of harboring terrorism: "The nation of Qatar, unfortunately, has historically been a funder of terrorism at a very high level," Trump said at the time.
Qatar's Emir Sheikh Tamim bin Hamad Al Thani welcomes President Donald Trump during an official welcoming ceremony at the Amiri Diwan in Doha, Qatar, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
From there, Qatar became a major non-NATO ally to the U.S. in 2022 under President Joe Biden and is home to Al Udeid Air Base, one of the U.S.'s largest Middle Eastern bases and a key hub for U.S. Central Command operations.
Qatar has been at the forefront of peace and hostage negotiations, especially in the war between Israel and Hamas. An Israeli delegation traveled to Doha on Tuesday to hash out a potential agreement on a hostage exchange and ceasefire in the Gaza Strip.
In March, weeks of negotiations led by U.S. and Qatari mediators led to the release of American George Glezmann, who had been imprisoned by the Taliban in Afghanistan for more than two years. Doha's negotiators were also involved in the U.S.-Hamas deal to release the last living American hostage, Edan Alexander, on Monday.
Qatar's government signed an intent agreement to purchase MQ-9 reaper drones. (John Moore/Getty Images)
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The Trump Organization has also cinched a new deal to build a luxury golf resort in Qatar, partnering with Qatari Diar, a real estate company backed by that country's sovereign wealth fund.
Fox News' Morgan Phillips contributed to this report.
Anders Hagstrom is a reporter with Fox News Digital covering national politics and major breaking news events. Send tips to Anders.Hagstrom@Fox.com, or on Twitter: @Hagstrom_Anders.
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The Justice Department announced 189 illegal immigrants were arrested in Washington, D.C., last week after an operation that occurred roughly around the same time federal immigration officers visited several restaurants in the area.
The DOJ billed the crackdown as part of the “Make D.C. Safe and Beautiful” initiative and did not mention specifically where the operation took place. It said it focused on “egregious criminal alien offenders” in the D.C. area from May 6 to 9. Outgoing Interim U.S. Attorney for D.C. Ed Martin said the arrests are “a major step forward in making Washington, D.C., safer for legal citizens and their families.”
Several restaurants in Washington reported visits last week by Immigration and Customs Enforcement agents with requests for completion of I-9 forms to verify the legality of their employees. Law enforcement officials said at the time that no arrests were made with the notices of inspection.
The DOJ did not connect the two operations in its Tuesday release, which listed some of the illegal immigrants targeted by the operation, including alleged criminal immigrants with multiple past crimes on their record from Guatemala.
“Working with our partner agencies, ICE officers and agents arrested 189 illegal aliens and removed them from the streets of our Nation's Capital. Throughout this enhanced enforcement operation, we targeted the most dangerous alien offenders in some of the most crime-infested neighborhoods in the city of Washington, D.C. Evil is powerless if the good are unafraid,” ICE Enforcement and Removal Operations D.C. Field Office Director Russell Hott said in a statement.
“I commend the efforts of everyone involved, as all were truly committed to the success of this operation. ICE Washington, D.C., remains dedicated to our mission of prioritizing public safety by arresting and removing criminal offenders from our Nation's Capital and surrounding communities,” Hott added.
TRUMP'S BIRTHRIGHT CITIZENSHIP BAN COULD SPUR SUPREME COURT TO CURB NATIONWIDE INJUNCTIONS
The Trump administration has taken a keen interest in Washington, vowing to curb crime and improve public safety in the district. President Donald Trump urged local officials to clean up homeless encampments and make other changes, and he threatened federal intervention into the district's home rule if improvements are not made.
The president's March executive order, “Making the District of Columbia Safe and Beautiful,” called for “directing maximum enforcement of Federal immigration law and redirecting available Federal, State, or local law enforcement resources to apprehend and deport illegal aliens in the Washington, D.C. metropolitan area,” among other efforts.
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We can keep saving lives when foreign aid is dying.
by Dylan Matthews
If the year 2025 has had a message for developing countries, it's this: “You're on your own.”
Most notably, the Trump administration began with an unprecedented and ongoing assault on foreign aid, including global health programs. But there have been further ill omens.
Other rich countries, including the UK and France, followed the US example by cutting their own aid programs as well. Meanwhile, President Donald Trump's tariff campaign has hit poor countries that had been achieving export-driven growth, like Bangladesh, especially hard.
If there's a silver lining for the Global South, it's that being on their own in 2025 means something very different than what it meant in, say, 1990. Countries where poverty was once near-universal, like India or Indonesia, are now considered middle-income. Some populous countries in sub-Saharan Africa, like Kenya or Nigeria, are, if not completely politically stable, now possessed of enough real state capacity to try ambitious projects like universal health coverage.
The resources available to these nations are still highly limited by rich-world standards. But they're still enough to achieve very impressive feats, and I recently heard of an intriguing project that could serve as a perfect test case.
If it works, it could show that major international health projects, saving hundreds of thousands of lives, can be funded largely by the countries they're meant to help, rather than by forces of philanthropy and foreign aid that have suddenly become unreliable.
It's called NeoTest.
The program targets an extremely common and preventable cause of death in young infants: neonatal sepsis. Sepsis is a catch-all term for infections that provoke an overwhelming immune response, damaging internal organs, and in the worst cases, leading to death. Sepsis can in principle be caused by anything — a virus, a fungus, a protozoa — but in practice, most infants who get it get it from a bacterial infection.
In one way, that's good: We have antibiotics! In another way, it's bad: The risk of antibiotic resistance means you don't want to overuse them. The challenge, then, is to match antibiotics to the babies who need them the most.
The tests we have now for bacterial sepsis in infants are slow and expensive. The main technique is “blood culturing,” which involves taking blood from the patient, putting it in a liquid “culture” that reacts if bacteria are present, and waiting to see the reaction show up. This is expensive and often takes two to three days, potentially delaying life-saving treatment. It also has very high “false negative” rates, with studies showing that a large share of neonatal sepsis cases occur in babies who test negative.
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So our targeting of antibiotics to babies is currently bad, with the result that hundreds of thousands of babies die every year from sepsis. The estimates we have on the toll of neonatal sepsis aren't precise, but the best figure I've seen, from the World Health Organization (WHO), is a range of 400,000 to 700,000 deaths a year. That's in the same ballpark as malaria (600 to 700,000 a year) and HIV/AIDS (630,000 deaths in 2023).
Other studies go lower (more like 200,000) but, because they exclude infant deaths from pneumonia-caused sepsis, underestimate the number of deaths that could be saved by better targeting antibiotics to babies.
The team behind NeoTest — which includes physician and global health research Akhil Bansal, Center for Global Development head Rachel Glennerster, economist and House of Lords member Jim O'Neill, and Nobel-winning economist Michael Kremer — aims to improve that targeting by getting a better test, one that gives results within minutes and is cheap to produce.
The NeoTest team does not, itself, consist of medical test manufacturers. But in Glennerster and Kremer, it includes two of the inventors of a tool called an “advance market commitment” (AMC).
AMCs are a way to communicate to companies that there's a big market for a product which doesn't yet exist. The participants, which can include governments or other businesses or philanthropists, commit to buying a set amount of the new product, at a set price, from any manufacturers who meet the deal's specifications. The hope is that this provides an incentive for manufacturers to develop the product, because they know for a fact there will be demand for it.
It's worked before. The first AMC, for better vaccines against pneumococcal bacteria at a time when that disease was killing as many as 1 million children a year, resulted in three new vaccines being developed, and in the number of vaccine doses growing from just 3 million in 2010 to around 150 million in 2016. By one estimate from Kremer and co-authors, the new vaccines enabled by the AMC saved some 700,000 lives between 2010 and 2020.
NeoTest is an attempt to put together funds — about $120 million in total — for an advance market commitment for a better neonatal sepsis test.
More famously, Operation Warp Speed, the US effort that got effective vaccines against Covid-19 on the market less than a year after the pandemic began, used a purchasing mechanism that worked quite a bit like an AMC. The government purchased hundreds of millions of doses from vaccine manufacturers months before the vaccines were in fact approved — giving the pharma firms confidence to start producing doses in large numbers, and encouraging them to keep up their R&D work.
NeoTest is an attempt to put together funds — about $120 million in total — for an advance market commitment for a better neonatal sepsis test. Test manufacturers who are willing to sell for $8 per test ($5 funded by the AMC, $3 by the government of the country receiving the tests) would be guaranteed at least 24 million subsidized orders. Ideally, the test will settle at around $3 as a final price, with the initial subsidy helping fund initial costs associated with developing the tests and setting up manufacturing.
A rapid test is not some outlandish dream. Neonatal sepsis experts have been saying we need better diagnostics for years; there's a whole Neonatal Sepsis Diagnosis Working Group that puts out papers explaining the problem. The WHO has put together a detailed description of what a useful rapid test for sepsis might look like, including elements like the size of the blood draw required and the ideal wait for results.
Rapid, point-of-care tests that can give answers in minutes are common at this point for viruses like Covid and the flu, and already exist for some bacterial infections like syphilis. But in part because neonatal sepsis is so concentrated in poor countries, developing a test for it hasn't been a priority for profit-driven firms to date. Dangling $120 million in front of them might change that.
One of the most intriguing aspects of NeoTest to me is that Akhil Bansal, the physician who first devised the idea, is pitching it first to governments of middle- income countries (India, Kenya, South Africa, etc.) that might actually use the test in large numbers.
$120 million is a decent sum, but not enormous for a global health project. The pneumococcal AMC, by contrast, was for $1.5 billion. And it's totally within the budgets of some middle-income countries to contribute a portion of that $120 million, especially when the result is a product that will save the lives of thousands of babies every year in their country.
Of course, money is money, and if any foreign aid professionals in upper-income countries or philanthropists reading this piece want to support NeoTest, they should — they're still actively fundraising and are in need of support. The most important thing is that the problem gets solved.
But I found the approach of going first to countries directly benefiting for funding intriguing, and surprisingly heartening at what is otherwise a dark time for global health
For one thing, it's remarkable and encouraging that enough middle-income countries have gotten to the point where funding an initiative like this is within their budgets. That wasn't true 20 years ago.
More importantly, though, it serves as a reminder that the work of development will continue with or without Western governments' support. That support is invaluable, and I hope it returns. But the Global South is resilient, and increasingly shows an ability to solve big problems for itself.
A version of this story originally appeared in the Future Perfect newsletter. Sign up here!
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One company dominated the competition: Impossible Foods.
Is Trump doing the right thing on animal research for the wrong reasons?
What if we measured success in terms of how much good we do?
From image generation to writing, ranking the best — and worst — of AI.
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Is Trump doing the right thing on animal research for the wrong reasons?
by Rachel Fobar
The Trump administration is not known for particularly prioritizing animal welfare. But in its first few months, alongside announcements that it would seek to gut federal funding for scientific research, Trump officials have taken steps toward a goal that animal advocates have been championing for decades: the end of animal experimentation.
On April 10, the Food and Drug Administration announced plans to phase out animal testing requirements for the development of monoclonal antibodies — used to treat a variety of diseases, including cancer and Covid-19 — and a range of other drugs.
The Environmental Protection Agency, which has long required animal testing for substances including pesticides and fuel additives, also plans to revive an agency ban on animal testing that dates back to the first Trump administration. The agency had set deadlines under President Donald Trump in 2019 to reduce animal testing 30 percent by 2025, then eradicate it altogether by 2035. The Biden administration eliminated those deadlines, but now, EPA administrator Lee Zeldin “is wholly committed to getting the agency back on track,” spokesperson Molly Vaseliou told Vox in an email.
Late last month came perhaps the most consequential announcement: a major new initiative from the National Institutes of Health (NIH), the largest public funder of biomedical research in the world, to reduce the use of animals in research and accelerate the development of novel, animal-free methods. Estimates suggest NIH-funded research relies on millions of animals every year in the US. That includes mostly rodents, but also monkeys, dogs, pigs, rabbits, and others. But Trump's NIH cited scientific literature that finds animal models can have limited relevance to human outcomes.
Advocacy groups that oppose animal testing, including PETA and Humane World for Animals (formerly known as the Humane Society of the United States), celebrated the news as the most significant commitment ever made by NIH to reduce its dependence on animal experimentation.
The recent announcements are “among the biggest news there's ever been for animals in laboratories,” Elizabeth Baker, director of research policy for the Physicians Committee for Responsible Medicine (PCRM), told me.
Together, these moves represent a potentially monumental shift in American science — one that could spare millions of animals from painful experiments and, advocates hope, speed up the adoption of cutting-edge technologies to produce better, more reliable research than animal models ever did.
But if the goal is not just to benefit animals, but also to make science better, the Trump administration is surely going about it in a strange way. It's waging war on scientific institutions, seeking to slash research budgets — massively, seemingly indiscriminately, and questionably legally — at the NIH and the National Science Foundation, undermining decades of American leadership in science and medicine. It hasn't committed any new funding toward its goal of advancing animal-free research methods.
In this light, scientists are understandably skeptical that research policy coming from this administration could benefit science, rather than just sabotage it. Putting animal research on the chopping block, many believe, could merely be a convenient and popular way to slash support for science across the board.
Yet those seeking to phase out government-funded animal research aren't just anti-science radicals — they're also animal testing critics who correctly point out that animal experiments are expensive, often ineffective, and come at a steep ethical cost. This has created a diverse, sometimes-uneasy coalition of animal welfare advocates, science reformers, and far-right political figures — some are willing to accept reforms any way they can get them; others are more wary of moves made by this administration, even when their agendas align.
In Vox's Future Perfect section, you'll find some of the deepest reporting and analysis available anywhere of the scientific, ethical, and political dimensions of animal experimentation.
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• The US uses endangered monkeys to test drugs. This law could free them.
• 43 lab monkeys escaped in South Carolina. They have a legal claim to freedom.
The Trump administration's NIH director, Jay Bhattacharya, embodies this alliance: An established scientist, albeit one who's publicly aligned himself with the political right in recent years, he has praised the watchdog group White Coat Waste, which campaigns aggressively against animal research, as “heroes.” Now, with the NIH's plan to reduce animal research, he's arguing for the need to transition to animal-free methods in the language of scientific progress rather than the tear-it-all-down approach of other members of the Trump administration.
Money and resources are powerful incentives in scientific research; allocate them in the right way, and scientists will be pushed to innovate in whatever direction is deemed important for societal progress. Evolving beyond the pervasive use of animals in science undoubtedly ought to be one of those priorities: Lab animals experience immense suffering in labs, living in intensive confinement and undergoing painful experiments involving blood draws, tube feeding, forced inhalation of substances, and other procedures. Finding alternatives that would end this agony would be one of American science's most important achievements.
It's unclear whether a moonshot for alternatives to animal research can emerge from an administration that's imposing widespread austerity on science. And there may be reason to worry that the Trump administration's broader anti-regulatory approach could have negative consequences for the welfare of animals that still remain in labs.
But many advocates of animal-free methods are willing to take the bet, hoping that they can use this uncertain, unsettled moment in American science policy to help usher in a paradigm shift in how the US uses animals in science.
For decades, animal advocates, and a growing number of scientists, have disputed whether animal trials are the most effective tools available in modern science.
Historically, animal dissection laid the groundwork for early medicine, and breakthroughs from animal research have helped lead to polio vaccines, the preventative HIV medication PrEP, and treatments for Parkinson's disease.
But animals are not necessarily suitable proxies for humans, and more than 90 percent of drug trials fail between animal and human testing trials, according to a 2023 review by animal welfare advocates. It's a problem many scientists acknowledge, albeit not always publicly. Former NIH director Francis Collins in 2014 privately discussed “the pointlessness of much of the research being conducted on non-human primates” in emails obtained by PETA via public records request.
That the government is now planning cuts to animal research is undeniably groundbreaking. But how these planned cutbacks and phase-outs will actually unfold is more complex.
In its announcement, the NIH said it will establish an Office of Research Innovation, Validation, and Application to scale the use of non-animal methods, expand funding for these approaches, evaluate human relevance, and include experts in alternative animal-free methods on grant review panels so that more of the agency's funding is allocated toward those methods.
Scientists are often incentivized to use animals in their research, as Celia Ford wrote for Voxearlier this year, a phenomenon sometimes called “animal methods bias.” Academic journals prefer to publish studies using animals, and internal research ethics review boards are mostly comprised of animal researchers.
Advancing technologies, such as computational modeling or organ-on-a-chip technology, offer alternatives to animal testing, and many scientists around the world are embracing these new methods. But the scientific community has been slow to adopt them.
To change that, the NIH's new initiative will “address any possible bias towards animal studies” among its grant review staff. The agency will also publicly report on its annual research spending, something it hasn't done in the past, “to measure progress toward reduction of funding for animal studies and an increase in funding for human-based approaches,” according to the recent announcement.
The EPA, meanwhile, requires toxicology tests on animals for many substances that it regulates, including fuel and fuel additives, certain pesticides, and wastewater from industrial facilities. It has not yet announced an official plan to reduce animal research, though a 2016 agency reform required increased reliance on non-animal methods. Many are hoping the agency — which previously estimated that between 20,000 and 100,000 or more animals are used in toxicology testing every year — will recommit to its 2019 directive to end animal testing requirements by 2035, Baker says.
Of course, announcements are meaningless without plans — and the FDA is the only agency to announce a plan that lays out a three-year timeline and alternative testing strategies.
The FDA's current requirements for animal testing in new drug approvals are somewhat unclear. The FDA Modernization Act 2.0, which Congress passed in 2022, authorized the use of non-animal alternatives in place of animal studies for FDA-regulated drugs, but some of the FDA's regulations and nonbinding guidelines specifically mention animal tests. Pharmaceutical companies that have tried to obtain drug approval without animal testing have faced expensive delays. As a result, in practice, most drugs approved by the FDA are still tested on animals.
According to the FDA, current regulations still require animal testing for monoclonal antibodies, which are lab-made proteins that can bind to and kill specific targets in the body. The FDA's phaseout of animal tests will start with these antibodies and expand to other treatments.
Lab animals' immune responses are not predictive of human responses “due to interspecies differences,” the agency's plan states. Safety risks may go undetected in animals, and the stress of laboratory life can affect their immune function and responses, a significant confounding factor in animal research that scientists have noted before.
Animal testing is also very expensive: Monoclonal antibody development often involves monkeys, which can cost up to $50,000 per animal, according to the FDA; its plan notes it can cost $650 million to $750 million and take up to nine years to develop monoclonal antibody treatments, delaying delivery of new therapies to patients.
While advancements like organ-on-a-chip and computer modeling are both exciting and laudable, counting on them to replace animals may be premature, Naomi Charalambakis, director of communications and science policy for Americans for Medical Progress, a nonprofit that supports the use of animals in research, said in an email. These tools, many of which are still under development, can't fully replicate “the complexity of living organisms” — which is why she says they should be integrated “alongside traditional animal studies.”
“Animal models remain vital for answering complex biomedical questions — particularly those involving whole-body systems, long-term effects, and unpredictable immune responses,” she says.
Scientists have also pointed out that the FDA's promise that animal testing will be “reduced, refined, or potentially replaced” is not new. In 2022, the FDA Modernization Act 2.0 paved the way for alternatives to animal testing, and in December 2023, an NIH advisory committee made similar recommendations to develop non-animal methods.
Regardless, the FDA's and NIH's recent announcements are among the first public statements by government organizations questioning the efficacy of animal testing.
In February, the Trump administration took the highly controversial step of capping “indirect costs,” the portion of universities' research grants that cover administrative and operations expenses not directly tied to the research itself, at 15 percent of an institution's grant. The research community has warned that the decision would be catastrophic for science — budgets will be slashed, young researchers may be laid off and see their careers ruined, and important science may fall by the wayside.
But for animals, the news is “fantastic,” argues Jeremy Beckham, a law student and animal advocate who's worked for organizations including PETA, PCRM, and the Beagle Freedom Project.
While indirect costs are not a “meritless concept,” Beckham says, he believes universities renew research grants that harm animals while yielding little to no benefit in order to continue receiving operational funding. Universities “are allowing a lot of extremely pointless and cruel animal experiments to happen, because it's such a gravy train for them for these indirect costs,” he says.
Oregon Health & Science University, for example, which receives 56 percent of its grant in indirect costs for animal studies, has racked up several critical Animal Welfare Act citations for 14 animal deaths at its research labs since 2018. At Wayne State University in Michigan, researchers have induced heart failure in hundreds of dogs in a cardiac research experiment that has been running since 1991 but has “failed to help a single patient,” according to PCRM. Wayne State receives an indirect cost rate of 54 percent, according to a recent statement from the university. In a statement about its dog experiments, Wayne State argued that it's important to continue the cardiovascular research, even if “science does not move at the pace we would like.”
Critics of the cuts to indirect costs, including Harvard immunologist Sarah Fortune, have argued that funding cuts will mean labs are forced to euthanize their animals. But many, if not all, were already going to be killed in experiments, Delcianna Winders, director of the Animal Law and Policy Institute at Vermont Law and Graduate School, points out.
In March, a federal judge blocked the NIH's proposed cap on indirect costs, and universities are looking to negotiate.
But if the proposal does go forward, “the number of animals in laboratories will plummet,” Beckham says.
Despite its promises to reduce the number of animals in labs, the Trump administration's disdain for regulation may mean those animals that still remain in labs will suffer more. During Trump's first presidency, enforcement of the Animal Welfare Act, the federal law that governs the welfare of animals used in research, took a nosedive. The US Department of Agriculture (USDA), the agency tasked with implementing that law, removed thousands of animal welfare reports, which had previously been publicly posted for decades, from its website.
Given this precedent, Winders fears that going forward, the research industry will violate animal welfare laws “with complete impunity.”
Research animals are already at a disadvantage under the Animal Welfare Act, and critics have insisted for decades that the act is insufficient and poorly enforced. The proverbial lab rat is not protected by the law — most mice and rats, birds, and cold-blooded animals are excluded from the Animal Welfare Act's definition of “animal.” By some estimates, it covers as little as 5 percent of research animals.
Nor does the law place any legal limits on what can be done to animals in experiments. “That's left completely to the research facility,” Winders says.
When a researcher violates the Animal Welfare Act, the USDA has few options for enforcement. Because inspectors cannot confiscate animals that are required for research, they can really only levy monetary fines. But for facilities that receive millions in funding and spend billions on research, fines — most of which are less than $15,000 — are so low that they're considered a “cost of doing business,” according to a 2014 USDA Office of Inspector General report.
The USDA calculates these fines using an internal penalty worksheet, which factors in a facility's size, compliance history, and the severity of its violations. The worksheet was recently obtained by Eric Kleiman, founder of research accountability group Chimps to Chinchillas, and it revealed that the USDA does not take a research institution's revenue or assets into account when calculating fines.
The USDA instead measures a facility's size via the number of animals it uses, according to the worksheet, which divides research facilities into four size categories, the largest being facilities with 3,500 or more animals. But this metric is flawed, Kleiman says, since many labs don't keep their animals on-site, instead contracting out with research organizations that perform the experiments on their behalf.
In a statement, USDA spokesperson Richard Bell said the agency “carries out enforcement actions consistent with the authority granted under the Animal Welfare Act and associated regulations.”
And in recent months, there have been alarming signs of an anti-regulation shift.
A 2024 Supreme Court decision, SEC vs. Jarkesy, calls government agencies' ability to issue fines into question. It's possible this ruling could be interpreted in a way that bars the USDA from assessing fines, Winders says.
“We're still waiting to see how broadly the government interprets it,” she says. “Given that other enforcement mechanisms are not available against research facilities…civil fines were really the only pathway, and now that's on the chopping block.” Since the June 2024 ruling, the USDA has issued few fines. The USDA is “still assessing the impact of the Jarkesy ruling,” Bell said.
In the past, the Office of Inspector General has held the USDA accountable for poor enforcement — but in January, the USDA inspector general was fired and escorted out of her office, Reuters reported.
The next month, the USDA OIG released a report on inspections of dog breeders — some of which supply dogs to research facilities. The report was critical of the USDA's enforcement, but key information including the number of facilities inspected, the number of animal welfare violations, and photos was redacted “due to privacy concerns.”
Winders has “never, ever seen that before,” she says, and it could set a new precedent for decreased transparency.
About 15 percent of USDA's workforce has accepted the Trump administration's buyout to leave the agency, including more than 1,300 people in the Animal and Plant Health Inspection Service, which inspects and enforces the Animal Welfare Act, Reuters reported on May 5.
“If inspectors aren't there, how are they going to have a window into what needs to be done?” says Sara Amundson, chief government relations officer for Humane World for Animals.
Regardless, the US is witnessing a seismic shift in how we use animals for research — or even whether we use them at all. It's too soon to say what the Trump administration's reforms to animal testing will accomplish, or whether they'll produce durable changes in American science that manage to outlive an administration that has declared war on the scientific community.
Although animal welfare is a bipartisan issue, it's rarely been a priority for previous administrations, Republican or Democrat. To have an administration that, within months of taking power, is already meeting with animal welfare groups, holding congressional hearings, and taking strong stances on animal research issues is unprecedented, experts say. “I am optimistic,” Baker says.
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TRUMP: ‘I DON'T LIKE PERMANENT ENEMIES': President Donald Trump, basking in the glow of an effusively warm welcome in the Saudi capital of Riyadh, laid out a vision of a new age of cooperation in the Middle East — praising countries in the region for a “great transformation” that he said has resulted in the “birth of a modern Middle East,” while criticizing Western “interventionists” who “had no idea how to do it themselves.”
“Before our eyes, a new generation of leaders is transcending the ancient conflicts of tired divisions of the past and forging a future where the Middle East is defined by commerce, not chaos, where it exports technology, not terrorism, and where people of different nations, religions, and creeds are building cities together, not bombing each other out of existence,” Trump said, delivering a major policy address at an investment forum on the first day of his trip.
“It's crucial for the wider world to note this great transformation has not come from Western intervention or flying people in beautiful planes, giving you lectures on how to live and how to govern your own affairs,” he said. “In the end, the so-called nation-builders wrecked far more nations than they've built, and the interventionalists were intervening in complex societies that they did not even understand themselves … Peace, prosperity, and progress ultimately came not from a radical rejection of your heritage but rather from embracing your national traditions and embracing that same heritage that you love so dearly.”
“My greatest hope is to be a peacemaker and to be a unifier. I don't like war,” Trump said. “I have never believed in having permanent enemies. I am different than a lot of people think. I don't like permanent enemies … In fact, some of the closest friends of the United States of America are nations we fought wars against in generations past, and now they're our friends and our allies.”
TRUMP DROPS SANCTIONS ON SYRIA AND PREVIEWS EXPANSION OF ABRAHAM ACCORDS IN SAUDI ARABIA
AN ‘OLIVE BRANCH' TO IRAN: Trump again professed a desire to resolve the issue of Iran's nuclear program peacefully, through negotiation, while underscoring his demand that they never acquire nuclear weapons.
“We'll never allow America and its allies to be threatened with terrorism or nuclear attack. The choice is theirs to make. We really want them to be a successful country, we want them to be a wonderful, safe, great country, but they cannot have a nuclear weapon,” Trump said.
“I want to make a deal with Iran. If I can make a deal with Iran, I'll be very happy,” Trump said. “But if Iran's leadership rejects this olive branch and continues to attack their neighbors, then we will have no choice but to inflict massive, maximum pressure, drive Iranian oil exports to zero like I did before.”
“This is an offer that will not last forever. The time is right now for them to choose, right now. We don't have a lot of time to wait. Things are happening at a very fast pace,” he said. “So they have to make their move right now. One way or the other, make your move.”
The pressure to close a deal with Tehran comes as Iranian media reports say Iranian foreign minister Abbas Araghchi has proposed a novel plan to create a joint nuclear-enrichment venture involving regional Arab countries and American investments. A spokesman for U.S. special envoy Steve Witkoff told the New York Times that the idea was “never floated or discussed” at the latest round of talks in Oman.
SEAN HANNITY SEES ‘DESIRE' FROM SAUDI ARABIA TO WORK WITH TRUMP
GIVING SYRIA ‘A CHANCE AT GREATNESS': Perhaps the loudest applause came when Trump announced he would ease sanctions on Syria and begin the process of normalization with the government that replaced dictator Bashir Assad in December.
“I will be ordering the cessation of sanctions against Syria in order to give them a chance at greatness,” as the room broke out in thunderous applause. “The sanctions were brutal and crippling and served as an important, really an important function nevertheless at the time,” Trump said. “We're taking them all off and … now it's their time to shine.”
To put a button on the moment, before departing Riyadh, Trump met briefly with the new Syrian President Ahmad al-Sharaa, the onetime insurgent leader who spent years imprisoned by U.S. forces.
Sharaa, who had ties to ISIS and al Qaeda in the past, is technically still designated a terrorist by the State Department, but is anxious to get U.S. aid in rebuilding the country after more than a decade of civil war.
TRUMP'S ‘AMERICA FIRST' POLICY LEAVES ISRAEL UNEASY
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HAPPENING TODAY: NEXT STOP, DOHA: President Trump has departed Saudi Arabia and will arrive in Doha, Qatar about 1:30 p.m. local time, where he will be honored with a state visit. In addition to meeting with Qatar's Emir Sheikh Tamim bin Hamad Al-Thani Trump is expected to meet with Indian billionaire Mukesh Ambani, who is Asia's richest man, according to Reuters.
US HAD PLANNED 8-MONTH WAR AGAINST THE HOUTHIS: Reuters news agency is the second media out to report that the U.S. campaign against Houthi rebels in Yemen was designed to go on for eight months, but was cut short when the Houthi began to seek an off-ramp.
After seven weeks of “unrelenting” U.S. bombings, Houthi leaders began reaching out around the first weekend in May to U.S. allies in the Middle East,” Reuters is reporting, citing two U.S. officials. “We started getting intel that the Houthis had had enough,” one of the officials said.
On Monday, the New York Times reported U.S. Central Commander Gen. Michael Kurilla had proposed “an eight-to-10-month campaign in which Air Force and Navy warplanes would take out Houthi air defense systems” followed by “targeted assassinations modeled on Israel's recent operation against Hezbollah.”
Citing sources, the New York Times said President Trump began to question the operation's progress, dubbed “Rough Rider,” by Defense Secretary Pete Hegseth, especially after losing a half-dozen expensive Reaper drones and three F-18 Super Hornet aircraft. With the U.S. strikes “burning through weapons and munitions at a rate of about $1 billion in the first month alone,” Trump was ready to take the Houthis at their word that they would stop shooting at American ships, even if Israel and its ships were still under fire.
At some point, the newspaper reported, “General Kurilla's eight-to-10-month campaign was given just 30 days to show results.”
“American strikes had hit more than 1,000 targets … but the cost of the operation was staggering,” the report said. “So many precision munitions were being used, especially advanced long-range ones, that some Pentagon contingency planners were growing increasingly concerned about overall stocks and the implications for any situation in which the United States might have to ward off an attempted invasion of Taiwan by China.”
OPINION: JOHN BOLTON: TRUMP'S FLAWED HOUTHI DEAL
THE PLANE, THE PLANE! Trump's plan to accept a $400 million “luxury” 747 jetliner to use as a stopgap Air Force One continues to draw fire from critics in his party.
“I think it will attract very serious questions, if and when it happens. At this point, all we've heard about is something that might be a hypothetical,” said Senate Majority Leader John Thune (R-SD). “I'm sure that if and when it's no longer a hypothetical, I can assure you there will be plenty of scrutiny of — of whatever that arrangement might look like.”
“Accepting gifts from foreign nations is never a good practice. It threatens intelligence and national security. Especially when that nation supports a terrorist organization and allows those terrorist regimes to live on its soil,” said former Trump U.N. Ambassador Nikki Haley on X. “Regardless of how beautiful the plane may be, it opens a door and implies the President and U.S. can be bought. If this were Biden, we would be furious.”
“I think many people don't realize the current Air Force Ones are flying offices. They're not flying palaces,” said former Trump national security adviser John Bolton on CNN, who noted the “free” jet isn't really free. “It would be a complete redo of the airplane, if he wanted it.”
“I think the major objection here is the security objection. We don't know what has happened to that plane. We don't know who's had access to it. And if they really wanted to bring it up to Air Force One standards, it would require significant overhaul for all kinds of reasons,” Bolton said. “The president needs air defense systems, it needs that and all the other things that go for Air Force One.”
TRUMP: ‘I BELIEVE THAT WE SHOULD HAVE THE MOST IMPRESSIVE PLANE': In an interview with Sean Hannity conducted on the 38-year-old Air Force One on which he flew to the Middle East, Trump continued to express amazement that anyone would object to what he argues is essentially a transfer of military hardware to the Pentagon.
“My attitude is, why wouldn't I accept a gift? We're giving to everybody else. Why wouldn't I accept a gift? Because it's going to be a couple of years, I think, before the Boeings are finished,” Trump said. “And they will be wonderful when they're finished. But that's a long time.”
“We give a lot of gifts. We give too many gifts to be honest with you. We give gifts to defend countries. They wouldn't even exist — many countries wouldn't even exist. All over the world, countries wouldn't even exist,” he continued. “I thought it was a beautiful gesture. Now, there are those that say we shouldn't be accepting gifts to the Defense Department, and I would say only a stupid person would say that. Why wouldn't we do that?”
“It helps us out because we'll have a relatively new plane instead of having 40-year-old planes. These planes are 40 years old and that's not representative of our country,” he said. “The United States of America. I believe that we should have the most impressive plane.”
WHAT IS THE EMOLUMENTS CLAUSE? THE ETHICS RULE QATAR'S PLANE TO TRUMP COULD FLOUT
THE RUNDOWN:
Washington Examiner: Trump drops sanctions on Syria and previews expansion of Abraham Accords in Saudi Arabia
Washington Examiner: Sean Hannity sees ‘desire' from Saudi Arabia to work with Trump
Washington Examiner: Trump's ‘America First' policy leaves Israel uneasy
Washington Examiner: Why the US needs Trump's Golden Dome: Intel agency illustrates the weapons that enemies are stockpiling
Washington Examiner: Trump's authority to declare tariffs 'emergency' challenged in first court hearing
Washington Examiner: Pope Leo XIV's brother says there could be ‘bumps' with Trump but dismisses idea of ‘woke' pope
Washington Examiner: US's global reputation faces blowback after Trump's resurgence
Washington Examiner: White House mocks criticism of news wires cut from Saudi trip
Washington Examiner: What is the emoluments clause? The ethics rule Qatar's plane to Trump could flout
Washington Examiner: Opinion: John Bolton: Trump's flawed Houthi deal
Washington Examiner: Opinion: Saudi Arabia will likely cooperate with Israel once Gaza war ends: Hugh Hewitt
Breaking Defense: At Nearly $142 Billion, White House Claims Largest Defense Deal ‘In History' with Saudi Arabia
Reuters: Exclusive: Houthi ceasefire followed US intel showing militants sought off-ramp –
Inside Defense: McConnell: White House ‘Skinny Budget' Sets Stage for Defense Investment ‘Cliff'
AP: Hegseth's Plan to Cut Senior Military Jobs Could Hit More Than 120 High-Ranking Officers
Wall Street Journal: Israel Targeted Hamas Leader Mohammed Sinwar in Gaza Airstrike
New York Times: In Private, Some Israeli Officers Admit That Gaza Is on the Brink of Starvation
Defense One: How China's Tech Giants Wired the Gulf
Air & Space Forces Magazine: Meink Confirmed as 27th Secretary of the Air Force
Air & Space Forces Magazine: Nominee for Air Force Manpower Faces Breezy Senate Hearing
Defense One: JSOC Commander Likely to Be SOCOM Pick, Sources Say
Air & Space Forces Magazine: USAF's Planned E-7 Fleet on Trump's Chopping Block
SpaceNews: How Earth Observation Satellite Operators Are Teaming Up to Tip and Cue One Another
Air & Space Forces Magazine: Air Force Launching New Artificial Intelligence ‘Center of Excellence'
Military.com: Dozens of Air Force Families Disenrolled from Day Care at New Mexico Base as Staffing Woes Grow
Forbes: Opinion: Prioritize Warfighting in Senior US Military Rank Reductions
THE CALENDAR:
WEDNESDAY | MAY 14
9:30 a.m. 1400 L St. NW — Atlantic Council and the Lithuanian Ministry of National Defense discussion: “Navigating a New Era of NATO,” with Rep. Mike Turner (R-OH); and Lithuanian Minister of National Defense Dovile Sakaliene https://www.atlanticcouncil.org/event/navigating-a-new-era-of-nato
10 a.m. 2362-A Rayburn — House Appropriations Homeland Security Subcommittee “Oversight Hearing – U.S. Immigration and Customs Enforcement, with testimony from Acting Immigration and Customs Enforcement Director Todd Lyons http://appropriations.house.gov
12 p.m. Antalya, Turkey — An informal two-day meeting of NATO foreign ministers begins. https://www.nato.int/cps/en/natohq/events
2 p.m. 2008 Rayburn — House Appropriations Committee Homeland Security Subcommittee “Oversight Hearing – The United States Coast Guard,” with testimony from Adm. Kevin Lunday, acting commandant of the Coast Guard http://appropriations.house.gov
2 p.m. H-140, U.S. Capitol — House Appropriations Defense Subcommittee “Oversight Hearing — The United States Navy and Marine Corps,” with testimony from Navy Adm. James Kilby, acting chief of naval operations; John Phelan, secretary of the Navy; and Gen. Eric Smith, commandant of the Marine Corps http://appropriations.house.gov
3 p.m. 2118 Rayburn — House Armed Services RDY Subcommittee hearing: “Energy, Installations, and Environment Update,” with testimony from Robert Thompson, acting assistant secretary of defense for energy, installations, and environment; Daniel Klippstein, performing the duties of assistant secretary of the Army for installations, energy and environment; Brenda Johnson-Turner, performing the duties of assistant secretary of the navy for energy, installations and environment; and Michael Saunders, acting assistant secretary of the Air Force for energy, installations and environment http://www.armedservices.house.gov
3:30 p.m. 2212 Rayburn — House Armed Services Strategic Forces Subcommittee hearing on “National Security Space Programs,” with testimony from Andrea Yaffe, acting principal deputy assistant secretary of defense for space policy Chris Scolese, director, National Reconnaissance Office; Vice Adm. Frank Whitworth, director, National Geospatial-Intelligence Agency; and Maj. Gen. Stephen Purdy, acting assistant secretary of the Air Force for space acquisition and integration http://www.armedservices.house.gov
3 p.m. 216 Hart — Senate Veterans' Affairs ranking member Richard Blumenthal (D-CN) holds a forum on how cuts to Veterans Affairs Department care and benefits are endangering implementation of the “PACT Act,” a “bipartisan law signed in August 2022 to deliver generations of toxic-exposed veterans and survivors their earned health care and benefits.” https://x.com/SVACDems
THURSDAY | MAY 15
7 a.m. Antalya, Turkey — An informal two-day meeting of NATO foreign ministers concludes with a press conference from NATO Secretary General Mark Rutte . https://www.nato.int/cps/en/natohq/events
8 a.m. 111 Fairview Park Dr., Falls Church, Virginia — Potomac Officers Club Cyber Summit, with Bridget Bean, executive director, Cybersecurity and Infrastructure Security Agency; and Acting assistant secretary of defense for Cyber Policy Ashley Manning https://potomacofficersclub.com/events/2025-cyber-summit/
8 a.m. 700 M St. NE — Politico Security Summit with House Intelligence ranking member Rep. Jim Himes (D-CN); and Rep. Michael Lawler (R-NY) chairman, House Foreign Affairs Middle East and North Africa Subcommittee https://2025politicosecuritysummit.splashthat.com/Invite
10:30 a.m. 419 Dirksen ‚ Senate Foreign Relations Committee hearing to consider the nominations of Joel Rayburn to be assistant secretary of State for near Eastern affairs, and Chris Pratt to be assistant secretary of State for political-military affairs https://www.foreign.senate.gov/hearings/nominations-05-15-2025
FRIDAY | MAY 23
9 a.m. 550 Taylor Ave., Annapolis, Maryland — U.S. Naval Academy 2025 graduation and commissioning ceremony at Navy-Marine Corps Memorial Stadium https://www.usna.edu/CommissioningWeek/schedule.php
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President Donald Trump is greeted by Emir Tamim bin Hamad Al Thani at the Qatar Royal Court.
The deepening U.S. relationship with Qatar is drawing fresh scrutiny this week as President Donald Trump began a Middle East tour amid reports that he may accept a free jet from the Qatari royal family to replace his current plane as Air Force One.
The prospect has drawn bipartisan pushback, which Trump has met with indifference.
"Qatar is not, in my opinion, a great ally. I mean, they support Hamas. So what I'm worried about is the safety of the president," Sen. Rick Scott, R-Fla., told reporters on Tuesday.
Sen. Rand Paul, R-Ky., told Fox News, "I think it's not worth the appearance of impropriety."
TRUMP DEFENDS QATAR JUMBO JET OFFER AS TROUBLED BOEING FAILS TO DELIVER NEW AIR FORCE ONE FLEET
Qatar's Emir Sheikh Tamim bin Hamad Al Thani welcomes President Donald Trump at the Amiri Diwan in Doha, Qatar, Wednesday, May 14, 2025. (AP Photo/Alex Brandon)
"[The Qataris] said to me, 'we would like to, in effect, we would like to make a gift. You've done so many things. and we'd like to make you a gift to the Defense Department,' which is where it's going. and I said, 'Well, that's nice.' Now, some people say, 'Oh, you shouldn't accept gifts for the country.' My attitude is, why wouldn't I accept the gift? We're giving to everybody else, why wouldn't I accept a gift?" Trump explained to Fox News' Sean Hannity on Tuesdsay.
U.S. relations with Doha have come a long way since 2017, when Trump accused Qatar of harboring terrorism: "The nation of Qatar, unfortunately, has historically been a funder of terrorism at a very high level," Trump said at the time.
From there, Qatar became a major non-NATO ally to the U.S. in 2022 under President Biden and is home to Al Udeid Air Base, one of the U.S.' largest Middle East bases and a key hub for U.S. Central Command operations.
Qatar has been at the forefront of peace and hostage negotiations, especially in the war between Israel and Hamas. An Israeli delegation traveled to Doha on Tuesday to hash out a potential agreement on a hostage exchange and ceasefire in the Gaza Strip.
"Qatar is an indispensable security and energy partner to the United States. It's a strategic partnership that has grown stronger and more expansive over time," Ali Al-Ansari, media attaché at the Qatari embassy, told Fox News Digital. "His highness the Amir and President Trump have a longstanding relationship over many years, and both leaders have the shared goals of peace, security and stability."
"Qatar is working closely with the president and his team to advance these shared goals, whether in Gaza, Ukraine, Congo or other areas of instability."
TRUMP SAYS HE'LL DROP SANCTIONS ON SYRIA IN MOVE TO NORMALIZE RELATIONS
Trump is expected to meet with Qatari Emir Sheikh Tamim bin Hamad Al Thani in Doha. (Reuters/Evgenia Novozhenina)
In March, weeks of negotiations led by U.S. and Qatari mediators led to the release of American George Glezmann, who had been imprisoned by the Taliban in Afghanistan for more than two years. Doha's negotiators were also involved in the U.S.-Hamas deal to release the last living American hostage, Edan Alexander, on Monday.
"They're very smart at making themselves useful," said Michael Makovsky, CEO of the Jewish Institute for National Security of America.
The Trump Organization has cinched a new deal to build a luxury golf resort in Qatar, partnering with Qatari Diar, a real estate company backed by that country's sovereign wealth fund.
"Their financial connections to people in Trump's orbit, their making themselves useful as our mediators, communicating that strategically, the Qataris have been very effective at making themselves important," Makovsky added.
And despite its relatively small population – less than 3 million – Qatar controls over 10% of the world's natural gas reserves.
U.S. Air Force B-52 Stratofortress aircraft from Barksdale Air Force Base, Louisiana, arrive at Al Udeid Air Base, Qatar, April 9, 2016. (Staff Sgt. Corey Hook/U.S. Air Force via AP))
"They have an enormous amount of influence as a result of the money they spend," said Jonathan Schanzer, executive director at the Foundation for Defense of Democracies.
Energy Secretary Chris Wright praised Qatar as a "valued energy partner" – the second-largest producer of liquid natural gas in the world. "I look forward to building on this new era of U.S.-Qatari relations together," he said. Middle East envoy Steve Witkoff has praised Qatar as a valued partner in negotiations.
Sen. Roger Marshall, R-Kans., joined Trump officials in defending Qatar during a Senate hearing on campus antisemitism recently.
As a witness described links between the Qataris donating billions to universities and antisemitic protests, Marshall shot back: "Qatar has been a great ally to America. So I don't know why you're attacking them."
But others are skeptical.
Doha prepares for Trump's visit. (Noushad Thekkayil/NurPhoto via Getty Images)
"The Qataris have been sponsoring a wide range of terror groups for decades," said Schanzer. "It's been a bipartisan decision to turn a blind eye to the problem."
Israel supporters have long accused Qatar of funding Hamas. Prior to the outbreak of war after Oct. 7, 2023, Doha for years sent millions of dollars per month to the Gaza Strip to prop up Hamas' governing structure there.
They've also spent billions in the U.S., including an aggressive lobbying operation in Washington.
"We have seen them invest billions of dollars into higher education. We know that they're investing in K-12 education in this country," said Schanzer. "They're buying up parcels of valuable real estate. They are … spending massive amounts of money in states like Texas and South Carolina, where you have the defense industry and the energy industry."
"Over the last two decades or so they have spent a lot of money, expended a lot of effort, and it's now paying dividends."
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Schanzer said he was pleased the discussion over the Boeing plane had spurred a national conversation over Qatar's influence in the U.S.
"This is a longstanding problem that has gone unaddressed by Barack Obama, by Joe Biden, by George W. Bush and by Trump."
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Homeland Security Secretary Kristi Noem criticizes attempts from Democrats to challenge immigration enforcement on ‘Jesse Watters Primetime.'
A House Democrat plans to introduce a resolution calling for the U.S. to spend trillions of dollars on reparations for Black Americans this week.
Rep. Summer Lee, D-Pa., plans to introduce the Reparations Now Resolution on Thursday. Lee met with other lawmakers and activists on Capitol Hill on Tuesday at an event titled "Why We Can't Wait: Advancing Reparative Justice in Our Lifetime." She argues that reparations are a "moral and legal obligation" for Americans.
"This is a moment in time where societies are shaped [and] new societies are built. We should be the ones who are shaping it," said Lee.
"Their real intention is to build up whatever comes next in their image," she said, referring to the Trump administration, "and we better fight like hell to make sure that we're building it in our image."
Lee added that "it took nothing but a stroke of a pen," for President Donald Trump to dismantle diversity, equity and inclusion (DEI) programs across the federal government.
'TIPPING THE SCALES': HOUSE GOP LEADERS RIP ACTBLUE AFTER DEM FUNDRAISING GIANT HIT WITH SUBPOENA
Rep. Summer Lee, D-Pa., is calling for the transfer of trillions of dollars to Black Americans in reparations. (Jemal Countess/Getty Images for Court Accountability)
"That's why we recognize that the fight to restore Black folks has to be so much more substantive," she added.
Lee's resolution cites U.S. slavery, Jim Crow laws, and other racially discriminatory laws and policies to justify spending trillions of dollars supporting the descendants of Black Americans in the U.S.
BLACK CAUCUS CHAIR ACCUSES TRUMP OF 'PURGE' OF 'MINORITY' FEDERAL WORKERS
Lee's push comes after Rep. Ayanna Pressley, D-Mass., introduced her own legislation in February calling for a federal commission to study U.S. slavery and reparation proposals.
"We are in a moment of anti-Blackness on steroids and we refuse to be silent," Pressley said at the time. "We will not back down in our pursuit of racial justice."
Rep. Ayanna Pressley, D-Mass., introduced reparations legislation in February. (Tom Williams/CQ-Roll Call, Inc via Getty Images)
The bill aims to create a federal commission charged with investigating the enduring impacts of slavery and its aftermath, along with developing concrete proposals for reparations to African Americans who are descendants of slaves, Pressley said.
Democratic politicians in blue states, including California, in recent years have floated reparations as a way to atone for what proponents describe as a legacy of racist policies that created disparities for Black people in housing, education and health.
HOUSE DEMS ORGANIZE RAPID RESPONSE TASK FORCE AND LITIGATION GROUP TO COMBAT TRUMP AGENDA
President Donald Trump has ushered in a time of "anti-Blackness on steroids," a House Democrat claims. (AP Photo/Mark Schiefelbein)
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Democrats on the Hill and in California have pushed for passage of reparations legislation, with other cities and states proposing ideas for reparations.
Anders Hagstrom is a reporter with Fox News Digital covering national politics and major breaking news events. Send tips to Anders.Hagstrom@Fox.com, or on Twitter: @Hagstrom_Anders.
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Costs have been creeping up for Chad Esslinger, who runs an interior design business outside of Chicago, ever since President Donald Trump first announced sweeping global tariffs in early April.
One business Esslinger often relies on to provide light fixtures, rugs, furniture and all manner of wholesale home goods for clients implemented a “temporary tariff surcharge” of 14% on all goods from China and a 2% charge on items imported from any other country beginning on May 12.
Another business that provides fabric, wallpaper and trim emailed Esslinger to say it would re-evaluate its pricing strategy on May 15.
“I've seen it where sometimes they don't even warn you. I've gone to a website to look at a product I might have sourced a month ago, and now suddenly it's a certain percentage more,” Esslinger said.
“Just like everything, you have to pass that cost along if you want to stay profitable,” he added.
For the last few years, the home renovation space has been booming, but Washington's ever-shifting tariff policies threaten to change that.
That's because the US imports billions of dollars worth of home goods from around the globe, from Tuscan tilework to Chinese refrigerators. Those products, along with raw construction materials, have been hit by Trump's tariff agenda.
Professionals in the home renovation space, from decorators to general contractors, told CNN their businesses have been bracing for higher prices since President Donald Trump first announced tariffs on imports from most countries in early April.
Though Trump has temporarily placed many of the largest tariff increases on pause, high tariffs remain in effect, and uncertainty about future costs persists, many said.
“It's top of mind at this point. On the contractor side, they're waiting to see how it unfolds,” said Julie Kheyfets, the CEO of Block Renovation, an online platform that connects contractors with homeowners. “The thing about renovations is, every renovation is different. You can't stock a bunch of extra materials ahead of time, because every homeowner wants something different.”
Some home goods have already been pulled from the market entirely due to sharp changes in tariffs.
Sandy Schargel, an interior decorator from Albuquerque, New Mexico, was recently informed that thousands of dollars in light fixtures she had ordered for a client were no longer available, due to tariff-induced discontinuations. By the time she was notified, alternative options from the same lighting company had all risen 10% in price.
Schargel told CNN that if she can no longer access some imported products, she would turn to American-made alternatives, which may add costs for homeowners.
“When you come to the lower price points, American-made does limit things, somewhat,” Schargel said. “Imported merchandise often has lower price options.”
Schargel said she has encouraged clients on tighter budgets to order what they need as soon as possible to avoid prices going up further down the line.
China is one of the largest exporters of home goods to the US. In 2024, the country sent more than $438 billion worth of goods into American homes. Nearly 19% of that total was machinery and mechanical appliances, such as refrigerators, dish washing machines and laundry machines, according to data from the US International Trade Commission. Furniture, bedding, lamps and lighting were a further 4% of last year's imports from China.
For a little more than a month, the 145% tariff Trump placed on imports from China vastly eclipsed tariffs on other nations' imports. However, on Monday, the US and China agreed to lower tariffs on each other – a positive step in trade relations between the two countries after tensions had ratcheted up in the last few weeks. For at least 90 days, most imports from China will be taxed at 30%.
Blanket 10% tariffs are also in place with most other US trading partners, though higher rates could kick back in on July 9.
It is too early to tell whether the pause in the highest tariffs on China will reverse price hikes and shortages. Esslinger said so far this week, no home goods importers he works with have said they planned to lower prices.
Earlier this year, a report from the National Association of Home Builders estimated that the remodeling industry is poised for growth amid an aging housing stock. As fewer new homes have been built in the last decade and fewer Americans move, homeowners would be more likely to renovate their older homes, the report said.
Esslinger, the interior designer from the Chicago area, along with other home renovation professionals CNN spoke to, said tariff whiplash was slowing down business, though.
“The word that just keeps coming up is uncertainty,” Esslinger said. “I think some folks just don't feel super confident. I've had some clients say they're going to hold off for a little bit and see how things go, while some have scaled back a little bit.”
But not everyone in the home renovation space has felt the full impact of tariffs yet.
Nina Sepiashvily, who runs I&N Builders, a New York City-based construction company, said that while she may have noticed a slight increase in prices so far, it pales in comparison to the soaring prices she experienced in the years after the start of the pandemic, when inflation began to take off.
As a construction company owner, she generally doesn't handle buying finished goods like appliances and furniture, but rather handles purchasing building materials, like lumber.
Although the US imports a significant percentage of lumber from Canada, the additional tariff increase on that import hasn't yet taken effect. The tariff on lumber currently sits at 14.5%, but the US Commerce Department has signaled it plans to hike tariffs on Canadian lumber by more than double, to 34.5%, in the coming months.
“We haven't really seen (tariffs) affect our costs yet,” Sepiashvily said. But while clients are still interested in planning renovations, many aren't ready to move forward yet, she added. Homeowners are “uncertain about tariffs, they're uncertain about their investments and they're afraid to pull the trigger.”
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The Trump family's crypto empire is expanding rapidly, and it's making earlier ethics debates over his hotel and casino business interests look downright quaint.
There are only so many rooms a foreign diplomat can book to curry favor with the president, and that might total into thousands of dollars, at most. And even President Donald Trump might have a limit on how many luxury Qatari jets he'd accept as gifts.
But in the opaque world of cryptocurrencies, where transactions are often anonymous and unbound by national borders, there is virtually no cap on the amount of money a person or government could funnel to the president, his family and the growing list of entities they control.
That list of entities already includes two “meme coins” — digital assets with no utility that serious crypto advocates tend to roll their eyes at — and an exchange called World Liberty Financial, which issues its own token.
And soon, anyone with a brokerage account will be able to buy shares on the open market of American Bitcoin, a crypto mining firm backed by the president's sons, Eric Trump and Donald Trump Jr.
News of American Bitcoin's plans to go public emerged Monday night, around the same time that another crypto side hustle was wrapping up: Bidding ended Monday in an auction for a private dinner with Trump, billed as an “unforgettable gala,” for the top holders of the $TRUMP meme coin. The top 25 were promised face time with Trump and a “VIP tour” of one of his private clubs.
The dinner auction may be the most flagrant pay-to-play effort Trump has engaged in as president so far.
“He is essentially selling access to the presidency of the United States,” said Jordan Libowitz, vice president for communications at the nonprofit Citizens for Responsibility and Ethics in Washington, or CREW.
Libowitz described the auction as “the sum of all fears” scenario — the exact thing that the United States' founders were worried about when they included the (unfortunately branded) emoluments clause in the Constitution. (Tl;dr: People working for the federal government can't receive gifts from foreign governments without Congress' approval.)
Presidents giving access to campaign donors is nothing new — in the '90s, the Bill Clinton administration lavished dozens of Democratic contributors with stays in the Lincoln Bedroom, in a scandal known as the Fat Cat Hotel. But crypto offers a level of anonymity and scale that the White House has never seen.
Over the past month, crypto investors plowed an estimated $148 million into Trump's meme coin, according to Reuters, which cited data from crypto research firm Chainalysis.
The vast majority of the coin's supply — 80% — is held by two Trump Organization affiliates, which make money through transaction fees. Chainalysis estimates that those entities raked in at least $1.3 million in fees in the weeks after Trump announced the private dinner auction.
The dinner auction is just part of the crypto controversy.
Earlier this month, the New York Times' David Yaffe-Bellany reported that World Liberty Financial had secured a deal to take $2 billion in deposits from a venture fund backed by the government of Abu Dhabi — a revelation that helped torpedo crypto industry-supported legislation in the Senate last week.
Even crypto advocates on the right aren't loving the optics of a president directly enriching himself and his family through an industry that he is not only actively working to deregulate but also bolster through the establishment of a “strategic” bitcoin reserve.
Related article
A crypto mogul who invested millions into Trump coins is getting a reprieve on civil fraud charges
Sen. Cynthia Lummis, Republican of Wyoming, one of the sponsors of the stalled legislation, told the Times in an interview that Trump's profit-seeking “does give me pause because it complicates our work here.”
The White House, for its part, has repeatedly pushed back on any questions about the president's business interests.
On Friday, White House press secretary Karoline Leavitt dismissed a question about whether the president would conduct personal business meetings on his trip to the Middle East.
“It's frankly ridiculous that anyone in this room would even suggest that President Trump is doing anything for his own benefit,” Leavitt said. “This White House holds ourselves to the highest of ethical standards.”
(Ethicists and legal experts disagree, as my CNN colleagues note in their investigation of Trump family's expansive financial interests in the Middle East.)
Trump's crypto entanglements are particularly worrying, according to Libowitz, for two reasons.
For starters, crypto is still niche, and a 2024 Pew study found just 17% of US adults have ever invested in, traded or used a cryptocurrency. (And if they know about the industry, they likely know it through names like Sam Bankman-Fried, the founder of crypto exchange FTX, who is serving a 25-year sentence for fraud.)
“There's almost a level of security by obscurity,” Libowitz said.
Second: The scale of the potential corruption is boundless.
“There's a limit to how many $800 hotel rooms you can book… And you're limited in the thousands or tens of thousands of dollars,” he said. “But someone can just make a $20 million crypto purchase, and that's a scale we've never seen before.”
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The feijoa, not the kiwi, is the unofficial fruit of New Zealand, but it remains unknown to much of the world. The perfumed green ovals are known elsewhere as pineapple guava and originate from South America, but they've found an unlikely and fervent popularity in New Zealand. (AP video shot by Charlotte Graham-McLay)
A box outside a house offering free feijoas is seen in Wellington, New Zealand, Sunday, May 11, 2025. (AP Photo/Charlotte Graham-McLay)
Feijoas is seen outside a house in Wellington, New Zealand, Monday, May 12, 2025. (AP Photo/Charlotte Graham-McLay)
A feijoa hangs from a backyard tree in Wellington, New Zealand, on Sunday, May 11, 2025. (AP Photo/Charlotte Graham-McLay)
A man rakes feijoas from the roof of his shed in Wellington, New Zealand, Sunday, May 11, 2025. (AP Photo/Charlotte Graham-McLay)
Feijoas offered for free in a box are seen outside a house in Wellington, New Zealand, Sunday, May 11, 2025. (AP Photo/Charlotte Graham-McLay)
WELLINGTON, New Zealand (AP) — The unofficial national fruit of New Zealand isn't native to the country – it's South American. It isn't exclusively found in New Zealand. And it's not, perhaps surprisingly, the kiwi. It's the feijoa.
Known as pineapple guava elsewhere, the fruit — a green perfumed oval with a polarizing taste — can be purchased in California or Canberra. Yet no country has embraced the feijoa with quite the fervor or the fixation of New Zealanders.
Due to its short shelf life, New Zealand — a nation of thriving fruit exports — has never been able to spin the feijoa (pronounced fee-jo-ah) into a global brand, as growers have done with apples and kiwi. But during the brief span of weeks each year when the fruit is ripe, the country goes feijoa wild.
The feijoa's allure comes partly from how it's acquired. In autumn, fallen fruit forms fragrant carpets beneath backyard trees and is swept into boxes, bags and buckets to be offered for free outside homes, in office breakrooms and on neighborhood Facebook groups. There's such abundance that some feijoa lovers take pride in never having paid for one.
“It's sort of non-commercialized. We turn up our noses at the idea of buying them in the shop,” said Kate Evans, author of the book Feijoa: A Story of Obsession and Belonging. “You just sort of expect to get them for free.”
In suburban Wellington, Diana Ward-Pickering said she had given away “thousands” of feijoas from her five backyard trees this season: in a box on the sidewalk, to neighbors, to coworkers, to her daughter's eyelash technician — in short, to any friend or stranger who wanted some.
On a recent Sunday, Ward-Pickering selected a feijoa from dozens on the ground, halved it with a spoon, and scooped the pale, creamy flesh into her mouth.
“Delicious,” she said. But while she could eat a kilogram (2.2 pounds) of the fruit in a sitting, she said, even her appetite couldn't keep up with the sudden and generous bounty that arrives each April.
“There are people who can't afford to pay for them,” Ward-Pickering said. “We happily give them away.”
Not everyone's an enthusiast, and every New Zealander has an opinion. What devotees of the fruit savor as a distinctive texture, flavor and smell, is gritty, soapy or sour to others.
Diana Ward-Pickering's daughter, Lizzy, gingerly slurped a piece of feijoa into her mouth and grimaced.
“It's giving snot,” she said. “My mind has not changed.”
But for New Zealanders abroad who love the fruit, feijoas are a nostalgic taste evocative of a kiwi childhood. Evans, who admitted to once paying 3 Australian dollars ($1.90) for a single feijoa at a market in Australia, said that in 12 years living overseas she often saw expatriates asking the same question online: Where can I find feijoas?
How a fruit that hails from the Brazilian highlands, Uruguay and a corner of Argentina first came to New Zealand remains something of a mystery, Evans said. But what's known is that feijoas have been in New Zealand for just over 100 years, probably originating from California, via Australia.
The trees grow “extremely well” in New Zealand, growers say, due to the soil, subtropical climate and relative lack of destructive insect species.
In spite of New Zealand's booming backyard feijoa economy there's still demand for them in stores, where they are currently sold for about 9 to 10 New Zealand dollars ($5-6) per kilogram. There are about 100 commercial feijoa growers in New Zealand almost solely supplying the domestic market, including for popular beverages such as feijoa cider, kombucha and juice.
But exporting the fruit is “tricky,” said Brent Fuller, spokesperson for the New Zealand Feijoa Growers Association. “They'll keep in the chiller for two or three weeks, but that's about it.”
Research is underway to increase the shelf life of the fruit. But with the name feijoa still unknown abroad, it remains for now an institution of New Zealand's autumn.
“It's something that kind of bonds us and gives us an excuse to talk to people around us,” Evans said. The kiwi, she added, has been a lucrative export for New Zealand.
“But we don't love it the way that we love feijoas.”
Copyright 2025 The Associated Press. All Rights Reserved.
A judge on Tuesday denied a Maui anesthesiologist's request to be released on bail while he fights an attempted murder charge on allegations that he tried to kill his wife on a Honolulu hiking trail.
Gerhardt Konig previously pleaded not guilty. His wife wrote in a petition for a temporary restraining order against him that they were hiking in Honolulu in March when he grabbed her, pushed her toward the edge of a cliff, attempted to inject her with a syringe and then bashed her head with a rock. Konig suggested they go on the hike while the couple were on a trip to celebrate the wife's birthday, the petition said.
In denying the motion for bail, Judge Paul Wong said there's evidence that Konig hid from police, presents a serious flight risk and is a danger to the victim.
She has since filed for divorce. An attorney representing her is asking a judge to withhold the divorce case, filed earlier this month, from the public to protect the privacy of the couple's young children and because of the “significant and arguably intrusive media coverage regarding the underlying events which precipitated this divorce.”
The Associated Press does not name people who are victims of domestic violence unless they consent to be identified or decide to tell their stories publicly.
What is known as “Pali Puka” trail is closed because the route is unsafe, the state Department of Land and Natural Resources said. Hikers often enter through a small clearing near a popular lookout point that offers stunning views despite a warning: “Area Closed! Do not go beyond this sign.”
Grand jury indicts Maui doctor after wife tells police he repeatedly bashed her head with a rock after she refused selfie
At one point, Konig grabbed her by her upper arms and started pushing her toward the cliff's edge while yelling that he was sick of her, she said.
They began wrestling, and she screamed and pleaded for him to stop, fearing for her life, the petition said. During the struggle, she said he took a syringe from his bag and tried to inject her with something.
She said that she bit his arm in an attempt to defend herself.
He appeared to calm down, but then grabbed a nearby rock and “began bashing me repeatedly on the head with it,” she said.
Konig's wife suffered major cuts to her head — from the jagged, softball-sized lava rock — and required surgery, prosecutors said.
While the couple were in Oahu, the two young sons stayed home on Maui with a nanny and family, according to the wife's petition filed in family court. A judge signed an order saying Konig must stay away from her and their children.
Prosecutors, in opposing the bail request, said Konig “faces a realistic prospect of life imprisonment.” He tried to flee after the attack and called his adult son, who he told he “tried to kill your stepmom” and told him he would turn off his phone so that police could not locate him, prosecutors said in a court filing.
He also hid in the bushes until nightfall, even though the attack happened in the morning, and led police on a search, prosecutors said.
When he was apprehended, he said, “Wait, she's not dead?” according to prosecutors.
Defense attorney Thomas Otake called it a “very small rock” and argued doctors said there wasn't a substantial risk of death or a concussion from the wife's injuries.
During Tuesday's hearing, Deputy Prosecuting Attorney Joel Garner said Konig was stashing lethal drugs at home, tried three different ways to kill his wife and has ties to South Africa, where he was born.
The petition for a restraining order said that in December, Konig accused his wife of having an affair.
In a court document filed Monday, prosecutors said Konig was storing at home syringes, needles and vials labeled anesthesia medication. On March 27, a few days after the alleged attack and when his wife was preparing to fly back to Honolulu for his grand jury proceedings, she discovered a fanny pack belonging to her husband that contained several syringes and several vials of what appeared to be drugs, the filing said.
“That's not unusual that a doctor who practices medicine would have drugs,” Otake said, noting that none of the drugs were found on Oahu where the attack took place.
Konig has been held without bail since his indictment on March 28. In a motion seeking “bail at a reasonable amount,” his defense attorneys said Konig, 46, has no prior criminal convictions.
In court, Otake suggested bail between $100,000 and $200,000, arguing that while the divorce is pending he doesn't have access to marital assets.
Otake said his client intends to go to trial: “This is going to be a ‘he said, she said' trial.”
Editor's Note: If you or someone you know is struggling with intimate partner violence, there are resources available, including the National Domestic Violence Hotline.
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The Okanogan County Search and Rescue team responds to a climbing accident in the North Cascades mountains in Washington on Sunday, May 11, 2025. (Okanogan County Sheriff's Office via AP)
This 2021 photo provided by shows Monkey Flowers along the trail in North Cascades National Park Service Complex in Washington. (U.S. National Park Service via AP)
The Okanogan County Search and Rescue team responds to a climbing accident in the North Cascades mountains in Washington on Sunday, May 11, 2025. (Okanogan County Sheriff's Office via AP)
The Okanogan County Search and Rescue team responds to a climbing accident in the North Cascades mountains in Washington on Sunday, May 11, 2025. (Okanogan County Sheriff's Office via AP)
A rock climber who fell hundreds of feet descending a steep gully in Washington's North Cascades mountains survived the fall that killed his three companions, hiked to his car in the dark and then drove to a pay phone to call for help, authorities said Tuesday.
The Okanogan County Search and Rescue team responds to a climbing accident in the North Cascades mountains in Washington on Sunday, May 11, 2025. (Okanogan County Sheriff's Office via AP)
The surviving climber, Anton Tselykh, 38, extricated himself from a tangle of ropes, helmets and other equipment after the fall Saturday evening. Despite suffering internal bleeding and head trauma, Tselykh eventually, over at least a dozen hours, made the trek to the pay phone, Okanogan County Undersheriff Dave Yarnell said.
The climbers who were killed were Vishnu Irigireddy, 48, Tim Nguyen, 63, Oleksander Martynenko, 36, Okanogan County Coroner Dave Rodriguez said.
Authorities haven't yet been able to interview the survivor, who is in a Seattle hospital, said Rodriguez, so much is still unknown of the fall and Tselykh's journey.
Falls like this leading to three deaths are extremely rare, said Cristina Woodworth, who leads the sheriff's search and rescue team. Seven years ago, two climbers were killed in a fall on El Capitan at Yosemite National Park in California.
The group of four were scaling the Early Winters Spires, jagged peaks split by a cleft that is popular with climbers in the North Cascade Range, about 160 miles (257 kilometers) northeast of Seattle. Tselykh was hospitalized in Seattle.
The group of four met with disaster that night when the anchor used to secure their ropes was torn from the rock while they were descending, Rodriguez said. The anchor they were using, a metal spike called a piton, appeared to have been placed there by past climbers, he said.
They plummeted for about 200 feet (60 meters) into a slanted gulch and then tumbled another 200 feet before coming to rest, Yarnell said. Authorities believe the group had been ascending but turned around when they saw a storm approaching.
The Okanogan County Search and Rescue team responds to a climbing accident in the North Cascades mountains in Washington on Sunday, May 11, 2025. (Okanogan County Sheriff's Office via AP)
A three-person search and rescue team reached the site of the fall Sunday, Woodworth said. The team used coordinates from a device the climbers had been carrying, which had been shared by a friend of the men.
Once they found the site, they called in a helicopter to remove the bodies one at a time because of the rough terrain, Woodworth said.
On Monday, responders poured over the recovered equipment trying to decipher what caused the fall, Woodworth said. They found a piton — basically a small metal spike that is driven into rock cracks or ice and used as anchors by climbers — that was still clipped into the climbers' ropes.
“There's no other reason it would be hooked onto the rope unless it pulled out of the rock,” said Rodriguez, the coroner, noting that pitons are typically stuck fast in the rock. Rodriguez added that when rappelling, all four men would not have be hanging from the one piton at the same time, but taking turns moving down the mountain.
Pitons are oftentimes left in walls. They can be there for years or even decades, and they may become less secure over time.
“It looked old and weathered, and the rest of their equipment looked newer, so we are making the assumption that it was an old piton,” Woodworth said.
This 2021 photo provided by shows Monkey Flowers along the trail in North Cascades National Park Service Complex in Washington. (U.S. National Park Service via AP)
Rock climbers secure themselves by ropes to anchors, such as pitons or other climbing equipment. The ropes are intended to arrest their fall if they should slip, and typically climbers use backup anchors, said Joshua Cole, a guide and co-owner of North Cascades Mountain Guides, who has been climbing in the area for about 20 years.
Generally, it would be unusual to rappel off a single piton, said Cole, adding that it is still unknown exactly what happened on the wall that night.
“We eventually, if possible, would like to get more information from surviving party,” Woodworth said.
The spires are a popular climbing spot. The route the climbers were taking, said Cole, was of moderate difficulty, and requires moving between ice, snow and rock.
But the conditions, the amount of ice versus rock for example, can change rapidly with the weather, he said, even week to week or day to day, changing the route's risks.
___
Bedayn reported from Denver.
Copyright 2025 The Associated Press. All Rights Reserved.
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Hannah Dugan
A Wisconsin state judge indicted for allegedly obstructing the arrest of a Mexican immigrant by federal authorities said the charges should be dismissed because she's immune from prosecution for her official acts.
The prosecution of Milwaukee County Circuit Judge Hannah C. Dugan, who was arrested last month for events that allegedly occurred in and around her courtroom, “is virtually unprecedented and entirely unconstitutional,” her lawyers argued Wednesday in a court filing seeking dismissal of the charges.
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California Governor Gavin Newsom unveiled a budget proposal that aims to close a $12 billion deficit, marking the third consecutive fiscal year in which state lawmakers need to plug significant shortfalls.
Newsom, a second-term Democrat, said that a projected $363 million discretionary surplus for the upcoming fiscal year has morphed into a deficit in the months since his office unveiled his January budget proposal as new federal trade policies under President Donald Trump have dampened California's revenue projections and its economic outlook.
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House Speaker Mike Johnson defended President Donald Trump's plans to receive a luxury jet from Qatar, saying he doesn't think the gift raises ethics concerns.
Trump's first major second-term foreign trip touring the Middle East this week has provoked criticism over a spate of business deals his family has made across the region and revelations the president is considering accepting a 747 jet from the government of Qatar. He said will use the jet temporarily as Air Force One, indicating he intends to accept the gift.
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Apple Inc. is developing a feature for its Vision Pro headset that lets users scroll through software with their eyes, aiming to enhance the device with a novel interface.
The eye-scrolling capability is being tested as part of visionOS 3, an upcoming version of the Vision Pro's operating system, according to people with knowledge of the matter. Already, the headset lets users navigate the software by looking at objects and then selecting them by pinching their fingers.
Shares of stock brokerage platform eToro popped in their Nasdaq debut on Wednesday after the company raised almost $310 million in its initial public offering.
The stock opened at $69.69, or 34% above its IPO, pushing its market cap to $5.6 billion. Shares were last up more than 40%.
The Israel-based company sold nearly six million shares at $52 each, above the expected range of $46 to $50. Almost six million additional shares were sold by existing investors. At the IPO price, the company was valued at roughly $4.2 billion.
Wall Street is looking to the Robinhood competitor for signs of renewed interest in IPOs after an extended drought. Many investors saw President Donald Trump's return to the White House as a catalyst before tariff concerns led companies to delay their plans.
Etoro isn't the only company attempting to test the waters. Fintech company Chime filed its prospectus with the U.S. Securities and Exchange Commission on Tuesday, while digital physical therapy company Hinge Health kickstarted its IPO roadshow, and said in a filing it aims to raise up to $437 million in its offering.
EToro had previously filed to go public in 2021 through a merger with a special purpose acquisition company, or SPAC, that would have valued it at more than $10 billion. It shelved those plans in 2022 as equity markets nosedived, but remained focused on an eventual IPO.
EToro was founded in 2007 by brothers Yoni and Ronen Assia and David Ring. The company makes money through trading-related fees and nontrading activities such as withdrawals. Net income increased almost thirteenfold last year to $192.4 million from $15.3 million in 2023.
The company has steadily built a growing business in cryptocurrencies. Revenue from crypto assets more than tripled to upward of $12 million in 2024, and one-quarter of its net trading contribution stemmed from crypto last year. That is up from 10% in 2023.
EToro said that for the first quarter, it expects crypto assets to account for 37% of its commission from trading activities, down from 43% a year earlier.
Spark Capital is the company's biggest outside investor, with 14% control after the offering, followed by BRM Group at 8.7%. CEO Yoni Assia controls 9.3%.
WATCH: Etoro IPO
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Keir Starmer, Emmanuel Macron and Friedrich Merz on a train to Kyiv on May 9.
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Boeing and GE Aerospace secured a $96 billion agreement to sell Qatar Airways up to 210 aircraft, the White House said Wednesday.
The deal for the 787 Dreamliner and 777X aircraft powered by GE engines is Boeing's "largest-ever widebody order and largest-ever 787 order," according to the White House.
The companies struck the agreement during President Donald Trump's state visit with the emir of Qatar.
The White House said in a fact sheet that the deal will support 154,000 U.S. jobs annually and more than one million total domestic jobs over the course of production and delivery of the planes.
Further details were unclear. Boeing did not immediately respond to CNBC's requests for comment.
Boeing has yet to deliver any 777X planes. The 426-seat jetliner is years behind schedule and has still not been certified by the Federal Aviation Administration.
Boeing CEO Kelly Ortberg appeared alongside Trump at the Amiri Diwan in Doha earlier Wednesday for a signing ceremony on the aircraft deal.
"It's the largest order of jets in the history of Boeing," Trump said after Ortberg signed the agreement.
The deal could be a boon for Boeing, which has not posted a profit since 2018.
The plane maker has been beset by major safety concerns, manufacturing defects, cost overruns and a nearly two-month-long machinist strike last year.
Its business dealings have also been disrupted by Trump's trade war. China stopped accepting deliveries of Boeing planes to its airlines in response to U.S. tariffs, Ortberg said last month.
But the company has recently narrowed its losses as it addresses a backlog worth more than $500 billion, Ortberg said in Boeing's first-quarter earnings call.
"This is great news for South Carolina and Boeing," said Sen. Lindsey Graham, R-S.C., calling the deal "a gamechanger."
Graham's office said the new planes will be assembled at Boeing's Charleston facility.
The deal announced Wednesday would nearly double Qatar Airways' fleet of 233 aircraft, according to its website.
It could also draw more scrutiny toward Trump's acceptance, and defense, of Qatar's offer to gift the U.S. a luxury 747 jet that will act as the new Air Force One.
Democrats have blasted the move as corrupt and unconstitutional, and some of Trump's Republican allies in government and media have also expressed unease.
— CNBC's Michele Luhn contributed to this report.
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Morten Christensen says he and four crypto-loving friends will be attending the dinner next week being held for the top holders of President Donald Trump's memecoin for just about $1,200 each.
The five were among the 220 people with the highest time-weighted holdings of the memecoin in the last three weeks on a special leaderboard used to keep track of the biggest buyers of the cryptocurrency. While it took at least $54,500 or so in time-weighted holdings during that period to secure a spot at the event on May 22, the actual amount Christensen and his friends spent basically boils down to trading fees.
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A Saks Fifth Avenue shopper in New York.
It was supposed to be just what Saks needed to turn things around. By taking over struggling rival Neiman Marcus, the pitch went, the iconic retailer would become a luxury powerhouse — one with enough bargaining and pricing power to cut costs and boost profitability.
So when the company turned to the bond market to finance the takeover last December, investors were drawn in. Sure, there was some skepticism, but a juicy 11% interest rate, pledges on some of its assets and big-time backers including Amazon.com Inc. and Salesforce Inc. assuaged their concerns. They shelled out $2.2 billionBloomberg Terminal, $200 million more than Saks originally sought.
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Sachin Kansal, chief product officer of Uber Technologies, speaks during a product unveiling event in New York on May 14.
Photographer: Yuki Iwamura/Bloomberg
Uber Technologies Inc. is introducing a cheaper pooled rides option and a price-lock pass for commuters, underscoring its focus on attracting more daily users as consumers confront rising costs.
The rideshare company on Wednesday announced “Route Share,” a budget-focused offering that's up to 50% cheaper than a regular UberX and only available during weekday commuting hours. In contrast, its existing pooled rides option cuts costs as much as only 20%. But there's a catch: Route Share pickups run every 20 minutes only “along busy corridors,” similar to a bus, and passengers may have to walk up to 15 minutes to the pick-up point and share a vehicle with two other people.
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A truck crosses the Peace Bridge at the Canada-US border in Fort Erie, Ontario.
Canada has effectively suspended almost all of its retaliatory tariffs on US products, tamping down inflation risks and improving its growth outlook, according to Oxford Economics.
The government imposed new import taxes of 25% on about C$60 billion ($43 billion) of US-made goods in March in response to the first round of tariffs from the Trump administration. Canada also retaliated against US auto tariffs in early April by putting its own levies on US vehicles.
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HBO became HBO Max, and then it became Max. Now, it will be HBO Max once more.
Warner Bros. Discovery is renaming its streaming platform again starting this summer, restoring a name it ditched just two years ago. The company announced the rebranding Wednesday during its upfront presentation in New York.
The change comes as Warner Bros. Discovery seeks to scale back its volume of content and focus on quality programming and storytelling.
"The powerful growth we have seen in our global streaming service is built around the quality of our programming," said David Zaslav, CEO of Warner Bros. Discovery, in a statement. "Today, we are bringing back HBO, the brand that represents the highest quality in media, to further accelerate that growth in the years ahead."
The company's streaming business has turned around its profitability by almost $3 billion over the past two years and scaled globally with around 22 million subscribers added in the past year. Warner Bros. Discovery aims to have more than 150 million subscribers by the end of 2026.
Still, Warner Bros. Discovery lost live rights to National Basketball Association games beginning next season. The company has focused on paying down debt rather than spending on new content to compete with Netflix, which has more than 300 million subscribers.
Ironically, the HBO Max branding was first introduced in 2019 to showcase HBO's competitive global streaming ambitions. Now, Warner Bros. Discovery is bringing back the same name, but emphasizing the opposite — quality over quantity.
"We will continue to focus on what makes us unique — not everything for everyone in a household, but something distinct and great for adults and families," said JB Perrette, president and CEO of streaming at Warner Bros. Discovery, in a statement. "It's really not subjective, not even controversial — our programming just hits different."
Competitor Disney has taken a similar tack, with CEO Bob Iger noting in recent investor calls that the way to win in streaming will be quality content.
The legacy media companies have all struggled to achieve profitability in their streaming businesses since launching their own services in recent years. That has led to an increased emphasis on advertising tiers, crackdowns on password sharing and more streaming service bundles.
The Upfronts week in New York has already been heavy on naming news. ESPN announced its upcoming flagship streaming app will be named simply ESPN. Fox said its forthcoming streamer will be named Fox One. Last week, Comcast's cable portfolio spinoff announced its new holding company name, Versant.
Warner Bros. Discovery first launched its stand-alone streaming service HBO Max in 2020 when the brand was still owned by AT&T. The "Max" moniker was added to signify that the platform would have a wide array of content, from reality TV, documentaries, kids programming and movies, as well as the prestige branding of HBO titles.
At the time, leadership believed HBO had too small of an audience, much of which was U.S.-based, and that there was more value in making HBO a sub-brand within a larger streaming offering.
The service was later renamed Max in 2023. That change came after the merging of Discovery Communications and WarnerMedia, which was divested from AT&T in 2022. Content from Discovery+ was added to HBO Max under the new name.
Now, two years later, Warner Bros. Discovery has reversed course.
Disclosure: Comcast is the parent company of CNBC. Versant will be the new parent company of CNBC under the proposed cable portfolio spinoff.
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Phil Knight
Nike Inc. cofounder Phil Knight has repeatedly expressed interest in buying the Portland Trail Blazers, but now that it's finally for sale, he has decided to pass on the chance to own the NBA franchise.
“Five years ago, when I was a younger man, I had a great interest in being a part of the Portland Trail Blazers franchise,” Knight, 87, said in a statement. “However, at my current age, I can confirm that I no longer have interest in acquiring the team.”
Volkswagen and Rivian are teaming up to build more affordable electric vehicles, but that doesn't mean they're planning to skimp on high-tech features.
The Tesla rival is partnering with Volkswagen to provide technology for a new $22,500 electric car, and Wassym Bensaid, Rivian's chief software officer, said the coming EV wouldn't compromise on tech despite its low price point.
VW and Rivian announced a deal last year for the German car giant to invest over $5 billion in the startup and form a joint company to develop next-generation software and EV technology, with Bensaid and VW exec Carsten Helbing as co-CEOs.
In March, VW unveiled the ID Every1, a compact electric hatchback set to be the first VW vehicle to include software developed in the joint venture.
The 13-foot-long four-seater is set to go on sale in Europe by 2027 for about 20,000 euros, roughly $22,500. VW has not said whether it has any plans to bring it to the US.
"It's something which is extremely close to my heart because it's a way to bring that technology into many more cars," Bensaid told Business Insider.
"Inexpensive cars shouldn't have low technology, and this is the beauty of the setup that we're enabling through the joint venture," said the Rivian executive, who spoke with BI on the sidelines of the Financial Times' Future of the Car conference.
Bensaid said the lower-cost hatchback would leverage Rivian's software architecture to cut costs.
Rather than individual computers controlling components like seats, lights, and doors, all of ID Every1's features are set to be handled by a central computer built on Rivian's technology, which Bensaid said would save VW money because it uses fewer parts and simplifies the design.
The ID Every1 will not be the first vehicle to use technology developed by the Rivian-VW joint venture — that's Rivian's R2, which is set to launch next year — but it's a huge step for both companies.
A lack of affordable EVs remains one of the main reasons customers are reluctant to go electric, and VW is betting that its cheapest-ever battery-powered offering will help fill that gap.
It's not the only one making that bet. The startup Slate Auto caused a stir last month when it unveiled a $25,000 pickup truck, which is set to go on sale in the US in 2026.
The Slate truck has bucked the trend of vehicles becoming more computerized and packed with smart technology.
The base model lacks power windows, a radio, and any kind of built-in infotainment system, with Slate's CEO telling BI that the company had focused on simplicity to keep the price as low as possible.
So far, consumers haven't seemed that bothered by the lack of bells and whistles, with the Jeff Bezos-backed startup receiving 100,000 refundable $50 reservations in just two weeks.
When asked about Slate's approach, Bensaid said Rivian welcomes more competition in the EV market but had made a "different choice" in how it approaches making electric cars more affordable.
"Inexpensive cars shouldn't be cars with limited features," he said, adding that Rivian believed it was possible to deliver a "rich user experience" at a low price point by making vehicle technology more efficient.
"That is our approach," Bensaid said. "We would like to enable choice for customers but without such severe compromise in terms of the overall experience."
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Kraft Heinz is spending $3 billion to upgrade its U.S. factories, its largest investment in its plants in a decade, even as executives say consumer sentiment is at its second-lowest point in 70 years, and it has cut sales and profit forecasts.
The upgrades will help lower costs by making the plants more efficient, which in turn may help offset President Donald Trump's tariffs, which factored into the company's decision to make the investment, said Pedro Navio, Kraft Heinz's president of North America, in an interview with Reuters.
The investment also allows the packaged food maker to come up with and sell new products faster, he said.
Kraft Heinz manufactures its market-leading Heinz ketchup, Kraft macaroni and cheese and Philadelphia cream cheese, among other products, at 30 plants across the United States. Kraft Heinz told Wall Street analysts last month that tariffs were adding to its costs and that consumers were buying less due to economic uncertainty.
But the company is moving forward and making the new investment now to defend its market share, Navio said.
"It goes beyond just efficiencies or dealing with the current tariff challenges," he said, saying the investment allows Kraft Heinz to produce food for the long term.
The company is currently facing tariffs on imports such as coffee, after the United States last month implemented a 10% levy on all imported goods. Its imports from China, which faces higher tariffs, are negligible, a spokesperson said.
Kraft Heinz, which also roasts and sells Maxwell House coffee, asked suppliers for a 60-day notice before putting through price hikes.
Nearly all of what Kraft Heinz sells in the United States is made domestically, Navio said, adding that the company grows its own tomatoes in California and potatoes in Idaho, for example. It exports some of what it manufactures in the United States to Canada, Navio said.
The company expects the investment will create about 3,500 new construction jobs where the plants are located. Navio said the company doesn't anticipate the need for additional employees beyond that.
Facial tissue manufacturer Kimberly-Clark and brewer Anheuser-Busch InBev have made similar announcements in recent weeks.
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A landmark resources deal between the U.S. and Ukraine is expected to lay the ground for further so-called "minerals for muscle" agreements.
Washington and Kyiv signed a highly anticipated minerals deal earlier this month. The agreement, which has since been ratified by Ukrainian lawmakers, is designed to deepen economic ties, bolster Ukraine's reconstruction and position the country as a supplier of strategically important minerals to the U.S.
Long coveted by U.S. President Donald Trump, the partnership followed months of tense negotiations and came more than three years since the start of Russia's full-scale invasion of Ukraine.
Ro Dhawan, CEO of the International Council on Mining and Metals (ICMM), a trade body representing roughly one-third of the global industry, said the U.S.-Ukraine deal is not the first and certainly won't be the last bilateral agreement where minerals and geopolitics mix so closely.
"I think we're likely to see more outreach to producer countries to make deals which could take the form of what I have previously called 'minerals for muscle.' So, 'give me your minerals and I'll give you security,' or other forms of trade agreement," Dhawan told CNBC by video call.
For instance, ICMM's Dhawan said he could "absolutely imagine" a deal between the U.S. and the Democratic Republic of the Congo, which has the world's largest reserves of cobalt, in the near future.
Natural resources could also play a pivotal role in the thawing of "pretty frosty" diplomatic ties between the U.S. and South Africa, Dhawan said, as well as the U.S. and Canada.
"We're at a turning point in the way minerals are a part of the global conversation. We've seen the first act, probably, with Ukraine, and I think there are a few more twists and turns to come in the way that this now starts to take shape," he added.
Critical minerals refer to a subset of materials considered essential to the energy transition. These minerals, which tend to have a high risk of supply chain disruption, include metals such as copper, lithium, nickel, cobalt and rare earth elements.
China is the undisputed leader of the critical minerals supply chain, accounting for roughly 60% of the world's production of rare earth minerals and materials. U.S. officials have previously warned that this poses a strategic challenge amid the pivot to low-carbon energy sources.
Heidi Crebo-Rediker, a senior fellow in the Center for Geoeconomic Studies at the Council on Foreign Relations, a U.S. think tank, said Washington and Beijing's geopolitical rivalry has put critical minerals at the center of the U.S. national security agenda.
Assuming they are commercially recoverable, Crebo-Rediker said Ukraine's vast reserves of critical minerals and rare earth elements could "provide a future potential secure supply chain of many materials the United States needs."
Timothy Puko, director of commodities at Eurasia Group, a political risk consultancy, said he was "a little bit skeptical" about the prospect of a wave of bilateral "minerals for muscle" agreements.
"There's certainly some truth to it. I think that's what you're seeing in Ukraine. I think that Kinshasa is very clearly trying to pursue that right now, with their cobalt-copper situation and the [Rwandan-backed] M23 rebels," Puko told CNBC by video call.
Aside from Ukraine and the Democratic Republic of the Congo, however, Puko said he was "hard-pressed" to foresee any further agreements. Canada, Australia, Indonesia and several mineral-rich Latin America countries would all be unlikely to pursue minerals for muscle-type deals with the U.S., he added.
"Outside of Ukraine and DRC, and possibly not even DRC, no other country right now really wants to trade away all that midstream business. Resource nationalism is the name of the game right now and the trend is really the opposite," Puko said.
"There's definitely horse-trading to be done here. It's a huge geopolitical issue. I'm sure it's coming up right now in the ongoing bilateral trade talks but there are huge barriers to replicating what Ukraine is trying to do with a lot of other countries."
Trump's trade tariff policy and repeated calls to make Canada the 51st state has strained diplomatic ties between the neighboring countries and fueled a swell of national pride and anger at the U.S.
Newly elected Canadian Prime Minister Mark Carney told Trump at the White House earlier this month that his country is "not for sale" — and "won't be for sale ever."
Trump replied: "Never say never."
Heather Exner-Pirot, director of energy, natural resources and environment at the Macdonald-Laurier Institute, a public policy think tank based in Ottawa, said Canada does not need a minerals for muscle agreement with the U.S.
"What we need is more certainty in our trade relationship. That is the biggest hurdle right now to reshoring mineral production and processing to North America in order to combat Chinese manipulation of global mineral markets," Exner-Pirot told CNBC via email.
Canada and the U.S. have developed interdependently over the course of 150 years and through world wars, Exner-Pirot said, noting that the countries are each another's largest suppliers and destinations of mineral exports.
What's more, Exner-Pirot said Canada and the U.S. already collaborate in both NATO and the North American Aerospace Defense Command (NORAD). A binational organization between Canada and the U.S., NORAD is primarily responsible for aerospace control and maritime warning in the defense of North America.
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The VC firm is making investments beyond private startups.
A Carvana vending machine in Uniondale, New York
Thrive Capital, the venture firm founded by Josh Kushner, told investors last week that one of its funds made $522 million on an unusual bet — an investment in publicly traded car marketplace Carvana Co.
The windfall, outlined in a letter to investors reviewed by Bloomberg, underscores Thrive's expansion beyond traditional startup investing, including public market trading and, recently, a plan to start and buy businesses it thinks can benefit from artificial intelligence. That's in addition to Thrive's large bets on private businesses like OpenAI and Stripe Inc.
Perplexity is extending its bet on chat-powered shopping, aiming to stand out in the crowded generative artificial intelligence market against OpenAI, Anthropic, and Google.
The company said on Wednesday that it's partnering with PayPal to let users make purchases directly in chat. U.S. customers will soon be able to book travel, buy products, and secure concert tickets without leaving the platform.
Payments will be completed in the chat with PayPal or Venmo, and PayPal will handle processing, shipping, tracking, and invoicing. Purchases will be completed with one click, with the help of the payment company's passkey checkout.
"Perplexity wants to be wherever users are asking questions and making decisions," said Ryan Foutty, Perplexity's vice president of business. "Our vision for assistive AI is that everything just gets better and easier for people — wherever they are and however they prefer to make decisions."
Perplexity jumped into e-commerce last year, adding a shopping feature for paid U.S. users and integrating with sellers using services like Shopify. Now Perplexity is allowing users to complete transactions within a chat, a feature that OpenAI's ChatGPT has yet to roll out.
PayPal is competing for AI deals against companies including Stripe, Visa, and Mastercard.
In April, Visa, Mastercard, and PayPal — three of the largest payment providers in the United States — each in quick succession began launching new tools to integrate artificial intelligence into online transactions.
Visa debuted Intelligent Commerce in April, a technology that lets AI systems select items and securely complete payments with tokenized credentials. They've partnered with Anthropic, Microsoft, Mistral AI, OpenAI, Perplexity, among others.
"Soon people will have AI agents browse, select, purchase and manage on their behalf," Visa's Chief Product and Strategy Officer Jack Forestell said in a statement. "These agents will need to be trusted with payments, not only by users, but by banks and sellers as well."
Mastercard unveiled Agent Pay also in April, describing it as a solution that will integrate Microsoft's leading AI technologies, including Microsoft Azure OpenAI Service and Microsoft Copilot Studio, with Mastercard's trusted payment solutions "to develop and scale agentic commerce, addressing the evolving needs of the entire commerce value chain."
Mastercard added that it plans to collaborate with Microsoft on new use cases and expects to expand these capabilities with "other leading AI platforms to follow," according to the release.
Meanwhile, PayPal introduced a developer toolkit designed to embed its payment capabilities into AI-powered shopping experiences.
The simultaneous announcements signal a broader industry shift toward leveraging AI agents to handle everything from product discovery to payment completion.
PayPal technology chief Srini Venkatesan said PayPal's system can directly connect to the merchants, handling payments, shipping, and billing information without requiring users to re-enter details. The company also manages support.
"The next generation of commerce is happening on the agentic side. People are starting to research and shop online through agents," Venkatesan said, referring to AI-driven systems that can complete tasks without human intervention. "Agentic commerce is not only the searching but making it all the way to the purchase — paying for it and then buying it from that merchant. So that's what PayPal has been leading, and we've been trying to get the agentic commerce piece right."
Venkatesan said PayPal's edge in this space comes from its ability to securely verify both buyers and sellers. PayPal authenticates users through their wallet and automatically fills in billing and shipping information, aiming to reduce friction.
"We provide the trust that the business is legitimate on one side, and then the customer is legitimate on the other side," he said.
The partnership comes as Perplexity is finalizing a $500 million funding round at a $14 billion valuation, down from an initial target of $18 billion.
The use of AI-driven chat for customer service jumped 42% in the past year, according to Salesforce data, based on 1.6 trillion page views on its platform. Buying decisions are also increasingly being influenced by AI chat, but not as dramatically, showing an increase of 6% over the past year in the Salesforce data.
Global sales influenced by AI climbed to $229 billion between November and December, up from $199 billion during the same period a year earlier.
ChatGPT, Anthropic's Claude and Google's AI Overviews have climbed ahead in search, building powerful real-time results and AI-enhanced answers. OpenAI launched its ChatGPT search feature last year, positioning it to compete directly with Perplexity, while Google's AI Overviews brought real-time insights to search.
WATCH: Perplexity CEO on AI race
CORRECTION: This story has been updated to state that AI-driven chat for customer service was up 42% over the last year. A previous version of this story incorrectly stated the nature of that number.
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Not long ago, Silicon Valley was where the world's leading artificial intelligence experts went to perform cutting-edge research.
Meta, Google and OpenAI opened their wallets for top talent, giving researchers staff, computing power and plenty of flexibility. With the support of their employers, the researchers published high-quality academic papers, openly sharing their breakthroughs with peers in academia and at rival companies.
But that era has ended. Now, experts say, AI is all about the product.
Since OpenAI released ChatGPT in late 2022, the tech industry has shifted its focus to building consumer-ready AI services, in many cases prioritizing commercialization over research, AI researchers and experts in the field told CNBC. The profit potential is massive — some analysts predict $1 trillion in annual revenue by 2028. The prospective repercussions terrify the corner of the AI universe concerned about safety, industry experts said, particularly as leading players pursue artificial general intelligence, or AGI, which is technology that rivals or exceeds human intelligence.
In the race to stay competitive, tech companies are taking an increasing number of shortcuts when it comes to the rigorous safety testing of their AI models before they are released to the public, industry experts told CNBC.
James White, chief technology officer at cybersecurity startup CalypsoAI, said newer models are sacrificing security for quality, that is, better responses by the AI chatbots. That means they're less likely to reject malicious kinds of prompts that could cause them to reveal ways to build bombs or sensitive information that hackers could exploit, White said.
"The models are getting better, but they're also more likely to be good at bad stuff," said White, whose company performs safety and security audits of popular models from Meta, Google, OpenAI and other companies. "It's easier to trick them to do bad stuff."
The changes are readily apparent at Meta and Alphabet, which have deprioritized their AI research labs, experts say. At Facebook's parent company, the Fundamental Artificial Intelligence Research, or FAIR, unit has been sidelined by Meta GenAI, according to current and former employees. And at Alphabet, the research group Google Brain is now part of DeepMind, the division that leads development of AI products at the tech company.
CNBC spoke with more than a dozen AI professionals in Silicon Valley who collectively tell the story of a dramatic shift in the industry away from research and toward revenue-generating products. Some are former employees at the companies with direct knowledge of what they say is the prioritization of building new AI products at the expense of research and safety checks. They say employees face intensifying development timelines, reinforcing the idea that they can't afford to fall behind when it comes to getting new models and products to market. Some of the people asked not to be named because they weren't authorized to speak publicly on the matter.
When Joelle Pineau, a Meta vice president and the head of the company's FAIR division, announced in April that she would be leaving her post, many former employees said they weren't surprised. They said they viewed it as solidifying the company's move away from AI research and toward prioritizing developing practical products.
"Today, as the world undergoes significant change, as the race for AI accelerates, and as Meta prepares for its next chapter, it is time to create space for others to pursue the work," Pineau wrote on LinkedIn, adding that she will formally leave the company May 30.
Pineau began leading FAIR in 2023. The unit was established a decade earlier to work on difficult computer science problems typically tackled by academia. Yann LeCun, one of the godfathers of modern AI, initially oversaw the project, and instilled the research methodologies he learned from his time at the pioneering AT&T Bell Laboratories, according to several former employees at Meta. Small research teams could work on a variety of bleeding-edge projects that may or may not pan out.
The shift began when Meta laid off 21,000 employees, or nearly a quarter of its workforce, starting in late 2022. CEO Mark Zuckerberg kicked off 2023 by calling it the "year of efficiency." FAIR researchers, as part of the cost-cutting measures, were directed to work more closely with product teams, several former employees said.
Two months before Pineau's announcement, one of FAIR's directors, Kim Hazelwood, left the company, two people familiar with the matter said. Hazelwood helped oversee FAIR's NextSys unit, which manages computing resources for FAIR researchers. Her role was eliminated as part of Meta's plan to cut 5% of its workforce, the people said.
OpenAI's 2022 launch of ChatGPT caught Meta off guard, creating a sense of urgency to pour more resources into large language models, or LLMs, that were captivating the tech industry, the people said.
In 2023, Meta began heavily pushing its freely available and open-source Llama family of AI models to compete with OpenAI, Google and others.
With Zuckerberg and other executives convinced that LLMs were game-changing technologies, management had less incentive to let FAIR researchers work on far-flung projects, several former employees said. That meant deprioritizing research that could be viewed as having no impact on Meta's core business, such as FAIR's previous health care-related research into using AI to improve drug therapies.
Since 2024, Meta Chief Product Officer Chris Cox has been overseeing FAIR as a way to bridge the gap between research and the product-focused GenAI group, people familiar with the matter said. The GenAI unit oversees the Llama family of AI models and the Meta AI digital assistant, the two most important pillars of Meta's AI strategy.
Under Cox, the GenAI unit has been siphoning more computing resources and team members from FAIR due to its elevated status at Meta, the people said. Many researchers have transferred to GenAI or left the company entirely to launch their own research-focused startups or join rivals, several of the former employees said.
While Zuckerberg has some internal support for pushing the GenAI group to rapidly develop real-world products, there's also concern among some staffers that Meta is now less able to develop industry-leading breakthroughs that can be derived from experimental work, former employees said. That leaves Meta to chase its rivals.
A high-profile example landed in January, when Chinese lab DeepSeek released its R1 model, catching Meta off guard. The startup claimed it was able to develop a model as capable as its American counterparts but with training at a fraction of the cost.
Meta quickly implemented some of DeepSeek's innovative techniques for its Llama 4 family of AI models that were released in April, former employees said. The AI research community had a mixed reaction to the smaller versions of Llama 4, but Meta said the biggest and most powerful Llama 4 variant is still being trained.
The company in April also released security and safety tools for developers to use when building apps with Meta's Llama 4 AI models. These tools help mitigate the chances of Llama 4 unintentionally leaking sensitive information or producing harmful content, Meta said.
"Our commitment to FAIR remains strong," a Meta spokesperson told CNBC. "Our strategy and plans will not change as a result of recent developments."
In a statement to CNBC, Pineau said she is enthusiastic about Meta's overall AI work and strategy.
"There continues to be strong support for exploratory research and FAIR as a distinct organization in Meta," Pineau said. "The time was simply right for me personally to re-focus my energy before jumping into a new adventure."
Meta on Thursday named FAIR co-founder Rob Fergus as Pineau's replacement. Fergus will return to the company to serve as a director at Meta and head of FAIR, according to his LinkedIn profile. He was most recently a research director at Google DeepMind.
"Meta's commitment to FAIR and long term research remains unwavering," Fergus said in a LinkedIn post. "We're working towards building human-level experiences that transform the way we interact with technology and are dedicated to leading and advancing AI research."
Google released its latest and most powerful AI model, Gemini 2.5, in March. The company described it as "our most intelligent AI model," and wrote in a March 25 blog post that its new models are "capable of reasoning through their thoughts before responding, resulting in enhanced performance and improved accuracy."
For weeks, Gemini 2.5 was missing a model card, meaning Google did not share information about how the AI model worked or its limitations and potential dangers upon its release.
Model cards are a common tool for AI transparency.
A Google website compares model cards to food nutrition labels: They outline "the key facts about a model in a clear, digestible format," the website says.
"By making this information easy to access, model cards support responsible AI development and the adoption of robust, industry-wide standards for broad transparency and evaluation practices," the website says.
Google wrote in an April 2 blog post that it evaluates its "most advanced models, such as Gemini, for potential dangerous capabilities prior to their release." Google later updated the blog to remove the words "prior to their release."
Without a model card for Gemini 2.5, the public had no way of knowing which safety evaluations were conducted or whether DeepMind checked for dangerous capabilities at all.
In response to CNBC's inquiry on April 2 about Gemini 2.5's missing model card, a Google spokesperson said that a "tech report with additional safety information and model cards are forthcoming." Google published an incomplete model card on April 16 and updated it on April 28, more than a month after the AI model's release, to include information about Gemini 2.5's "dangerous capability evaluations."
Those assessments are important for gauging the safety of a model — whether people can use the models to learn how to build chemical or nuclear weapons or hack into important systems. These checks also determine whether a model is capable of autonomously replicating itself, which could lead to a company losing control of it. Running tests for those capabilities requires more time and resources than simple, automated safety evaluations, according to industry experts.
The Financial Times in March reported that Google DeepMind CEO Demis Hassabis had installed a more rigorous vetting process for internal research papers to be published. The clampdown at Google is particularly notable because the company's "Transformers" technology gained recognition across Silicon Valley through that type of shared research. Transformers were critical to OpenAI's development of ChatGPT and the rise of generative AI.
Google co-founder Sergey Brin told staffers at DeepMind and Gemini in February that competition has accelerated and "the final race to AGI is afoot," according to a memo viewed by CNBC. "We have all the ingredients to win this race but we are going to have to turbocharge our efforts," he said in the memo.
Brin said in the memo that Google has to speed up the process of testing AI models, as the company needs "lots of ideas that we can test quickly."
"We need real wins that scale," Brin wrote.
In his memo, Brin also wrote that the company's methods have "a habit of minor tweaking and overfitting" products for evaluations and "sniping" the products at checkpoints. He said employees need to build "capable products" and to "trust our users" more.
"We can't keep building nanny products," Brin wrote. "Our products are overrun with filters and punts of various kinds."
A Google spokesperson told CNBC that the company has always been committed to advancing AI responsibly.
"We continue to do that through the safe development and deployment of our technology, and research contributions to the broader ecosystem," the spokesperson said.
The debate of product versus research is at the center of OpenAI's existence. The company was founded as a nonprofit research lab in 2015 and is now in the midst of a contentious effort to transform into a for-profit entity.
That's the direction co-founder and CEO Sam Altman has been pushing toward for years. On May 5, though, OpenAI bowed to pressure from civic leaders and former employees, announcing that its nonprofit would retain control of the company even as it restructures into a public benefit corporation.
Nisan Stiennon worked at OpenAI from 2018 to 2020 and was among a group of former employees urging California and Delaware not to approve OpenAI's restructuring effort. "OpenAI may one day build technology that could get us all killed," Stiennon wrote in a statement in April. "It is to OpenAI's credit that it's controlled by a nonprofit with a duty to humanity."
But even with the nonprofit maintaining control and majority ownership, OpenAI is speedily working to commercialize products as competition heats up in generative AI. And it may have rushed the rollout of its o1 reasoning model last year, according to some portions of its model card.
Results of the model's "preparedness evaluations," the tests OpenAI runs to assess an AI model's dangerous capabilities and other risks, were based on earlier versions of o1. They had not been run on the final version of the model, according to its model card, which is publicly available.
Johannes Heidecke, OpenAI's head of safety systems, told CNBC in an interview that the company ran its preparedness evaluations on near-final versions of the o1 model. Minor variations to the model that took place after those tests wouldn't have contributed to significant jumps in its intelligence or reasoning and thus wouldn't require additional evaluations, he said. Still, Heidecke acknowledged that OpenAI missed an opportunity to more clearly explain the difference.
OpenAI's newest reasoning model, o3, released in April, seems to hallucinate more than twice as often as o1, according to the model card. When an AI model hallucinates, it produces falsehoods or illogical information.
OpenAI has also been criticized for reportedly slashing safety testing times from months to days and for omitting the requirement to safety test fine-tuned models in its latest "Preparedness Framework."
Heidecke said OpenAI has decreased the time needed for safety testing because the company has improved its testing effectiveness and efficiency. A company spokesperson said OpenAI has allocated more AI infrastructure and personnel to its safety testing, and has increased resources for paying experts and growing its network of external testers.
In April, the company shipped GPT-4.1, one of its new models, without a safety report, as the model was not designated by OpenAI as a "frontier model," which is a term used by the tech industry to refer to a bleeding-edge, large-scale AI model.
But one of those small revisions caused a big wave in April. Within days of updating its GPT-4o model, OpenAI rolled back the changes after screenshots of overly flattering responses to ChatGPT users went viral online. OpenAI said in a blog post explaining its decision that those types of responses to user inquiries "raise safety concerns — including around issues like mental health, emotional over-reliance, or risky behavior."
OpenAI said in the blogpost that it opted to release the model even after some expert testers flagged that its behavior "'felt' slightly off."
"In the end, we decided to launch the model due to the positive signals from the users who tried out the model. Unfortunately, this was the wrong call," OpenAI wrote. "Looking back, the qualitative assessments were hinting at something important, and we should've paid closer attention. They were picking up on a blind spot in our other evals and metrics."
Metr, a company OpenAI partners with to test and evaluate its models for safety, said in a recent blog post that it was given less time to test the o3 and o4-mini models than predecessors.
"Limitations in this evaluation prevent us from making robust capability assessments," Metr wrote, adding that the tests it did were "conducted in a relatively short time."
Metr also wrote that it had insufficient access to data that would be important in determining the potential dangers of the two models.
The company said it wasn't able to access the OpenAI models' internal reasoning, which is "likely to contain important information for interpreting our results." However, Metr said, "OpenAI shared helpful information on some of their own evaluation results."
OpenAI's spokesperson said the company is piloting secure ways of sharing chains of thought for Metr's research as well as for other third-party organizations.
Steven Adler, a former safety researcher at OpenAI, told CNBC that safety testing a model before it's rolled out is no longer enough to safeguard against potential dangers.
"You need to be vigilant before and during training to reduce the chance of creating a very capable, misaligned model in the first place," Adler said.
He warned that companies such as OpenAI are backed into a corner when they create capable but misaligned models with goals that are different from the ones they intended to build.
"Unfortunately, we don't yet have strong scientific knowledge for fixing these models — just ways of papering over the behavior," Adler said.
WATCH: OpenAI closes $40 billion funding round, largest private tech deal on record
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Iowa's Grinnell College for years was in an enviable position. Bolstered by Warren Buffett's guidance decades ago, the tiny liberal arts school has grown its endowment to $2.7 billion, helping fund one of the most generous financial-aid programs in the country.
That success is now a problem.
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The plenary room of the Ritz Carlton Riyadh was packed to the brim on Tuesday as guests awaited the arrival of U.S. President Donald Trump and Saudi Crown Prince Mohammed bin Salman.
Attendees of the U.S.-Saudi Investment Forum included scores of the world's most powerful CEOs, among them Elon Musk, Nvidia's Jensen Huang and BlackRock's Larry Fink, to name a few.
The event's security corralled guests — billionaires and junior consultants alike — into the plenary to wait in suspense while the Saudi and American leaders held their meetings.
"We were locked in the plenary for three hours before they showed up," Tarik Solomon, head of the American-Saudi business chamber in Riyadh, told CNBC. "Nothing says diplomacy like strategic patience."
Guests described amusing scenes as Fortune 500 executives sat cross-legged on the floor because of a shortage of seats.
"They put the CEOs on the stage as well for the whole three hours, and they didn't have anywhere to sit. So they're like, sitting on the ground, literally, with their legs crossed, talking to each other, which was a funny scene," one attendee, who asked to remain anonymous due to professional restrictions on speaking to the press, told CNBC.
"The event was really unorganized," the guest said, but attested to the energy in the room as the president took the stage.
"It was amazing being in that room. No matter what you say about Trump, he is a star. He knows how to work a room."
Trump stood alone onstage while Lee Greenwood's patriotic ballad "God Bless the U.S.A." played on the surround sound speakers before launching into a roughly 50-minute long speech that covered U.S. relations with the region, but focused heavily on his domestic agenda and legacy.
"I feel like I just attended my first Trump rally," another attendee said, also speaking anonymously due to professional restrictions.
The American leader dedicated much of his speech to praising the Saudi kingdom, with which he has enjoyed warm relations for years, and where he made his first state visit in 2017 during his initial White House term.
"Riyadh is becoming not just a seat of government but a major business, cultural and high-tech capital of the entire world," Trump said.
"Mohammed, do you sleep at night? How do you sleep?" he said, addressing the 39-year-old crown prince, who was seated directly across from him in the audience. "Critics doubted that it was possible, what you've done, but over the past eight years, Saudi Arabia has proved the critics totally wrong."
The crowd applauded as Trump said: "He's your greatest representative, greatest representative. And if I didn't like him, I'd get out of here so fast. You know that, don't you? He knows me well. I do — I like him a lot. I like him too much."
Bin Salman sat beaming at the president, often placing his hand on his heart in a gesture of appreciation.
"That's why we give so much, you know? Too much," Trump said, smiling. "I like you too much."
Saudis on social media expressed pride over their de-facto leader's relationship with the U.S. president, and regional analysts noted the stark difference between this administration's relationship with the kingdom and that of the Biden administration, which was significantly cooler.
"Trump and MBS? It's a bromance for the ages," one summit attendee told CNBC, referring to the crown prince by his initials.
The event's main news was the announcement of $600 billion in investments by Saudi Arabia into the U.S., including a record $142 billion deal to purchase American weapons.
"Overall, the mood was very optimistic," Solomon of the American Chamber of Commerce Saudi Arabia said. "The right people were in the room, and the deals felt less performative this time. Probably because they confirmed $300B+ in real agreements, rather than stitching together flashy $1B headlines."
Correction: "God Bless the U.S.A." is a patriotic ballad by Lee Greenwood. An earlier version misstated the song's title.
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Social Security beneficiaries are at risk of receiving a smaller benefit if they've fallen behind on their student loans.
The Trump administration recently announced it would move to offset defaulted student loan borrowers' federal benefits, and warned that payments could be garnished as soon as June.
That involuntary collection activity could have serious consequences on those who rely on the benefits to pay most, if not all, of their bills, consumer advocates say.
More from Personal Finance:Wage garnishment for defaulted student loans to beginWhat loan forgiveness opportunities remain under TrumpIs college still worth it? It is for most, but not all
There are some 2.9 million people age 62 and older with federal student loans, as of the first quarter of 2025, according to Education Department data. That is a 71% increase from 2017, when there were 1.7 million such borrowers, according to the data.
More than 450,000 borrowers in that age group are in default on their federal student loans and likely to be receiving Social Security benefits, the Consumer Financial Protection Bureau found.
Here's what borrowers need to know.
Social Security recipients can typically see up to 15% of their monthly benefit reduced to pay back their defaulted student debt, but beneficiaries need to be left with at least $750 a month, experts said.
The offset cap is the same "regardless of the type of benefit," including retirement and disability payments, said higher education expert Mark Kantrowitz.
The 15% offset is calculated from your total benefit amount before any deductions, such as your Medicare premium, Kantrowitz said.
Student loan borrowers facing offsets of their federal benefits seem to be getting less notice under the Trump administration, Kantrowitz said.
While a 65-day heads-up used to be the norm, it seems the Education Department is now assuming borrowers who are in default were already notified about possible collection activity prior to the Covid-19 pandemic, he said.
"The failure of the U.S. Department of Education to provide the 65-day notice limits the ability of borrowers to challenge the Treasury offset of their Social Security benefit payments," Kantrowitz said.
Still, borrowers should get at least a 30-day warning, Kantrowitz said. The notice should be sent to your last known address, so borrowers should make sure their loan servicer has their most recent contact information.
The Education Department provided defaulted federal student borrowers with the required notice, a spokesperson told CNBC after collections efforts resumed May 5.
"The notice may be sent only once, and borrowers may have received this notice before Covid," the spokesperson said.
Once you receive a notice that your Social Security benefits will be offset, you should have the option to challenge the collection activity, Kantrowitz said. The notice is supposed to include information on how you can do so, he said.
You may be able to prevent the offset if you can prove a financial hardship or have a pending student loan discharge, Kantrowitz added.
"Borrowers who receive these notices should not panic," said Nancy Nierman, assistant director of the Education Debt Consumer Assistance Program. "They should reach out for help as soon as possible."
The best way to avoid the offset of your Social Security benefits is to get current on your loans, said Betsy Mayotte, president of The Institute of Student Loan Advisors, a nonprofit.
You can contact the government's Default Resolution Group and pursue several different avenues to get out of default, including enrolling in an income-driven repayment plan.
"If Social Security is their only income, their payment under those plans would likely be zero," Mayotte said.
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Monday - Friday, 10:00 - 11:00 SIN/HK | 0400 - 05:00 CET
This report is from this week's CNBC's The China Connection newsletter, which brings you insights and analysis on what's driving the world's second-largest economy. Each week, we'll explore the biggest business stories in China, give a lowdown on market moves and help you set up for the week ahead. Like what you see? You can subscribe here.
The world got a taste of an effective U.S.-China trade embargo, and after a breakthrough on Monday with lowered tariffs, there's no going back. China now has the "mutual respect" it has long craved from the U.S.
U.S. Treasury Secretary Scott Bessent told CNBC's Joe Kernen that "there is a sense of mutual respect" during the talks, a point that U.S. Trade Representative Jamieson Greer also emphasized in his remarks to the press on Monday.
That's in stark contrast to how the first high-level bilateral meeting under the Biden administration kicked off with an exchange of insults in Alaska, followed by a "balloon incident" that delayed then-U.S. Secretary of State Antony Blinken's first visit to China for months.
What's also rare is that on Monday, the U.S. and China released a joint statement — something both sides haven't done since November 2023 with the "Sunnylands" statement on climate cooperation.
Looking ahead, it will be critical to see whether joint statements will be issued after major meetings, or revert to separate readouts, a senior advisor to world governments and business leaders, who has regular dialogue with top officials from both countries, told CNBC. The source requested anonymity due to the sensitive nature of the conversations.
The source expects volatility is likely around tariffs — an important point of flexibility for Trump as a tool for managing relations with major powers. The source added that a possible resolution could involve large Chinese purchases from the U.S., investments in the U.S. that create jobs, while Beijing gets concessions core to its interests.
While the elevated tariffs didn't last long, the trauma is real. Businesses now know they need to mitigate tariff uncertainty.
"The post-WWII trade framework that once underpinned stable expectations is gone; even further tariff rollbacks won't restore it," Jianwei Xu, senior economist at Natixis, said in a LinkedIn post Monday.
Xu added that large businesses will continue supply chain diversification, but small businesses may stop production — as overall confidence fades in the U.S. dollar as the world's ultimate reserve currency.
In a better-than-expected outcome, the U.S. and China agreed Monday to cut back on most new tariffs on each other's goods for 90 days while the two sides negotiate economic and trade policy.
That's after China, the second-largest supplier of U.S. goods last year, was the only country across the 180 nations and territories hit by "reciprocal" U.S. tariffs to retaliate.
Hong Kong's Hang Seng Index has recovered to levels seen just before the early April escalation in trade tensions, while the S&P 500 clawed back into positive territory for the year.
"It might be just the beginning of the inevitable collision of the two largest economies," Ting Lu, chief China economist at Nomura, said in a note Monday, adding that "the U.S. is still on the offensive, but China might learn much better on how to dig itself in for the future attack."
Within half an hour of releasing the Chinese-language version of the joint U.S. trade agreement on Monday, China's Commerce Ministry announced that several ministries and provinces held a meeting that day for strengthening export controls on critical minerals, another area in which China dominates the supply chain.
The State Council, China's top executive body, on Monday also published a whitepaper on national security that began by citing the Opium War, which marked the start of a traumatic period known as the "century of humiliation" in China, seared into its national consciousness. The whitepaper had similar narratives, calling for self-reliance and playing up the country's role as a stabilizing force amid global uncertainty.
However, China's growing emphasis on national security tends to come at a cost for some foreign entities, according to business associations.
"A 90-day suspension, while welcome, still creates significant uncertainty for U.S. companies' business planning and costs, undermining their long-term global competitiveness," the U.S.-China Business Council said in a statement Monday, urging China to "end unfair trade practices and market-entry barriers."
But Beijing continued to make thinly veiled swipes at the U.S. on Tuesday at a conference with Latin American and Caribbean leaders on Tuesday.
Chinese President Xi Jinping said that "bullying and coercion only lead to isolation," without naming any country in particular, to an audience that included the presidents of Colombia, Brazil and Chile.
Even as China's exports to the U.S. plunged by more than 20% in April, trade data show that China ramped up its exports to Southeast Asia, the European Union and Latin America.
"Despite the temporary tariff‑war reprieve, China continues to signal that it is looking to diversify away from U.S. agricultural goods," Dennis Voznesenski, agricultural economist at CBA, said in a note Tuesday.
He cautioned that seasonality and weather in South America would impact China's ability to reduce its U.S. purchases.
But he pointed to reports that China, on May 9, signed a letter of intent with exporters in Argentina to buy about $900 million in soybeans, corn and vegetable oil, while China has resumed soybean imports from five Brazilian firms.
China's imports from Argentina grew by 6.4% last year to $7.03 billion, according to official data accessed through financial data provider Wind Information.
Established trade routes can't easily be unwound overnight, and Peking University professor Justin Yifu Lin told reporters last month he didn't expect full decoupling between the U.S. and China — largely because of U.S. reliance on Chinese goods.
U.S. products headed to China also saw tariff exemptions "being pretty liberally, leniently enforced," Jacob Cooke, co-founder and CEO of WPIC Marketing + Technologies, told CNBC on Tuesday. The company helps foreign brands — such as Vitamix and IS Clinical — sell online in China and other parts of Asia.
He said that, as was the case during the first Trump administration, most products being shipped to China ended up being exempted from tariffs, largely since the products had a large share of China-made components.
Looking ahead, he expects that tariffs are going to be cut, and that "the largest trading relationship in the world is going to continue."
But for many companies that once solely relied on China-based suppliers, the sudden surge in U.S. tariffs last month is just the latest reason to broaden out.
"Smarter importers have realized that long-term, they are most secure when they are diversified, and hence will continue looking for alternative sources," said Ash Monga, founder and CEO of Guangzhou-based Imex Sourcing Services, a supply chain management company. He launched a website last month called "Tariff Help" for small businesses to find ways to diversify from China-based suppliers.
— CNBC's Bernice Ooi contributed to this report
Treasury Sec. Bessent: Likely to meet with China again 'in next few weeks' on a bigger agreement
Treasury Secretary Scott Bessent joined CNBC's "Squawk Box" to discuss the U.S.-China trade agreement to suspend most tariffs on each other's goods, how the deal came about, what comes next for both countries, impact on the administration's goals to bring manufacturing back to the U.S., and more.
The most significant result of Geneva truce is 'paving a way' for U.S. and Chinese Presidents to talk: Former PBOC advisor
David Li from Tsinghua University said the trade truce announced by the U.S. and China suggests that Trump's tariff plans are "much for nothing" and global trade for Chinese businesses will evolve into 3 hubs going forward.
WeRide CEO on expanding partnership with Uber on robotaxi services in 15 cities globally in 5 years
Tony Han, Founder and CEO of WeRide talked about the growth strategy for the company and its safety records.
The U.S. and China are talking. Bessent and Chinese Finance Minister Lan Fo'an met in Washington, D.C., on the sidelines of an international meeting there late last month, the Financial Times reported, citing sources. After the two countries met in Switzerland over the weekend and reached a deal, investment banks have started revising up their China growth forecasts.
China's property sector nears stabilization. That's according to an S&P report Sunday that predicts primary home sales volume is set to moderate its decline to a 2% drop this year, versus a 17% plunge last year.
Nvidia still wants the Chinese market. The U.S. chipmaker plans to release a downgraded version of its most powerful H20 artificial intelligence chip for China in the next two months, after U.S. officials imposed export restrictions on the original model, Reuters reported Friday, citing sources.
Chinese and Hong Kong stocks climbed Wednesday as investors continue to assess the U.S.-China trade talks.
Mainland China's CSI 300 was up 1.15% while Hong Kong's Hang Seng Index — which includes major Chinese companies — rose 1.73% as of 2 p.m. local time.
The benchmark 10-year Chinese government bond yield is at 1.672%.
The offshore Chinese yuan weakened 0.22% against the greenback to 7.2114.
May 14: Tencent to report quarterly earnings after the Chinese market close
May 15: Alibaba to report quarterly earnings after the Chinese market close
May 19: China to report April retail sales, industrial production and investment data
May 20: Chinese battery giant CATL to list in Hong Kong; China's law to support the private sector takes effect
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A Ukrainian drone maker released footage on Tuesday showing what's believed to be the first time a grenade launcher was fired in combat from a first-person-view uncrewed aerial system.
The Wild Hornets firm published the clips on its Telegram channel, crediting the "Bulava" drone unit of the 3rd Mechanized Battalion in the Bohdan Khmelnytsky Separate Presidential Brigade.
The footage shows two instances of the mounted grenade launcher firing over open terrain.
In the first clip, a soldier can be seen caught in the resulting explosion and being knocked to the ground. Their fate was unclear based on the footage, but the Wild Hornets said the target was a Russian soldier who died. The target in the second clip was not clearly visible.
The drone maker said both clips featured one of its designs, the "Queen of Hornets" drone, as the platform for the grenade launcher. With a 15- to 17-inch frame, the quadcopter is among the largest FPV drones commercially produced for combat in Ukraine, and it's typically used as a bomber.
Wild Hornets did not say when the footage was shot, nor did it specify which grenade launcher was used. But during September testing with the "Bulava" unit, the company said the "Queen of Hornets" drone was fitted with the Bulspike AP, a Bulgarian anti-personnel grenade launcher. The platform is meant to be reusable.
The Bulspike AP fires a 2-kilogram fragmentation grenade at an effective range of about 100 meters, or 328 feet.
A drone mounted with such a weapon could thus give Ukrainian operators far more options to strike, since FPV combat drones are typically either used to fly directly into a target as a munition or to drop explosives from above.
The clips released on Tuesday demonstrated the launcher's range capability, showing the mounted weapon firing at enemy targets positioned well ahead of the drone itself.
"From now on, an ordinary rocket launcher can work at a distance of 5+ km. This opens up new opportunities for the military," Wild Hornets wrote at the time of testing in September.
💥 Successful test of the world's first rocket launcher droneThe Bulava drone unit of the Separate Presidential Brigade named after Bohdan Khmelnytsky installed a rocket launcher on the Queen Hornet FPV drone and conducted a successful test.From now on, an ordinary rocket… pic.twitter.com/AAkaHgcS7z
Still, it's unclear whether Ukraine can or will produce and deploy these drone-mounted launchers at scale. Dozens of Ukrainian companies have developed and tested a massive variety of drone weapons, such as mounted shotguns and Kalashnikov rifles, but troops are still widely relying on loitering munitions and bombers as their bread and butter.
Wild Hornets, in particular, has been recognized for producing some of the war's most exotic drone weapons, including FPV drones that spew thermite from above or interceptors designed to fly faster than 100 mph.
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According to Bernstein analysts, Ethereum's recent surge is attributed to the increasing adoption of digital assets for purposes beyond store of value, as well as the rising interest from institutions and retail investors in blockchain and stablecoin payments. The note also highlights the potential for brokerages like Robinhood to offer tokenized equities on Ethereum's blockchain.
According to Bernstein analysts, Ethereum's recent surge is attributed to the increasing adoption of digital assets for purposes beyond store of value, as well as the rising interest from institutions and retail investors in blockchain and stablecoin payments. The note also highlights the potential for brokerages like Robinhood to offer tokenized equities on Ethereum's blockchain.
According to Bernstein analysts, Ethereum's recent surge is attributed to the increasing adoption of digital assets for... Read Summary
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Metaplanet posts record operating profit, adds over 5,000 BTC to its Bitcoin treasury, and increases its shareholders.
Metaplanet Inc. widely recognized as Japan's leading Bitcoin treasury company, has reported its strongest quarter to date for Q1 FY2025, marked by record operating profit and a significant expansion of its balance sheet.
Metaplanet Q1 Financials released: – Revenue: ¥877M (+8% QoQ) (88% from BTC Income Generation business)– Operating Profit: ¥593M (a new company record)– Net Assets: ¥50.4B (+197% QoQ)Full 48 Page Presentation with outlook on mNAV & much more: https://t.co/W5UP01Srtf pic.twitter.com/a8SMEKNODh
Revenue reached ¥877 million, an 8% increase quarter-over-quarter (QoQ), while operating profit hit a record ¥593 million, up 11% QoQ. This marks the company's highest operating profit ever. Total assets surged to ¥55.0 billion, up 81%, and net assets soared to ¥50.4 billion, a 197% increase compared to the previous quarter.
Despite a ¥7.4 billion valuation loss due to the lower Bitcoin price at the end of March, Metaplanet has rebounded strongly. As of May 12, the company holds ¥13.5 billion in unrealized gains thanks to a recovery in Bitcoin's market value. The temporary dip impacted net income, which came in at ¥5.0 billion for the quarter, but core operations remained strong.
The company's Bitcoin holdings have skyrocketed to 6,796 BTC — a 3.9x increase year-to-date. In 2025 alone, Metaplanet added over 5,000 BTC to its treasury, reinforcing its commitment to the Bitcoin Treasury Standard. Since adopting this strategy, the company has seen its BTC net asset value increase 103.1x and its market cap grow by 138.1x.
“Guided by this conviction, we pivoted in 2024 to become Japan's first dedicated Bitcoin Treasury Company,” said Metaplanet's management in their Q1 2025 Earnings Presentation. “In Q1 2025, we launched—and have already executed 87% of—a two-year, ¥116 billion “moving-strike” warrant program: the largest and lowest-cost equity financing of its kind ever placed in Japan.”
Metaplanet also reported a substantial rise in shareholders, growing from 10,854 in December 2023 to 63,654 by March 2025. The growth trend saw major jumps throughout the year, with 29,796 shareholders in June 2024,37,537 in September, 41,553 in October, and 47,292 in December 2024, before surging to its current peak.
Member of Metaplanet's Board of Directors Tyler Evans posted on X, “Congrats $MTPLF, Metaplanet, Simon Gerovich, Yoshimi Abe, and Dylan LeClair on a record quarter! 3.9x growth in BTC YTD is incredible.”
Congrats $MTPLF @Metaplanet_JP @gerovich @Yoshimi3350Abe @DylanLeClair_ on a record quarter! 3.9x growth in BTC YTD is incredible. The most important takeaways from the earnings call 👇 https://t.co/H4GKaxZYXK
“Our results speak for themselves: we don't set targets to feel safe—we set them to exceed them, quarter after quarter,” said Metaplanet's management. “The global feedback loop between capital markets and Bitcoin is just beginning. Metaplanet intends to be its premier conduit.”
For those interested in reading the full Metaplanet earnings report, you can do so here.
Disclaimer: Tyler Evans is a co-founder and Chief Investment Officer of UTXO, which is also owned and operated by BTC INC, Bitcoin Magazine's parent company.
Established in 2012, Bitcoin Magazine is the oldest and most established source of trustworthy news, information and thought leadership on Bitcoin.
© 2025 BTC INC
Highlights
The Federal Reserve Bank of New York's Project Pine demonstrated that central banks can effectively implement monetary policies using blockchain-based smart contracts in tokenized asset environments.
It comes against a backdrop where tokenization — the digital representation of money and securities — has emerged as an innovation reshaping global financial markets, with major players launching tokenized money market products.
Despite demonstrating feasibility, the Project Pine authors emphasized the need for further research, especially in multi-currency applications and interoperability between blockchain-based systems and traditional financial infrastructures.
In many ways, it's no longer a question of when blockchain technology will go mainstream across financial services. It's becoming a question of when regulations will catch up for its use.
But when, or even if, cryptocurrency policy frameworks are brought to life, many observers from the traditional financial space are asking: what happens next — and how do any resultant fiscal policies get implemented across on-chain and tokenized asset environments?
That core question of policy implementation in a tokenized financial setting is one that the Federal Reserve Bank of New York sought to answer with its Project Pine initiative, the results of which were released on Wednesday (May 14).
After all, traditional monetary policy tools may struggle to operate efficiently in tokenized markets without adopting new technology. To study this, Project Pine built a flexible toolkit prototype for central banks using smart contracts, which are blockchain-based computer programs that execute financial transactions automatically once predefined conditions are met.
The project explored the ways monetary policy could be implemented programmatically in a system with tokenized money and securities. It found, by developing a prototype of a central bank toolkit with smart contracts and testing it, that it was feasible.
“Project Pine is a first step in showing that monetary policy implementation is possible in a tokenized world,” the whitepaper's authors wrote.
The findings come against a backdrop where major traditional players have already announced plans to register money market funds on blockchains, and the U.S. Securities and Exchange Commission (SEC) has said Monday (May 12) that it is eying regulatory changes to accommodate on-chain securities and other crypto assets.
Read also: What Treasury Teams Can Learn From Central Banks' Tokenization Projects
The mainstream integration of tokenized financial infrastructures could mark a profound shift in how assets are traded, managed and regulated.
Tokenization transforms assets including real estate, commodities, stocks, bonds and even intellectual property into blockchain-based digital tokens. This can enable things such as fractional ownership, as well as enabling greater liquidity, transparency and accessibility compared to traditional financial instruments.
The New York Fed's primary ambition with Project Pine was straightforward yet critical: to demonstrate how central banks could practically and effectively use smart contracts to manage monetary policy within tokenized financial infrastructures.
Tokenization effectively bridges traditional finance and cryptocurrency markets, which can create new hybrid opportunities. This convergence is already manifesting in real-world examples.
“Banks are in the state where they are thinking about blockchains as public infrastructure that they need to rely on,” Chainalysis Co-founder and CEO Jonathan Levin told PYMNTS. “Back in 2014 … cryptocurrency only meant blockchains that had native cryptocurrency tokens. Today, people are putting all types of financial instruments on the blockchain.”
As recently as Wednesday (May 14), the investment firm VanEck announced the VanEck Treasury Fund, Ltd. (VBILL), its first tokenized fund.
“By bringing U.S. Treasuries on-chain, we are providing investors with a secure, transparent, and liquid tool for cash management, further integrating digital assets into mainstream financial markets,” VanEck Director of Digital Assets Product Kyle DaCruz said in the announcement.
Read more: Crypto's Institutional Future Could Hinge on Solving the Risk Puzzle
Project Pine's prototype toolkit was designed with input from advisers from seven central banks, including the Federal Reserve Board of Governors, the European Central Bank and the Bank of England. The resulting system, built on a permissioned blockchain platform using Hyperledger Besu and Ethereum-compatible smart contracts, specifically sought to address central banks' unique operational needs.
The project prototyped blockchain-based tools for paying interest on reserves, executing asset swaps, creating or absorbing reserves temporarily through collateralized loans and outright purchasing or selling assets. Each of these tools utilized ERC-20 tokens — widely accepted digital standards — to represent money and securities. This toolkit allows the central bank to swiftly alter monetary policy conditions, such as interest rates or collateral requirements, directly through smart contracts.
The system's visualization tools were able to help allow central bank advisers to clearly track and analyze interactions within market scenarios. For instance, during a simulated market crisis, the toolkit demonstrated rapid response capabilities by automatically adjusting collateral haircuts, managing collateral substitutions and deploying new emergency facilities, all in real time.
Still, while Project Pine has demonstrated the feasibility and benefits of central bank smart contracts, it is still an early exploration. The paper's authors stressed that more research is needed, particularly around multi-currency toolkits and interoperability between tokenized and traditional financial systems.
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The new chair of the U.S. Securities and Exchange Commission (SEC) says he's prioritizing developing new regulations for crypto asset issuance, custody and trading.
Paul Atkins, who was sworn in as SEC Chair in April, spoke at the Commission's Crypto Task Force Roundtable on Tokenization this week.
The new chair says the SEC's “legacy rules and regulations” don't contemplate the novel use cases of blockchain technology.
“In order for the United States to be the ‘crypto capital of the planet' as envisioned by President Trump, the Commission must keep pace with innovation and consider whether regulatory changes are needed to accommodate on-chain securities and other crypto assets. Rules and regulations designed for off-chain securities may be incompatible with or unnecessary for on-chain assets and stifle the growth of blockchain technology.
A key priority of my Chairmanship will be to develop a rational regulatory framework for crypto asset markets that establishes clear rules of the road for the issuance, custody, and trading of crypto assets while continuing to discourage bad actors from violating the law.”
In terms of issuance, Atkins says he will direct SEC officials to draft “clear and sensible guidelines” for distributions of crypto assets that are securities or subject to an investment contract.
“I have asked the Commission staff to consider whether additional guidance, registration exemptions, and safe harbors are needed to create pathways for crypto asset issuances within the United States. I believe that the Commission has broad discretion under the securities acts to accommodate the crypto industry, and I intend to get it done.”
He also wants to provide “greater optionality” in terms of how to custody crypto.
“It is important to provide clarity on the types of custodians that qualify as a ‘qualified custodian' under the Advisers Act and Investment Company Act, as well as reasonable exceptions from the qualified custody requirements to accommodate certain common practices within crypto asset markets. Many advisers and funds have access to self-custodial solutions that incorporate more advanced technology to safeguard crypto assets as compared to some of the custodians in the market. Consequently, the custody rules may need to be updated to allow advisers and funds to engage in self-custody under certain circumstances.”
Additionally, the new SEC chair says he supports broker-dealers that want to offer securities and non-securities trading and other financial services all in the same app.
“Nothing in the federal securities laws prohibits registered broker-dealers with an alternative trading system from facilitating trading in non-securities, including via ‘pairs trading' between securities and non-securities. I have asked the staff to help us devise ways to modernize the ATS (alternative trading system) regulatory regime to better accommodate crypto assets.”
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JPMorgan Settles First Tokenized Treasury Transaction on Public Blockchain, Using Chainlink, Ondo Finance
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JPMorgan Chase has completed its first transaction on a public blockchain—a sign of the financial powerhouse's deepening involvement with the Web3 world.
The global bank on Wednesday settled a transaction involving tokenized U.S. Treasuries on Ondo Finance, using Chainlink to connect between private and public networks, according to a joint statement from the companies. The experiment marks the latest development in JPMorgan's decentralized finance project called Kinexys—a platform that aims to bridge the gap between traditional finance and DeFi.
"The debut transaction…isn't just a major milestone, it's a statement about the future of finance,” Ondo Finance CEO Nathan Allman said Thursday in a statement shared with Decrypt.
JPMorgan and Chainlink didn't immediately respond to Decrypt's request for comment.
JPMorgan's latest push into Web3 comes as real-world-asset tokenization gains traction, particularly among institutional investors.
The total-value locked of RWAs on blockchains topped $12 billion as of the time of writing, with assets spread across more than 80 decentralized finance platforms, DeFi Llama data shows. Meanwhile, BlackRock's USD Institutional Digital Liquidity Fund holds nearly $3 billion in assets, up roughly 19% in the past month as institutional investors pour funds into tokenized treasuries, according to data provider rwa.xyz.
JPMorgan has experimented with distributed-ledger technology since at least 2019, when it debuteda private blockchain called JPM Coin. Later renamed Kinexys, it has processed approximately $2 billion in daily transaction volumes and amassed $1.5 trillion in underlying assets of derivatives contracts, JPMorgan said in a statement last year.
The decentralized platform is built on distributed-ledger technology, with the aim of facilitating near real-time, 24/7 cross-border transactions while paring down transaction costs for builders and traders, among other functions.
JPMorgan is one of several financial institutions that is increasing its involvement in Web3 as of late. Earlier this month, Citi unveiled a patlrtnership with SDX to tokenize private companies' shares for wealthy investors.
Edited by James Rubin
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Technology evolves every day, while student curricula don't. For many, the future seems uncertain. Important political voices are shaping the general opinion on crypto and blockchain. Statements about potentially including Bitcoin and other cryptocurrencies in the national reserve contribute to drastic market fluctuations and leave the industry uncertain.
The future seems uncertain in many ways: what jobs will there be in ten years' time? What about financial security? Universities and education systems are lagging behind in educating students about financial opportunities. Many students are already calling for better educational programs on campus. Until then, students need to educate themselves.
Everyday life is getting more entangled with technology: daily use of smartphones, computers, and payment apps is a given. Entertainment has also shifted more towards technology-based fun. Studies show that gambling is becoming a more popular form of entertainment in the US. According to Statista, sports betting in particular appeals to people aged 25 to 34. While technology advances, the potential risk of cyberattacks is also growing, leaving many worried about handling money online.
This is where blockchain technology becomes relevant: Since blockchain operates with a decentralized system, meaning that there is not a single person or entity overseeing transactions, it promises better security measures and builds trust between companies and customers. Students who enjoy entertainment like online gambling and sports betting are increasingly interested in payment options based on blockchain. When evaluating platforms that support cryptocurrencies, BetOnline and Bovada often come up in comparison. While preferences are subjective, a detailed breakdown of how BetOnline measures up to Bovada in terms of payments, bonuses, and user experience can help make an informed decision on which features best fit students' needs.
Considering the rising popularity of technology-based entertainment and the fact that transactions today are almost exclusively conducted online, many agree that crypto knowledge should be common sense. Furthermore, the traditional stock and fund market is changing and expanding to include digital assets.
To be able to deal with smart investments in the future, students need to start being educated early. However, most students are occupied with tasks and assignments, which makes it hard to make time to study another highly complex topic. To really prepare students for their future outside of campus, many argue that crypto and financial education should be part of the curriculum.
In the fourth quarter of 2024, the cryptocurrency market hit its highest level. Contributing to this rise were the elections in the US and the government's opinion on crypto. In January 2025, Bitcoin experienced major fluctuations, which also led back to these events. Considering the rising value of cryptocurrencies, they can be a smart alternative to traditional investment and payment methods.
Because blockchain isn't regulated by any government or bank, it offers better security. Blockchain creates a record of every transaction with a time stamp that can't be changed, which rules out unauthorized access and the possibility of fraud. Additionally, the data is stored across multiple networks, which makes it almost impossible to hack. Blockchain technology also limits privacy concerns since user data is stored anonymously. Depositing money to online platforms and receiving money doesn't require sharing any sensitive data.
Compared to conventional investment methods like stocks and funds, investing in cryptocurrencies can be more lucrative. While keeping the potential risks in mind, like drastic fluctuations, investing in big names like Bitcoin or Ethereum can deliver higher growth in a shorter timeframe. Of course, a stock fund, too, can be lucrative, but it will take several years to grow. To make informed decisions, education on these topics is crucial.
Moreover, storing money in crypto is more financially viable than keeping it in a bank account. While a traditional bank transfer can take up to days to deliver money, using crypto is much faster. Additionally, banks often charge high transaction fees while crypto payment doesn't.
According to TripleA, the number of people owning crypto is growing worldwide. They estimated the global market penetration to reach 6.8% with more than 560 million people owning crypto by 2024. The rising number suggests that the crypto market will have a major impact on developing industries such as tech, finance, and entertainment. Of course, this fast-developing industry poses challenges for many sectors. This is why education on the topic is more relevant than ever.
This post is provided by a third party who may receive compensation from the products or services they mention.
Ethereum is trading firmly above the $2,600 mark after a surge in buying pressure over the past several days, marking a strong shift in momentum across the broader market. After months of choppy action and bearish sentiment, bulls are clearly back in control. ETH has reclaimed several key levels with conviction, signaling a potential continuation toward higher targets.
Price action now looks structurally bullish, with Ethereum pushing through resistance zones that previously capped upside for weeks. This rally has reignited investor confidence and brought renewed attention to Ethereum's medium-term outlook, especially as altcoins start to show strength alongside Bitcoin's recent consolidation.
According to fresh data from Glassnode, the next major resistance area to watch is at $3,100, where Ethereum is likely to encounter heavier sell pressure. This level, derived from pricing bands, now defines Ethereum's current trading range and will likely dictate price direction in the coming sessions. With volatility returning and sentiment improving, Ethereum appears poised for a critical breakout or a decisive retest of support, depending on how bulls handle the next leg.
Ethereum Nears Key Resistance As Altseason Expectations Grow
Ethereum has rallied over 98% since its April 9th low, marking one of its most powerful recoveries in recent years. This explosive move has not only flipped sentiment from bearish to bullish, but also reignited speculation around a broader altseason — a period in which altcoins significantly outperform Bitcoin.
After months of heavy selling pressure that began in late December, Ethereum is now showing sustained strength for the first time. The price has reclaimed critical levels, and momentum continues to build as traders and investors rotate capital back into ETH and other large-cap altcoins. Market participants are watching closely to see if Ethereum can maintain this pace and confirm a longer-term trend reversal.
Top analyst Ali Martinez shared Ethereum's MVRV Extreme Deviation Pricing Bands, offering a clear technical framework for what's next. According to the data, the next key resistance level is at $3,100 — a region that could act as a short-term ceiling if buying pressure fades. On the downside, the major support zone sits at $2,233, a critical level to hold in the event of a pullback.
As Ethereum continues to climb, these levels will become increasingly important. A clean breakout above $3,100 could open the door to a broader rally across altcoins, while a rejection or correction would likely test the market's true conviction. For now, ETH remains in a bullish structure, supported by growing volume, on-chain signals, and renewed investor enthusiasm. The coming days will be crucial in determining whether Ethereum leads the charge into a full-fledged altseason.
ETH Price Action: Testing Resistance After Massive Rally
Ethereum (ETH) is currently trading around $2,604, consolidating after a sharp surge that lifted it from under $1,400 to a high of $2,725 in just two weeks. The daily chart shows that ETH is now approaching the 200-day simple moving average (SMA) at $2,702.60, which is acting as a key resistance level. This zone also coincides with recent local highs from early February, making it a critical area to break for further upside continuation.
The recent rally brought strong volume and bullish momentum, with ETH closing multiple daily candles above the 200-day exponential moving average (EMA) at $2,435.66. This is a positive sign for trend reversal after months of sustained bearish pressure. However, today's pullback signals that bulls are losing some steam as the price tests this crucial resistance.
If ETH can consolidate above the $2,500–$2,600 range and break through the 200-day SMA with convincing volume, the next upside target lies near the $3,100 level, as noted in recent technical studies. On the downside, maintaining support above $2,435–$2,450 is essential to avoid a deeper correction. The coming days will reveal whether Ethereum can turn this consolidation into a true breakout or if further cooling is needed before the next leg up.
Featured image from Dall-E, chart from TradingView
Select market data provided by ICE Data services. Select reference data provided by FactSet. Copyright © 2025 FactSet Research Systems Inc.© 2025 TradingView, Inc.
This is a daily technical analysis by CoinDesk analyst and Chartered Market Technician Omkar Godbole.
A momentum indicator, with a strong track record of forecasting major bitcoin (BTC) price moves, has flipped bullish, reinforcing analysts' recent predictions of a rally to $150K–$200K.
The technical analysis indicator is called the Moving Average Convergence Divergence (MACD) histogram, which represents the difference between the MACD line and its signal line. The MACD line is calculated by subtracting the 26-period (days or weeks) exponential moving average (EMA) from the 12-period EMA of an asset's price. The signal line is a 9-period EMA of the MACD line itself.
A positive shift in the MACD histogram is interpreted as a transition from bearish to bullish momentum and is widely considered a buy signal by traders.
BTC's weekly chart MACD has crossed above zero, indicating a renewed bullish momentum.
The latest bullish signal follows bitcoin's bounce from the 50-week simple moving average (SMA), replicating patterns observed in mid-2024 and early 2023. On both occasions, BTC subsequently experienced strong rallies.
Note how the MACD flipped positive in the second half of October, warning of a big move higher. BTC broke above $70K in early November and eventually reached record highs in December.
Over the past five years, the MACD has crossed into positive territory five times, with only one false signal in March 2022, which trapped bulls (marked by circle) on the wrong side of the market.
The latest signal is consistent with the bullish macro picture and analysts' calls for a rally to higher levels. Early this week, Standard Chartered said that institutional adoption and investment lows could lift bitcoin as high as $200K.
In a report shared with CoinDesk on Tuesday, analysts at Bitfinex said BTC is evolving into a global macro reserve asset and could rise to $150K-$180K in 2025-26.
Omkar Godbole is a Co-Managing Editor on CoinDesk's Markets team based in Mumbai, holds a masters degree in Finance and a Chartered Market Technician (CMT) member. Omkar previously worked at FXStreet, writing research on currency markets and as fundamental analyst at currency and commodities desk at Mumbai-based brokerage houses. Omkar holds small amounts of bitcoin, ether, BitTorrent, tron and dot.
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JPMorgan (JPM) took its first step onto a public blockchain network through its Kinexys Digital Payments platform, settling a tokenized U.S. Treasury transaction on Ondo Chain's testnet.
The pilot, detailed in a press release shared with CoinDesk, marks the debut of a Delivery versus Payment (DvP) transaction on the testnet, a new layer-1 blockchain designed to support institutional-grade real-world assets.
Kinexys, which the release says processes an average of over $2 billion in daily transaction volume, handled the payment leg, while Ondo Finance's tokenized short-term Treasury fund (OUSG) formed the asset leg. Chainlink Runtime Environment — a system for coordinating cross-chain workflows —secured the settlement across the two networks.
This is the first time Kinexys, the Wall Street bank's permissioned network, has executed a transaction on a public blockchain. The move signals a shift as the bank explores ways to extend its institutional payments infrastructure into the growing market for real-world asset tokenization.
“ By securely and thoughtfully connecting our institutional payments solution with both external public and private blockchain infrastructures seamlessly, we can offer our clients and the broader financial ecosystem a wider range of benefits and scalable solutions for settling transactions,” Nelli Zaltsman, head of settlement solutions at Kinexys, said in the statement.
Traditional finance often struggles with DvP transactions, which require payments to be made before or at the same time as delivery of securities, due to fragmented systems and manual steps that delay settlement, the release notes.
It points to data suggesting payment and settlement failures have cost market participants over $900 billion in the past 10 years. Blockchain technology, it says, can be leveraged to conduct simultaneous cross-chain transactions.
JPMorgan has been expanding its blockchain-based payments network, having recently added support for British-pound denominated accounts.
Francisco is a reporter for CoinDesk with a passion for cryptocurrencies and personal finance. Before joining CoinDesk he worked at major financial and crypto publications. He owns bitcoin, ether, solana, and PAXG above CoinDesk's $1,000 disclosure threshold.
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Ethereum's crypto market dominance has reached its most overheated levels since May 2021, which may lead to a sharp pullback in ETH prices.
Key takeaways:
Ethereum's market dominance has hit overbought RSI levels not seen since May 2021, historically followed by major pullbacks.
ETH/USD is showing a bearish divergence on the four-hour chart, hinting at a potential 10–15% price correction.
Despite the near-term risks, some analysts view a pullback as a “buy-the-dip” setup before a possible move toward $3,500–$3,800.
Ether (ETH) has surged over 50% month-to-date in May, vastly outperforming the broader crypto market's 15.25% gain. The rally has pushed Ethereum's market dominance (ETH.D) toward the critical 10% threshold for the first time since March.
But the rising dominance accompanies signs of overheating, indicating that Ethereum bulls should not celebrate the rally just yet.
The strong recovery in Ethereum's crypto market share has pushed its daily relative strength index (RSI) to its most overbought zone since May 2021, raising red flags for traders betting on further upside, at least in the short term.
Historically, such extreme RSI levels on ETH.D have marked the beginning of major pullbacks. One notable instance occurred in early July 2024, when ETH dominance peaked near similar RSI levels.
Over the following 315 days, ETH.D dropped by more than 17.5%. The current RSI spike, again above 80, mimics a similar setup, suggesting that Ethereum could be nearing a local top in its market share.
Adding to the bearish outlook, ETH.D remains below its 200-day exponential moving average (200-day EMA; the blue wave). This resistance level has repeatedly capped Ethereum's dominance during previous recovery attempts.
Previous overbought pullbacks have initially pushed Ethereum's market share toward its 50-day EMA (the red wave).
The ETH.D metric, therefore, risks declining toward its current 50-day EMA support at around 8.24% by June, suggesting potential capital rotation out of Ethereum markets to other coins in the coming weeks.
On the four-hour ETH/USD chart, a classic bearish divergence is emerging, where Ethereum's price continues to print higher highs, but momentum indicators trend lower.
Crypto trader AlphaBTC noted that ETH is showing “three clear drives of divergence,” a setup often preceding trend exhaustion. He added that key Fibonacci levels align with potential support zones, suggesting a pullback could be imminent.
With ETH hovering near the $2,740 Fibonacci extension, profit-taking pressure may intensify, opening the door for a short-term correction toward lower Fib levels at around $2,330 or even $2,190, down 10%-15% from the current prices.
Independent market analyst Michaël van de Poppe suggests ETH's decline in the coming weeks could serve as a “buy-the-dip opportunity,” indicating that the cryptocurrency would eventually climb over $3,500.
Related: Altcoins' roaring returns and falling USDT stablecoin dominance suggest ‘altseason' is here
Veteran trader Peter Brandt further predicts a “moon shot” rally to over $3,800.
This article does not contain investment advice or recommendations. Every investment and trading move involves risk, and readers should conduct their own research when making a decision.
Strategy, the largest corporate holder of Bitcoin, may one day rise to become the top publicly traded company in the world, according to a bold forecast by one of its own analysts.
Jeff Walton, an analyst at Strategy, shared this view in , a new Financial Times documentary exploring the firm's aggressive crypto strategy.
Walton believes the company's unprecedented exposure to Bitcoin, which recently crossed $104,000, gives it a unique edge.
“Strategy holds more of the best asset and most pristine collateral on the planet than any other company, by multiples,” he said.Strategy Owns Over 560k BTC
As of now, Strategy owns approximately 568,840 BTC, valued around $59 billion.
A major factor behind Walton's confidence is the firm's fundraising capability.
He highlighted that Strategy raised $12 billion in just 50 days in late 2024, noting how rare that is in traditional finance.
“It's incredibly hard to raise $100 million in capital, and they just did that 120 times in 50 days. And all of it went into Bitcoin.”
The documentary also features Strategy executive chairman Michael Saylor outlining his long-term vision for the company.
Saylor sees a path for Strategy to evolve into a multi-trillion-dollar business. “We can grow from a $100 billion enterprise to a $1 trillion enterprise to a $10 trillion enterprise,” he said.
Saylor's personal forecast for Bitcoin is equally ambitious. He predicts Bitcoin could hit $1 million within the next decade and potentially reach $13 million per coin by 2045.
Currently, Strategy is the 151st largest public company globally, with a market capitalization of $117 billion, according to CompaniesMarketCap.
To fulfill Walton's prediction, the firm would need to overtake Microsoft, which currently leads the public markets with a valuation north of $3.3 trillion.
Notably, the Virginia-based company recently announced it would double its capital-raising efforts to $84 billion in order to acquire more Bitcoin.
This includes plans to sell an additional $21 billion in common stock, following the full utilization of a prior program approved in October.
In addition to equity sales, Strategy has also expanded its debt issuance target from $21 billion to $42 billion, with $14.6 billion still available under the current authorization.Public Companies Ramp Up Bitcoin Exposure
Public companies continue to increase their exposure to Bitcoin.
On Monday, Metaplanet also expanded its Bitcoin treasury, acquiring an additional 1,241 BTC for approximately 18.4 billion yen ($126 million).
The latest purchase brings the company's total Bitcoin holdings to 6,796 BTC, currently valued at over $706 million.
More recently, microcap firm GD Culture Group Limited announced plans to raise up to $300 million through a stock offering to fund the purchase of Bitcoin and Trump Coin ($TRUMP), despite facing a potential delisting from the Nasdaq over financial shortcomings.
This trend reflects a broader institutional interest in Bitcoin.
During the first quarter of the year, publicly listed firms collectively grew their Bitcoin holdings by 16.1%, indicating continued confidence in the asset despite persistent market volatility.
Select market data provided by ICE Data services. Select reference data provided by FactSet. Copyright © 2025 FactSet Research Systems Inc.© 2025 TradingView, Inc.
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Ethereum leads the broader crypto market rally with a 9% gain, reaching $2,700, while other altcoins like XRP, Solana, and Dogecoin show 4-10% increases.
Altcoins are showing major strength once again in today's broader crypto market rally as Ethereum
ETH
$1 845
24h volatility:
2.6%
Market cap:
$222.72 B
Vol. 24h:
$14.22 B
leads with over 9% gains, moving all the way to $2,700. Other altcoins like XRP
XRP
$2.22
24h volatility:
0.8%
Market cap:
$129.99 B
Vol. 24h:
$2.17 B
, Solana
SOL
$150.7
24h volatility:
2.6%
Market cap:
$78.04 B
Vol. 24h:
$3.80 B
, Dogecoin
DOGE
$0.18
24h volatility:
5.1%
Market cap:
$27.07 B
Vol. 24h:
$1.05 B
are also showing strength with 4-10% gains as Bitcoin
BTC
$96 611
24h volatility:
2.1%
Market cap:
$1.92 T
Vol. 24h:
$29.09 B
dominance nosedives. Market analysts have already started predicting the start of a full-blown altcoin season.
Cryptocurrency enthusiasts are abuzz as a key market signal has reappeared, sparking hopes of an incoming altseason. A “golden cross” has been confirmed for altcoins, suggesting the beginning of a major upward trend.
The last time this pattern emerged during the 2021 bull run, altcoins surged by an astonishing 28,000% with investors minting heavy returns. Now, in 2025, the same setup has materialized, fueling speculation of a repeat performance.
Altseason incoming. golden cross hit.
Last time this happened in 2021, alts went +28,000%
2025 just did the same.if you fumble this run, you deserve to stay broke.
Don't fade the rotation.#crypto #altcoins #bullrun pic.twitter.com/ZZp7z2nrcT
— Bitcoin Duniya (@bitcoin_duniya) May 13, 2025
On the other hand, Bitcoin seems to have entered a strong consolidation period as BTC price continues to flirt around $103,500 levels.
A pretty normal consolidation on #Bitcoin before the breakout above the all-time high.
In the meantime; #Altcoins are significantly breaking out and continuing their momentum.
The signs of a bull market. pic.twitter.com/GCPuPsGkjg
— Michaël van de Poppe (@CryptoMichNL) May 14, 2025
Ethereum price is up by another 9% today, trading at $2,690 levels, while extending its weekly gains to more than 45%. The recent ETH-BTC pair upside screams for a major rally moving ahead. Market analysts believe that once ETH price claims $3,000, it will set the stage for the next leg of rally to $4,000 and beyond.
On the other hand, Ripple's XRP is up 3.5% to $2.58 resistance levels, with its weekly gains standing above 20%. Crypto analyst Ali Martinez reports that XRP faces no significant resistance clusters ahead, suggesting the potential for further upward momentum.
On-chain data indicates that the key support level to monitor is at $2.38, which could serve as a strong foundation for XRP's price stability.
On-chain data shows $XRP has no major resistance clusters ahead, while the key support zone to watch sits at $2.38. pic.twitter.com/vvXjsSUYG1
— Ali (@ali_charts) May 13, 2025
Similarly, Dogecoin (DOGE) has bounced back by 6% to $0.238, taking its weekly gains to more than 37.5%.
Bitcoin dominance ($BTC.D) recently saw a sharp rejection following a rally in ETH/BTC, creating a mixed outlook for the market. If altcoin/BTC pairs show resilience, Bitcoin dominance could test range lows near 60%, presenting opportunities for altcoins to capitalize on the momentum.
$BTC.D With a sharp rejection after the recent $ETH/BTC rally.
Currently in the middle of this range. If BTC Dominance were to grind back to the highs then I think it's safe to say this was just a big squeeze on ETH/BTC and alts and BTC takes the spotlight back for a while.
If… pic.twitter.com/9poOrcsYYU
— Daan Crypto Trades (@DaanCrypto) May 13, 2025
Note: this is a sponsored message from our partners
Additionally, the Bitcoin meme coin BTCBULL is also gaining traction recently. BTC Bull promises rewards and recognition for dedicated supporters. As Bitcoin progresses towards the $1 million milestone, BTC Bull will implement token burns tied to Bitcoin's price growth and distribute BTC to steadfast holders.
Key statistics:
Ticker: BTCBULL
Current price: $0.00251
USDT raised: $5,708,660.89 / $6,690,863
Total supply: 21,000,000,000
A massive $BTCBULL airdrop is set to occur when Bitcoin reaches the $250,000 mark, further incentivizing commitment from the community. BTC Bull also rewards loyal holders with every $25K increase in Bitcoin's price. With each milestone, the project either burns a portion of the $BTCBULL token supply or distributes BTC to its committed community.
Disclaimer: Coinspeaker is committed to providing unbiased and transparent reporting. This article aims to deliver accurate and timely information but should not be taken as financial or investment advice. Since market conditions can change rapidly, we encourage you to verify information on your own and consult with a professional before making any decisions based on this content.
Bhushan is a FinTech enthusiast and holds a good flair in understanding financial markets. His interest in economics and finance draw his attention towards the new emerging Blockchain Technology and Cryptocurrency markets. He is continuously in a learning process and keeps himself motivated by sharing his acquired knowledge. In free time he reads thriller fictions novels and sometimes explore his culinary skills.
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Strategy co-founder Michael Saylor told the Financial Times in a new documentary that his company is well-positioned to become a $10 trillion enterprise one day.
Michael Saylor's Strategy, the world's largest corporate holder of Bitcoin, may become the top publicly traded equity one day, according to a Strategy analyst.
Strategy will be the “number one publicly traded equity in the entire market” because of its future financial strength enabled with Bitcoin (BTC), Strategy analyst Jeff Walton predicted in the new Financial Times documentary, Michael Saylor's $40 billion Bitcoin bet.
The company currently holds about 568,840 Bitcoin, worth roughly $59 billion, and Walton said that advantage could push it past all other publicly listed firms in the future.
“Strategy holds more of the best assets and the most pristine collateral on the entire planet than any other company, by multiples,” Walton said.
The analyst pointed to the firm's ability to rapidly raise capital as another indicator of its strength. In November 2024, Strategy raised $12 billion in just 50 days.
“It's incredibly hard to raise $100 million of capital, and they just raised $100 million of capital 120 times in 50 days, and they were able to buy Bitcoin with that capital. That's insane,” Walton said.
In the documentary, Saylor also paints a bullish picture of the future due to Bitcoin adoption by Strategy, formerly MicroStrategy.
“I think that MicroStrategy is in a position where we can grow from a $100 billion enterprise to a $1 trillion enterprise to a $10 trillion enterprise,” Saylor said.
He also predicted that Bitcoin would one day reach a price of $13 million per coin:
Related: Coinbase considered Saylor-like Bitcoin strategy before opting out: Bloomberg
Walton and Saylor's predictions on Strategy potentially beating all publicly traded equities in the future come as the company ranks as the 151st largest company in the world, with a market capitalization of $117 billion, according to CompaniesMarketCap.
To become the largest, Strategy would need to surpass Microsoft, whose current market cap exceeds $3.3 trillion.
Despite his bullish stance on the future of both Strategy and Bitcoin, Saylor has not ignored the possibility that BTC could suffer major losses.
Reiterating his previous claims, Saylor emphasized that Strategy's capital structure is constructed so that it would still be stable even if Bitcoin falls 90% and “stays there for four or five years.”
“It wouldn't be a good outcome for the equity holders. The people at the top of the capital structure would suffer because they're levered, but everybody else in the capital structure would get paid out,” he said.
Magazine: Bitcoin to $1M ‘by 2029,' CIA tips its hat to Bitcoin: Hodler's Digest, April 27 – May 3
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Vignesh is a young journalist with a decade of experience. A proud alumnus of IIJNM, Bengaluru, he spent six years as a Sub-Editor for a leading business magazine, published from Kerala. His interest in futuristic technologies took him to a US-based software company specialising in Web3, Blockchain and AI. This stint inspired him to view the future of journalism through the lens of next generation technologies. Now, he covers the crypto scene for Coinpedia, uncovering a vibrant new world where technology and journalism converge.
The Bank of France is actively testing Ripple's private ledger for a potential Euro CBDC.
This trial signifies strong institutional validation for Ripple's blockchain technology in the EU.
Ripple's readily available ledger gives it a potential first-mover advantage in the global CBDC race.
A recent academic study from Ulster University has revealed that the Bank of France is officially testing Ripple's private ledger as a foundation for a Euro-based Central Bank Digital Currency (CBDC).
The update was shared on X by crypto analyst WrathofKahneman, marking what appears to be the first confirmed trial of Ripple's blockchain for a national CBDC in France.
According to Kahneman, the findings show that Ripple's private ledger is currently undergoing active testing by the Bank of France. This positions Ripple as a serious contender in the fast-evolving race to provide blockchain infrastructure for government-issued digital currencies.
As more governments explore blockchain-backed currencies, France's involvement is especially significant due to its influence as a leading member of the European Union.
With major players like China already moving forward with advanced CBDC programs, Europe risks falling behind. Ripple's ready-to-deploy solution gives it an advantage over other platforms that are still in development.
Why This Matters
Ripple's quiet entry into CBDC testing in France might just be the beginning of something much bigger. As central banks around the world look for trusted partners to power the future of money, Ripple is positioning itself as a key player in the next phase of digital finance.
Stay ahead with breaking news, expert analysis, and real-time updates on the latest trends in Bitcoin, altcoins, DeFi, NFTs, and more.
If successful, France's Ripple-based trial may influence broader EU discussions on using Ripple tech for a digital euro rollout.
Ripple is proving itself as a blockchain infrastructure provider for central banks, not just a crypto token issuer.
Yes, post-SEC victory, Ripple and XRP are seeing increased global adoption and institutional recognition for cross-border solutions.
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Bruno Retailleau will meet with entrepreneurs Friday after a particularly brazen incident on Tuesday was caught on camera.
AI generated Text-to-speech
PARIS ― French Interior Minister Bruno Retailleau is organizing an emergency meeting with cryptocurrency entrepreneurs in the country to discuss their security after a brazen kidnapping attempt on Tuesday.
“I will be bringing together at Beauvau [France's interior ministry] the cryptocurrency entrepreneurs, there are a few in France, to work with them on their security, to make them aware of the risks, and to take together measures to protect them,” Retailleau said in an interview with French media Europe1/CNews Wednesday.
On Tuesday, four people attempted to abduct a woman and her son off the street in broad daylight but were stopped thanks to the quick work of those nearby. Much of the ordeal, which took place in Paris' 11th arrondissement, was caught on camera.
French media reported that the victims were the daughter and grandson of the CEO of French cryptocurrency platform Paymium.
Retailleau said this was the third case of an attempted or successful kidnapping involving the relatives of crypto bosses this year, and that all of them are likely linked. Ledger cofounder David Balland was abducted in January and the father of another crypto entrepreneur was kidnapped earlier this month.
The kidnappers in both of those cases reportedly cut a finger off of their victims to obtain a ransom before releasing them a few days later. Retailleau said the assailants in the early May case also threatened to pierce their victim's knee with a drill.
U.S. president's tariff threat will be a hot topic at this month's Cannes film festival.
As U.S. productions flock overseas, Trump wants to target foreign moviemakers, opening a new front in the transatlantic trade war.
The European Commission chief and the French president are trying to woo American researchers with a new program called “Choose Europe for Science.”
German lawmaker Nils Schmid argues there is no need to open the subject as the U.S. has not said it would withdraw its nuclear umbrella.
After a meeting of European Union finance ministers, Eurogroup President Paschal Donohoe said there's been progress on legislation for the digital euro central bank digital currency (CBDC). The legislative work was interrupted by the European elections mid-last year, plus the member of parliament coordinating the legal drafting, Stefan Berger, stepped aside as he has reservations about the digital currency.
Mr Donohoe said that the European Council (of governments), the Commission and Parliament have been working on a new draft and have made “good progress, but there are some areas that require further work.”
The Trump administration's desire to expand the global usage of stablecoins has been used to stir backing for digital euro legislation, despite safeguards in the EU's MiCA crypto regulations. MiCAR restricts the scale of foreign currency stablecoin usage and gives authorities intervention powers if monetary sovereignty is threatened. However, from the early days a key digital euro motivation of the European Central Bank (ECB) has been to reduce retail payment dependence on foreign companies such as Visa and Mastercard. President Trump's April tariff announcements underlined that risk.
“We agreed again that this initiative is crucial, given the changing geopolitical landscape and the importance of diversification of strategically important payment systems,” said Mr Donohoe. “The sense of urgency for this project is increasing for ministers. So we agreed to speed up work and aim to find compromises on the remaining issues as soon as possible.”
The mention of Polish and Danish EU Council presidencies implies the aim is to finalize legislation this year.
The digital euro refers to a CBDC targeted at retail users. In the last couple of years there has been increasing interest in a wholesale CBDC (wCBDC) for institutional usage. During 2024 the European Central Bank, Eurosystem and 64 institutions participated in trials of three wholesale DLT settlement solutions, including a wCBDC solution from the Banque de France, DL3S. In February this year, the ECB announced plans for an interim solution, with the aim of introducing a wholesale CBDC as a longer term solution.
During a speech yesterday, Denis Beau, First Deputy Governor of the Banque de France, indicated that a wholesale CBDC will be launched first.
He said, “Our first objective is to develop a wholesale central bank digital currency (wCBDC) for use by market participants, followed by a CBDC for everyday retail payments (digital euro). Then, in the medium term, we need to develop a European unified ledger to modernise securities transactions.” He continued, “The US authorities' recent announcements in support of crypto-assets and stablecoins make it even more vital we complete this project, to maintain our monetary and financial sovereignty in the new world we are entering. The goal now is to move as quickly as possible from experimentation to operationalisation. Rest assured that the Banque de France and other Eurosystem central banks are working very actively and resolutely to complete this project.”
The complexity and potential societal impact of a retail CBDC is more significant than a wCBDC. Hence, it should be easier to roll out a wCBDC far quicker.
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The report particularly emphasises the fact the recovery in prices since 9 April was partly triggered by Trump Administration's decision to suspend tariffs for 90 days, which had a positive impact on the market mood. This suggest that the coffee price is searching for direction, with both bullish and bearish factors affecting the market, although the former appears to have the upper hand, says the report
Share your coffee stories with us by writing to info@comunicaffe.com.
MILAN – According to data contained in the latest Coffee Market Report from the International Coffee Organization (ICO), world coffee exports remained stable in March. In fact, exports of all forms of coffee totalled 13 million bags, a slight increase of 0.6% compared to the same month last year. Arabica shipments showed a positive trend, reaching a total of 7.879 million bags (+6.4%).
Exports of Colombian Milds increased by almost a third (24.1%) to reach 1.432 million bags. Other Milds also saw an increase in volumes (+9.7%), amounting to 2.655 million. Brazilian Naturals fell slightly to 3.792 million (-1.1%).
Robusta exports continued to decline, amounting to 5.122 million, or 7.1% less than a year ago.
On the other hand, exports of all forms of coffee fell by 2.1% to 67.731 million in the first half of CY 2024/25 (October–March).
Arabica exports increased by 3.3% to 42.298 million. Colombians Milds saw a strong leap forward (+20.4%), soaring to 8.056 million. Exports of Brazilian Naturals increased to 23.776 million (+2.8%). Conversely, there was a negative trend for Other Milds, which fell by 5.9% to 10.466 million.
Robusta exports were 10% down to 25.433 million, compared to 28.263 million in the first half of CY 2023/24.
In April, the ICO Composite Indicator Price (I-CIP) marked the second consecutive monthly decrease (-3.5%) to reach an average of 335.76 cents. The most pronounced declines were seen in Robustas (-4.4%) and the London indicator (-4.8%). On the Arabica side, Colombian Milds, Other Milds and Brazilian Naturals fell by 2.7%, 2.8% and 3.6% respectively. The New York indicator was down by 3.2%.
It is interesting to observe the development of the daily price, which fluctuated between a low of 308.93 cents on 8 April (the lowest since 21 January) and a peak of 357.21 cents on 28 April. This happened due to specific market fundamentals, but was also the consequence of the uncertainty in the global economic and geopolitical landscape.
The ICO report particularly emphasises the fact the recovery in prices since 9 April was partly triggered by Trump Administration's decision to suspend tariffs for 90 days, which had a positive impact on the market mood.
This suggest that the coffee price is searching for direction, with both bullish and bearish factors affecting the market, although the former appears to have the upper hand, says the report.
The Ico Report summarises the main bullish and bearish factors currently affecting the coffee markets as follows:
Bullish factors:
Bearish factors:
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Since the first issue, on May 1st 2002, the objective of Comunicaffe International has been to provide an updated, punctual and essential information service to operators in the sector. The idea is to be useful, providing information on the coffee, cocoa and tea supply chains in order to develop critical thinking and debate. Stay with us. Comunicaffe International is also a daily newsletter sent to 38.000 professionals in Italy and more than 85.000 worldwide. Follow us. Contact us: info@comunicaffe.com | tel. +39 335 5967702
More countries are adopting digital currencies and tokens, with Dubai and Thailand grabbing the headlines this week. These moves put cryptocurrency wallets like Best Wallet in a great position to fulfill a growing demand for a secure way to store crypto.
In the sections below, we'll cover the details of this latest news along with more information on the Best Wallet Token ($BEST) presale.
On Monday, Dubai's Department of Finance signed a memorandum of agreement with Crypto.com, which allows individuals and business customers to pay government service fees using crypto.
The move aligns with Dubai's Cashless Strategy, which aims to shift 90% of transactions in the public and private sectors to cashless by 2026.
Meanwhile, Thailand's Ministry of Finance revealed on Tuesday that it will issue 5B baht worth of digital investment tokens in the next two months.
Called the G-Token, it will allow the Thai government to raise funds while empowering citizens to join the country's digital economy, as they can purchase government bonds for as little as 100 baht.
The increased adoption of digital tokens and cryptocurrencies by governments worldwide will also drive more individuals to use wallets to store their digital assets.
By 2029, over two-thirds of the world's population is expected to own a digital wallet, with top crypto wallets like Best Wallet in a strong position to address this demand.
Best Wallet is a crypto wallet that lets you buy, sell, and swap crypto within a constantly evolving DeFi ecosystem. By the end of 2026, it aims to capture 40% of the crypto wallet market.
A Best Card is also in the works, which will let you spend your crypto directly, just as you would fiat currency.
If you're also considering investing in new cryptocurrencies and meme coins, Best Wallet's Token Launchpad is worth checking out. This will give you exclusive access to token presales of Best Wallet's partners, letting you get in early and enjoy perks like boosted APYs when you stake.
Powering the platform is the Best Wallet Token ($BEST). Purchasing this token gives you exclusive benefits within the Best Wallet Ecosystem. These include reduced transaction fees and higher staking rewards. You also get governance rights, which let you vote on key decisions relating to the platform.
Currently, you can get $BEST tokens via the Best Wallet Token presale page.
To get started, follow our guide on how to buy $BEST – it's all you really need.
Alternatively, you can stake your tokens immediately after buying. This lets you earn passive rewards at 119% p.a. As it's a dynamic rewards rate, the staking APY may still change throughout the presale as more investors lock in their tokens.
To learn more about the project, you can read the Best Wallet Token whitepaper. You can also follow their X profile or subscribe to their Telegram channel for the latest updates.
Today's news from Dubai and Thailand confirms that the world's shift to digital currencies is not stopping. Consequently, more people will need a secure way to store their digital assets.
Best Wallet is perfectly positioned to grab a large piece of this lucrative pie as it expands the capability of its ecosystem.
As always, remember that crypto investing has risks, so do your research and only invest money you can afford to lose. Finally, note that the information in this article is only for educational purposes and not investment advice.
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An academic report by Professor Daniel Broby of Ulster University has reintroduced discussions around Ripple's involvement in the development of the digital euro CBDC.
The report, titled “Central Bank Digital Currencies – Lessons from China,” presents a study of China's digital yuan testing but also includes a comparison of transaction throughput among digital currency systems. This comparison connected Ripple's private ledger to European CBDC experimentation.
The paper, recently spotlighted by WrathofKahneman, a notable voice in the XRP community, mentions Ripple's private ledger as one of the tested platforms for the digital euro by the Bank of France.
Ripple designed the ledger for central bank use cases, and it delivers 1,500 transactions per second, well above public blockchain options like Ethereum 2.0, and competing against Visa's capabilities.
While the report does not suggest there is official adoption, its inclusion of Ripple's technology among CBDC test platforms by the Bank of France has brought renewed speculation over Ripple's potential involvement in the digital euro CBDC project.
For context, the Ulster University report focuses primarily on the e-CNY, China's retail digital currency. It presents a theory-based analysis of its design, phased rollout, and impact on monetary policy and privacy.
Yet, in assessing global CBDC efforts, Broby's included Ripple's private ledger. This mention arrives amid a series of earlier disclosures and community observations that have hinted at Ripple's involvement with the European Central Bank's digital euro project.
In February 2022, the Digital Euro Association (DEA) announced a partnership with Ripple to collaborate on CBDC innovation, focusing on technological design. Also, in March 2023, Ripple's Head of Digital Currency Product, Anthony Ralphs, contributed to a DEA whitepaper exploring privacy features in CBDC frameworks.
By June 2024, Ripple CBDC advisor Antony Welfare publicly highlighted key components of the digital euro project, including progress on privacy, offline transaction capabilities, and standardized rules.
Progress being made on the #DigitalEuro
"….the results of the technical work conducted in the following areas: privacy, the digital euro's offline functionality, and the rulebook."
Key Design features of the Digital $EUR:
Online Privacy ✅ "For online digital euro payments,… https://t.co/YHr1pNQyT9
— Antony Welfare (@AntonyWelfare) June 24, 2024
Additionally, several posts on X from last year claimed that the Central Bank of France had praised Ripple's infrastructure. However, critics indicated that these documents originated in 2022.
However, despite these signals and indirect acknowledgments, no formal confirmation has been issued by either Ripple or European monetary authorities that Ripple's technology is officially selected or integrated into the digital euro's development.
Nonetheless, Ripple's involvement in other CBDC projects has been clear. In 2021, Bhutan's Royal Monetary Authority launched a CBDC pilot on Ripple's private ledger. That same year, Ripple partnered with the government of Palau to explore a USD-backed stablecoin.
More recently, Colombia's central bank began testing Ripple's ledger for financial use cases, while in 2023, Ripple announced CBDC pilot collaborations with both the Hong Kong Monetary Authority and the Central Bank of Montenegro.
DisClamier: This content is informational and should not be considered financial advice. The views expressed in this article may include the author's personal opinions and do not reflect The Crypto Basic opinion. Readers are encouraged to do thorough research before making any investment decisions. The Crypto Basic is not responsible for any financial losses.
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Ripple's latest blog post about RLUSD's use case in the Hidden Road setup has triggered concerns among XRP proponents, questioning the coin's role in the deal.
On Tuesday, Ripple published a blog post highlighting the use case of stablecoins like RLUSD. The San Francisco-based payments company emphasized that stablecoins bridge the gap between DeFi and TradFi.
The blog post further highlighted RLUSD's role in the Hidden Road deal. Recall that Ripple reached an agreement with Hidden Road to acquire the prime broker for $1.25 billion.
In its recent blog post, Ripple stated that Hidden Road, which clears over $3 trillion for 300 financial institutions annually, will leverage RLUSD as a collateral asset across its prime brokerage platform.
Meanwhile, part of the deal would see Hidden Road transition its post-trade activities onto XRPL, XRP's underlying blockchain, allowing it to reduce costs. With XRPL handling Hidden Road's post-trades, the prime broker would leverage XRP to pay all post-trade transaction fees.
The company initially disclosed this in April when it announced the Hidden Road acquisition. At the time, the disclosure elicited major controversy, with some community members expressing concerns about the company sidelining XRP.
These concerns have resurfaced with Ripple reiterating that Hidden Road will use RLUSD as a collateral asset across its platform.
Several users have once again questioned XRP's role in the Hidden Road setup, with some suggesting that XRP's function is now limited to paying transaction fees.
Earlier this month, XRP community member Elena Schoen echoed this sentiment on X. She indicated that while RLUSD's utility spans cross-border settlements to multi-fiat onboarding, XRP is used to settle transactions only on the XRP Ledger (XRPL).
According to her, XRP was once the preferred bridge asset on XRPL. However, she suggested that the coin is gradually losing its relevance, alleging that RLUSD is gaining traction as Ripple's favorite.
For context, Ripple launched the USD-pegged stablecoin on the XRPL in December 2024. After its launch, it was integrated into Ripple's payments solution, giving financial institutions access to a fiat-backed digital currency with zero volatility.
Since its launch, RLUSD has gained widespread adoption across the broader crypto market and has been listed on major exchanges like Gemini, Uphold, Bitso, and MoonPay. Interestingly, thanks to the Hidden Road acquisition, it is now poised to become the first stablecoin to enable cross-margining between traditional markets and digital assets.
While XRP proponents are concerned that RLUSD is gradually replacing their favorite coin, Ripple executives have continued to dismiss this assertion.
Earlier this year, Ripple CEO Brad Garlinghouse said RLUSD and XRP would complement each other. He asserted that both have different functions, noting that while XRP functions as a bridge asset to provide liquidity between two fiat currencies, RLUSD serves as an on-chain fiat.
Additionally, Ripple CTO David Schwartz stated that RLUSD is good for XRP rather than harmful. He emphasized that stablecoins like RLUSD are crucial in maintaining price stability. The Ripple CTO also mentioned that XRP would continue to render key functions like auto-bridging that favor its liquidity.
DisClamier: This content is informational and should not be considered financial advice. The views expressed in this article may include the author's personal opinions and do not reflect The Crypto Basic opinion. Readers are encouraged to do thorough research before making any investment decisions. The Crypto Basic is not responsible for any financial losses.
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Bitcoin (BTC), Ethereum (ETH), and Ripple (XRP) continue to show strength as the broader crypto market sustains its bullish momentum. BTC is testing a critical resistance level that could mark a fresh push toward record highs, while ETH remains supported by a key level, signaling potential for upward continuation. Meanwhile, XRP flirts with a major resistance zone, and a breakout here could spark renewed interest and gains.
Bitcoin faced resistance at around $105,000 on Sunday, declining by 2% until the next day. However, BTC recovers slightly on Tuesday and retests the $105,000 level. At the time of writing on Wednesday, it trades down to around $103,600.
If BTC continues its pullback, it could extend the decline to retest the psychological support level at $100,000.
The Relative Strength Index (RSI) on the daily chart reads 69, slipping below its overbought level of 70 and pointing downwards, indicating a weakening bullish momentum. If the RSI continues to decline and moves below the neutral level of 50, it would lead to a sharp fall in Bitcoin prices.
BTC/USDT daily chart
However, if BTC recovers and closes above the $105,000 resistance level, it could open the door for a rally toward the all-time high of $109,588 set on January 20.
Ethereum price retested and found support around its 200-day Exponential Moving Average (EMA) around $2,436 on Monday and rallied 7.38% the next day. At the time of writing on Wednesday, it hovers at around $2,640.
If the 200-day EMA at $2,436 continues to hold as support, it could extend the rally to retest its key psychological level at $3,000.
The RSI on the daily chart reads 78 above its overbought levels of 70, indicating strong bullish momentum. However, traders should be cautious as the chances of a pullback are high due to its overbought condition. Another possibility is that the RSI remains above its overbought level of 70 and continues its upward trend.
ETH/USDT daily chart
On the other hand, if ETH faces a pullback, it could find support around its 200-day EMA at around $2,436.
XRP price broke and closed above its 50-day EMA level at $2.26 on April 8 and rallied 21% until Tuesday. At the time of writing on Wednesday, it hovers at around $2.55.
If XRP continues its upward trend and closes above its daily resistance at $2.72, it could trigger a rally toward the psychological $3.00 barrier.
However, the RSI on the daily chart reads 66, rejecting from its overbought levels at 70 on Tuesday, indicating fading bullish momentum. The RSI must move above its current levels for the bullish momentum to be sustained.
XRP/USDT daily chart
Conversely, if XRP faces a pullback, it could extend the correction toward its 50-day EMA at $2.26.
The developer or creator of each cryptocurrency decides on the total number of tokens that can be minted or issued. Only a certain number of these assets can be minted by mining, staking or other mechanisms. This is defined by the algorithm of the underlying blockchain technology. On the other hand, circulating supply can also be decreased via actions such as burning tokens, or mistakenly sending assets to addresses of other incompatible blockchains.
Market capitalization is the result of multiplying the circulating supply of a certain asset by the asset's current market value.
Trading volume refers to the total number of tokens for a specific asset that has been transacted or exchanged between buyers and sellers within set trading hours, for example, 24 hours. It is used to gauge market sentiment, this metric combines all volumes on centralized exchanges and decentralized exchanges. Increasing trading volume often denotes the demand for a certain asset as more people are buying and selling the cryptocurrency.
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Ripple's price trades broadly stable at around $2.60 on Wednesday, upholding the recent bullish trend as crypto markets cheer amid improved sentiment. An increase in exposure to XRP among the whales, especially those holding more than 10 million XRP, could accelerate the rally.
Bonk price consolidates gains of around $0.000023 on Wednesday after breaking out of a cup and handle pattern. The technical breakout, eyeing almost a 60% increase to $0.000034, is part of a broader bullish wave in the cryptocurrency market, accentuated by high risk-on sentiment.
Bitcoin price stabilizes near $103,500 on Wednesday after repeated rejections at the $105,000 resistance over the past four days. Ukraine-Russia negotiations in Istanbul this week could act as a bullish catalyst for risk assets, including BTC, if talks bear fruit.
Monero price extends its gains for a seventh consecutive day on Wednesday, trading above $340 for the first time since August 2021. With the latest price rally, the privacy-focused cryptocurrency's market capitalization has reached $6.43 billion, overtaking that of popular meme coinPepe.
Bitcoin price stabilizes around $103,000 on Friday after rallying nearly 10% this week. Risk-on sentiment prevails as Trump announced a trade deal with the UK and ahead of the meeting with China this weekend.
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Ethereum rallied nearly 50% to over $2,700 after the Pectra upgrade and is now around 6% below what it held when Eric Trump publicly promoted the asset, TradingView data shows.
The president's son voiced bullish sentiment toward Ethereum in a Feb. 3 post, tweeting, “In my opinion, it's a great time to add $ETH. You can thank me later.” He later edited the statement to remove the last sentence.
His post came on the heels of a market-wide selloff tied to President Trump's tariff proposal, during which Ether lost more than 15% over February 2 and 3, bottoming out at around $2,300 at the time.
Despite brief recoveries, the downturn intensified amid mounting fears of escalating trade tensions and inflation, following Trump's early April announcement of sweeping tariffs. On April 7, Ether briefly fell below $1,400—its lowest level since November 2023.
The current price rally is fueled by the activation of the Pectra upgrade on May 7, renewed bullish sentiment driven by positive developments in US-China trade relations, and rising institutional accumulation.
Pectra introduces a suite of Ethereum Improvement Proposals (EIPs) designed to enhance staking efficiency, wallet usability, and layer 2 scalability. This helps lay critical groundwork for Ethereum's next phase of network growth.
The upgrade represents a pivotal step for the platform, advancing user-friendliness and enabling systematic, programmable staking. Ethereum has surged more than 40% in the five days since the upgrade went live.
On the institutional front, UK-based investment firm Abraxas Capital has acquired 211,030 ETH, valued at approximately $477 million, over the past six days, according to data from Arkham Intelligence.
Ethereum has again exceeded Alibaba and Coca-Cola in market capitalization to rank as the 33rd most valuable asset, after its price jumped over 40% in five days post-Pectra upgrade, CompaniesMarketcap data shows.
Ethereum's market cap now stands at roughly $325 billion, surpassing Coca-Cola's valuation of around $297 billion and Alibaba's $320 billion.
On Monday, the second-largest crypto asset briefly overtook Alibaba with a market cap of $308 billion, but the Chinese tech giant regained the lead after its stock surged roughly 6%, lifting Alibaba's market cap to over $317 billion, per Market Watch data.
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Severe burns remain one of the most challenging injuries to treat, causing high disease and death rates worldwide, but Australian researchers have flagged some promising new approaches that could save lives and dramatically improve patient recovery.
In a comprehensive review published in Advanced Therapeutics, researchers from the University of South Australia (UniSA), University of Adelaide and Royal Adelaide Hospital (RAH) explore the latest advancements in dermal substitutes -- biochemicals used to replace damaged skin -- with a particular focus on combating infection and enhancing tissue regeneration following catastrophic burns.
The researchers say that despite decades of progress, traditional treatments such as skin grafting often fail to provide adequate healing and infection control, leading to prolonged hospital stays and soaring healthcare costs.
According to the lead authors Dr Zlatko Kopecki and Dr Bronwyn Dearman, the urgency to develop safer, more effective solutions has never been greater.
"Infections are a major cause of complications and mortality in burn patients," says Dr Kopecki, a Research Fellow at UniSA's Future Industries Institute.
"We must innovate beyond conventional methods and develop therapies that regenerate tissue while actively preventing infections."
Each year, approximately 2423 Australians are admitted to hospital with burn-related injuries, 74% of whom require surgery, including a skin graft. Globally, 180,000 people die from burns each year, and approximately 10 million are hospitalised, costing healthcare systems $112 billion worldwide.
The review highlights that while many commercial skin substitutes exist, very few offer integrated antimicrobial protection -- a critical factor given the vulnerability of burn wounds to bacterial invasion and sepsis.
The paper discusses emerging technologies such as Kerecis, a novel fish skin graft with inherent antimicrobial properties, and NovoSorb BTM, a synthetic biodegradable matrix that resists bacterial colonisation without relying on antibiotics.
Both products represent a new generation of dermal substitutes with enhanced potential to protect and heal complex burns.
Kerecis comes from wild Atlantic cod, caught from a sustainable fish stock in pristine Icelandic waters and processed using renewable energy. It stands out for retaining natural omega-3 fatty acids, which have strong antimicrobial effects and promote wound healing.
Meanwhile, NovoSorb BTM's unique polyurethane matrix offers structural resilience even in infected wounds, providing a vital scaffold for tissue regeneration.
"These materials demonstrate a shift towards multifunctional therapies that combine structural support with infection resistance," says Dr Dearman, Principal Medical Scientist for the Skin Engineering Laboratory at the RAH and an Adjunct Lecturer at the University of Adelaide.
"Such innovations are crucial, particularly as antibiotic-resistant infections continue to rise globally," she says.
The review calls for the next wave of research to integrate active antimicrobial agents directly into 3D dermal scaffolds that support cell growth, reducing the reliance on antibiotics and temporary dressings.
Beyond infection control, the research points to scarless healing as the future frontier of burn care.
By combining smart biomaterials with cell-based therapies, scientists aim to regenerate skin that restores its full function -- an outcome that could revolutionise the recovery for millions of burn survivors worldwide.
The research team includes experts from the Future Industries Institute at UniSA, the Adult Burn Service at the Royal Adelaide Hospital, and the Faculty of Health and Medical Sciences at the University of Adelaide.
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Scientists at Northwestern University have developed a new approach that directly combats the progression of neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis (ALS).
In these devastating illnesses, proteins misfold and clump together around brain cells, which ultimately leads to cell death. The innovative new treatment effectively traps the proteins before they can aggregate into the toxic structures capable of penetrating neurons. The trapped proteins then harmlessly degrade in the body.
The "clean-up" strategy significantly boosted the survival of lab-grown human neurons under stress from disease-causing proteins.
Designated as an ACS Editor's Choice article, the study will be published on May 14 in the Journal of the American Chemical Society.
"Our study highlights the exciting potential of molecularly engineered nanomaterials to address the root causes of neurodegenerative diseases," said Northwestern's Samuel I. Stupp, the study's senior author. "In many of these diseases, proteins lose their functional folded structure and aggregate to make destructive fibers that enter neurons and are highly toxic to them.
"By trapping the misfolded proteins, our treatment inhibits the formation of those fibers at an early stage. Early stage, short amyloid fibers, which penetrate neurons, are believed to be the most toxic structures. With further work, we think this could significantly delay progression of the disease."
A pioneer in regenerative medicine, Stupp is the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine. He also is the founding director of the Center for Regenerative Nanomedicine (CRN). Zijun Gao, a Ph.D. candidate in Stupp's laboratory, is the paper's first author.
The Stupp group led the development and characterization of the new therapeutic materials. Co-corresponding author Zaida Alvarez -- a researcher at the Institute for Bioengineering of Catalonia (IBEC) in Spain, former postdoctoral fellow in Stupp's laboratory and current visiting scholar at CRN -- led testing of the therapies in human neurons.
A sugar-coated solution
According to the World Health Organization, as many as 50 million people worldwide might have a neurodegenerative disorder. Most of these diseases are characterized by the accumulation of misfolded proteins in the brain, leading to the progressive loss of neurons. While current treatments offer limited relief, a dire need for new therapies remains.
To tackle this challenge, the researchers turned to a class of peptide amphiphiles, pioneered by the Stupp laboratory, that contain modified chains of amino acids. Peptide amphiphiles are already used in well-known pharmaceuticals including semaglutide, or Ozempic. In fact, the Northwestern investigators developed a similar molecule in 2012 that boosted insulin production.
"The advantage of peptide-based drugs is that they degrade into nutrients," Stupp said. "The molecules in this novel therapeutic concept break down into harmless lipids, amino acids and sugars. That means there are fewer adverse side effects."
Over the years, Stupp's research group has designed many peptide-based materials for different therapeutic purposes. To develop a peptide amphiphile to treat neurodegenerative diseases, his team added an extra ingredient: a natural sugar called trehalose.
"Trehalose is naturally occurring in plants, fungi and insects," Gao said. "It protects them from changing temperatures, especially dehydration and freezing. Others have discovered trehalose can protect many biological macromolecules, including proteins. So, we wanted to see if we could use it to stabilize misfolded proteins."
Instability is key
When added to water, the peptide amphiphiles self-assembled into nanofibers coated with trehalose. Surprisingly, the trehalose destabilized the nanofibers. Although it seems counterintuitive, this decreased stability exhibited a beneficial effect.
By themselves, the nanofibers are strong and well-ordered -- and resistant to rearranging their structure. That makes it more difficult for other molecules, like misfolded proteins, to integrate into the fibers. Less stable fibers, on the other hand, became more dynamic -- and more likely to find and interact with toxic proteins.
"Unstable assemblies of molecules are very reactive," Stupp said. "They want to interact with and bond to other molecules. If the nanofibers were stable, they would happily ignore everything around them."
Searching for stability, the nanofibers bonded to amyloid-beta proteins, a key culprit implicated in Alzheimer's disease. But the nanofibers didn't just stop the amyloid-beta proteins from clumping together. The nanofibers fully incorporated the proteins into their own fibrous structures -- permanently trapping them into stable filaments.
"Then, it's no longer a peptide amphiphile fiber anymore," Stupp said. "But a new hybrid structure comprising both the peptide amphiphile and the amyloid-beta protein. That means the nasty amyloid-beta proteins, which would have formed amyloid fibers, are trapped. They can no longer penetrate the neurons and kill them. It's like a clean-up crew for misfolded proteins.
"This is a novel mechanism to tackle progression of neurodegenerative diseases, such as Alzheimer's, at an earlier stage. Current therapies rely on the production of antibodies for well-formed amyloid fibers."
Improving neuron survival
To assess the therapeutic potential of the new approach, the scientists conducted laboratory tests using human neurons derived from stem cells. The results showed the trehalose-coated nanofibers significantly improved the survival of both motor and cortical neurons when exposed to the toxic amyloid-beta protein.
Stupp says the novel approach of using unstable nanofibers to trap proteins offers a promising avenue for developing new and effective therapies for Alzheimer's, ALS and other neurodegenerative conditions. Much like cancer treatments combine multiple therapies -- like chemotherapy and surgery or hormone therapy and radiation -- Stupp said the nanotherapy might be most effective when combined with other treatments.
"Our therapy might work best when targeting diseases at an earlier stage -- before aggregated proteins enter cells," Stupp said. "But it's challenging to diagnose these diseases at early stages. So, it could be combined with therapies that target later-stage symptoms of the disease. Then, it could be a double whammy."
The study was supported by the Center for Regenerative Nanomedicine, the Chemistry of Life Processes Institute, the Spanish Ministry of Science, the National Institute on Aging of the National Institutes of Health and the European Union's NextGenerationEU.
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Signals from the microenvironment are known to be critical for development, stem cell self-renewal and oncogenic progression. Although some niche-driven signals that promote cancer progression have been identified1,2,3,4,5, concerted efforts to map disease-relevant microenvironmental ligands of cancer stem cell receptors have been lacking. Here, we use temporal single-cell RNA-sequencing (scRNA-seq) to identify molecular cues from the bone marrow stromal niche that engage leukaemia stem-enriched cells (LSCs) during oncogenic progression. We integrate these data with our human LSC RNA-seq and in vivo CRISPR screen of LSC dependencies6 to identify LSC–niche interactions that are essential for leukaemogenesis. These analyses identify the taurine–taurine transporter (TAUT) axis as a critical dependency of aggressive myeloid leukaemias. We find that cysteine dioxygenase type 1 (CDO1)-driven taurine biosynthesis is restricted to osteolineage cells, and increases during myeloid disease progression. Blocking CDO1 expression in osteolineage cells impairs LSC growth and improves survival outcomes. Using TAUT genetic loss-of-function mouse models and patient-derived acute myeloid leukaemia (AML) cells, we show that TAUT inhibition significantly impairs in vivo myeloid leukaemia progression. Consistent with elevated TAUT expression in venetoclax-resistant AML, TAUT inhibition synergizes with venetoclax to block the growth of primary human AML cells. Mechanistically, our multiomic approaches indicate that the loss of taurine uptake inhibits RAG-GTP dependent mTOR activation and downstream glycolysis. Collectively, our work establishes the temporal landscape of stromal signals during leukaemia progression and identifies taurine as a key regulator of myeloid malignancies.
Signals from the tumour microenvironment (TME) can regulate initiation, progression and immune evasion of tumours1,2,3,4,5,7,8,9,10. While scRNA-seq analysis has identified cellular TME components, especially in solid tumours11,12, concerted efforts to link ligands from the changing TME landscape with cognate receptors on cancer cells have been lacking. As cell surface proteins are particularly amenable to therapeutic targeting, functional characterization of their interactions with the TME are of considerable clinical interest.
Aggressive therapy-resistant myeloid leukaemias, such as blast-crisis-phase chronic myeloid leukaemia (bcCML) and AML, initiate and expand in a complex bone marrow microenvironment. Although previous studies have described the cellular composition of normal bone marrow niche13,14,15, their dynamic alterations during leukaemia progression remain undefined. We use scRNA-seq to establish temporal changes in bone marrow microenvironment populations, and in niche-driven signals during disease progression. To define TME ligands that are essential for leukaemogenesis, we focused on cognate cell surface receptors enriched in LSCs as compared to healthy controls, and those essential for in vivo leukaemia progression6. This approach identified signals that are known to be critical for cancer growth, such as KIT–KITL and CD47–thrombospondin 116, as well as multiple new signalling axes.
Of these signals, TAUT, encoded by SLC6A6, was strongly associated with poor prognosis in human leukaemias and emerged as a key regulator of AML. As taurine can be neuroprotective, mitigate the side-effects of chemotherapy17 or support anti-cancer immunity18, a cancer-promoting role of taurine has not been considered. We examined if blocking taurine production in the TME impairs LSC function. We used genetic tools to establish whether TAUT expression in cancer cells controls the growth of aggressive myeloid leukaemias. Using metabolomic, proteomic and transcriptomic approaches, we identify downstream mechanisms by which taurine regulates leukaemia growth.
To define temporal changes in non-immune bone marrow microenvironment populations during myeloid leukaemia progression, we used bcCML LSCs, which can grow in unirradiated mouse recipients (Extended Data Fig. 1a,b). Bone marrow stromal populations (leukaemia−CD45−TER119−) were isolated from leukaemic cohorts at distinct stages of disease progression and analysed using scRNA-seq (Fig. 1a). Gene-expression-based clustering identified 21 lineage clusters with transitional subsets covering endothelial cells, chondrocytes, fibroblasts, pericytes, mesenchymal stromal cells (MSCs) and osteo-associated populations (Fig. 1b and Extended Data Fig. 1c,d) and showed significant remodelling with disease progression (Fig. 1c,d). Our flow-cytometry-based analyses of an independent cohort of leukaemic mice validated these changes, showing increases in MSCs, osteolineage and arteriolar endothelial cells, with a concomitant decline in sinusoidal endothelial populations (Fig. 1e,f and Extended Data Fig. 1e).
a, The experimental strategy used to determine the impact of bcCML progression on bone-marrow microenvironment remodelling. b, A uniform manifold approximation and projection (UMAP) analysis of 15,695 non-haematopoietic cells from bone and bone marrow shows 21 distinct bone marrow stromal cell clusters (n = 3 (naive), n = 6 (initiation), n = 7 (expansion) and n = 9 (end) mice). The colour key indicates subclusters. Chrondro, chondrocyte; fibro, fibroblast; osteo, osteo-associated cell. c, UMAP plot of major population clusters over time (naive, 0 days; initiation, 2 and 4 days; expansion, 7 and 9 days; end, 11 and 14 days after transplant; the colours represent different stages of disease). d, The proportion (prop.) of MSCs/osteolineage cells (top) and endothelial cells (bottom) over time. e, Representative fluorescence-activated cell sorting (FACS) plots and quantification of MSC frequency over time. f, Representative FACS plots and quantification of the osteolineage cell frequency over time. For e and f, data are mean ± s.e.m. n = 3 animals per timepoint. Statistical analysis was performed using one-way analysis of variance (ANOVA). g, Unbiased Enrichr analysis showing the top 10 downregulated pathways by population cluster in MSCs, and osteo-associated, arteriolar and sinusoidal endothelial populations. Blue text represents pathways of interest. ER, endoplasmic reticulum. The mouse image in a is adapted from ref. 6, Springer Nature America.
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Clustering analyses of genes expressed in major lineages identified gene sets with similar changes in expression (Extended Data Fig. 1f), suggesting that these may represent altered stromal cell fate. Pathway analysis showed that osteoblast differentiation and bone mineralization were downregulated in MSCs and osteo-associated cells, and focal adhesion and cell migration were downregulated in endothelial populations, indicating that MSC and endothelial function may be impaired with disease progression (Fig. 1g and Extended Data Fig. 2a). Collectively, our temporal analysis of the TME identifies dynamic changes in gene expression of stromal subpopulations during leukaemia progression.
To define the functional relevance of microenvironmental changes on leukaemogenesis, we focused on proteins expressed on LSC cell surface that act as receptors for niche-driven signals. To identify LSC receptors associated with disease progression, we performed RNA-seq analysis of human AML and bcCML CD34+ cells, and healthy donor bone marrow CD34+ haematopoietic stem and progenitor cells (HSPCs; Extended Data Fig. 2b). We noted significant (adjusted P (Padj) < 0.05) upregulation of 1,569 genes in bcCML, 2,842 genes in AML and 2,331 genes in both bcCML and AML compared with normal HSPCs. To identify signals that are functionally relevant for disease progression, we found cell surface genes19 that drop out by twofold or more in our genome-wide in vivo leukaemia CRISPR screen6. This identified 13 cell surface signals common to both bcCML and AML, 18 unique to AML and 7 unique to bcCML. Of these 38 genes, 16 were misannotated as cell surface in the reference dataset19 and were removed from further analysis (Methods and Extended Data Fig. 2c,d). We used NicheNet and the published literature to identify ligands for these receptors, especially those that were significantly upregulated in our TME scRNA-seq data and in the human AML immune microenvironment20 (Extended Data Fig. 2e). This led to the exclusion of receptors with no known ligands (MR1, TMCO3 and TSPAN15) as well as those of which the ligands were not significantly enriched in any TME population (LGALS3BP, CD96, CD274 and CD3D). We therefore generated a unique map of TME ligands for 15 LSC receptors that are essential for disease progression (Fig. 2a).
a, Circos plot showing leukaemia cell surface receptors and cognate stromal-cell-derived ligands. b, Kaplan–Meier curves of human patients with leukaemia with low (<11.14, n = 80) or high (≥11.14, n = 81) SLC6A6 expression (TCGA-LAML; Xena Browser; log-rank test). CI, confidence interval; HR, hazard ratio. c, Normalized SLC6A6 expression in CD43+ cells from normal human bone marrow (BM) samples and samples from patients with bcCML and AML. n = 7 (bone marrow), n = 10 (bcCML) and n = 11 (AML). For the box plots, the centre line shows the median, the box limits show the interquartile range and the whiskers represent the minimum and maximum values, respectively. Statistical analysis was performed using DESeq2-implemented Wald tests. d–g, Representative IHC images (d,f) and quantification (e,g) of CDO1 expression in matched patient bone marrow biopsies at MDS diagnosis and after AML transformation (d,e), or at AML diagnosis (AML-D) and relapse (AML-R) (f,g). n = 5 independent patients per cohort. Each colour represents a patient sample. Statistical analysis was performed using two-tailed ratio paired t-tests. h, The strategy used to determine the impact of inhibiting CDO1 in human bone marrow MSCs on co-cultured AML cells (MSCs and AML cells were derived from the same patient). CFU, colony-forming unit. i, The number of live LSCs (left; data are mean ± s.e.m.; n = 11 independent culture wells per cohort; data were combined from two independent experiments) and their colony-forming ability (right; data are mean ± s.d.; n = 3 independent culture wells per cohort) after coculture with AML MSCs. j, Taurine quantity per femur in control and leukaemic mice, as determined using colourimetric analysis, 12 days after transplant. Data are mean ± s.e.m. n = 5 animals per cohort. Data were combined from two independent experiments. For i and j, statistical analysis was performed using unpaired two-tailed Student's t-tests. k, Experimental strategy and survival curve, showing the impact of blocking taurine production by MSC/osteolineage populations in vivo on bcCML progression in unirradiated recipients. n = 18 (Cdo1fl/fl/Cdo1+/+) and n = 14 (Cdo1fl/flPrrx1-cre+). Data were combined from four independent experiments. Statistical analysis was performed using the log-rank test. WT, wild type. Scale bars, 50 µm (d and f). The mouse images in h and k are adapted from ref. 6, Springer Nature America.
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We next determined whether disease progression could alter the expression of LSC-specific TME ligands, and identified four distinct patterns of ligand expression. While the expression of some genes remained steady, for example, Jam2 in arteriolar endothelial cells and Ihh in chondrocytes, the expression of Vcam1, Pcdh7 and Il7 was lost in the TME, especially at the end point. Expression of Anxa1 first increased but then declined towards the end. The fourth category of genes was always expressed, but the microenvironmental populations expressing them changed. These included Pvr, Cdo1, Apoe and Agt (Extended Data Fig. 3a–d). Our analysis capturing dynamic changes in the TME identifies signals that may be necessary not only at different stages of disease progression, but also those critical during the entire course of disease.
Multiple TME–LSC signalling axes identified in our interactome may have a functional role in leukaemia progression. However, we were interested in genes associated with unfavourable outcomes in human patients with AML. Of the 22 genes upregulated in human LSCs, only low-density lipoprotein receptor (LDLR) and SLC6A6 were significantly associated with poor prognosis in AML (Fig. 2a–c and Extended Data Fig. 4a,b). We therefore tested the functional requirement of TME-derived ligands of LDLR and SLC6A6 on LSC growth. One of the primary LDLR ligands, apolipoprotein E (APOE)21, was highly expressed in MSCs (Extended Data Fig. 3d). To test the role of APOE from MSCs on LSC function, we co-cultured bcCML LSCs with MSCs transduced with short hairpin RNAs (shRNAs) targeting Apoe or LacZ (control; Extended Data Fig. 4c). Co-culture with MSCs lacking Apoe expression led to significant reduction in both the viability and colony-forming ability of LSCs (around 2.1-fold lower than the controls; Extended Data Fig. 4d–f).
SLC6A6 encodes TAUT, which has high affinity for the non-essential amino acid taurine, and low affinity for β-alanine (taurine Km = 4.5 μM versus β-alanine Km = 56 μM)22. Our experiments indicate that Slc6a6 expression can be directly induced by oncogenes (Extended Data Fig. 4g). While the leukaemia TME did not express enzymes required for β-alanine synthesis (Gadl1 and Cndp1), those needed for taurine biosynthesis were expressed in osteo-associated cells (Cdo1 and Csad; Extended Data Fig. 4h,i). Our analysis of publicly available human bone marrow stromal cell scRNA-seq data using surgical samples from osteoarthritis patients23 showed that CDO1 expression is restricted to MSC and osteolineage populations (Extended Data Fig. 4j). To test whether CDO1 is expressed in the human leukaemia TME, we performed an scRNA-seq analysis of CD45− stromal cells from three myelodysplastic syndrome (MDS) and AML bone marrow aspirates. Our analysis of the limited numbers of stromal cells in these samples indicate that CDO1 expression is restricted to the MSC/osteolineage cells (Extended Data Fig. 4k,l), as we see in mouse samples. Notably, we found a marked increase in CDO1 protein expression in nearly all matched biopsies of patients who progressed from MDS to secondary AML, and those who relapsed after AML diagnosis (Fig. 2d–g and Extended Data Fig. 4m–p). While CDO1 protein was expressed in undifferentiated human AML MSCs, its expression increased during in vitro mouse and human AML MSC osteogenic differentiation (Extended Data Fig. 5a–c). Thus, CDO1 may be broadly expressed in immature MSCs as well as differentiating osteolineage cells in human bone marrow. Importantly, taurine levels in extracellular medium increased during MSC differentiation, indicating that elevated CDO1 expression is correlated with taurine production (Extended Data Fig. 5d).
To determine a functional role of taurine from osteolineage cells, we tested the impact of inhibiting taurine biosynthesis in mouse and human leukaemia bone-marrow-derived MSCs on co-cultured leukaemia cells. Our experiments showed that mouse LSCs co-cultured with osteolineage cells lacking Cdo1 expression were significantly less viable (about 2-fold lower than the controls) and formed fewer colonies (3.4-fold less than controls), which could be rescued by supplementing cultures with taurine (Extended Data Fig. 5e–g). Similarly, inhibiting CDO1 in osteolineage cultures from MSCs derived from patients with AML impaired survival and colony-formation of co-cultured AML cells from the same patient by 2- to 3.2-fold (Fig. 2h,i and Extended Data Fig. 5h), indicating that taurine produced by osteolineage cells promotes LSC growth and survival.
Consistent with a functional role of taurine from the TME in leukaemia progression, taurine levels were 1.7-fold higher in leukaemic bone marrow interstitial fluid as compared to the controls (Fig. 2j). In mice, the majority of taurine is synthesized in the liver from cysteine24. To determine whether taurine produced locally in the bone marrow niche is essential for leukaemia growth, we generated a new Cdo1fl/fl mouse model and crossed it to MSC/osteolineage-specific Prrx1-cre mice (Extended Data Fig. 5i–k). We used these as recipients for LSCs and monitored survival, and the impact on bone marrow microenvironment populations. Our experiments showed that Cdo1fl/flPrrx1-cre+ mice lived around 13.5% longer than the controls, indicating that taurine produced locally in the leukaemia TME can support disease progression, at least in part (Fig. 2k). We did not find any significant changes in the composition of TME in Cdo1fl/flPrrx1-cre+ leukaemic mice as compared to the controls (Extended Data Fig. 5l–n), suggesting that leukaemia-driven remodelling of the bone marrow niche does not depend on taurine produced by osteolineage cells. We finally tested whether exogenous taurine supplements can promote leukaemia growth. Our experiments showed that the colony-forming ability of mouse LSCs and patient-derived AML cells increased by 1.2- to 3.3-fold in the presence of taurine (Extended Data Fig. 5o–q). Taurine supplements could significantly accelerate disease progression in immunocompetent mice (around threefold higher likelihood of death relative to the controls; Extended Data Fig. 5r), indicating that taurine can promote leukaemic progression.
Collectively, these data indicate a key role of taurine and APOE from the bone marrow niche in sustaining LSCs. As SLC6A6 expression was significantly enriched in both human bcCML and AML LSCs as compared to the controls, we focused our studies on SLC6A6, as it may be broadly required for growth of aggressive leukaemias.
To determine whether TAUT has a functional role in leukaemia progression we used global Slc6a6-knockout mice25 (Fig. 3a,b). While Slc6a6-knockout mice are born at Mendelian ratios, they can develop ageing-related defects in bone mass and retinal degeneration25,26,27. Our experiments showed that TAUT loss in LSCs significantly reduced their ability to grow when co-cultured with osteolineage cells expressing either control shRNA or shRNA against Cdo1 (shCdo1; Extended Data Fig. 6a), indicating that they could not respond to taurine being produced by the niche. TAUT loss impaired initiation of bcCML in mouse models (3.9-fold higher likelihood of survival; Fig. 3c,d), which could not be rescued with taurine supplements (Extended Data Fig. 6b). TAUT loss also led to functional depletion in bcCML LSCs, as indicated by a 2.3-fold reduction in their colony-forming ability (Fig. 3e), as well as a marked increase in the survival of mice transplanted with Slc6a6−/− LSCs (40%) relative to control LSCs (0%) in secondary transplant assays (21.2-fold higher likelihood of survival; Fig. 3f). The 8.5-fold reduction in colony-forming ability of bcCML LSCs from secondary transplants suggests that these leukaemias remain dependent on TAUT expression and taurine uptake for their continued propagation (Fig. 3g,h). We noted no significant differences in bone marrow microenvironmental populations of mice bearing Slc6a6−/− leukaemias as compared to the controls, indicating that leukaemia-driven niche remodelling possibly reflects the extent of the tumour burden, and may be independent of taurine levels within leukaemia cells (Extended Data Fig. 6c–g).
a, Relative Slc6a6 mRNA expression in whole bone marrow cells from Slc6a6+/+ (+/+) and Slc6a6−/− (−/−) mice. Data are mean ± s.d. n = 3 replicates per cohort. b, Taurine in normal bone marrow cells. Data are mean ± s.e.m. n = 6 pelvic bones from three animals per cohort; data were combined from two independent experiments. c,d, The experimental strategy (c) and primary bcCML survival curve (d). n = 12 (+/+) and n = 11 (−/−). Data were combined from three independent experiments. e, CFU analysis of Lin− bcCML cells from primary transplants. Data are mean ± s.d. n = 3 culture wells per cohort. f, Survival curve of secondary bcCML transplants. n = 11 (+/+) and n = 10 (−/−); data were combined from two independent experiments. g, CFU of Lin− cells from secondary transplants. Data are mean ± s.d. n = 3 independent culture wells per cohort. h, Taurine in Lin− LSCs. Data are mean ± s.e.m. n = 8 independent replicates per cohort from two independent samples. i,j, The experimental strategy (i) and survival curve (j) show the impact of TAUT loss on de novo MLL-AF9-driven AML. n = 17 (+/+) and n = 20 (−/−); data were combined from four independent experiments. k, Taurine in KIT+ AML cells. Data are mean ± s.e.m. n = 4 animals per cohort. l, CFU analysis of KIT+ AML cells. Data are mean ± s.d. n = 3 culture wells per cohort. m,n, Experimental strategy (m) and survival curve (n), showing the impact of TAUT loss on de novo AML-ETO9a-driven AML. n = 7 (+/+) and n = 10 (−/−). Data were combined from two independent experiments. o, Representative FACS plots and quantification of the Lin−CD150−SCA1+FLT3+ bcCML stem cell frequency in the bone marrow (left) and spleen (right) of recipients. Data are mean ± s.e.m. n = 11 animals per cohort. Data were combined from three independent experiments. p, Representative FACS plots and quantification of early apoptosis and necrosis in bcCML at 14 days after transplant. Data are mean ± s.e.m. n = 8 animals per cohort. Data were combined from two independent experiments. q, Representative FACS plots and graph showing the frequency of in vivo BrdU incorporation in bcCML. Data are mean ± s.e.m. n = 3 animals per cohort. Statistical analysis was performed using unpaired two-tailed Student's t-tests (b, e, g, h, k, l and o–q) and log-rank tests (d, f, j and n). The mouse images in c, i and m are adapted from ref. 6, Springer Nature America.
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To determine whether TAUT is broadly required for de novo AML growth, we tested the impact of its loss on initiation of leukaemia driven by MLL-AF9/NRAS(G12V) and by AML-ETO9a/NRAS(G12V). Our experiments showed that TAUT loss markedly delays the initiation of MLL-driven AML relative to the control (6.1-fold higher likelihood of survival; Fig. 3i–k). Slc6a6−/− KIT+ AML LSCs from established disease formed 2.9-fold fewer colonies compared with the controls (Fig. 3l), indicating that TAUT loss depleted functional LSCs. Consistent with a key role of TAUT expression in myeloid leukaemia initiation, TAUT loss in disease driven by AML-ETO9a resulted in a marked increase in survival (70%) relative to the controls (0%) (36.3-fold higher likelihood of survival; Fig. 3m,n). At the cellular level, TAUT loss led to a 2.4- to 3.6-fold reduction in primitive Lin−CD150−FLT3+SCA1+ LSCs6 (Fig. 3o). Furthermore, TAUT loss increased necrosis and the Lin+ differentiated cells (Fig. 3p and Extended Data Fig. 6h) and promoted cell proliferation (Fig. 3q). These data demonstrate a critical requirement for TAUT in the initiation, self-renewal and propagation of myeloid leukaemia.
We next tested the impact of TAUT loss on normal haematopoiesis. Our analysis indicates that TAUT loss does not severely impact bone marrow cellularity, or the total numbers of HSCs, progenitors and differentiated cells at steady-state (Extended Data Fig. 7a–e). While TAUT loss did not impair initial HSC engraftment (1 month after transplant), donor chimerism dropped over time (Extended Data Fig. 7f,g). Although overall bone marrow chimerism 4 months after transplant was 2.4-fold lower in Slc6a6−/− HSC recipients as compared to Slc6a6+/+ HSC recipients, these Slc6a6−/− HSCs were able to contribute to all haematopoietic lineages (Extended Data Fig. 7h–k). Serial transplantation of Slc6a6+/+ and Slc6a6−/− bone marrow cells showed a similar loss in Slc6a6−/− engraftment over time (Extended Data Fig. 7l–q). These results suggest that, while TAUT loss does not impair steady-state haematopoiesis, it can impact long-term HSC self-renewal and maintenance. These data are consistent with previous studies showing that genetic loss of LSC-enriched genes such as CD981, STAU26, MSI228,29, BRD430 and BCL231 can impair HSC self-renewal. However, therapeutic inhibition of CD98 showed minimal toxicity in AML phase I trials1 and BCL2 inhibitors are approved for AML therapy. It is therefore possible that non-genetic approaches using small-molecule inhibitors or gene silencing may identify a therapeutic window for TAUT targeting in human cells. We therefore tested the impact of TAUT inhibition on growth and proliferation of normal human HSPCs as well as patient-derived AML cells.
Our analyses of available gene expression datasets indicate that SLC6A6 expression is enriched in leukaemia stem/progenitors as compared to more mature blasts (Extended Data Fig. 8a). While SLC6A6 is broadly expressed in AML irrespective of karyotype or FAB subtype (TCGA; Extended Data Fig. 8b), increased expression correlates with venetoclax resistance (BEAT-AML; Fig. 4a). SLC6A6 expression is also enriched in reactive oxygen species (ROS)-low LSCs from human monocytic AMLs (subtype clinically associated with venetoclax resistance; CD45brightSSChighCD117−CD11b+CD68+) compared with primitive AML (Fig. 4b; CD45medSSClowCD117+CD11b−CD68−)32. We find increased SLC6A6 expression in leukaemia cells carrying RAS mutations as compared to wild-type cells, consistent with data correlating RAS mutations with venetoclax resistance33 (Fig. 4c). SLC6A6 is also highly expressed in relapsed AML originating from stem/progenitor like cells compared with more committed populations34 (Extended Data Fig. 8c). These data collectively indicate that inhibiting SLC6A6 may be of value across AML subtypes, including those commonly associated with venetoclax resistance.
a, SLC6A6 expression based on venetoclax (Ven) response (BEAT-AML). n = 193; dot plots show individual patients. Statistical analysis was performed using the DESeq2 log-rank test. b, SLC6A6 expression in primitive and monocytic ROSlow AML LSCs32 (Gene Expression Omnibus (GEO): GSE132511). n = 7 (primitive) and n = 5 (monocytic). For the box plots in a and b, the centre line shows the median, the box limits show the interquartile range and the whiskers represent 1.5 × interquartile range. c, SLC6A6 expression of human NRASG12D+ versus wild-type cells (GEO: GSE253715). Statistical analysis was performed using the Seurat Findmarker function with the Wilcoxon rank-sum test33. d,e, CFU analysis of primary human AML (d) or normal human CD34+ bone marrow HSPCs (e) treated with dimethyl sulfoxide (DMSO)/water (control) or the indicated doses of TAG and GES. For d and e, data are mean ± s.e.m. n = 3 independent culture wells per sample from two independent samples; each colour represents a sample. f,g, CFU analysis of human AML cells treated with DMSO/water (control) or venetoclax (ABT-199) in combination with the indicated doses of TAG (f) or GES (g). Data are mean ± s.e.m. n = 3 independent culture wells per sample from two independent primary human AML samples. Each colour represents a sample. h, The combination index of GES and venetoclax calculated per fraction affected (left) and the normalized isobologram (right), as determined using the Chou–Talalay method. n = 2 independent primary human AML samples. Colours represent independent samples; shapes represent indicated venetoclax and GES combinations. D, drug dose; Dx, median-effect dose. i,j, CFU analysis of primary human AML cells (i) or normal CD34+ HSPCs (j) that were transduced with lentiviral shRNAs targeting LacZ (control) or human SLC6A6. Data are mean ± s.e.m. n = 3 independent culture wells from n = 3 independent primary human patient samples. Each colour represents an independent sample. k–m, Experimental strategy (k) and representative FACS plots and graph, showing bone marrow engraftment of primary human AML (l) or primary human normal CD34+ HSPC (m) cells. The black lines show the mean. n = 9 animals per cohort from n = 4 independent primary human AML samples (l); and n = 13 animals per cohort from n = 5 independent normal human CD34+ HSPC samples (m). Each dot represents an animal; each colour represents an independent sample. Statistical analysis was performed using two-sample Wilcoxon tests (b), one-way ANOVA (d–g) and unpaired two-tailed Student's t-tests (i, j, l and m). The mouse and culture well images in k are adapted from ref. 6, Springer Nature America.
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To determine whether small-molecule inhibitors of TAUT can effectively block leukaemia growth, we used two well-characterized structural analogues of taurine that inhibit uptake: 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide hydrochloride35 (TAG) and guanidinoethyl sulphonate36 (GES; Extended Data Fig. 8d,e). TAG and GES treatment led to a substantial reduction in colonies formed by Slc6a6+/+ mouse LSCs but not Slc6a6−/− cells (Extended Data Fig. 8f–h). Importantly, while TAG and GES impaired growth of primary human AML cells in colony assays by 1.8- to 20-fold, they did not impact normal human CD34+ HSPC colony growth (Fig. 4d,e). We next tested whether venetoclax can exacerbate the impact of TAUT loss and/or inhibition on LSC function. Our experiments showed that venetoclax reduced the viability of mouse Slc6a6−/− LSCs by 3.2-fold and lowered their colony formation by 13.2-fold as compared to the controls (Extended Data Fig. 8i,j). While TAG, GES or venetoclax alone could impair mouse LSC colony formation by 1.4- to 3.9-fold, their combination was synergistic and led to 2.3- to 7.2-fold fewer colonies as compared to the controls (Extended Data Fig. 8k–m). While primary human AML cells that were treated with GES, TAG or venetoclax alone formed 1.3- to 8.3-fold fewer colonies as compared to the controls, combining the treatments substantially impaired colony formation by 2.4- to 150-fold. These data indicate that taurine inhibitors can synergize with venetoclax in blocking the growth of human AML cells (Fig. 4f–h).
As TAG and GES did not effectively block taurine uptake in vivo (Extended Data Fig. 9a–j), we used shRNA-based approaches to determine the impact of inhibiting TAUT expression on human AML growth. Knocking down SLC6A6 expression using two independent shRNAs significantly impaired taurine uptake by 2.2 to 3.4-fold, as well as the colony-forming ability of human bcCML, AML and MDS cell lines by 2- to 12-fold (Extended Data Fig. 9k–p). Our experiments showed that SLC6A6 knockdown in samples from patients with AML reduced their colony-forming ability by 2.33- to 9.12-fold as compared to the controls (Fig. 4i). By contrast, SLC6A6 knockdown did not impact colonies formed by normal human CD34+ HSPCs (Fig. 4j). Importantly, while SLC6A6 knockdown reduced the engraftment of primary AML cells by 1.2- to 40-fold in patient-derived xenograft models (Fig. 4k,l), it did not significantly impair engraftment of normal human CD34+ HSPCs in xenograft models (Fig. 4m).
Collectively, our data identify a critical requirement for SLC6A6 expression in primary human AML growth and indicate that blocking taurine transport may be of value in aggressive myeloid leukaemias.
To establish the mechanisms by which taurine uptake in leukaemia cells promotes disease progression, we determined metabolic changes in the absence of taurine. Our untargeted metabolomic analysis of mouse LSCs identified significant downregulation of glycolysis/TCA related pathways and metabolites such as pyruvate, glyceraldehyde-3-phosphate and 3-phosphoglycerate in Slc6a6−/− cells, suggesting that taurine may regulate energy metabolism (Fig. 5a–c and Extended Data Fig. 10a). Consistent with this, we noted a 1.3- to 1.8-fold reduction in basal glycolysis, glycolytic capacity, maximal oxygen consumption and spare respiratory capacity in Slc6a6−/− LSCs as compared to the controls (Fig. 5d,e and Extended Data Fig. 10b). To functionally test the role of glycolysis and TCA associated metabolites, we determined whether bypassing these could rescue Slc6a6−/− defects. Our experiments showed that the colony-forming ability of Slc6a6−/− LSCs could be significantly rescued by pyruvate, sodium acetate and lactate, but not glucagon (Fig. 5f and Extended Data Fig. 10c–e). These data suggest that glycolysis, and not gluconeogenesis, is the primary downstream effector of taurine in leukaemia cells.
a, The untargeted metabolomics strategy. b, Unbiased Enrichr analysis (MetaboAnalyst; Padj ≤ 0.05). TCA, tricarboxylic acid. c, Quantification of glycolysis-associated metabolites. Data are mean ± s.e.m. n = 16 samples from n = 6 Slc6a6+/+ leukaemic mice and n = 9 samples from n = 3 Slc6a6−/− leukaemic mice. Statistical analysis was performed using unpaired Student's t-tests with Welch's correction. AUC, area under the curve; G3P, glyceraldehyde-3-phosphate; 3PG, 3-phosphoglyceric acid. d,e, Extracellular acidification (ECAR) curve (d) and quantification (e). Data are mean ± s.e.m. n = 18 independent culture wells per cohort from four bcCML samples. Data are combined from four independent experiments. f,g, CFU analysis of Lin− bcCML cells supplemented with 1 mM pyruvate (f) or 80 μM cell-permeable taurine conjugates (g). Data are mean ± s.e.m. n = 3 independent culture wells per cohort. Data were combined from two independent experiments. h, Experimental strategy. i, Unbiased Enrichr analysis of transcriptomic data. ChIP–seq, chromatin immunoprecipitation followed by sequencing; g-6-p, glucose-6-phosphate; ncRNA, non-coding RNA. j, Gene sets significantly enriched in Slc6a6+/+ leukaemic mice. GSEA, gene set enrichment analysis. k–m, Schematic (k), immunoblot (l) and quantification (m) of the indicated proteins (Extended Data Fig. 11e). Data are mean ± s.e.m. n = 9 (Slc6a6+/+) and n = 7 (Slc6a6−/−) for p-mTOR and p-pS6K. Data were combined from two independent experiments, indicated by the two colours. n = 5 (Slc6a6+/+) and n = 3 (Slc6a6−/−) for p-EIF4B. For d, e and m, statistical analysis was performed using unpaired two-tailed Student's t-tests. n,o, CFU analysis of Lin− bcCML cells treated with rapamycin (n) or 2 μM mTOR activator MHY1485 (o). Data are mean ± s.e.m. n = 6 independent culture wells per cohort. Data were combined from two independent experiments. p, CFU analysis of Lin− bcCML cells infected with vector, RAGA(Q66L) or RHEB(Q64L). Data are mean ± s.e.m. n = 9 independent culture wells per cohort. Data were combined from three independent experiments. q–s, The strategy to determine mTOR and LAMP1 co-localization in Lin− bcCML cells infected with RAGA(Q66L) or vector (vec) with or without taurine (q), microscopy images (r) and analysis (s). n = 83 (Slc6a6+/+, vector, −taurine), 58 (Slc6a6−/−, vector, −taurine), 125 (Slc6a6+/+, RAGA, −taurine), 43 (Slc6a6−/−, RAGA, −taurine), 78 (Slc6a6+/+, vector, +taurine), 68 (Slc6a6−/−, vector, +taurine), 40 (Slc6a6+/+, RAGA, +taurine) and 23 (Slc6a6−/−, RAGA, +taurine). Data were combined from two independent experiments. mTOR and LAMP1 co-colocalization is indicated by white arrows. AA, amino acids; KO, knockout. For f, g, n–p and s, statistical analysis was performed using one-way ANOVA. Scale bars, 5 μm (r). Blue text in b, i and j represents pathways of interest. The mouse and culture well images in a, h, k and q are adapted from ref. 6, Springer Nature America.
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We next tested whether taurine contributed to any cellular metabolite by determining 13C-taurine incorporation in K562 leukaemia cells. Our untargeted metabolomic approach identified 13C label only in known taurine conjugates, N-acetyl taurine and glutaurine (Extended Data Fig. 10f,g). Membrane-permeable taurine fully rescued colonies formed by Slc6a6−/− cells (Fig. 5g), and N-acetyl-taurine partly rescued this defect (Extended Data Fig. 10h), perhaps by breakdown to taurine and acetate37. By contrast, glutaurine was unable to rescue the Slc6a6−/− colony formation (Extended Data Fig. 10i). These experiments indicate that taurine, and not a secondary metabolite, promotes leukaemia growth due to an indirect effect on glycolysis, possibly through downstream signalling.
To identify signals downstream of taurine, we performed RNA-seq as well as phosphoproteome and total-proteome analyses of primary mouse leukaemia cells (Fig. 5h). Our RNA-seq analysis identified 932 downregulated and 1,158 upregulated genes in the absence of TAUT (Padj < 0.05). The 1,158 upregulated genes included pathways associated with haematopoietic cell lineage and cell cycle regulation (Extended Data Fig. 11a,b). The 932 downregulated genes primarily constituted pathways associated with glycolysis (Fig. 5i and Extended Data Fig. 11b–d), consistent with reduced abundance of glycolysis associated metabolites in these cells (Fig. 5c). To determine effectors of glycolytic downregulation on TAUT loss, we performed gene set enrichment analysis. This identified profound downregulation of oncogenic MYC and mTOR pathways (Fig. 5j and Extended Data Fig. 11c).
As mTOR signalling is known to regulate expression of glycolysis-related genes38, we tested whether TAUT loss impairs mTOR activation. Western blot analysis showed that TAUT loss results in a 2.2- to 3-fold reduction in activated mTOR, p70S6k and pEIF4B as compared to the controls (Fig. 5k–m and Extended Data Fig. 11e). Our global phosphoproteome and total-proteome analyses also showed reduced expression of phosphorylated proteins associated with mTOR signalling, as well as 3.3-fold reduced BCL2 and 1.5-fold increased LC3A expression in the absence of TAUT (Extended Data Fig. 11f,g). Like TAUT loss, TAUT inhibition with TAG and GES downregulated glycolysis-related gene expression (Extended Data Fig. 11h,i) and impaired phosphorylation of mTOR signalling (Extended Data Fig. 12a,b). Consistent with a direct impact of taurine on mTOR signalling, acute treatment in vitro and long-term taurine dosing in vivo could activate mTOR signalling (Extended Data Fig. 12c–h). Inhibiting mTOR with rapamycin impaired the growth of wild-type cells but did not impact Slc6a6−/− cells in vitro or in vivo (Fig. 5n and Extended Data Fig. 12i,k). By contrast, mTOR activation with MHY148539 rescued the colony-forming ability of Slc6a6−/− LSCs to 60% of the control, and membrane-permeable taurine rescued mTOR activation (Fig. 5o and Extended Data Fig. 12j–l). Collectively, these data indicate that mTOR signalling has a key role downstream of taurine in leukaemia cells.
Amino acid availability can be sensed by RAG GTPases to facilitate mTORC1 localization to the outer lysosomal membrane40 and its interaction with RHEB GTPases41, thereby promoting mTORC1 activation. We hypothesized that taurine may activate mTOR by promoting its interaction with RAG GTPases. To test this, we determined the effect of expressing constitutively active RAGA(Q66L) or RHEB(Q64L) on the colony-forming ability of Slc6a6 wild-type and null cells. Our experiments showed that, while RHEB(Q64L) partially rescued Slc6a6−/− colony formation, this could be fully rescued by RAGA(Q66L) (Fig. 5p). Furthermore, mTOR phosphorylation in Slc6a6−/− cells could be rescued by RAGA(Q66L) (Extended Data Fig. 12m). Finally, we directly tested whether taurine could promote mTOR interactions with lysosomes in wild-type and Slc6a6−/− leukaemia cells expressing RAGA(Q66L) (Fig. 5q). Our immunofluorescence-based analysis showed that, at the baseline, Slc6a6−/− cells have 1.2-fold lower mTOR–LAMP1 interaction, which could be fully rescued by RAGA(Q66L). Taurine supplements increased mTOR–LAMP1 co-localization to levels seen in cells expressing RAGA(Q66L). However, this interaction could not be increased further by adding taurine to RAGA(Q66L)-expressing cells (Fig. 5r,s), consistent with our colony-forming assays (Extended Data Fig. 12n).
Collectively, our studies show that the taurine–TAUT axis regulates glycolysis in myeloid leukaemia cells by promoting RAG-mediated activation of mTOR signalling.
We use scRNA-seq to define the changing landscape of the non-immune cancer microenvironment with disease progression, and to identify unique niche driven signals that promote disease progression. scRNA-seq has been effectively used to characterize the immune microenvironment of both solid tumours and leukaemias20,42,43,44,45. Despite technical limitations in detecting non-immune stromal cells, a few studies have identified antigen-presenting fibroblasts and immune-suppressive endothelial cells in lung and pancreatic cancers46,47,48. A reduction in osteoblasts has been noted during leukaemia initiation in bone marrow niche damaged by irradiation13. However, dynamic changes in the TME during leukaemia progression have not been defined.
Our temporal scRNA-seq based TME analysis identifies an expansion in MSCs and their immature osteo-associated progeny, along with a loss in mature osteo-associated cells. This skew in osteolineage populations possibly results from downregulation of MSC differentiation signals during leukaemia progression, and may explain conflicting findings using candidate osteoblast markers49,50. Our data indicate that temporal expansion in arteriolar endothelial cells is accompanied by a loss in signals that are essential for endothelial cell integrity and function, consistent with leaky blood vessels seen by in vivo imaging of the AML niche1,3,51. In addition to population-level changes, our studies identify signals such as KIT, thrombospondin, taurine and apolipoproteins from the TME that are essential for cancer progression. While multiple TME ligands such as APOE and PVR are detected through the disease trajectory, the populations expressing these can change over time. Thus, therapeutic approaches aimed at targeting TME-driven signals may be more effective than blocking TME remodelling or inhibiting individual stromal populations.
Consistent with clinicopathological similarities between AML and bcCML52, our gene expression analysis of human AML and bcCML CD34+ LSCs identifies distinct overlap. Our unbiased approach to determine LSC-enriched cell surface receptors that are essential for disease progression identified multiple genes that are known to be critical for AML, including CD9653, CD4754 and protein kinase D255. Although these are required for leukaemic progression, they are not associated with poor prognosis (TCGA-LAML), in contrast to LDLR and SLC6A6 that we describe here. It is therefore possible that other cell surface receptors identified by our analysis also have a functional role in disease progression and should be explored further to determine new therapeutically relevant signals. As the APOE–LDLR and taurine–TAUT axes that we identify are known to have a role in ageing27,56, it is possible that cancer-associated signals in our TME–LSC interactome may be of broad relevance in ageing-related disorders such as MDSs, as we see with TAUT.
Biosynthesis of taurine from cysteine is known to occur in the liver, kidneys, adipose tissues and pancreas24. Our data identify bone marrow osteolineage cells as a novel source of taurine in the leukaemia niche. Our studies blocking taurine produced by osteolineage cells establish a key role of TME-driven taurine synthesis in LSC survival and self-renewal. However, it is possible that taurine or β-alanine produced outside the bone marrow niche also contribute to disease progression. Consistent with this, our data suggest that taurine supplements can accelerate myeloid leukaemia progression in mouse models. As taurine is a common ingredient in energy drinks, and is often provided as a supplement to mitigate the side-effects of chemotherapy17, our work suggests that it may be of interest to carefully consider the benefits of supplemental taurine in patients with leukaemia.
Mechanistically, we identify a critical requirement of taurine from the microenvironment in regulating mTOR-driven glycolysis in leukaemia cells (Extended Data Fig. 12o). We can rescue the growth of Slc6a6-null LSCs by circumventing glycolysis with pyruvate or by ectopically activating mTORC1 using GTP-bound RAGA mutants. Our data showing that constitutively active Rag-GTPases can rescue mTOR interactions with lysosomes, and rescue mTOR phosphorylation, in Slc6a6−/− LSCs indicate that taurine levels in leukaemia cells may be detected by hitherto unidentified sensors, like those for arginine and leucine57,58. Our in vivo data showing a strong impact of targeting taurine uptake using genetic approaches in AML suggest that it would be of considerable interest to develop stable and effective in vivo inhibitors of taurine in future studies. In light of early clinical success of glutamine inhibitors in MDS and AML59,60, our work suggests that evaluating taurine-transport inhibitors in normal and leukaemic cells may be of therapeutic interest.
The Slc6a6 mice were bred as described previously25. For all mouse leukaemia experiments, male and female Slc6a6+/+ and Slc6a6−/− mice were used as donors and B6-CD45.1 (B6.SJL-PtprcaPepcb/BoyJ) or C57BL6/J mice were used as transplant recipients. For xenograft experiments with human cells, NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) were used as transplant recipients. All mice were 6–16 weeks of age. All animals used for in vivo studies were randomly selected to receive either control or treatments. Animals were selected based on genotype, age and sex. No statistical method was used to predetermine sample size for experiments. Adequate sample size was determined based on previous publications1,3,6. Mice were bred and maintained in the animal care facilities at the University of Rochester. All animal experiments were performed according to protocols approved by the University of Rochester's Committee on Animal Resources. Mice were housed with the same sex in ventilated cages, under a 12 h–12 h light–dark cycle with temperature (64–79 °F) and humidity (winter levels, <30%; summer levels, >70%) control. Mice were given enrichment material and fed a standard chow diet. Irradiated recipients were maintained on acid water HYDROPAC (pH 2.5–3.0) and irradiated sulfatrim diet (Mod LabDiet 5P00 with 0.025% trimeth and 0.124% sulfameth). NSG recipients were housed in BSL-2 facility. Cdo1fl/fl mice were generated in collaboration with the Transgenic and Genome Editing Core Facility at Augusta University using CRISPR–Cas9 gene editing. These mice were bred to the MSC-specific Prrx1-cre (B6.Cg-Tg(Prrx1-cre)1Cjt/J) to generate a Cdo1fl/flPrrx1-cre+ mice, where taurine production is blocked in the MSC/osteolineage cells. As Prrx1-Cre can be expressed in the female germline, only male Prrx1-cre+ mice were used for breeding and experiments. Blinding was not relevant to mouse experiments as researchers needed to know the conditions for each experiment. Flow cytometry, FACS, western blots, Seahorse analysis, sequencing and imaging used analytical machines and blinding was therefore not necessary.
Cells were suspended in Hanks' balanced salt solution (Gibco) with 5% FBS and 2 mM EDTA. Cells were prepared for FACS analysis and sorting as previously described1,6. Antibodies used for defining haematopoietic cell populations were as follows: CD3ε, CD4, CD8, GR1, CD11b, TER119, CD45R and CD19 (all for lineage), KIT, SCA1, CD48 and CD150. All antibodies were purchased from, eBioscience, BioLegend or BD Biosciences. A detailed list of antibodies is provided in Supplementary Table 2. Analysis was performed on LSRFortessa (BD Biosciences), and cell sorting was performed on the FACSAria II (BD Biosciences). Data were analysed using FlowJo.
Retroviral MSCV-BCR-ABL-IRES-GFP (or -tNGFR) and MSCV-NUP98-HOXA9-IRES-YFP (or -huCD2 and -tNGFR) were used to generate bcCML. AML was generated with MSCV-MLL-AF9-IRES-tNGFR and MSCV-NRAS(G12V)-IRES-huCD2 or MSCV-AML-ETO9a and MSCV-NRAS(G12V)-IRES-YFP. RAGA (Q66L; Addgene, 99712) and RHEB (Q64L; Addgene, 64607) were cloned into the MSCV-mCherry backbone (Addgene, 52114). Lentiviral shRNA constructs were designed and cloned into the pLV-hU6-EF1a-green or pLV-hU6-EF1a-red backbone (Biosettia) according to the manufacturer's protocol. A detailed list of shRNA sequences is provided in Supplementary Table 1. Virus was produced in 293T cells (ATCC) transfected with viral constructs along with VSV-G, Gag-Pol (retroviral production) or pRSV-rev, phCMV and pMDlg/pRRE (lentivirus production) using X-tremeGENE-HP reagent (Roche). Viral supernatants were collected for 3 to 6 days followed by ultracentrifugal concentration at 20,000 rpm for 2 h.
Bone marrow KLS cells were sorted from Slc6a6+/+ or Slc6a6−/− mice and cultured overnight in X-VIVO15 (Lonza) medium supplemented with 10% FBS (GeminiBio), 50 μM 2-mercatpoethanol, SCF (100 ng ml−1, R&D Systems), TPO (10 ng ml−1, R&D Systems) and penicillin–streptomycin (Gibco). Cells were retrovirally infected with MSCV-BCR-ABL-IRES-GFP (or -tNGFR) and MSCV-NUP98-HOXA9-IRES-YFP (or -huCD2 or -tNGFR) to generate bcCML. AML was generated by sorting bone marrow KLS cells from Slc6a6+/+ or Slc6a6−/− mice and culturing in RPMI medium (Gibco) supplemented with 20% FBS, 50 μM 2-mercaptoethanol, 100 ng ml−1 SCF (R&D Systems), 10 ng ml−1 IL-3, and 10 ng ml−1 IL-6 (R&D Systems). Cells were retrovirally infected with MSCV-MLL-AF9-IRES-tNGFR and MSCV-NRAS(G12V)-IRES-YFP cells were collected 48 h after infection, sorted by FACS for BCR-ABL+ and NUP98-HOXA9+ (bcCML only) and retro-orbitally transplanted into cohorts of sublethally irradiated (6 Gy) C57BL/6J mice. For AML-ETOa9 and NRAS, cells were transplanted into lethally irradiated (9.5 Gy) C57BL/6J recipients along with 3 × 105 RBC lysed bone marrow rescue cells. For secondary transplants, Lin− cells from primary bcCML recipient mice were transplanted into secondary sublethally irradiated recipients. The recipients were maintained on acid water HYDROPAC and irradiated sulfatrim diet and evaluated daily. Recipients receiving additional taurine (T8691, Sigma-Aldrich) were maintained on regular chow without taurine (D10012Gi, Research Diets). Taurine was dissolved in autoclaved acid water from the HYDROPAC and supplied in sterile water bottles. For in vivo venetoclax treatments, venetoclax (ABT-199; Tocris Bioscience) solution was made fresh daily in a solvent containing 10% ethanol with 60% Phosal 50 PG and 30% PEG-400, and delivered by oral gavage at a final dose of 50 mg per kg. GES (Toronto Research Chemicals or MedChemExpress) and TAG-HCl (synthesized by Enamine) were dissolved in autoclaved acid water from the HYDROPAC and supplied in sterile water bottles (GES) or intraperitoneally (i.p.) (TAG-HCl). For in vivo rapamycin treatments, rapamycin (Selleck Chemicals) stock solution (50 mg ml−1) was made in ethanol (Sigma-Aldrich). Single-use aliquots of the stock were diluted fresh each day in vehicle containing equal parts of 10% PEG-40 with 8% ethanol and 10% Tween-80 solutions. Mice received i.p. 5 mg per kg rapamycin or vehicle from days 5–10 after transplant. Premorbid animals were euthanized at the indicated experimental timepoints or at the end point. For all experiments, mice were monitored closely for signs of disease or morbidity daily and were euthanized after visible signs of hunched dorsum, failure to thrive or any signs of infection. These limits were not exceeded for any experiment. Relevant tissues were collected and analysed by flow cytometry, RNA-seq, proteomics, metabolomics or fixed for histology. Apoptosis assays were done using annexin V and 7AAD (eBiosciences). Analysis of in vivo bromodeoxyuridine (BrdU) incorporation was performed using the APC BrdU Flow Kit (BD Biosciences) after a single i.p. injection of BrdU (2 mg at 10 mg ml−1).
RNA was extracted using the RNeasy Micro or Mini kits (Qiagen) according to the manufacturer's protocols. RNA concentrations were determined using NanoDrop 1000 Spectrophotometer (Thermo Fisher Scientific). RNA quality was assessed with the Agilent Bioanalyser 2100 (Agilent Technologies). Quantitative PCR with reverse transcription (RT–qPCR) was performed on the Bio-Rad CFX96 C100 Thermocycler using Bio-Rad CFX Manager 1.1 v.4.1 (Bio-Rad) or Thermo Fisher Scientific Quant Studio 12K Flex Real Time PCR using Quant Studio v.1.2 (Thermo Fisher Scientific). RT–qPCR data were analysed using Bio-Rad CFX Manager 1.1 v.4.1 or Quant Studio v.1.2.
Microenvironmental populations were isolated as previously described61. In brief, bone and bone marrow were isolated from long bones and pelvis in 1× Media 199 (Gibco) with 2% FBS (GeminiBio). Bone marrow cells from 3–5 mice per timepoint were digested for 30 min in HBSS containing 2 mg ml−1 dispase II (Gibco), 1 mg ml−1 collagenase type IV (Sigma-Aldrich) and 20 ng ml−1 DNase type II (Sigma-Aldrich). Bone spicules were digested for 60 min in PBS supplemented with 2.5 mg ml−1 collagenase type I (Stem Cell Technologies) and 20% FBS. Digested bone marrow was red-blood-cell-lysed using RBC Lysis Buffer (eBioscience). Bone and bone marrow cells were pooled and CD45+TER119+ haematopoietic cells were magnetically depleted on the autoMACS cell separator (Miltenyi Biotec). The CD45−TER119− stromal cells were either stained and analysed for candidate populations by flow cytometry (BD LSRFortessa) or further enriched by sorting (BD FACSAria II) and processed for scRNA-seq.
Cell suspensions were processed to generate scRNA-seq libraries using the Chromium Next GEM Single Cell 3′ GEM, Library and Gel Bead Kit v3.1 (10x Genomics) according to the manufacturer's recommendations. The samples were loaded onto the Chromium Single-Cell Instrument (10x Genomics) to generate single-cell gel bead in emulsions (GEMs). GEM reverse transcription (GEM-RT) was performed to produce a barcoded, full-length cDNA from polyadenylated mRNA. After incubation, GEMs were broken, the pooled GEM-RT reaction mixtures were recovered and cDNA was purified with silane magnetic beads (DynaBeads MyOne Silane Beads, Thermo Fisher Scientific). The purified cDNA was further amplified by PCR to generate sufficient material for library construction. Enzymatic fragmentation and size selection was used to optimize the cDNA amplicon size and indexed sequencing libraries were constructed by end repair, A-tailing, adaptor ligation and PCR. The final libraries contained the P5 and P7 priming sites used in Illumina bridge amplification. Mouse samples were sequenced on the Illumina NovaSeq 6000 S2 flowcell while human samples were sequenced across several lanes of the Illumina NovaSeq X-plus 25B flowcell. The samples were demultiplexed and counted using cellranger v.4.0.0 mkfastq and count, using the default parameters. The samples were aligned to a custom reference containing the 10x provided mm10-2020-A mouse reference and an additional eGFP sequence.
Seurat v.4.1.0 within R v.4.1.1 was used for most of processing. Moreover, dplyr v.1.2.0 and tidyverse v.1.3.2 were used extensively for data piping and transformation. Samples were imported and cells were filtered for at least 200 features captured per cell and features were filtered for expression in at least 3 cells. Additional filters were applied, filtering out all cells with higher than 5% mitochondrial content and filtering out all cells positive for CD45, CD71, TER119 and eGFP. All samples were merged using ‘merge' and normalized using SCTransform, regressing out the impact of mitochondrial features. Principal component analysis was performed using the first 40 principal components (RunPCA) and clusters were generated using FindNeighbors and FindClusters (resolution=0.5). UMAP dimensional reduction was also performed using RunUMAP using the first 30 principal components. Clusters were initially typed using scMCA v.0.2.0. Populations typed as non-stromal (B cell, pre-B cell, pro-erythrocyte, pro-erythroblast, neutrophil and megakaryocyte) were filtered from the dataset. Populations were further typed using published bone marrow stroma markers13. FindAllMarkers was used within the context of specific populations to determine which genes change significantly over time. DEGreport-implemented (v.1.30.3) degPatterns was used to tie lineage-specific expression patterns to the timepoints. Expression patterns corresponding to broadly increased or decreased expression over time were passed to gene set enrichment against KEGG_2019, GO_Biological_Process_2021, WikiPathways_2019_Mouse and ChEA_2022 databases using EnrichR-3.0.
Bone marrow aspirates were obtained from patients with MDS/AML after written informed consent in accordance with the Declaration of Helsinki and approval of University of Rochester institutional review board (IRB). To isolate the bone spicules, bone marrow aspirates were passed through a 40 μm cell strainer. The filter containing spicules was washed with PBS and placed in a six-well plate. The spicules were digested for 1 h in collagenase (Stem Cell Technologies) at 37 °C. After filtering, the filtered aspirate was used to isolate bone marrow mononuclear cells by density centrifugation (Ficoll-Paque, GE Healthcare). Digested bone cells and bone marrow mononuclear cells were pooled and stained with CD45–APC (BD Biosciences) followed by staining with anti-APC microbeads (Miltenyi Biotec). The stained cells were magnetically depleted for CD45− cell fraction using LD columns (Miltenyi Biotec). The CD45− cells were processed for scRNA-seq as described above.
Samples containing cells expressing COL1A1 were integrated into a single dataset using Seurat v.4.1.0 within R v.4.1.1. Cells with mitochondrial features making up greater than 25% of the detected transcripts were removed. The samples were scaled and normalized together, regressing out mitochondrial and globin-related content. Globin-related content was determined using HBB, HBA2, HBA1, HBD and HBM. Further regression was performed using Harmony v.0.1.0 to reduce the impact of sample specific effects. From there, the standard Seurat procedure was used, clustering to a resolution of 0.8.
A normal bone marrow reference was created using GEO GSE253355 (ref. 23). Data from this submission were normalized, PCA was run using the first 50 principal components, and UMAP was run using the first 50 principal components within Seurat v.5.0.3.9911. This dataset was then used within Azimuth v.0.5.0 to create the reference using Azimuth standard methods. The samples were then typed using this reference with the RunAzimuth function against the L1, L2 and coarse annotations.
Total RNA was purified with Qiagen RNeasy PLUS kit according to the manufacturer recommendations and eluted in nuclease-free water. The total RNA concentration was determined using the NanoDrop 1000 spectrophotometer (NanoDrop), and the RNA quality was assessed using the Agilent Bioanalyser (Agilent Technologies). The TruSeq Stranded mRNA Sample Preparation Kit (Illumina) was used for next generation sequencing library construction according to the manufacturer's protocols. In brief, mRNA was purified from 200 ng total RNA with oligo-dT magnetic beads and fragmented. First-strand cDNA synthesis was performed with random hexamer priming followed by second-strand cDNA synthesis using dUTP incorporation for strand marking. End repair and 3′ adenylation was then performed on the double-stranded cDNA. Illumina adaptors were ligated to both ends of the cDNA, purified by gel electrophoresis and amplified with PCR primers specific to the adaptor sequences to generate cDNA amplicons of approximately 200–500 bp in size. The amplified libraries were hybridized to the Illumina single end flow cell and amplified using the cBot (Illumina). Single-end reads of 100 nucleotides were generated for each sample using Illumina's HiSeq2500v4.
Raw reads generated from the Illumina basecalls were demultiplexed using bcl2fastq v.2.19.0. Quality filtering and adapter removal was performed using FastP v.0.20.1. Processed reads were then mapped to the human reference genome (hg38 + gencode v36; https://www.gencodegenes.org/human/release_36.html) using STAR_2.7.6a. Reads mapping to genes were counted using subread featurecounts v.2.0.1. Differential expression analysis was performed using DESeq2 v.1.28.1 with a Padj threshold of 0.05 within R v.4.0.2. Gene Ontology analyses were performed using the EnrichR-3.0 package.
To determine significantly expressed receptors, the differential expression results from human RNA-seq described above were first filtered for significantly changing (Padj < 0.05) genes with a log-transformed fold change value of greater than 0. A list of potential cell surface receptors was generated using this gene list in conjunction with cell surface proteins detailed within the Cell Surface Protein Atlas19 and essential for LSC growth in vivo6. The resultant gene list was further reviewed for genes that are not truly expressed within the cell surface, leading to the removal of CHST11, ST3GAL4, ACAA1, CLCN6, CHPF2, CTSK, ATP6AP1, CTSD, PNPLA6, DMXL2, TUBB6, MAN2B2, CLN3, MGAT4B, MYH9 and PIGG from further review. Ligand expression from the temporal scRNA-seq dataset corresponding to bcCML and AML expressed receptors was determined by differential expression across the populations. Differentially expressed genes were filtered for corresponding ligands using a combination of nichenetr (v.1.1.0)62 and literature-supported interactions. These included NRP163, ADSL64,65, CDO1 and CSAD for taurine synthesis66, GADL1 and CNDP1 for β-alanine synthesis67,68, KIT69, CD15570 and CD3371 for those not captured within this mapping. The Broad Institute hosted dataset20 was used as a stand in for healthy immune microenvironment within the context of AML. Counts (RNA_soupX1.mtx.gz) and metadata (metadata_clustering_w_header_upd.csv) were downloaded from the Broad Single Cell Portal (https://singlecell.broadinstitute.org/single_cell/study/SCP1987/an-inflammatory-state-remodels-the-immune-microenvironment-and-improves-risk-stratification-in-acute-myeloid-leukaemia) and imported using Seurat. FindMarkers was used to determine which genes were upregulated within the microenvironment in relation to the other populations. Significantly expressed genes were then filtered for ligands using the same method as the stromal microenvironment. Significantly expressed ligand and receptor mappings within the stroma microenvironment, the immune microenvironment and within bcCML and AML human bulk RNA-seq data were visualized using circlize v.0.4.15. For illustration purposes, ligands expressed with a log-transformed fold change of 5 or higher were limited to 5.
The RNeasy Plus Micro Kit (Qiagen) was used for RNA extraction. RNA concentration was determined using the NanoDrop 1000 spectrophotometer (NanoDrop), and the RNA quality was assessed using the Agilent Bioanalyser 2100 (Agilent Technologies). A total of 1 ng of total RNA was pre-amplified using the SMARTer Ultra Low Input kit v4 (Clontech) according to the manufacturer's recommendations. The quantity and quality of the subsequent cDNA was determined using the Qubit Fluorometer (Life Technologies) and the Agilent Bioanalyser 2100 (Agilent). Then, 150 pg of cDNA was used to generate Illumina-compatible sequencing libraries using the NexteraXT library preparation kit (Illumina) according to the manufacturer's protocols. The amplified libraries were hybridized to the Illumina flow cell and sequenced using the Illumina NextSeq 550 (Illumina). Single-end reads of 100 nucleotides were generated for each sample. The mouse bulk RNA-seq samples were processed otherwise identical to the human bulk RNA-seq with two exceptions: m38 + gencode M27 reference (https://www.gencodegenes.org/mouse/release_M27.html) for use within alignment and counting, and ‘-s 0' being used within subread featureCounts. See the ‘Primary human CD34+ cell RNA-seq analysis' section for details on differential expression analysis.
For human RNA-seq experiments and other studies, CD34+ cells were isolated from bone marrow samples of healthy donors and samples from patients with AML and bcCML obtained under University of Rochester institutional review board-approved protocols with written informed consent in accordance with the Declaration of Helsinki. The normal human CD34+ HSPCs used in all functional assays were purchased (Stem Cell Technologies). Cells were cultured in Iscove's modified Dulbecco's medium with 10% FBS, 100 IU ml−1 penicillin–streptomycin (Gibco) and 55 μM 2-mercaptoethanol, 1× LDL (Sigma-Aldrich) and supplemented l-glutamine with 100 ng ml−1 SCF and TPO (R&D Systems). Human leukaemia cell lines K562, THP1 and M-V-411 (ATCC) were maintained in RPMI/IMDM with 10% FBS, 100 IU ml−1 penicillin–streptomycin (Gibco). These cell lines were validated by vendor. MDS-L cells (from K. Tohyama) were authenticated in house by flow cytometry as CD45+CD34+CD38+ and maintained in RPMI with 10% FBS supplemented with 20 ng ml−1 IL-3 (PeproTech). Cell lines were not tested for mycoplasma. For colony-forming assays with shRNAs, leukaemia and normal cells were transduced with the indicated lentiviral shRNAs. Cells were sorted 24 h after infection and plated in CFU assays or transplanted in sublethally irradiated NSG mice.
MSCs were isolated from leukaemic mice and cultured in 10 cm dishes in MEMα with no ascorbic acid (Gibco) supplemented with 15% FBS and 100 IU ml−1 penicillin–streptomycin (Gibco). Then, 6 days after culture initiation, the cells were sorted for CD45−CD3−B220−TER119−GR1−CD31−CD51+SCA1+ MSCs. Sorted cells were expanded in the medium descried above. For co-culture experiments, 50,000 MSCs were plated in a 48-well plate, and transduced with the indicated lentiviral shRNAs. Then, 3 days after infection, osteogenic differentiation was induced by switching to MEMα (Gibco) supplemented 15% FBS, 100 IU ml−1 penicillin–streptomycin (Gibco) along with 50 μg ml−1 ascorbic acid (Sigma-Aldrich), 10 mM β-glycerolphosphate (Sigma-Aldrich) and 100 nM dexamethasone (Sigma-Aldrich) for 6 days. On day 6 after differentiation, 100,000 Lin− bcCML cells were added in X-Vivo supplemented with 10% FBS, 50 μM 2-mercatpoethanol and penicillin–streptomycin. Then, 3 days after co-culture, leukaemia cells were analysed for cell viability and plated in methylcellulose for colony-forming assays. Microscopy images were obtained on THE Olympus CKX41 SYSTEM using CellSens Entry v.2.3 (Olympus).
For bone marrow transplants, 500 HSCs were isolated from bone marrow of Slc6a6+/+ or Slc6a6−/− mice and transplanted into lethally irradiated (9.5 Gy) CD45.1 mice along with 2 × 105 SCA1-depleted bone marrow rescue cells. For subsequent secondary transplants, 2 × 106 red-blood-cell-lysed bone marrow cells isolated from primary recipient mice were transplanted into lethally irradiated (9.5 Gy) CD45.1 mice. Peripheral blood of recipient mice was collected every 4 weeks for 4 months after transplant and bone marrow analysed at the end of 4 months.
For colony assays with mouse cells, the indicated numbers of Lin− bcCML cells or KIT+ AML cells were plated in methylcellulose medium (M3234, StemCell Technologies). Colonies were scored at 7 days. For colony assays with human cell lines or patient-derived AML samples, cells were plated in methylcellulose medium (H4434; StemCell Technologies). Colony numbers were counted 10–14 days after plating. Taurine antagonist or TAG (synthesized by Enamine; 92% pure), GES (G827500, Toronto Research Chemicals), taurine (T8691, Sigma-Aldrich), mTOR activator (MHY1485, Sigma-Aldrich) and Venetoclax (ABT-199, Tocris Bioscience) were used as described. Venetoclax and GES Synergy quantification was calculated using Chou-Talalay method72.
The Seahorse XF Glycolysis Stress Test Kit (Agilent Technologies, 103020-100) and the Seahorse XF cell mito stress test kit (Agilent Technologies, 103015-100) were used to measure glycolytic flux (ECAR) and oxygen consumption (OCR) respectively. Mouse Lin− bcCML cells were sorted and cultured for 48 h in X-Vivo supplemented with 10% FBS, SCF and TPO. Then, 1 h before the analysis, 50,000–100,000 cells were seeded in Cell-Tak-coated (Corning, 324240) 96-well XF96 well plates in Seahorse XF medium (Agilent Technologies, 102353-100), and the plate was incubated at 37 °C. ECAR data were measured after sequential addition of glucose (10 mM), oligomycin (1μM) and 2-deoxyglucose (50 mM) using the XF96 analyser (Agilent Technologies). OCR data were measured after sequential addition of oligomycin (1.5 μM), carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone (FCCP) (0.5 μM), rotenone and antimycin (0.5 μM) using the XF96 analyser. Data were analysed using Wave v.2.6.3 (Agilent Technologies).
Cell lysates prepared in 1× RIPA (Thermo Fisher Scientific) supplemented with 1× protease, 1× phosphatase inhibitors (Cell Signaling Technology) and 250 IU benzonase nuclease (Millipore Sigma) were separated on gradient polyacrylamide gels and transferred to nitrocellulose blotting membrane (0.45 μM; GE Healthcare). Primary antibodies against phosphorylated mTOR, mTOR, phosphorylated S6K, S6K, pEIF4B, EIF4B and β-actin (Cell Signaling Technology) or tubulin (Abcam) were used. Horse-radish peroxidase (HRP)-conjugated anti-rabbit antibodies (Cell Signaling Technology) were used to detect primary antibodies. Immunoblots were developed using SuperSignal West Femto Maximum Sensitivity Substrate (Thermo Fisher Scientific). Immunoblots were imaged using the LI-COR Odyssey M system using Empiria Studio v.2.3 (LI-COR). Images were analysed using Empiria Studio v.3.2.0.186 (LI-COR). Raw gel images are provided in Supplementary Fig. 1.
Cells were lysed in 50 μl of 5% SDS, 100 mM triethylammonium bicarbonate (TEAB, Thermo Fisher Scientific) and 50 μg of protein from each sample was reduced with dithiothreitol (Sigma-Aldrich). Proteins were alkylated and trapped to S-Trap micros (Protifi), digested with trypsin and extracted by sequential additions of 0.1% trifluoroacetic acid (TFA) in acetonitrile. Then, 1% of each sample was used for global DIA analysis, and the remaining sample was frozen and dried down in the Speed Vac (Labconco) before TMT labelling. The samples were reconstituted in TEAB and labelled with TMT 10-plex reagents (Thermo Fisher Scientific) according to the manufacturer's protocol. All of the samples were combined and dried down in a speed vac before desalting with 0.1% TFA in acetonitrile using the 130 mg C18 sorbent sep-pak attached to a 3 ml syringe (Waters). Desalted samples were frozen and dried down before phosphorylation enrichment using the High-Select FeNTA Enrichment Kit (Thermo Fisher Scientific) according to the manufacturer's protocol. Enriched phosphorylated samples were frozen, dried down and fractionated using C18 spin columns. The fractions were eluted by stepwise addition of 10 mM AmmOH with increasing acetonitrile concentrations: 3.5, 6.5, 9.5, 12.5, 15.5, 18.5, 27, 50%. The eight fractions were concatenated to four by combining fractions 1/5, 2/6, 3/7, 4/8. Fractionated samples were frozen, dried down and reconstituted in 0.1% TFA for MS analysis.
Non-TMT-tagged peptides were injected onto a 75 μm × 2 cm trap column before refocusing on a 100 μm × 15 cm C18 column with 1.8 μm beads (Sepax) using the Vanquish Neo UHPLC (Thermo Fisher Scientific) system connected to the Orbitrap Astral mass spectrometer (Thermo Fisher Scientific). Ions were introduced to the mass spectrometer using a Nanospray Flex source operating at 2 kV. Solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in 80% acetonitrile) formed the gradient starting at 1% B and ramped to 99% B for a total runtime of 14 m. After each run was completed, the column was re-equilibrated with 1% B before the next injection. The Orbitrap Astral was operated in data-independent acquisition (DIA) mode for global proteomic analysis, with MS1 scans acquired at a resolution of 240,000 with a maximum injection time of 5 ms over a range of 390–980 m/z. DIA MS2 scans were acquired using 2 Da windows, a 3 ms maximum injection time, an HCD collision energy of 25% and a normalized automatic gain control (AGC) of 500%. Fragment ions were collected over a scan range of 150–2,000 m/z. Phosphoprotein analysis was carried out on the same Vanquish Neo UHPLC and Orbitrap Astral mass spectrometer system, but with several changes to the LC and instrument settings. To account for ratio compression inherent with TMT, samples were high-pH fractionated to reduce complexity before MS analysis. A longer gradient of 5–30% B over 48 min was used to further separate phosphopeptides. A data-dependent acquisition method using a FAIMS Pro Duo (Thermo Fisher Scientific) was used with three compensation voltages (−40 V, −60 V, −80 V) to further reduce the sample complexity. For each CV, a full scan was acquired over a range of 400–1,500 m/z in the Orbitrap, while MS2 scans were analysed in the Astral analyser for 1 s, after which the instrument switched to the next CV and the process was repeated for a total cycle time of 3 s. Peptides with a charge state of between 2 and 6 were isolated based on intensity with a 0.5 Da isolation window, and were fragmented with an HCD collision energy of 35%. The maximum injection time was 20 ms, and the normalized AGC target was 100%. Dynamic exclusion was set to 15 s.
The global DIA raw data were processed with DIA-NN v.1.8.1 (https://github.com/vdemichev/DiaNN) using library-free analysis mode. The library was annotated using the Mus musculus UniProt database (UP000005640_9606). For precursor ion generation, the maximum number of missed cleavages was set to 1, maximum number of variable modifications to 1 for Ox(M), peptide length range to 7–30, precursor charge range to 2–3, precursor m/z range to 380–980, and fragment m/z range to 150–2,000. The quantification was set to ‘Robust LC (high precision)' mode with RT-dependent median-based cross-run normalization enabled, MBR enabled, protein inferences set to ‘Genes' and ‘Heuristic protein inference' turned off. Precursors were filtered at library precursor q-value (1%), library protein group q-value (1%) and posterior error probability (50%). Protein quantification was carried out using the MaxLFQ algorithm (https://github.com/vdemichev/diann-rpackage) and the number of peptides quantified in each protein group was determined using the DiannReportGenerator Package (https://github.com/URMC-MSRL/DiannReportGenerator). Further filtering, missing value imputation and statistical tests were performed using Perseus73. Phosphoproteome raw data were searched using the CHIMERYS within the Proteome Discoverer software platform v.3.1 (Thermo Fisher Scientific), allowing for up to two missed cleavages, with a fragment mass tolerance of 10 ppm. Carbamidomethyl on cysteine, and TMT on lysine and peptide N terminus were set as fixed modifications, while oxidation of methionine and phosphorylation of serine, threonine and tyrosine were set as variable modifications. Reporter ions were quantified using the Reporter Ions Quantifier node, with an integration tolerance of 20 ppm, and the integration method was set to ‘most confident centroid'.
Paraffin-embedded 4 μm human bone marrow biopsy sections were deparaffinized in xylene and antigen epitopes were retrieved using BOND epitope retrieval solution (pH 9) for 10 min. Endogenous peroxidases were quenched with a 10 min incubation in 3% H2O2-methanol solution. The sections were then blocked in 10% donkey serum for 60 min. The sections were either incubated with anti-CDO1 (Proteintech) overnight or with anti-osterix (Abcam) for 2 h at room-temperature. The sections were washed in PBS and stained with HRP-conjugated donkey anti-rabbit secondary antibody (Jackson Immunoresearch) for 1.5 h at room temperature. After three washes, colour was developed using the ImmPACT DAB Substrate kit (Vector laboratories, SK-4105) according to the manufacturer's protocol. The sections were then counterstained with haematoxylin. Three different areas of each section were imaged on the Olympus BX41 microscope with a ×20 (0.5 NA) objective. Images were analysed using the IHC plugin toolbox in Fiji v.1.54g.
Leukaemia cells were cultured in RPMI without amino acids (US Biologicals) in the presence or absence of taurine (Sigma-Aldrich) and seeded on eight-well cover glass chambers (BD biosciences) coated with Cell-Taq (Corning) according to the manufacturer's protocols. MSCs were grown and differentiated in 35 mm glass-bottom dishes with 14 mm microwell (MatTek Life Sciences). Cells were fixed with 4% PFA and blocked in blocking buffer (PBS with 5% donkey serum, 1% BSA and 0.1% Triton X-100) and incubated overnight in primary antibodies diluted in the blocking buffer. Primary antibodies used included mTOR (Cell Signaling Technologies), LAMP1 (DHSB) or CDO1 (Proteintech). Cells were washed in PBS containing 0.1% Tween-20 (Sigma-Aldrich), stained with Alexa-Fluor-conjugated secondary antibodies (Thermo Fisher Scientific), and mounted in Fluormount G (Thermo Fisher Scientific).
Immunofluorescence images were acquired with the Teledyne Photometrics Prime BSI express sCMOS camera mounted on the Nikon ECLIPSE Ti2 inverted microscope equipped with the NIS-Elements 6D imaging acquisition module (v.5.42.06). The Nikon D-LEDI fluorescence LED illumination system (equipped with 385 nm, 488 nm, 568 nm and 621 nm excitation wavelengths) was used as the primary illumination source. Specific illumination wavelengths were selected by combining a large field of view quad-filter cube (DAPI/FITC/TRITC/CY5; 96378) with specific Lumencor emission filters (FF01-474/27-32, FF01-515/30-32, FF01-595/31-32, FF02-641/75-32). MSC and osteolineage cultures were imaged with the Nikon CFI60 Plan Apochromat Lambda D ×20 (0.8 NA) objective lens, and leukaemia cells were imaged using the Nikon CFI60 Plan Apochromat Lambda D ×100 (1.45 NA) objective lens. Images were deconvoluted using Imaris v.10.2 (Oxford instruments), and Pearson's co-localization analysis was performed using the JACoP BIOP plugin in Fiji v.1.54g.
Lineage depleted Slc6a6+/+ and Slc6a6−/− mouse leukaemia cells were fixed using BD Cytofix/Cytoperm Fixation/Permeabilization Kit (BD Bioscience) according to the manufacturer's protocols. Cells were stained with primary antibodies against phosphorylated mTOR (Cell Signaling Technology). Cells were then stained with donkey anti-rabbit secondary antibody conjugated with Alexa Fluro 488 (Invitrogen) to detect p-mTOR. Analysis was performed on the LSRFortessa (BD Biosciences) system. Data were analysed using FlowJo software.
Bone marrow cells or bone marrow peripheral fluid were isolated from femurs in Hanks' balanced salt solution (Gibco) with 5% FBS and 2 mM EDTA. For taurine analysis of bone marrow cells after genetic loss of Slc6a6 or treatment of leukaemia cells with taurine inhibitor treatments, cells were lysed in RIPA buffer (Thermo Fisher Scientific) with benzonase nuclease (Sigma-Aldrich). For bone marrow interstitial fluid analysis, one femur was crushed in 1 ml of buffer, filtered and centrifuged at 1,500g for 5 min. The supernatant was concentrated using 10,000 MWCO spin columns (Corning). Then, 25 μl of concentrated samples was quantified using the Taurine Assay kit (Sigma-Aldrich/Abcam) according to the manufacturer's protocols on the BioTek Synergy 2 plate reader using Gen5 v.3.11 (BioTek). The samples were corrected for taurine amounts in unconditioned fresh medium or buffer. Alternatively, cell pellets were processed as described in the liquid chromatography–mass spectrometry (LC–MS) section below, and taurine levels were measured by LC–MS (Orbitrap Exploris 240).
For untargeted metabolomics, spleens from mice bearing Slc6a6+/+ or Slc6a6−/− leukaemias were quickly dissected and dissociated in Hanks' balanced salt solution (Gibco) with 5% FBS and 2 mM EDTA at 4 °C. Leukaemia cells were collected and maintained at 4 °C all through the process of isolation, staining and magnetic sorting to minimize metabolic changes. Lin+ (CD3ε−CD4−CD8−GR1−CD11b−TER119−CD45R−CD19−) leukaemia cells were magnetically depleted using LD columns (Milteny Biotec). Lin− leukaemia stem cell fractions were washed with PBS containing 5 mM glucose and centrifuged at 3,000g for 1 min, snap-frozen and processed for metabolomics as described in the ‘LC–MS analysis' section below.
K562 cells were cultured in serum-free RPMI-1640 medium in six-well plates for 48 h. The cells were then cultured in serum free RPMI-1640 supplemented with 200 μM taurine (1,2 13C2, 98%; Cambridge Isotope Labs) or no additional taurine for 24 h. The cells were washed with PBS containing 5 mM glucose and centrifuged at 3,000g, snap-frozen and processed for metabolomics as described below in the ‘LC–MS analysis' section.
Frozen cell pellets were resuspended at 2 million cells per 1 ml of 80% methanol by vortexing, transferred to −80 °C for 30 min and then to regular ice for 30 min with vortexing every 10 min. Next, the samples were centrifuged at 17,000g for 10 min and 90% of supernatant was dried down in a vacuum evaporator (Thermo Fisher Scientific). The samples were reconstituted in 50% acetonitrile (A955, Thermo Fisher Scientific) at a volume equal to 10% of the dried down volume and transferred to glass vials for LC–MS analysis. The metabolite extracts were analysed by high-resolution MS with the Orbitrap Exploris 240 (Thermo Fisher Scientific) system coupled to the Vanquish Flex LC system (Thermo Fisher Scientific). Then, 2 µl of the samples was injected onto the Waters XBridge XP BEH Amide column (150 mm length × 2.1 mm inner diameter, 2.5 µm particle size) maintained at 25 °C, with a Waters XBridge XP VanGuard BEH Amide (5 mm × 2.1 mm inner diameter, 2.5 µm particle size) guard column. For positive-mode acquisition, mobile phase A was 100% LC–MS-grade H2O with 10 mM ammonium formate and 0.125% formic acid. Mobile phase B was 90% acetonitrile with 10 mM ammonium formate and 0.125% formic acid. For negative-mode acquisition, mobile phase A was 100% LC–MS-grade H2O with 10 mM ammonium acetate, 0.1% ammonium hydroxide and 0.1% medronic acid (Agilent). Mobile phase B was 90% acetonitrile with 10 mM ammonium acetate, 0.1% ammonium hydroxide and 0.1% medronic acid. The gradient was 0 min, 100% B; 2 min, 100% B; 3 min, 90% B; 5 min, 90% B; 6 min, 85% B; 7 min, 85% B; 8 min, 75% B; 9 min, 75% B; 10 min, 55% B; 12 min, 55% B; 13 min, 35% B; 20 min, 35% B; 20.1 min, 35% B; 20.6 min, 100% B; 22.2 min, 100% B; all at a flow rate of 150 μl min−1, followed by 22.7 min, 100% B; 27.9 min, 100% B at a flow rate of 300 μl min−1, and finally 28 min, 100% B at flow rate of 150 μl min−1, for a total length of 28 min. The H-ESI source was operated in positive mode at spray voltage 3,500 V or negative mode at spray voltage 2,500 V with the following parameters: sheath gas 35 au, aux gas 7 au, sweep gas 0 au, ion transfer tube temperature 320 °C, vaporizer temperature 275 °C, mass range 70 to 1,000 m/z, full scan MS1 mass resolution of 120,000 FWHM, RF lens at 70% and standard AGC. LC–MS data were analysed using Compound Discover (v.3.3, Thermo Fisher Scientific) and El-Maven software74 for peak-area determination and compound identification. Compounds were identified by matching to LC–MS method-specific retention time values of external standards and MS2 spectral matching to external standards and the mzCloud database (Thermo Fisher Scientific). Raw P values were calculated using pairwise Mann–Whitney–Wilcoxon rank-sum tests and Padj values were computed using Benjamini–Hochberg false-discovery rate correction. Data were uploaded to the Metabolomics Workbench75.
Statistical analyses were performed using GraphPad Prism software v.6.0 (GraphPad). Data are mean ± s.e.m. One-way ANOVA, two-way ANOVA, unpaired two-sided Student's t-tests, multiple unpaired t-tests corrected with the Benjamin–Hochberg method, ratio-paired t-tests, and log-rank tests were used to determine statistical significance. Combination index and isobologram plots were made using CompuSyn72.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
The scRNA-seq and bulk RNA-seq data for this publication are available under GEO accessions GSE226372 (human bulk RNA-seq), GSE227082 (mouse bulk RNA-seq), GSE226644 (mouse temporal scRNA-seq) and GSE288862 (scRNA-seq of human MDS and AML bone marrow microenvironment). A shiny app hosting the mouse temporal scRNA-seq is available online (https://wilmot-genomics.shinyapps.io/gse226644/). Receptor and ligand interactions were determined using the NicheNet62, Cell Surface Protein atlas19, AML and healthy immune microenvironment20 datasets. The link between SLC6A6 and LDLR expression and AML prognosis was determined using UCSC Xena Browser (https://xenabrowser.net/). Wild-type and Slc6a6−/− proteomics data are available at ProteomeXchange (PXD062322). The library was annotated using M. musculus UniProt ‘one protein sequence per gene' database (UP000005640_9606, downloaded April 2021). WT and Slc6a6−/− metabolomics data (ST003835) and 13C-taurine tracing data (ST003836) are available online. Source data are provided with this paper.
Mouse and human scRNA datasets were processed using Seurat (v.4.1.0; https://github.com/satijalab/seurat/releases/tag/v4.1.0) within R (v.4.1.1; https://github.com/r-hub/R/releases/tag/v4.1.1). Time-course analysis was performed using DEGreport (v.1.30.3; https://lpantano.github.io/DEGreport/index.html). Pathway enrichment was performed using EnrichR (v.3.0; https://cran.r-project.org/web/packages/enrichR/). Sample integration within human scRNA datasets was performed using Harmony (v.0.1.0; https://github.com/immunogenomics/harmony). Integrating external datasets into the human scRNA dataset was done using Seurat (v.5.0.3.99911; https://github.com/satijalab/seurat/releases/tag/v5.0.3) and Azimuth (v.0.5.0; https://github.com/satijalab/azimuth) within R (v.4.3.1; https://github.com/r-hub/R/releases/tag/v4.3.1). Mouse and human bulk RNA datasets were trimmed and quality-filtered using FastP (v.0.20.1; https://github.com/OpenGene/fastp/releases/tag/v0.20.1). Read data were aligned using STAR (v.2.7.6a; https://github.com/alexdobin/STAR/releases/tag/2.7.6a) and counted using subread-featureCounts (v.2.0.1; https://subread.sourceforge.net/). Differential expression analysis was performed using DESeq2 (v.1.28.1; https://bioconductor.org/packages/release/bioc/html/DESeq2.html) within R (v.4.0.2; https://github.com/r-hub/R/releases/tag/v4.0.2). Pathway enrichment analysis within the bulk RNA datasets was performed using EnrichR (v.3.0, above). Ligand–receptor visualization was performed using NicheNetR (v.1.1.0; https://github.com/saeyslab/nichenetr) and Circlize (v.0.4.15; https://github.com/jokergoo/circlize) within R (v.4.1.1, above). Ggplot2 (https://github.com/tidyverse/ggplot2) and dplyr (https://github.com/tidyverse/dplyr) were used for figure generation and data manipulation throughout. A shiny app hosting the mouse temporal scRNA-seq is available online (https://wilmot-genomics.shinyapps.io/gse226644/) and was generated using ShinyCell (v.2.1; https://github.com/SGDDNB/ShinyCell).
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We thank H. Land for scientific discussions and advice; J. Tran for technical support; K. Tohyama for MDS-L cells; W. Pear and A. M. Pendergast for the BCR-ABL construct; D.G. Gilliland for the NUP98-HOXA9 construct; C. Counter for the NRAS(G12V) construct; S. Armstrong for the MLL-AF9 construct; S. Lowe for the AML-ETO9a construct; the staff at the Cytometry, Genomics, Imaging and Radiation, and Metabolomics Shared Resources supported in part by University of Rochester Wilmot Cancer Institute Support Grant P30CA272302; the staff at the URMC Histology, Biochemistry and Molecular Imaging facility supported by P30AR069655; and the members of the Metabolomics Workbench/National Metabolomics Data Repository supported by U2C-DK119886 and OT2-OD030544. Open access funding was provided by Wilmot Cancer Institute. C.M.K. was supported by NIH Training Grant T32AR076950; and C.T.J. by the Nancy Carroll Allen Chair in Hematology Research and a Leukemia and Lymphoma Society SCOR grant (7033-24). J.B. is a recipient of American Society of Hematology Scholar Award, and Leukemia Research Foundation New Investigator Award. This work was supported by NIH grants R01AG079556 awarded to L.M.C. and J.L.L.; R35CA242376 to C.T.J.; and R01DK133131 and R01CA266617 to J.B.
These authors contributed equally: Sonali Sharma, Benjamin J. Rodems, Cameron D. Baker, Christina M. Kaszuba
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA
Sonali Sharma, Benjamin J. Rodems, John M. Ashton & Jeevisha Bajaj
Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
Sonali Sharma, Benjamin J. Rodems, Christina M. Kaszuba, Edgardo I. Franco, Francisco A. Chaves, Laura M. Calvi, Michael W. Becker, Jane L. Liesveld, Joshua C. Munger, John M. Ashton & Jeevisha Bajaj
Genomics Research Center, University of Rochester Medical Center, Rochester, NY, USA
Cameron D. Baker & John M. Ashton
Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
Christina M. Kaszuba & Edgardo I. Franco
Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA
Bradley R. Smith & Joshua C. Munger
Department of Bioscience and Technology, Graduate School of Bioscience and Technology, Fukui Prefectural University, Fukui, Japan
Takashi Ito
Mass Spectrometry Resource Laboratory, University of Rochester, Rochester, NY, USA
Kyle Swovick, Kevin Welle & Sina Ghaemmaghami
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
Yi Zhang, Philip Rock & W. Richard Burack
Department of Biology, University of Rochester, Rochester, NY, USA
Sina Ghaemmaghami
Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
Laura M. Calvi, Michael W. Becker & Jane L. Liesveld
Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
Archan Ganguly
Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA
Paul S. Brookes
Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Craig T. Jordan
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S.S. performed most of the cell culture experiments and the biochemical analyses. B.J.R. and C.M.K. carried out the in vivo leukaemia progression experiments. C.D.B. performed all of the mouse and human microenvironment scRNA-seq analyses. E.I.F. provided experimental data and performed image analysis. B.R.S., P.S.B. and J.C.M. carried out the metabolomic analysis and provided experimental advice. T.I. provided the Slc6a6-knockout mice. K.S., K.W. and S.G. performed the proteomic analyses. Y.Z., P.R. and F.A.C. helped to process the patient samples. L.M.C., M.W.B., W.R.B. and J.L.L. provided the patient samples. A.G. carried out the imaging experiments. J.M.A. and C.T.J. performed the human leukaemia sequencing experiments and analyses. J.B. conceived of the project, planned and guided the research, and wrote the manuscript.
Correspondence to
Jeevisha Bajaj.
The authors declare no competing interests.
Nature thanks Peter van Galen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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a, Survival curve shows bcCML progression in unirradiated recipients, indicating time course for scRNA-seq experiment (naïve, initiation, expansion, and end). b, Representative FACS plots and graph show changes in leukaemia engraftment over time (2 or 3 mice pooled per timepoint). c, Heatmap of significantly expressed marker genes for non-haematopoietic Bone Marrow (BM) populations. d, Line graphs show temporal changes in the proportion of all major lineages, and in sub-clusters of chondrocyte and fibroblasts. e, Representative FACS plots and graph show changes in BM sinusoidal and arteriolar endothelial cell frequency over time (mean ± s.e.m.; n = 3 animals per timepoint, two-way ANOVA). f, Gene clusters associated with changes in MSC, chondrocyte, and arteriolar endothelial populations during disease progression.
Source data
a, Unbiased Enrichr analysis shows top 10 upregulated pathways by population cluster in MSCs, osteo-associated, arteriolar, and sinusoidal endothelial populations. b, PCA-plot shows the distribution of 7 CD34+ healthy donor BM HSPCs, 10 bcCML CD34+ LSCs, and 11 AML CD34+ LSCs from human samples. c, Overlap between genes upregulated in bcCML and AML CD34+ cells compared to normal CD34+ cells, proteins expressed on cell surface19, and those that drop-out by 2-fold or more in the leukaemia in vivo CRISPR screen6. d, Heatmap shows r-log normalized RNA expression of cell surface receptors upregulated in AML, bcCML or both. e, Average expression of ligands for cell surface proteins in primary human adult and paediatric AML cells, human AML immune microenvironment populations, and in normal cells20.
a-d, UMAP plot of indicated gene expression in microenvironmental populations over time (naïve: 0 d, initiation: 2 and 4 days, expansion: 7 and 9 days and, end:11 and 14 days post-transplant).
a, Kaplan-Meier curves of human leukaemia patients with high (<9.32, n = 80) or low (≥9.32, n = 81) LDLR expression (TCGA-LAML; Xena Browser; log-rank test). b, Normalized LDLR expression in CD34+ cells from human bcCML, AML, or normal BM (n = 7 normal BM, n = 10 bcCML, n = 11 AML; central line, box, and whiskers represent median, interquartile range or IQR, minimum/maximum within 1.5*IQR respectively; DESeq2 implemented Wald test). c, d, Experimental strategy (c) and relative Apoe expression (d) in MSCs transduced with shRNAs targeting LacZ or Apoe (mean ± s.d.; n = 3 technical replicates per cohort). e,f, Number of live leukaemia cells (e) and their colony forming ability (CFU) (f) post co-culture with MSCs (mean ± s.e.m.; e, n = 8 independent culture wells; f, n = 6 independent culture wells, data combined from two independent experiments; unpaired two-tailed Student's t-test). g, Slc6a6 expression in KLS cells infected with BCR-ABL and NUP98-HOXA9 (BA-NH) oncogenes for 48 h (mean ± s.d.; n = 3 technical replicates per cohort). h, Taurine biosynthesis pathway. i, Dot plot of Cdo1 and Csad expression during disease progression. j, UMAP plot of CDO1 and CSAD expression in normal human BM23. k, UMAP plot of microenvironmental cells in three human MDS or AML BM aspirates. l, UMAP plot of CDO1 and CSAD in human MDS and AML BM aspirates. m-p, Representative IHC images and quantification of Osterix expression in matched human BM biopsies at MDS diagnosis and AML transformation (m, n) or AML diagnosis and relapse (o,p) (n = 5 independent patients per cohort; each colour represents a patient sample; two-tailed ratio paired t-test). The mouse image in c is adapted from ref. 6, Springer Nature America.
Source data
a, b, Alizarin red staining (a), and Cdo1 and Csad expression (b) in MSCs undergoing osteogenic differentiation (mean ± s.d.; n = 3 technical replicates per cohort). c, CDO1 expression in murine leukaemia and patient AML MSCs undergoing osteogenic differentiation (mean ± s.e.m.; n = 3 replicates per time point). d, Taurine in MSC culture media during osteogenic differentiation (mean ± s.e.m.; n = 3 replicates; secreted over 48–72 h). e,f, Experimental strategy (e) and Cdo1 expression (f) in MSCs transduced with shRNAs targeting LacZ or Cdo1 (mean ± s.d.; n = 3 technical replicates per cohort). g, Live leukaemia cells (left), and CFU (right), post coculture with bcCML MSCs (mean ± s.e.m.; n = 7 independent culture wells per cohort (live); n = 6 (CFU); data combined from 2 independent experiments; one-way ANOVA). h, CDO1 expression in 293 T transduced with shRNAs targeting LACZ or CDO1 (mean ± s.d.; n = 3 technical replicates per cohort). i, Cdo1fl/fl model. j,k, PCR of Cdo1 (j) and Cdo1 expression (k) in Cdo1fl/fl and Cdo1fl/fl;Prrx1-Cre+ MSCs following osteogenic differentiation (mean ± s.d.; n = 3 technical replicates per cohort). l-n, BM stroma in leukaemic control and Cdo1fl/fl;Prrx1-Cre+ mice: MSCs (l), osteolineage cells (m), and, endothelial cells (n) (mean ± s.e.m.; n = 7 Cdo1fl/fl and n = 3 Cdo1fl/fl;Prrx1-Cre+; data combined from three independent experiments; unpaired two-tailed Student's t-test). o-q, CFU of murine cKit+ AML cells (o), murine Lin− LSCs (p), or primary human AML cells (q) with taurine (mean ± s.e.m.; n = 3 independent culture wells from n = 2 murine AML, n = 2 murine bcCML, and n = 3 primary human AML samples; data combined from two independent experiments; one-way ANOVA). r, Impact of taurine supplements on murine bcCML progression in unirradiated recipients (n = 14 no taurine and 0.01 mg/ml taurine, n = 15 10 mg/ml taurine; data combined from three independent experiments; log-rank test). The mouse image in e is adapted from ref. 6, Springer Nature America.
Source data
a, Number of live LSCs (left) and their CFU (right) post co-culture with leukaemic MSCs transduced with shCdo1 or shLacZ (mean ± s.e.m.; n = 6 independent culture wells; data combined from 2 independent experiments; one-way ANOVA). b, Survival curve shows the impact of taurine supplements on murine leukaemia progression in irradiated recipients (n = 10 per cohort; data combined from two independent experiments; log-rank test). c, Representative FACS plots and quantification of BM engraftment in cancer at initiation and end point (mean ± s.e.m.; n = 3 +/+ and n = 5 −/−; data combined from two independent experiments). d-g, Graph (d) shows number of microenvironmental cells per mouse leg. Representative FACS plots and quantification of MSC (e), osteolineage (f), and endothelial (g) frequency (left) and total cell number (right) at initiation and end point (mean ± s.e.m.; n = 3 +/+ and n = 5 −/−; data combined from two independent experiments). h, Representative FACS histogram and quantification of Lin+ frequency in bcCML BM (mean ± s.e.m.; n = 14 animals per cohort; data combined from three independent experiments; c, e-h unpaired two-tailed Student's t-test).
Source data
a, Average number of BM cells in +/+ and −/− mice (mean ± s.e.m.; n = 5 animals per cohort). b-d Representative FACS plots, and quantification of frequency (left) and cell number (right) of hematopoietic stem cells (b, HSC: Lin−cKit+Sca+CD150+CD48−) and multipotent progenitors (b, MPPs: Lin−cKit+Sca+CD150−CD48−), committed granulocyte–macrophage progenitors (c, GMP: Lin−IL7Ra−Kit+Sca1−CD34+CD16/3+), common myeloid progenitors (c, CMP: Lin−IL7Ra−Kit+Sca1−CD34+CD16/32−), megakaryocyte–erythroid progenitors (c, MEP: Lin−IL7Ra−Kit+Sca1−CD34−CD16/32−), and differentiated haematopoietic cells (d) in the BM of +/+ and −/− mice (mean ± s.e.m.; n = 5 animals per cohort; data combined from four independent experiments). e, Complete blood count of indicated cells and haemoglobin content in the peripheral blood of age and sex-matched 8-week-old littermates (mean ± s.e.m.; n = 11 +/+ and n = 13 −/−; data combined from two independent experiments). f-g, Experimental strategy (f), donor engraftment in peripheral blood over time (g). h-k, Average donor chimerism (h), frequency of KLS (Lin−cKit+Sca+), HSCs, and MPPs (i), committed progenitors GMP, CMP, and MEP (j) and, differentiated haematopoietic cells (k) in primary recipient BM four months post-transplant (f-k: mean ± s.e.m.; n = 9 +/+ and n = 10 −/−; data combined from two independent experiments). l, Donor engraftment in peripheral blood of secondary recipients (mean ± s.e.m.; n = 6 animals per cohort; g, l, two-way ANOVA). m-q, Average donor chimerism (m), frequency of KLS, HSCs, and MPPs (n), committed progenitors GMP, CMP, and MEP (o), and differentiated haematopoietic cells (p, q) in BM of secondary recipients four months post HSC transplant (mean ± s.e.m.; n = 6 animals per cohort; a-e, h-k, m-q unpaired two-tailed Student's t-test). The mouse images in f are adapted from ref. 6, Springer Nature America.
Source data
a, SLC6A6 expression in human AML stem cells, progenitors and mature blasts (Gene Expression Commons). b, SLC6A6 expression by karyotype or FAB subtype (TCGA-AML, n = 146 karyotype and n = 149 FAB subtype; dot represents an individual patient). c, SLC6A6 expression in relapse origin-committed (ROC) and relapse origin-primitive (ROP) AML34 (n = 29 ROC and n = 10 ROP); (b-c central line, box, and whiskers represent median, interquartile range, minimum/maximum point within 1.5*IQR respectively; unpaired two-samples Wilcoxon test). d, Taurine in Lin− bcCML cells treated with DMSO or TAG (mean±s.e.m.; n = 8 independent wells combined from 2 experiments). e, Taurine in Lin− bcCML cells treated with GES or water (mean±s.e.m.; n = 5 independent culture wells; d-e unpaired two tailed Student's t-test). f-h, CFU of Lin− bcCML (f), ckit+ AML LSC (g) with DMSO or indicated doses of TAG, or Lin− bcCML with water or indicated doses of GES (h)(mean±s.e.m.; n = 3 independent culture wells per cohort; data combined from two independent experiments for f,h). i, j, Viability (i) and CFU (j) of murine Lin− bcCML cells treated with 0.5 mM venetoclax (ABT-199, Ven) for 48 h (n = 3 independent culture wells per cohort; data combined from two (i) or three (j) independent experiments; two-way ANOVA). k, CFU of Lin− bcCML cells with DMSO/water, Ven, or indicated doses of TAG (left) and GES (right), or indicated combinations (mean ± s.e.m.; n = 3 per independent culture wells; data combined from 2 or 3 independent experiments). l, CFU of cKit+ AML LSC with DMSO/water, Ven, GES, or indicated combinations (mean±s.e.m.; n = 3 independent culture wells; data combined from 2 independent experiments, f-h, j-l one-way ANOVA). m, Combination index of GES and Ven per fraction affected (left) and isobologram (right) by Chou-Talalay method (n = 3 independent culture wells; data combined from 3 independent experiments; colours represent sample type, shapes represent Ven/GES combinations).
Source data
a, Survival curve showing the impact of treating mice transplanted with Lin− bcCML cells with GES (2.5%), Ven (50 mg/kg), or their combination (n = 10 control, n = 12 GES, n = 6 Ven, n = 8 GES/Ven); data combined from three independent experiments; lines below graph represent days of treatment; log-rank test). b, Taurine in 107 BM cells from leukaemic mice treated with indicated amounts of GES for 13–16 d (mean ± s.e.m.; n = 3 technical replicates per cohort). c, d, Experimental strategy (c) and mass (d) of mice during treatment with GES, TAG, or control (mean ± s.e.m.; n = 3 animals per cohort; two-way ANOVA). e,f, Viability (e) and average number of BM cells (f) (mean ± s.e.m.; n = 6 mice per cohort; data combined from two independent experiments). g-h, Representative FACS plots (left), and number (right) of HSC and MPP (g), and differentiated haematopoietic cells (h) (mean ± s.e.m.; n = 6 animals per cohort; data combined from two independent experiments; two-way ANOVA). i, Haematoxylin & Eosin staining of indicated tissues in treated animals. j, Intracellular taurine levels by LC/MS in BM cells from treated animals (mean ± s.e.m.; n = 8 independent replicates from n = 3 control, n = 10 from 4 GES, n = 9 from 3 TAG treated animals; each colour represents a mouse). k, l, SLC6A6 expression (k) and taurine levels (l) in K562 cells transduced with shRNAs targeting LacZ and SLC6A6 (mean ± s.d.; n = 3 technical replicates per cohort). m-o, CFU of human leukaemia cell lines transduced with lentiviral shRNAs targeting LacZ or SLC6A6, K562 (m), THP1 (n), and MV-4-11 (o) (mean ± s.d.; n = 3 independent culture wells per cohort). p, Relative SLC6A6 expression (left; mean ± s.d.; n = 3 technical replicates per cohort) and CFU (right) in MDS-L cells transduced with shRNAs targeting Luc and SLC6A6 (mean ± s.e.m.; n = 9 independent culture wells per cohort; data combined from 3 independent experiments; b, e-h, j, l-p one-way ANOVA). The mouse image in c is adapted from ref. 6, Springer Nature America.
Source data
a, Quantification of taurine and glycolysis associated metabolites in +/+ and −/− Lin− bcCML cells (mean ± s.e.m.; n = 16 samples from n = 6 +/+ leukaemic mice and n = 9 samples from n = 3 −/− leukaemic mice; unpaired two-tailed Student's t-test with Welch's correction). b, Curve and quantification of normalized of oxygen consumption rate (OCR) in Lin− bcCML cells (mean ± s.e.m.; n = 10 independent culture wells per cohort from 3 bcCML samples; data combined from three independent experiments; unpaired two-tailed Student's t-test). c-e, Impact of supplementing 5 mM sod. acetate (c), lactate (d), or indicated amounts of glucagon (e) on the CFU of Lin− bcCML cells (mean ± s.e.m.; n = 3 independent culture wells per cohort; data combined from 2 independent experiments; one-way ANOVA). f, Experimental strategy used to determine 13C taurine tracing in K562 cells by untargeted metabolomics. g, Incorporation of 13C label from taurine in indicated metabolites (mean ± s.e.m.; n = 5 independent biological replicates). h,i, Colony-forming ability of Lin− bcCML cells in the presence of 160 mM N-acetyl taurine (h) or indicated amounts of glutaurine (i) (mean ± s.e.m.; n = 3 independent culture wells per cohort; data combined from two independent experiments; one-way ANOVA).
Source data
a, Top 20 upregulated pathways in −/− time matched bcCML cells as compared to +/+ controls. b, Heatmap of glycolysis associated genes in bcCML samples. c, GSEA showing downregulation of genes associated with Myc and mTORC1 pathways on TauT loss (a-c, n = 3 animals per cohort). d, Relative expression of glycolysis associated genes in +/+ and −/− Lin− bcCML cells (mean ± s.d.; n = 3 technical replicates per cohort). e, Western blot shows phospho-mTOR (pmTOR), mTOR, phosopho-p70S6k (p-p70S6K), p70S6K, and actin protein expression in +/+ and −/− Lin− bcCML cells (also see Fig. 5k–m, n = 4 independent disease end point samples/cohort). f, Volcano plot of global proteome (upper panel) and phosphoproteome (bottom panel) with differential abundance in +/+ and −/− leukaemia cells from time matched recipients (n = 5 animals per cohort). g, Normalized abundance of mTOR pathway proteins (mean ± s.e.m.; n = 5 animals per cohort; unpaired two-tailed Student's t-test). h, Expression of glycolysis related genes in +/+ Lin− bcCML treated with indicated doses of TAG for 72 h (mean ± s.d.; n = 3 technical replicates per cohort). i, Expression of glycolysis related genes in +/+ Lin− bcCML treated with 1 mM GES for 72 h (mean ± s.d.; n = 3 technical replicates per cohort).
Source data
a,b, Immunoblot and quantification of mTOR pathway proteins in +/+ Lin− bcCML treated with indicated doses of TAG (a, mean ± s.d.; n = 2 replicates per cohort) or 1 mM GES (b, mean ± s.e.m.; n = 4 samples per cohort). c-f, Experimental strategy (c), immunoblot (d, f), and quantification (e) of indicated proteins in Lin− bcCML cells +/− 200 mM taurine (mean ± s.e.m.; n = 3 biological replicates; gels processed in parallel; tubulin run on each gel as sample processing control). g,h, Immunoblots (g), and quantification (h) of mTOR pathway proteins in Lin− bcCML cells from leukaemic mice supplemented with taurine for 10 days (mean ± s.e.m.; n = 4 control and n = 5 taurine; b, e, h unpaired two-tailed Student's t-test). i, Survival curve shows impact of 5 mg/kg rapamycin treatment for 6 d on leukaemia progression. Line represents treatment days (n = 9 +/+ and n = 5 −/−; data combined from two independent experiments; log-rank test). j, Histogram and geometric Mean Fluorescence Intensity (MFI) of p-mTOR in Lin− bcCML cells treated with DMSO or N-Oleoyl taurine for 36–40 h. (mean ± s.e.m.; n = 4 samples per cohort; data combined from two independent experiments). k,l, Expression of glycolysis genes in +/+ Lin− bcCML cells treated with rapamycin for 24 h (k; mean ± s.d.; n = 3 technical replicates per cohort) or 2 mM MHY1485 for 48 h (l; mean ± s.e.m.; n = 3 technical replicates per cohort; data combined from two independent experiments). m, Histogram and MFI of p-mTOR in Lin− bcCML cells infected with vector or RagA(Q66L) (mean ± s.e.m.; n = 6 samples per cohort; data combined from two independent experiments). n, CFU of Lin− bcCML cells infected with vector or RagAQ66L and treated with indicated amounts of taurine (mean ± s.e.m.; n = 3 independent culture wells per cohort; data combined from two independent experiments; j, l-n one-way ANOVA). o, Schematic shows taurine from BM osteolineage cells promotes RagA-dependent mTOR activation and glycolysis in leukaemia cells to drive disease progression. The culture well image in c is adapted from ref. 6, Springer Nature America.
Source data
Uncropped western blots.
List of shRNA and primer sequences.
List of antibodies used.
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Sharma, S., Rodems, B.J., Baker, C.D. et al. Taurine from tumour niche drives glycolysis to promote leukaemogenesis.
Nature (2025). https://doi.org/10.1038/s41586-025-09018-7
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Immune checkpoint blockade (ICB) has transformed cancer therapy1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation3,4. However, the relationship between the key transcription factors in dendritic cells and ICB efficacy remains unknown. Here we found that ICB reprograms the interplay between the STAT3 and STAT5 transcriptional pathways in dendritic cells, thereby activating T cell immunity and enabling ICB efficacy. Mechanistically, STAT3 restrained the JAK2 and STAT5 transcriptional pathway, determining the fate of dendritic cell function. As STAT3 is often activated in the tumour microenvironment5, we developed two distinct PROTAC (proteolysis-targeting chimera) degraders of STAT3, SD-36 and SD-2301. STAT3 degraders effectively degraded STAT3 in dendritic cells and reprogrammed the dendritic cell–transcriptional network towards immunogenicity. Furthermore, STAT3 degrader monotherapy was efficacious in treatment of advanced tumours and ICB-resistant tumours without toxicity in mice. Thus, the crosstalk between STAT3 and STAT5 transcriptional pathways determines the dendritic cell phenotype in the tumour microenvironment and STAT3 degraders hold promise for cancer immunotherapy.
Immunotherapy, including ICB and T cell therapy, uses the immune system to eliminate cancer cells1,2,6. However, most patients are either poorly responsive to ICB or develop therapeutic resistance. Emerging evidence suggests that ICB does not trigger potent immune responses in patients with limited and impaired dendritic cells3 (DCs) in the tumour microenvironment (TME). DCs present tumour antigens to prime and activate T cells, thereby driving anti-tumour immunity4,7,8,9,10,11. In line with this, increased type 1 dendritic cell (DC1) infiltration correlates with prolonged survival in patients with cancers12,13,14. However, the TME can impede DC1 maturation and function, partly owing to disruptive environmental signals4,15,16,17. Thus, understanding how the DC phenotype is shaped in the TME and exploring strategies to enhance DC1 function are crucial for developing more effective cancer immunotherapy.
Alterations in STAT signalling pathways exert profound effects on anti-tumour responses in the TME18. For example, STAT3 is often activated and mediates immune inhibition in the TME5,19. STAT3 activation leads to the production of various pro-tumour factors, including VEGF and IL-6, impeding DC maturation and function20,21. Moreover, STAT3 signalling can inhibit T helper 1 (TH1)-type chemokine expression and subdue DC tumour trafficking, resulting in the exclusion of T cells from the TME21. By contrast, STAT5 is activated in response to cytokine signals, such as GM-CSF and IL-222, and has a positive role in the anti-tumour immune response23,24. On this basis, we hypothesized that the balance between the STAT5 and STAT3 transcriptional pathways in DCs may shape the fate of distinct immune responses in the TME, determining ICB responses in patients with cancer.
In this study, we analysed single-cell and bulk RNA-sequencing (RNA-seq) datasets from tumour tissues in patients with cancer who were receiving ICB. We found that the transcriptional pathways of STAT5 and STAT3 in DC1s correlated with T cell immunity and was associated with clinical outcome in patients treated with ICB. Moreover, genetic deletion and pharmacologic inhibition of STAT3 signalling led to DC1 activation and profound anti-tumour T cell immune responses. Furthermore, we provide proof of concept that pharmacological degradation of STAT3 can treat multiple tumour types as monotherapy and sensitize tumours to ICB.
The STAT5 and STAT3 transcriptional pathways regulate tumour immune responses21,23,24. We thus reasoned that interplay between these two transcriptional pathways in immune cells, particularly in DCs, influences ICB responses in patients with cancer. To examine this possibility, we analysed RNA-seq data from tumour tissues collected before ICB treatment in a patient cohort (cohort 1) at the University of Michigan25 (Extended Data Table 1). As previously reported25, among these patients, 17% achieved a complete response to ICB, whereas 14% achieved partial response, 17% had stable disease and 51% had progressive disease according to RECIST (response evaluation criteria in solid tumours) criteria (Fig. 1a), and the complete response group exhibited the longest overall survival rate in cohort 1 (Fig. 1b). To determine whether the clinical response is associated with the effector T cell-mediated anti-tumour response, we evaluated outcomes stratified by expression of T effector cell signatures26. Patients with a high CD8+ effector T cell score exhibited improved overall survival (Fig. 1c). Furthermore, we calculated a DC1 maturation score27. We found that patients with a high DC1 maturation and function score demonstrated improvements in overall survival resembling those in patients with a high CD8+ effector T cell score (Fig. 1d). This similarity in survival was mirrored by a strong positive correlation between CD8+ effector T cell and DC1 maturation scores (Fig. 1e). Thus, DC-mediated antigen cross-presentation and T cell activation may drive ICB response in patients with cancer.
a–d, DC1 score and overall survival. a, Pie chart of number and percentages show RECIST-defined responses to ICB in cohort 1. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. b–d, Kaplan–Meier survival curves were stratified by clinical response groups (b), cytotoxic T lymphocyte (CTL) score (c) and median DC1 maturation score (d). n = 92; log-rank test. e, Pearson correlation analysis shows a correction between CTL score and DC1 maturation score. The shaded area represents the 95% confidence interval. n = 92. f,g, Kaplan–Meier curves of overall survival in patients from cohort 1 were stratified by DC score and STAT5/STAT3 expression (f) or STAT5 transcriptional pathway/STAT3 expression (g). n = 92; P = 0.049 (f) and P = 0.00018 (g), log-rank test. h, Kaplan–Meier curves of overall survival in cohort 2 were stratified by DC score and the ratio of STAT5 versus STAT3. n = 114; P = 0.0041, log-rank test. i–l, STAT5 and STAT3 signalling signatures in DCs in cohort 3. i,j, STAT5 (i) and STAT3 (j) gene signatures in DCs were analysed in post-ICB samples of responders and the respective pre-ICB samples. k,l, STAT5 (k) and STAT3 (l) gene signatures within DCs were compared between non-responders and responders. In box plots, the central line represents the median, the box extends from the 25th to 75th percentiles, and whiskers span the smallest and largest values within 1.5× the interquartile range. Outliers are shown as individual points. Responders: pre- (332 DCs) and post- (170 DCs) treatment (4 patients). Non-responders: pre- (215 DCs), post- (194 DCs) treatment (6 patients). **P = 0.0012 (j), ***P = 0.00092 (k), **P = 0.0045 (l) and ****P < 0.0001 (i), Wilcoxon rank-sum test. P values are two-sided without correction for multiple comparisons.
To explore the role of the relationship between the STAT5 and STAT3 transcriptional pathways in the context of DC1 maturation and function, we stratified patients (cohort 1) by the median DC1 maturation score and the median ratio of STAT5/STAT3 expression into four groups: DC1hiSTAT5/STAT3hi, DC1hiSTAT5/STAT3low, DC1lowSTAT5/STAT3hi, and DC1lowSTAT5/STAT3low. Among the four patient groups, those classified as DC1hiSTAT5/STAT3hi had the longest overall survival, whereas the other groups exhibited similar survival trends to each other (Fig. 1f). We observed similar results when we stratified patients by the median ratio of STAT5 transcriptional pathway activation and STAT3 expression (Fig. 1g) and by excluding patients with tumours that were inherently unresponsive to ICB (Extended Data Fig. 1a). We analysed additional patients with melanoma28,29 (cohort 2), a type of cancer that is sensitive to anti-PD-1 and anti-CTLA-4 therapy (Extended Data Table 2). DC1hiSTAT5/STAT3hi in cohort 2 exhibited the longest overall survival, whereas the DC1lowSTAT5/STAT3low patients had the shortest (Fig. 1h and Extended Data Fig. 1b,c). Thus, the relationship between DC1 maturation and the STAT5 and STAT3 transcriptional pathways may affect responsiveness to ICB.
To solidify this finding, we analysed a single-cell RNA-sequencing (scRNA-seq) dataset from patients with triple-negative breast cancer (TNBC) (cohort 3), and examined DCs in tumour tissues collected before and after ICB treatment30. We conducted an analysis of the STAT5 and STAT3 transcriptional pathways in DC clusters. The analysis revealed a bimodal distribution of the STAT3 transcriptional pathway, with the second mode exhibiting a relatively high STAT3 signalling activity (Extended Data Fig. 1d). We conducted a detailed analysis of the STAT5 and STAT3 transcriptional pathways in DC clusters with relatively high STAT3 expression. Of note, STAT5 transcriptional signalling increased in post-ICB samples compared with pre-ICB samples among responders to ICB (Fig. 1i), but such an increase was not observed in non-responders (Extended Data Fig. 1e). Conversely, STAT3 transcriptional signalling showed a decrease in post-ICB samples of responders compared with their pre-ICB samples (Fig. 1j), with no significant change observed in non-responders (Extended Data Fig. 1f). Furthermore, post-ICB samples showed an increase in STAT5 transcriptional signalling and a reduction in STAT3 transcriptional signalling in responders relative to non-responders (Fig. 1k,l). We then examined the STAT5 and STAT3 transcriptional signalling pathways in specific DC subsets in these patients30 (cohort 3). Using the Louvain algorithm for shared nearest neighbours clustering and uniform manifold approximation and projection (UMAP) visualization to distinguish the cells, we conducted an analysis with two major distinct DC clusters, conventional DCs (cDCs) and monocyte-derived DCs (moDCs) (Extended Data Fig. 1g). In the cDC subset, the post-ICB samples from responders displayed increased STAT5 transcriptional signalling and decreased STAT3 transcriptional signalling compared with pre-ICB samples (Extended Data Fig. 1h,i). These changes were not discernible in the non-responder group (Extended Data Fig. 1j,k). In moDCs, an increase in STAT5 signalling was observed in the post-ICB samples from responders, whereas STAT3 transcriptional signalling remained unchanged compared with pre-ICB samples in both responders and non-responders (Extended Data Fig. 1l–o). Furthermore, in the post-ICB samples, we observed a noticeable increase in STAT5 transcriptional signalling and a corresponding decrease in STAT3 transcriptional signalling in the responders compared to the non-responders within cDCs (Extended Data Fig. 1p,q). In moDCs, neither STAT5 nor STAT3 transcriptional signalling showed significant differences between post-ICB samples from responders and non-responders (Extended Data Fig. 1r,s). Collectively, ICB treatment dynamically reprograms the STAT5 and STAT3 transcriptional signalling pathways in cDCs, affecting ICB efficacy.
Given the negative effect of STAT3 transcriptional activity on DC maturation and ICB response, we examined whether alteration of STAT3 activity would affect DC phenotype. We used short hairpin RNAs (shRNAs) targeting Stat3 (shStat3) in JAWSII cells, a DC line31,32 (Fig. 2a). Knocking down STAT3 expression resulted in a robust increase in phosphorylation of STAT5 (pSTAT5) and a minor increase in pSTAT1, but had no effect on pSTAT6 and p-p65 in JAWSII cells cultured with GM-CSF (Fig. 2a). We crossed Stat3fl/fl mice with Xcr1cre mice (which express mCherry under the control of the Xcr1 promoter) and generated cDC1-specific STAT3 knockout (Stat3−/−) mice. We used Stat3fl/flXcr1+/+ mice as the Stat3+/+ controls, enabling us to use mCherry fluorescence to validate knockout specificity in the mouse offspring (Extended Data Fig. 2a). No mCherry expression was detected in other immune cells in Stat3−/− mice (Extended Data Fig. 2b). We confirmed the absence of STAT3 protein in cDC1s generated from Stat3−/− mice (Fig. 2b and Extended Data Fig. 2c). At 6 to 10 weeks of age, Stat3+/+ and Stat3−/− mice exhibited similar body size (Extended Data Fig. 2d), similar appearance of lymphoid organs (Extended Data Fig. 2e) and equivalent levels of CD8+ and CD4+ T cells in tissues (Extended Data Fig. 2f,g). Notably, we detected an increase in STAT5 activation in Stat3−/− cDC1s compared with Stat3+/+ cDC1s (Fig. 2b). An unbiased phospho-receptor kinase array showed higher levels of pSTAT5 in Stat3−/− cDC1s than Stat3+/+ cDC1s (Fig. 2c). Thus, STAT3 restrains STAT5 activation in DCs. Flow cytometry analysis revealed higher levels of typical DC maturation markers, including major histocompatibility complex class I (MHCI; Fig. 2d), major histocompatibility complex class II (MHCII; Fig. 2e), CD80 (Fig. 2f and Extended Data Fig. 2h) and CD86 (Fig. 2g and Extended Data Fig. 2h) in Stat3−/− cDC1s than in Stat3+/+ cDC1s.
a,b, Immunoblots of transcription factors in shStat3 JAWSII cells (a) and Stat3+/+ and Stat3−/− cDC1s (b). n = 3. c, Scatter plots of relative pixel density versus corresponding −log10(P value) for a phospho-antibody array incubated with lysate from LPS-stimulated Stat3+/+ and Stat3−/− cDC1s. n = 4. d,e, Fluorescence-activated cell sorting (FACS; left) and mean fluorescence intensity (MFI; right) of MHCI (d) and MHCII (e) in Stat3+/+ and Stat3−/− cDC1s. Data are mean ± s.e.m., n = 3; **P = 0.0084 (d) and *P = 0.0125 (e), unpaired two-tailed t-test. f,g, FACS and MFI of CD80 (f) and CD86 (g) in Stat3+/+ or Stat3−/− cDC1s. Data are mean ± s.e.m., n = 3; **P = 0.0098 (f) and *P = 0.0453 (g), unpaired two-tailed t-test. h,i, Immunoblots of transcription factors in JAWSII cells cultured with GM-CSF and transfected with shGmrβ (h) or shJak2 (i). n = 3. j,k, Immunoprecipitation with anti-GMRβ (j) or anti-JAK2 (k) shows the interaction between GMRβ and transcription factors in activated Stat3+/+ and Stat3−/− cDC1s. n = 2. l,m, FACS analysis of MHCII (l) and IL-12 enzyme-linked immunosorbent assay (ELISA; m) in Stat3+/+ and Stat3−/− cDC1s cultured with STAT5i. Data are mean ± s.e.m., n = 3, **P = 0.0079 (l); n = 4, ****P < 0.0001 (m); one-way ANOVA. n–q, Heat map comparing expression of DC maturation genes in Stat3+/+ versus Stat3−/− cDC1s as z-scores (n) or calculated with EdgeR (o), and GSEA shows differences in expression of genes associated with antigen processing and presentation (p) and IL-12 production (q). NES, normalized enrichment score. r,s, RNA-seq analysis of LPS-stimulated Stat3+/+ and Stat3−/− cDC1s shows changes in genes associated with multiple signalling pathways (r) and STAT5 signalling (s). t–w, ChIP–qPCR shows promoter occupancy of H2-D1 (t), H2-Eb1 (u), Cd80 (v) and Cd86 (w) in LPS-treated Stat3+/+ or Stat3−/− cDC1s. Data are mean ± s.e.m. fold change over control, n = 3; **P = 0.0017 (t), ***P = 0.0003 (u), *P = 0.0271 (v) and **P = 0.0074 (w); one-way ANOVA.
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To explore how STAT5 activation is regulated in DCs, we assessed the expression profile of a range of cytokine receptors that are capable of activating STAT5, including the receptors for IL-2, IL-3, IL-5, IL-7, IL-15, IL-21 and GM-CSF, in cDC1s. Among these cytokine receptors, we detected higher transcript levels of GM-CSF receptors, Gmrα (also known as Csf2ra) and Gmrβ (also known as Csf2rb), compared with other cytokine receptors in cDC1s (Extended Data Fig. 2i). Knocking down GMRβ with specific shRNAs resulted in a decrease in phosphorylation of JAK2, STAT5 and STAT3 (Fig. 2h), but not of JAK1, TYK2, JAK3 and STAT1 in JAWSII cells cultured with GM-CSF (Extended Data Fig. 2j). Moreover, knocking down JAK2 caused a profound reduction of pSTAT5 and a moderate reduction of pSTAT3, but not pSTAT1, in JAWSII cells in response to GM-CSF (Fig. 2i). GM-CSF stimulation induced the phosphorylation of JAK2, but not JAK1, JAK3 or TYK2 in JAWSII cells (Extended Data Fig. 2k). Similar findings have been reported in human neutrophils33. Thus, GM-CSF and signalling pathways downstream of the GM-CSF receptor may regulate STAT5 activation via JAK2 in DCs.
We next investigated whether STAT3 is involved in the GMR–JAK2–STAT5 axis in DCs. We found that Stat3−/− and Stat3+/+ cDC1s expressed similar levels of GM-CSF (Extended Data Fig. 2l) and GMRβ (Extended Data Fig. 2m). Then, we performed a reciprocal co-immunoprecipitation assay with anti-GMRβ and anti-JAK2 in Stat3−/− and Stat3+/+ cDC1s. Co-immunoprecipitation experiments demonstrated the co-existence of GMRβ, JAK2 and STAT5 in activated cDC1s (Fig. 2j,k). Despite similar levels of GMRβ and JAK2 in the co-immunoprecipitation products of Stat3−/− and Stat3+/+ cDC1s (Fig. 2j,k), genetic deletion of STAT3 led to an increase in the interaction between GMRβ and STAT5 (Fig. 2j) and between JAK2 and STAT5 (Fig. 2k). shStat3 JAWSII cells (Fig. 2a) and Stat3−/− cDC1s (Fig. 2b) expressed higher levels of pSTAT5 than their counterparts. The data suggest that STAT3 may restrain the GMRβ–JAK2–STAT5 signalling pathway, thereby affecting DC phenotype and function in vitro (Fig. 2d–g and Extended Data Fig. 2h). Given that increased IL-6 and activated STAT3 are often observed in the TME, we assessed the expression of IL-6 and its receptors in human and mouse DCs. IL-6-expressing DCs represented a negligible fraction among IL-6-positive cells from patients with TNBC30 (cohort 3) (Extended Data Fig. 2n). Mouse Stat3+/+ and Stat3−/− cDC1s expressed low levels of IL-6 (Extended Data Fig. 2o,p). Moreover, cDC1s expressed similar amounts of IL-6 receptor transcripts (Il6ra and Il6st) (Extended Data Fig. 2q,r) and proteins (IL-6Rα and GP130) (Extended Data Fig. 2s) in Stat3+/+ and Stat3−/− cDC1s. These results suggest that a paracrine-activated IL-6–STAT3 pathway regulates the GMRβ–JAK2–STAT5 signalling pathway in DCs, affecting DC phenotype in the TME.
To validate this possibility in vivo and elucidate the biological involvement of JAK2, we treated B16F10 or MC38 colon carcinoma-bearing Stat3−/− and Stat3+/+ mice with the JAK2 inhibitor FLLL32. As expected, Stat3−/− cDC1s expressed higher levels of pSTAT5 (Extended Data Fig. 2t,u) and maturation markers compared with Stat3+/+ cDC1s (Extended Data Fig. 2v–x), whereas treatment with FLLL32 abolished this effect (Extended Data Fig. 2t–x). Then, we treated Stat3−/− and Stat3+/+ cDC1s with the STAT5 inhibitor STAT5i34. We observed higher expression levels of MHCII (Fig. 2l) and IL-12 (Fig. 2m) in Stat3−/− cDC1s than in Stat3+/+ cDC1s, and these effects were abolished by the STAT5i (Fig. 2l,m). Therefore, STAT3 may restrain JAK2-mediated STAT5 activation in DC1s and the functional maturation of these cells.
To complement these observations and systemically explore how STAT3 regulates DC phenotype, we conducted RNA-seq analysis of Stat3+/+ and Stat3−/− cDC1s. We observed a noticeable difference in the expression levels of maturation- and function-related genes between Stat3+/+ and Stat3−/− cDC1s (Fig. 2n,o). Gene set enrichment analysis (GSEA) also showed a positive enrichment of maturation and function signatures in differentially expressed genes in Stat3−/− cDC1s relative to Stat3+/+ cDC1s, including antigen processing and presentation (Fig. 2p), IL-12 production (Fig. 2q), CCR chemokine receptor binding (Extended Data Fig. 2y) and IFNγ-production pathways (Extended Data Fig. 2z). Consistently, the top upregulated canonical pathways in response to lipopolysaccharide (LPS) in Stat3−/− cDC1s compared with Stat3+/+ cDC1s included antigen presentation, DC maturation and interferon signalling (Fig. 2r). Differential gene expression analysis revealed that genes associated with the STAT5 pathway were upregulated with LPS treatment in Stat3−/− cDC1s compared with Stat3+/+ cDC1s (Fig. 2s). Furthermore, STAT5 chromatin immunoprecipitation followed by quantitative PCR (ChIP–qPCR) analysis revealed enhanced STAT5 binding at the promoter sites of H2-D1 (Fig. 2t), H2-Eb1 (Fig. 2u), Cd80 (Fig. 2v) and Cd86 (Fig. 2w) in Stat3−/− cDC1s compared with Stat3+/+ cDC1s. Thus, STAT3 inhibits DC1 maturation and function in a JAK2–STAT5-dependent transcriptional manner.
We next investigated the role of STAT3 in DC1-mediated anti-tumour response. We primed OT-I cells with Stat3+/+ and Stat3−/− cDC1s with the SIINFEKL peptide (Fig. 3a–d) or without antigen (Extended Data Fig. 3a–d), and subsequently assessed T cell response. We observed that Stat3−/− cDC1s induced increased proliferation (Fig. 3a), effector cytokine expression (Fig. 3b,c) and GZMB production (Fig. 3d) compared with Stat3+/+ cDC1s. These effects were not observed in the absence of SIINFEKL peptide-loaded cDC1s (Extended Data Fig. 3a–d).
a–d, OT-I cells were cultured with Stat3+/+ or Stat3−/− cDC1s in the presence of SIINFEKL peptides. a–d, FACS analysis of Ki-67+ (a), IFNγ+ (b), TNF+ (c) and GZMB+ (d) T cells. Data are mean ± s.e.m., n = 4; ****P < 0.0001 (a–c) and **P = 0.009 (d), unpaired two-tailed t-test. e–r, MC38 tumours were inoculated into Stat3+/+ and Stat3−/− mice. e–g, Tumour volume (e), images (f) and mass (g). h–r, FACS analysis of pSTAT5 (h–j), MHCII (k,l) and CD86 (m,n) in tumour-infiltrating cDC1s, and the percentage of tumour-infiltrating IFNγ+ (o,p) and GZMB+ (q,r) CD8+ T cells. One representative flow histogram or dot plot is shown (h,k,m,o,q). Data are mean ± s.e.m., n = 5 (e,g), n = 3 (i,j,r) and n = 4 (l,n,p); ****P < 0.0001 (e) **P = 0.0067 (g), *P = 0.0144 (i), *P = 0.0198 (j), *P = 0.0231 (l), **P = 0.003 (n), *P = 0.0223 (p) and *P = 0.0405 (r); two-way ANOVA (e), unpaired two-tailed t-test (g,i,j,l,n,p,r). s–z, B16F10 tumours were inoculated into Stat3+/+ and Stat3−/− mice. s,t, Tumour volume (s) and mass (t). u–z, FACS analysis of MHCII (u,v) and CD86 (w,x) in tumour-infiltrating cDC1s, and the percentage of tumour-infiltrating IFNγ+ (y) and GZMB+ (z) CD8+ T cells. One representative flow histogram or dot plot is shown (u,w,y,z). Data are mean ± s.e.m., n = 5 (s,t), n = 3 (v,x) and n = 4 (y,z); **P = 0.0018 (s), *P = 0.045 (t), *P = 0.0197 (v), **P = 0.0015 (x), ***P = 0.0005 (y) and **P = 0.0085 (z); two-way ANOVA (s), unpaired two-tailed t-test (t,v,x–z).
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To explore the in vivo effect of STAT3 on DCs in response to tumour challenge, we inoculated MC38 cells subcutaneously into Stat3+/+ and Stat3−/− mice. Loss of STAT3 in cDC1s resulted in reduced tumour progression compared with Stat3+/+ mice, as indicated by tumour size (Fig. 3e,f) and mass (Fig. 3g). To examine whether STAT3 deficiency affected STAT5 activation in intratumoral cDC1s, we gated on tumour-infiltrating cDC1s and detected higher levels of STAT5 activation in Stat3−/− cDC1s than in Stat3+/+ cDC1s (Fig. 3h–j and Extended Data Fig. 3e). Genetic deletion of STAT3 in cDC1s led to a marked increase in the interaction between JAK2 and STAT5 in cDC1s in the TME (Extended Data Fig. 3f). Stat3−/− cDC1s in the TME (Fig. 3k–n) and tumour-draining lymph nodes (TDLNs) (Extended Data Fig. 3g–j) exhibited higher expression levels of MHCII and CD86 compared with Stat3+/+ cDC1s. This was accompanied by enhanced effector T cell responses in the TME and TDLN, as indicated by higher percentages of IL-2+ (Extended Data Fig. 3k–o), IFNγ+ (Fig. 3o,p and Extended Data Fig. 3p,q) and GZMB+ (Fig. 3q,r) CD8+ T cells in Stat3−/− mice compared with Stat3+/+ mice.
We extended our studies to B16F10 melanoma, a less immunogenic type of tumour. Again, B16F10 tumours progressed more slowly in Stat3−/− mice compared with Stat3+/+ mice (Fig. 3s,t). B16F10 tumour-infiltrating Stat3−/− cDC1s exhibited higher levels of maturation and function markers compared with Stat3+/+ cDC1s (Fig. 3u–x and Extended Data Fig. 3r–u). Moreover, we also observed higher percentages of IFNγ+ (Fig. 3y), GZMB+ (Fig. 3z), IL-2+ (Extended Data Fig. 3v,w) and TNF+ (Extended Data Fig. 3x,y) CD8+ T cells in the TME in Stat3−/− mice than in Stat3+/+ mice. Thus, STAT3 deficiency in DCs enhances T cell function, leading to improved tumour control in vivo.
STAT3 has been pursued as a cancer therapeutic target5,35. Small-molecule inhibitors or oligonucleotides have been developed to target STAT35, with limited clinical success35. An indirect strategy to target STAT3 is through inhibition of JAK2 activity, such as with pacritinib5. However, JAK2 inhibition may affect the positive effects of STAT5 on DC1s (as we show here) and T cells24. Thus, we used SD-36, a highly selective and effective PROTAC degrader of the STAT3 protein36 (Extended Data Fig. 4a). We treated cDC1s with SD-36 and observed a dose-dependent reduction in the amount of STAT3 protein (Fig. 4a). Next, we treated Stat3+/+ and Stat3−/− cDC1s and subsequently stimulated them with LPS. We observed enhanced STAT5 activation in Stat3+/+ cDC1s treated with SD-36 (Fig. 4b). Knocking out Stat3 led to increased STAT5 activation, and the addition of SD-36 did not further increase STAT5 activation in Stat3−/− cDC1s (Fig. 4b). To pharmacologically validate our genetic studies on the role of STAT3 in DCs (Fig. 2 and Extended Data Fig. 2), we performed a reciprocal co-immunoprecipitation assay with anti-GMRβ and anti-JAK2 in cDC1s treated with SD-36. Pharmacological degradation of STAT3 by SD-36 led to a dose-dependent increase in the interaction between GMRβ and STAT5 (Fig. 4c) and between JAK2 and STAT5 (Fig. 4d). Moreover, DCs treated with SD-36 exhibited increased expression of MHCI (Fig. 4e,f), MHCII (Fig. 4g,h), CD80 (Fig. 4i,j) and CD86 (Fig. 4k,l) compared with the control group. As genetically knocking down STAT3 caused a slight increase in pSTAT1 in JAWSII cells (Fig. 2a), we tested whether STAT1 is involved in SD-36-mediated modification of DC phenotype. Knocking down STAT1 (Extended Data Fig. 4b) had no effect on the expression of MHCI (Extended Data Fig. 4c), MHCII (Extended Data Fig. 4d) or CD80 (Extended Data Fig. 4e) compared with the control group, and SD-36 remained equally effective in enhancing the expression of these DC maturation molecules in shStat1 JAWSII cells and wild-type JAWSII cells (Extended Data Fig. 4c–e). Genetic deletion of STAT1 (Extended Data Fig. 4f) had no effect on STAT5 activation in cDC1s (Extended Data Fig. 4g), as shown in Stat1+/+ and Stat1−/− cDC1s. Stat1+/+ and Stat1−/− cDC1s expressed similarly high levels of MHCI, MHCII and CD80 in response to SD-36 (Extended Data Fig. 4h–j). Thus, depletion of STAT3 improves DC function via STAT5 activation.
a, Immunoblot showing STAT3 expression in mouse cDC1s treated with different concentrations of SD-36 in vitro. b, Immunoblot showing expression of pSTAT5 and STAT5 in cDC1s from Stat3+/+ and Stat3−/− mice treated with SD-36 (200 nM) for 48 h and LPS (20 ng ml−1) for 1 h. In a,b, one of three experiments is shown. c,d, cDC1s were treated with different doses of SD-36 for 24 h and were immunoprecipitated (IP) with anti-GMRβ (c) or anti-JAK2 (d). The immunoprecipitation shows the interaction between GMRβ, JAK2, STAT3 and STAT5 in cDC1s. One of two experiments with repeats is shown. e–l, FACS analysis of MHCI (e,f), MHCII (g,h), CD80 (i,j) and CD86 (k,l) on cDC1s treated with SD-36 (e–h) and SD-36 plus LPS (i–l). Representative histograms are shown. Data are mean ± s.e.m., n = 4; *P = 0.0241 (h), *P = 0.023 (j), *P = 0.0329 (l) and **P = 0.0015 (f), unpaired two-tailed t-test. m–p, Mice were inoculated with 4T1 (m), MC38 (n), ID8 (o) or LLC (p) cells and were treated with SD-36 (20 mg kg−1) every 3 days, and tumour volumes were monitored. Data are mean ± s.e.m.; n = 6 (m,p) and n = 5 (n,o); **P = 0.0021 (p) and ****P < 0.0001 (m–o), two-way ANOVA. q–r. Mice bearing CT26 tumours (500 mm3 per tumour) were treated with SD-36 or vehicle and tumour volumes (q) and mouse survival (r) were monitored. Data are mean ± s.e.m.; n = 8; *P = 0.0111 (r), log-rank test. s,t, Luciferase radiance images (s) and total fluxes of metastatic 4T1 tumours (t) from mice treated with SD-36. Data are mean ± s.e.m.; vehicle: n = 5, SD-36: n = 6; *P = 0.0348, two-way ANOVA.
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We examined the role of SD-36 in the tumour immune response in vivo. We inoculated B16F10 melanoma into C57BL/6J mice and treated them with different doses of SD-36. SD-36 at 10 mg kg−1 moderately but significantly slowed down B16F10 tumour progression compared with controls (Extended Data Fig. 4k). We observed a marked inhibitory effect of SD-36 at 20 mg kg−1 on tumour growth in mice bearing 4T1 mammary carcinoma (Fig. 4m), MC38 colon carcinoma (Fig. 4n and Extended Data Fig. 4l,m), ID8 ovarian cancer (Fig. 4o) or Lewis lung carcinoma (LLC) (Fig. 4p). Consistently, we observed that mice treated with SD-36 at 100 mg kg−1 also exhibited a slower rate of progression of B16F10, CT26 and EMT6 tumours compared with the control group (Extended Data Fig. 4n–p) and had no obvious effect on the body weight of these mice (Extended Data Fig. 4q–s). Thus, SD-36 monotherapy attenuates the growth of multiple tumours including LLC, an ICB-resistant tumour37. Large, metastatic cancers are often resistant to ICB38,39. We initiated the treatment with SD-36 in CT26 tumour-bearing mice with tumour volumes greater than 500 mm3. Of note, SD-36 remained therapeutically effective at this late stage (Fig. 4q and Extended Data Fig. 4t,u) as shown by increased mouse survival compared with the control group (Fig. 4r). Finally, we treated 4T1 metastatic tumour-bearing mice with SD-36. This treatment effectively reduced metastatic 4T1 tumour volume (Fig. 4s,t). Thus, SD-36 monotherapy is effective in treating advanced, metastatic and ICB-resistant cancers.
We next studied whether the anti-tumour effect of SD-36 was immune- and/or DC-dependent. To this end, we treated MC38 tumour-bearing NOD.SCID γcnull (NSG) mice with a low dose of SD-36 (20 mg kg−1). This dose of SD-36 had no effect on tumours, as shown by tumour volume (Fig. 5a) and mass (Fig. 5b) in NSG mice. A high dose of SD-36 (100 mg kg−1) had a modest but significant inhibitory effect on tumour progression in NSG mice (Extended Data Fig. 5a). Given that both innate and adaptive immunity are deficient in NSG mice, we treated MC38-bearing Rag1−/− mice, which have functional innate immunity, with SD-36. Similarly, a low dose of SD-36 (20 mg kg−1) did not have any effect on tumour volume (Fig. 5c), weight (Fig. 5d) or appearance (Fig. 5e) in Rag1−/− mice. Thus, the therapeutic effect of SD-36 is dependent on an intact adaptive immune system. We treated MC38-bearing wild-type mice with anti-CD8 antibody to deplete CD8+ T cells (Extended Data Fig. 5b). CD8+ T cell depletion resulted in the loss of SD-36 therapeutic effectiveness (Fig. 5f). Indeed, SD-36 treatment increased the fraction of CD8+ T cells that express TNF (Fig. 5g,h), IFNγ (Fig. 5i,j) and GZMB (Fig. 5k,l) in 4T1 tumours and TDLNs (Extended Data Fig. 5c–f) and LLC (Extended Data Fig. 5g–r). Thus, STAT3 degradation enhances CD8+ T cell-mediated anti-tumour efficacy.
a–e, Tumours in MC38-bearing NSG (a,b) and Rag1−/− mice (c–e) treated with SD-36 were monitored. n = 5 (a,b) and n = 6 (c,d); two-way ANOVA (a,c) and unpaired two-tailed t-test (b,d). Scale bar, 1 cm. NS, not significant. f, Tumour volume was monitored in MC38-bearing mice treated as indicated. Data are mean ± s.e.m., n = 6; **P = 0.0018, two-way ANOVA. g–l, FACS analysis of 4T1-infiltrating TNF+ (g,h), IFNγ+ (i,j) and GZMB+ (k,l) CD8+ T cells from mice treated with SD-36. Data are mean ± s.e.m., n = 6; *P = 0.0175 (h), *P = 0.0232 (j) and *P = 0.0404 (l), unpaired two-tailed t-test. m,n, Tumour volumes were monitored in Batf3−/− and wild-type mice bearing MC38 (m) or B16F10 (n) tumours and treated with SD-36. Data are mean ± s.e.m.; n = 5 (m), and n = 8 (n); *P = 0.0158 (m) and *P = 0.0126 (n), two-way ANOVA. o, FACS analysis of STAT3 expression in different cell types from LLC-bearing mice. Data are mean ± s.e.m., n = 4; ****P < 0.0001, one-way ANOVA. p–r, FACS analysis of pSTAT3 (p,q) and pSTAT5 (r) in MC38-infiltrating cDC1s from mice treated with SD-36. Data are mean ± s.e.m., n = 5; *P = 0.0335 and ***P = 0.0002, unpaired two-tailed t-test. s–u, FACS analysis of MHCI (s), MHCII (t) and CD80 (u) in B16F10-infiltrating cDC1s from mice treated with SD-36. Data are mean ± s.e.m., n = 5; **P = 0.0021 (s), **P = 0.0035 (t) and **P = 0.0023 (u), unpaired two-tailed t-test. v, Tumour volume in B16F10-bearing Stat3+/+ and Stat3−/− mice treated with SD-36. Data are mean ± s.e.m., n = 7; **P = 0.0067 and ***P = 0.0006, two-way ANOVA. w, B16F10-bearing Batf3−/− mice were transferred with Stat3+/+ and Stat3−/− cDC1s and treated with SD-36, and tumour volume was monitored. Data are mean ± s.e.m., n = 7; **P = 0.0094, two-way ANOVA. x, Stat5+/+ and Stat5−/− cDC1s were transferred into MC38-bearing Batf3−/− mice, treated with SD-36, and tumour volume was monitored. Data are mean ± s.e.m., n = 7; ****P < 0.0001, two-way ANOVA. y,z, Tumour volume was monitored in mice bearing MC38 (y) and B16F10 (z) tumours and treated as indicated. Data are mean ± s.e.m.; n = 6 (y) and n = 7 (z); **P = 0.0094 (z) and ***P = 0.0009 (y), two-way ANOVA.
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To investigate whether DC1s were involved in the therapeutic efficacy of SD-36, we treated tumour-bearing Batf3−/− mice lacking cDC1s40. The anti-tumour efficacy of SD-36 therapy was absent in Batf3-deficient mice bearing MC38 (Fig. 5m), B16F10 (Fig. 5n) or LLC (Extended Data Fig. 5s) tumours. STAT3 was highly expressed in intratumoral DCs in wild-type mice bearing LLC tumours (Fig. 5o), and SD-36 treatment resulted in a rapid and efficient degradation of STAT3 protein in DCs compared with tumour cells (Extended Data Fig. 5t). Of note, the intracellular concentration of SD-36 was four times higher in DCs than in tumour cells (Extended Data Fig. 5u). These results suggest that SD-36 effectively induces degradation of STAT3 in DCs to achieve its therapeutic efficacy in vivo.
Next, we found that SD-36 treatment reduced pSTAT3 and increased pSTAT5 in MC38 tumour-infiltrating cDC1s (Fig. 5p–r). We also observed enhanced STAT5 activation in DCs isolated from the spleens of MC38-bearing mice after SD-36 treatment (Extended Data Fig. 5v). SD-36 treatment increased DC maturation and function markers in cDC1s in B16F10 tumours (Fig. 5s–u).
We examined whether STAT3 in DCs is a direct functional target of SD-36 therapy in vivo in tumour-bearing mice. We treated B16F10-bearing Stat3+/+ and Stat3−/− mice with SD-36. SD-36 treatment inhibited tumour growth in Stat3+/+ mice, whereas this effect was abolished in Stat3−/− mice (Fig. 5v). Similar results were observed in MC38 tumour-bearing mice (Extended Data Fig. 5w). We next transferred Stat3+/+ or Stat3−/− cDC1s into B16F10 or MC38 tumour-bearing Batf3−/− mice and treated these mice with SD-36. Again, SD-36 improved the anti-tumour effect in Batf3−/− mice that received Stat3+/+ cDC1s, but not in those that received Stat3−/− cDC1s (Fig. 5w, Extended Data Fig. 5x).
We used STAT5i34 to assess the interplay between STAT3 and STAT5 in DCs (Fig. 2l,m). STAT5i can have off-target effects. To genetically validate whether STAT5 in DCs contributes to SD-36-mediated anti-tumour immunity, we transferred Stat5b−/− cDC1s or Stat5b+/+ cDC1s into MC38 tumour-bearing Batf3−/− mice and treated these mice with SD-36. SD-36 effectively controlled tumour progression in mice receiving Stat5b+/+ cDC1s, but not Stat5b −/− cDC1s (Fig. 5x). Therefore, SD-36 reprograms key transcription factors in cDC1s by degrading STAT3 and enhancing STAT5 signalling, thereby inducing potent anti-tumour immunity in vivo.
Finally, we examined whether SD-36 could synergize with ICB. To this end, we treated mice bearing MC38 or B16F10 tumours with PD-L1 monoclonal antibody, SD-36 or both. Anti-PD-L1 inhibited MC38 tumour growth but had no effect on B16F10 tumours, whereas SD-36 monotherapy efficiently slowed down MC38 and B16F10 tumour growth. The combined treatment profoundly inhibited progression of MC38 and B16F10 tumours (Fig. 5y,z). We further tested SD-36 in human DC-mediated T cell activation in the context of ICB. We isolated DCs from fresh human ovarian cancer tissues and treated these DCs with SD-36 and/or anti-human PD-L1 monoclonal antibody, and co-cultured these DCs with T cells. Treatment with SD-36 or anti-PD-L1 increased the numbers of polyfunctional human T cells, as shown by GZMB+IFNγ+ (Extended Data Fig. 6a). The combined treatment additionally upregulated the levels of polyfunctional T cells (Extended Data Fig. 6a,b).
To further investigate degradation of STAT3 as a potential immunotherapeutic strategy, we have developed SD-2301, another highly potent and selective STAT3 degrader (Extended Data Fig. 6c). In contrast to SD-36, which engaged the cereblon–cullin 4A complex for induced STAT3 degradation, SD-2301 used a high-affinity VHL ligand to recruit VHL–cullin 2 for STAT3 degradation. SD-2301 effectively degraded STAT3 in DCs in vitro (Extended Data Fig. 6d). Treatment with SD-2301 resulted in a potent STAT3 degradation in DCs in vivo in B16F10 tumour-bearing mice (Extended Data Fig. 6e). Of note, SD-2301 exhibited four- to five-fold improved potency compared with SD-36 towards STAT3 degradation in DCs (Extended Data Fig. 6f). An efficacy experiment showed that 5 mg kg−1 SD-2301 was effective in reducing B16 tumour progression and was four times more potent than SD-36 (Extended Data Fig. 6g). Treatment with SD-2301 also increased the number of effector CD8+ T cells, as shown by IFNγ (Extended Data Fig. 6h,i) and GZMB (Extended Data Fig. 6j,k) expression. In line with this, SD-2301 treatment increased DC maturation and function markers in cDC1s in B16F10 tumours (Extended Data Fig. 6l–n). Treatment with SD-2301 had no effect on CD31+ blood vessel densities in B16F10 (Extended Data Fig. 6o) and MC38 (Extended Data Fig. 6p) tumour tissues and did not affect the body weight of mice bearing B16F10 tumours (Extended Data Fig. 6q).
In addition, whereas anti-PD-L1 monotherapy had no effect on B16F10 tumour growth, combined SD-2301 and anti-PD-L1 synergistically inhibited tumour growth (Extended Data Fig. 6r). In the MC38 tumour model, anti-PD-L1 or SD-2301 monotherapy effectively inhibited tumour growth, and the combined therapy profoundly suppressed MC38 tumour progression (Extended Data Fig. 6s). Accordingly, SD-2301 treatment increased the proportion of MC38 tumour neoantigen-specific (KSPWFTTL) tetramer+CD8+ T cells compared with the control treatment (Extended Data Fig. 6t,u). These results highlight that SD-2301 may enhance DC-mediated antigen specific T cell priming and presentation in vivo.
Next, we explored whether DC1s and STAT3 are direct cellular and molecular targets of SD-2301 therapy in vivo. To address this, we treated B16F10-bearing Stat3+/+ and Stat3−/− mice with SD-2301. As expected, SD-2301 treatment inhibited tumour growth in Stat3+/+ mice, whereas this effect was abolished in Stat3−/− mice (Extended Data Fig. 6v). The anti-tumour efficacy of SD-2301 therapy was absent in Batf3-deficient mice bearing MC38 tumours (Extended Data Fig. 6w). These results indicate that cDC1s have a key role in the therapeutic efficacy of SD-2301 in vivo.
Pharmacokinetic evaluation showed that SD-2301 had an excellent pharmacokinetic profile in mice, as characterized by a slow clearance and high plasma exposure (Extended Data Fig. 6x). Moreover, SD-2301 was highly potent and selective in inducing degradation of STAT3 over all other STAT proteins in human peripheral blood monocyte cells in vitro (Extended Data Fig. 6y). Together, our results suggest that STAT3 serves as a brake to restrain JAK2-mediated STAT5 activation in DCs and STAT3 degradation in DCs elicits potent anti-tumour immunity, thereby being a promising approach for cancer immunotherapy (Extended Data Fig. 6z).
This study offers support for several undocumented perspectives in the field of tumour immunology and immunotherapy. First, STAT3 counteracts STAT5 activation, which restrains DC maturation in the TME. Second, STAT3 degradation is a potential immunotherapeutic modality for treating patients with advanced and ICB-resistant cancer. Third, STAT3 degraders work in an DC-dependent manner, supporting STAT5-mediated DC maturation and function.
DCs prime and activate T cells against cancer cells3,41,42. We found that ICB can reprogram the STAT5 and STAT3 transcriptional pathways in DCs, thereby normalizing DC function in the TME. It has long been thought that DCs are potential immunotherapeutic targets. However, it is challenging to therapeutically manipulate DCs owing to their numeric scarcity, subset diversity and lack of specific molecular targets. Our results suggest that STAT3 is a druggable molecular target in DC1s using our potent and highly selective PROTAC STAT3 degraders.
Despite the identification of STAT3 and STAT5 many years ago20,43,44,45, the interplay between STAT3 and STAT5 signalling pathways in specific immune cells remain poorly understood. STAT3 is frequently activated in the TME owing to abundant stimulating factors, including IL-6, IL-10 and VEGF20,21, whereas STAT5 is often activated by T cell-derived cytokines, such as GM-CSF and IL-2. Given that T cells are limited or dysfunctional in the TME, the balance between STAT5 and STAT3 in immune cells, including DCs, may be biased towards STAT3 overactivation. In support of this possibility, we demonstrate that there is an imbalance between these two transcriptional pathways in DC1s in the TME, tilting towards an activation in STAT3 over STAT5. At the molecular level, DC1s express high levels of GM-CSF receptor and the STAT3 transcriptional signalling pathway restrains the GMR–JAK2–STAT5 signalling axis in DCs in the TME. The interaction between GMR and JAK2 appears to regulate both the STAT3 and STAT5 transcriptional pathways in DC1s. In support of this possibility, we observed that GM-CSF stimulation or genetically knocking down GM-CSF receptor alters the phosphorylation of JAK2, STAT3 and STAT5, but not JAK1, JAK3, TYK2 and STAT1 in cDC1s. Of note, targeting STAT3 has no effect on the expression levels of GM-CSF and GMRβ but enhances the interaction of GMRβ and JAK2 with STAT5, leading to the phosphorylation of STAT5 and DC maturation. Therefore, STAT3 restrains JAK2-mediated STAT5 activation in DCs, thereby impairing DC1-mediated T cell immunity.
To rescue the STAT3-impaired DC phenotype, we developed two PROTAC molecules (SD-36 and SD-2301) that target STAT3 protein for degradation. There are several key functional characteristics of our STAT3 degraders. First, they are highly selective and efficacious in degrading STAT3. Second, low doses of SD-36 and SD-2301 effectively target DCs. Furthermore, low doses of SD-36 and SD-2301 mediate an immune-dependent anti-tumour effect, whereas high doses of SD-36 can directly control tumour progression in the absence of a functional immune system36. Intriguingly, SD-36 or SD-2301, as a monotherapy, exhibit remarkable efficacy in treating large, advanced tumours and ICB-resistant tumours. Given that the anti-tumour effect of SD-2301 is four to five times more potent than that of SD-36 in degrading STAT3 and it has excellent pharmacokinetics, we are evaluating SD-2301 as a potential drug candidate for clinical development. Notably, although STAT3 degraders efficaciously target DCs, the involvement of STAT3 in other cell types may also influence immune responses in the TME. Together, our study provides strong support for potential human clinical trials of STAT3 degraders in treating patients with large and metastatic tumours and/or ICB-resistant tumours.
Western blot analyses were performed using primary antibodies at a dilution of 1:1,000 unless otherwise specified. Anti-STAT1 (D1K9Y, 14994), anti-STAT2 (D9J7L, 72604), anti-STAT3 (Rabbit, 79D7, 4904; Mouse, 124H6, 9139), anti-STAT4 (C46B10, 2653), anti-STAT5 (D2O6Y, 94205), anti-STAT6 (D3H4, 5397), anti-JAK1 (6G4, 3344), anti-JAK2 (D2E12, 3230), anti-JAK3 (D7B12, 8863), anti-TYK2 (E9H4T, 35615), anti-p65 (D14E12, 8242), anti-CD80 (E6J6N, 54521), anti-CD86 (E5W6H, 19589), anti-IL-6Rα (E7H4J, 39837), anti-GP130 (3732), anti-pSTAT1 (58D6, 9167), anti-pSTAT3 (D3A7, 9145), anti-pSTAT5 (D47E7, 4322), anti-pSTAT6 (D8S9Y, 56554), anti-pJAK1 (D7N4Z, 74129), anti-pJAK2 (C80C3, 3776), anti-pJAK3 (D44E3, 5031), anti-pp65 (93H1, 3033) and anti-β-actin (4967) were from Cell Signaling Technology. Anti-JAK2 (C-10, sc-390539), anti-GMRβ (F-12, sc-393281) and anti-β-actin (C4, sc-47778) were from Santa Cruz Biotechnology. Anti-pTYK2 (PA5-37762) was from Invitrogen. HRP horse anti-mouse IgG antibody (PI-2000, 1:5,000) and HRP goat anti-rabbit IgG (PI-1000, 1:5,000) were from Vector Laboratories.
For the in vivo experiments, anti-mouse CD8 (clone YTS 169.4, BE0117), anti-mouse PD-L1 (clone 10F.9G2, BE0101) and anti-IgG2b (clone LTF-2, BE0090) were from BioXcell. SD-36 and SD-2301 were designed and synthesized in our laboratory. FLLL32 (JAK2 inhibitor X, 5301530001) and STAT5 inhibitor (573108) were purchased from Sigma-Aldrich. Plasmids expressing shRNAs targeting Stat3 (TRCN0000071453, TRCN0000301946), Stat1 (TRCN0000054924), Jak2 (TRCN0000023649, TRCN0000023651, TRCN0000023652) and Gmrβ (TRCN0000067025, TRCN000067026) were from Sigma-Aldrich.
JAWSII, 293T, B16F10, CT26, EMT6, LLC and 4T1 cells were purchased from the American Type Culture Collection (ATCC). MC38 mouse colon cancer cell line was obtained from the University of Texas Southwestern Medical Center (Y.-X. Fu). Ovarian cancer cell line luciferase-ID8 cells were previously reported24. All cell lines were tested for mycoplasma contamination by MycoAlert Mycoplasma Detection kit and confirmed negative for Mycoplasma.
The 293T cells were transfected with packaging plasmids and non-targeting lentivirus vector, or a lentivirus vector encoding shRNAs targeting Stat3, Stat1, Jak2 or Gmrβ. The virus-containing supernatant was collected 48 h after transfection. JAWSII cells were transfected with the lentivirus. Then the cell lysates were analysed by immunoblotting.
Bone marrow was collected from the femurs and tibias of mice. Red blood cells were lysed using ACK lysis buffer. Bone marrow-derived DCs (BMDCs) were generated with GM-CSF (20 ng ml−1) and FLT3 ligand (100 ng ml−1) in IMDM (Iscove's Modified Dulbecco's Medium; Gibco, 12440-053) supplemented with 10% FBS, 1% penicillin-streptomycin and 55 μΜ β-mercaptoethanol for 7–10 days. BMDCs were either sorted as cDC1s (CD11c+XCR1+) using a FACSAria flow cytometry sorter (BD Biosciences) or purified using biotin anti-mouse XCR1 antibody (BioLegend,148212) and anti-biotin microbeads (Miltenyi Biotec, 130-090-485) following the manufacturer's protocols for subsequent experiments. Primary cell cultures were tested to be mycoplasma-free by MycoAlert Mycoplasma Detection kit.
Culture media were collected from Stat3+/+ and Stat3−/− cDC1s and centrifuged at 8,000g for 5 min. GM-CSF (MGM00) and IL-6 (DY406) were detected in the culture supernatants using the ELISA kit.
CD8+ T cells were depleted with anti-CD8 (YTS 169.4, BioXCell) antibodies. Anti-CD8 (100 μg per mouse) antibodies were injected intraperitoneally at the beginning of tumour inoculation and continuously administered every three days.
DCs and LLC tumour cells were treated with 1 μM SD-36 for 12 h. Then, DCs and LLC (106 each) were centrifuged at 1,500 rpm for 5 min at 4 °C and washed 3 times with ice-cold PBS. The pellets were resuspended in 100 μl of a 50% (v/v) water/methanol solution and subjected to 3 freeze–thaw cycles. After the final thaw cycle, these samples were centrifuged at 14,000 rpm, 4 °C for 20 min, and the supernatant were collected. All samples were submitted to the pharmacokinetics core (University of Michigan) for analysis.
Cells were lysed in immunoprecipitation lysis buffer (50 mM Tris-HCl pH 7.4, 120 mM NaCl, 1 mM EDTA and 0.5% NP-40) and supplemented with Halt Protease and Phosphatase Inhibitor Cocktail (Thermo Fisher Scientific). Cells were repeatedly passed through a 21-gauge needle with sonication. Then 1,000 µg total cell lysates were incubated with the appropriate antibody (2 µg), with rotation overnight at 4 °C, followed by a 3-h incubation with Protein A/G Sepharose beads (Santa Cruz Biotechnology). Immune complexes were washed three times with wash buffer (20 mM Tris-HCl pH 7.4, 100 mM NaCl, 1 mM EDTA and 0.2% NP-40); then the immunoprecipitated proteins were denatured by the addition of sample buffer (Bio-Rad) and boiled for 10 min, resolved by SDS–PAGE, and immunoblotted with indicated antibodies.
Cells were lysed in RIPA buffer (Thermo Fisher Scientific) supplemented with Halt Protease and Phosphatase Inhibitor Cocktail (Thermo Fisher Scientific). The protein concentrations of cell lysates were determined by BCA protein assay kit (Thermo Fisher Scientific). Equivalent amounts of total cellular protein were separated by SDS–PAGE, transferred to polyvinylidene fluoride membranes, and immunoblotted with the indicated antibodies.
For phospho-antibody array cDC1s were treated with LPS (20 ng ml−1) for 3 h and lysed for protein extraction. Lysates were analysed using the Proteome Profiler Phospho-Kinase Array Kit (R&D Systems, number ARY003C) according to the manufacturer's instructions. Western blotting data were processed and analysed by image lab 6.1 (Bio-Rad) and ImageJ 1.51n (NIH).
For histological analysis, tissue samples were collected, fixed in 10% formalin (Sigma) and processed for formalin-fixed paraffin-embedded tissue analysis. Four-micrometre paraffin sections underwent heat-induced epitope retrieval. Staining was performed with anti-mouse CD31 antibody (Cell Signaling Technology, D8V9E, 77699, 1:100) using an automated immunostainer (Biocare Intellipath, Biocare Medical). Sections were counterstained with haematoxylin (Biocare Medical), and slides were scanned with the Aperio AT2 Scanner (Leica Biosystems Imaging). Quantification was performed with QuPath v0.5.1.
Total RNA was isolated from cells by column purification (RNeasy Micro Kit, Qiagen) with DNase treatment. cDNA was synthesized using the RevertAid First Strand cDNA Synthesis Kit (Thermo Fisher Scientific) with random hexamer primers. Quantitative PCR was performed on cDNA using Fast SYBR Green Master Mix (Thermo Fisher Scientific) on a QuantStudio 3 Real-Time PCR System (Thermo Fisher Scientific). Gene expression was quantified using specific primers (Extended Data Table 3). Fold changes in messenger RNA expression were calculated with the ΔΔCt method using Actb as an endogenous control. The results are expressed as fold changes normalized to the controls.
The synthesis of SD-2301 is outlined in scheme 1 (Supplementary Fig. 1). It began with a known compound, 1, which was converted into compound 2 through a two-step process. First, compound 1 was reacted with hept-6-ynoic acid to form an amide, which was then saponified using LiOH in aqueous media to yield acid intermediate 2 in 65% overall yield. Azide 6 was synthesized in 80% yield from commercially available amine 5 using a previously reported method. A click reaction between alkyne acid 2 and azide 6, with sodium ascorbate and CuSO4, resulted in acid intermediate 3 in 78% yield. Amine 7 was prepared from Boc-l-glutamine through a two-step procedure. Initially, Boc-l-glutamine was coupled with substituted benzyl amine in the presence of HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium) and DIPEA (N,N-diisopropylethylamine) in DMF (N,N-dimethylformamide) to form a Boc-protected amide, which was then Boc-deprotected using 4 (N) HCl in DCM to give amine 7 in 70% yield over two steps. The coupling of acid 3 with amine 7 in the presence of HATU and DIPEA in DMF produced a Boc-protected intermediate. This intermediate was then Boc-deprotected using 4 (N) HCl in dioxane to yield amine intermediate 4 in 75% yield over two steps. Finally, compound 4 was converted into SD-2301 in 86% yield through an amide formation reaction with literature known intermediate 8, using HOBt and DIPEA in DMF.
The purity of SD-2301 was confirmed by ultra-performance liquid chromatography (UPLC) to be >99%. UPLC−MS (ESI) m/z: calculated, 683.7 for C64H80N13O15PS2 [M + 2H]+/2; found, 684.09 (Supplementary Fig. 2). Proton nuclear magnetic resonance (1H-NMR) and carbon nuclear magnetic resonance (13C-NMR) spectroscopies were performed on Bruker Advance 400 NMR spectrometers, and chemical shifts are reported in parts per million (ppm) relative to an internal standard (Supplementary Figs. 3 and 4).
Animal studies were approved by the Institutional Animal Care and Use Committee at the University of Michigan. All mice were maintained under specific pathogen-free housing (about 22 °C with approximately 40% humidity) on a 12-h dark:12-h light cycle. The following mice (at 6–8 weeks of age) (The Jackson laboratory) were used for this study: C57BL/6J, BALB/cJ, NOD-scid IL2Rγ null (NSG), Rag1tm1Mom (Rag1–/–), C57BL/6-Tg(TcraTcrb)1100Mjb/J (OT-I), B6.129S(C)-Batf3tm1Kmm/J (Batf3−/−), B6.129S(Cg)-Stat1tm1Dlv/J (Stat1−/−), B6(129S4)-Xcr1tm1.1(cre) Kmm/J (Xcr1cre), B6.129S1-Stat3tm1Xyfu/J (Stat3fl/fl) mice and CD-1 mice were obtained from Charles River Laboratories. Stat5b–/– C57BL/6J mice were from the National Institutes of Health (Warren Leonard). Stat3fl/fl mice were crossed with Xcr1cre mice to obtain specific STAT3 deficiency in DC1s (Stat3−/− mice). In-house littermates were used in the control arm when specific mouse strains were generated in-house.
MC38 (2 × 106), CT26 (105), EMT6 (105), B16F10 (2 × 105) and LLC (2 × 105) cells were injected subcutaneously into syngeneic mice. Luciferase-expressing ID8 cells (2 × 106) were injected into the peritoneal cavity of female mice. Luciferase-expressing 4T1 cells (105) were injected into female mouse mammary fat pad. From day 5–7, SD-36 (low doses: 10 or 20 mg kg−1; high dose: 100 mg kg−1) or SD-2301 (5 mg kg−1) was administered intravenously every 3 days. In 4T1 tumour metastasis model, treatment with SD-36 (20 mg kg−1) started on day 14, followed by every 3 days. In some cases, peritoneal tumour-bearing mice were similarly treated with SD-36 (20 mg kg−1) or SD-2301 (5 mg kg−1) or were injected intraperitoneally with FLLL32 (30 mg kg−1) for 24 h. For the ICB experiments, PD-L1 monoclonal antibody or isotype antibody (BioXcell, 200 μg) were administrated intraperitoneally into tumour-bearing mice, starting on day 3, then repeated this treatment every 3 days. For DC1 transfusion experiments, bone marrow-derived cDC1s (2 × 106) were sorted and injected intravenously into tumour-bearing Batf3−/− mice on day −2 and day 8. SD-36 (20 mg kg−1) was administered intravenously every three days, starting on day 5. Tumour inoculation time was considered day 0. Tumour cells were inoculated into age-, sex- and source-matched mice. Tumour size was measured using calipers with a Vernier scale and calculated as previously46.
To evaluate tolerability and toxicity, tumour-bearing C57BL/6J mice received intravenous injections of SD-2301 (5 mg kg−1) every 3 days for 18 days, with body weights were monitored throughout.
For pharmacokinetic evaluation, female CD-1 mice were administered a single intravenous dose of SD-2301 at 5 mg kg−1 with 25% of PCP as the dosing vehicle. Then, 250–300 μl blood samples were collected from 5 min to 24 h. Following centrifugation at 15,000 rpm for 10 min, at least 100 μl of plasma was collected. All samples were analysed by the Pharmacokinetic and Mass Spectrometry core at the University of Michigan. Compound concentrations in plasma were determined using a validated LC-MS/MS method with an internal control. Chromatographic separation was achieved with a Waters XBridge-C18 column (5 cm × 2.1 mm, 3.5 μm) on a Shimadzu HPLC system. Detection was performed on an AB Sciex QTrap 5500 mass spectrometer in positive-ion MRM mode. The mobile phases were 0.1% formic acid in water (A) and in acetonitrile (B). The gradient for B was: 10% (0–0.3 min), increased to 95% at 0.7 min, held for 2.3 min, and returned to 10% for a 2-min re-equilibration. Flow rate was 0.4 ml min−1. Pharmacokinetic parameters were calculated using noncompartmental methods in WinNonlin v.3.2 (Pharsight).
All clinical records used in this study were acquired and used with the approval of Institutional Review Boards. Patients (cohort 1) who underwent ICB therapy were recruited from the University of Michigan Hospital, Ann Arbor, MI, USA. Inclusion in the analysis applied to those who were enroled in the Michigan Center for Translational Pathology's (MCTP) continuous comprehensive clinical sequencing programme39,47,48,49, MI-Oncoseq, and who possessed sequenced libraries of pre-treatment tumours. From the initiation of therapy, overall survival times were measured. Treatment responses were determined according to RECIST1.1 criteria50 and imRECIST51. Integrative clinical sequencing was conducted using standard protocols approved for use in MCTP's Clinical Laboratory Improvement Amendments-compliant sequencing laboratory, as previously described47,48,52. After purification with the AllPrep DNA/RNA/miRNA kit (Qiagen), total RNA was sequenced using the exome-capture transcriptome platform on an Illumina HiSeq 2000 or HiSeq 2500 in paired-end mode. Quality control, alignment, and expression quantification was executed through the standard clinical RNA-seq pipeline, CRISP53. Read count tables were then normalized into fragments per kilobase million (FPKM) then transcripts per million (TPM) using the edgeR 4.2.2 package54. Gene scores in RNA-seq data were generated using the rank-based inverse normal transformation (INT) as demonstrated previously55. The CTL score and DC1 maturation score were generated using the following respective gene sets: (CD8A, CXCL10, CXCL9, GZMA, GZMB, PRF1, IFNG and TBX21) and (CD40, CD80, CD86, HLA-DQA1, XCR1, CLEC9A, IL12A, IL12B, HLA-DRA and IDO1). STAT5/STAT3 expression was calculated as the ratio of combined TPM of STAT5A and STAT5B (STAT5AB) to STAT3 TPM for all patients (Extended Data Table 1). Stratification was performed at the median STAT5AB/STAT3 TPM ratio and at the median DC1 maturation score. This was performed for cohort 2 (Extended Data Table 2) in each dataset, before combining group-wise. STAT5 pathway INT score was calculated using the GM-CSF reactome gene set (R-HSA-512988). STAT5 pathway/STAT3 was calculated by dividing the INT score by the STAT3 TPM in each respective sample, this value was stratified by the median.
The single-cell RNA-seq analysis of TNBC (cohort 3) (dataset GSE169246) was conducted in R using Seurat (v.4.3.0), ssGSEA, and standard data wrangling and plotting packages. All analyses were carried out after subsetting the data for immunotherapy treatment. DCs were extracted based on the original authors' annotations. Only cells expressing 200 or more genes in at least 3 cells were included in the analysis, and cells with mitochondrial reads greater than 10% were excluded. The STAT5 signalling score for each cell was calculated by applying the GM-CSF reactome gene set (R-HSA-512988) as input to the enrichIt function from the escape (v.2.0.0) package, which implements ssGSEA. Similarly, the STAT3 signalling score was determined using the same approach. The genes used for the IL-10-driven STAT3 signalling score were obtained from previously reported gene orthologues in murine DCs56. This gene set comprised: RAP1GAP, CAMKK1, CASR, KIF1A, HPCAL4, DRAM1, RAMP2, MT2A, IGFBP6, GATA3, CXCR5, GDA, FAM65C (also known as RIPOR3), PLET1, SOCS3, MUC1 and GBP5. The DC maturation score was computed using the same method with genes canonically associated with DC maturation, including CD40, CD80, CD83, CD86, LAMP3, CCL19, IL12A, IL12B, CCL5, CCL22, CXCL9, CXCL10, NFKB1, NFKB2, NFKBIA, NFKBIB, FSCN1 and CCR7. The binary division of high and low STAT3 signalling scores was determined by visually identifying two distinct clusters. The monocyte-DCs versus conventional DC distinction was determined through a combination of iterative clustering and expression of CD14. The Wilcoxon signed-rank test was used to compare the ssGSEA scores using the stat_compare_means function from the ggpubr (v.0.6.0) package.
For the in vitro human ICB study, lin−CD45+CD11c+MHCII+ DCs were enriched and sorted from fresh cancer tissues of patients with high grade serous ovarian carcinoma. DCs (106 per ml) were pretreated with SD-36 (1 μM), washed, and co-cultured with normal peripheral blood T cells (2 × 106 per ml) in the presence of anti-human PD-L1 (10 μg ml−1), anti-CD3 (2 μg ml−1), and anti-CD28 (1 μg ml−1) for 3 days. T cell cytokine profile was analysed by FACS. For detecting the effect of SD-2301 on STAT members in human immune cells in vitro, normal human peripheral blood mononuclear cells (PBMCs) were treated with SD-2301 for 14 h, followed by immunoblotting to analyse STAT protein levels. Normal human immune cells were collected from commercial buffy coats (Carter BloodCare).
cDC1s were purified from BMDCs as described above. The RNA was isolated by column purification (Qiagen, 217048) with DNase treatment. The RNA-seq was conducted by BGI Genomics. Bulk RNA-seq analysis was performed using the edgeR (v.4.2.2) and limma (v.3.60.6) package workflows. Preliminary quality control measures were performed including the filtering of lowly expressed genes, and the calculation and assessment of library sizes across samples. The raw counts were then transformed to log counts per million (CPM) values.
A design matrix was created containing cell population information (Stat3−/− versus Stat3+/+) and then contrasts for pairwise comparisons between Stat3−/− and Stat3+/+ were determined in limma using the makeContrasts function. As an additional normalization measure, removal of heteroscedasticity from the normalized counts data was achieved using the voom function. To identify differentially expressed genes, the mean-variance relationship of the normalized counts was assessed and then the normalized data were modelled as a linear combination of factors and covariates. The cutoff for the P value was P = 0.05. Differential expression analysis was performed on non-treated Stat3−/− versus Stat3+/+ cDC1s and LPS-treated Stat3−/− versus Stat3+/+ cDC1s, respectively.
To assess the DC maturation signature, the log fold change and P values of DC maturation genes reported in the literature including (Cd40, Cd80, Cd83, Cd86, Ido1, Irf7, Tnfsf8, H2-Aa, H2-ab1, Tlr4, Il12b, Il12rb1, Il12rb2 and Cxcl9) was observed from the differential expression analysis results. To assess the significantly upregulated DC maturation pathways, gene set enrichment analysis (GSEA) was performed on the Stat3−/− versus Stat3+/+ differentially expressed genes in R using the gseGO function. To assess the significantly upregulated DC activation pathways in the DCs treated with LPS, GSEA was performed on the LPS-treated Stat3−/− versus Stat3+/+ differentially expressed genes in R using the gseGO function.
The z-score of the normalized counts were computed and plotted as a heat map using GraphPad Prism 10.2.2. DC maturation genes were selected from the differential expression analysis results and the log fold change and P values were plotted using GraphPad Prism 10.2.2. The GSEA plots were generated in R using the gseaplot function. The GSEA dot plot was generated by plotting key pathways from the GSEA results using the dotplot function from clusterProfiler 4.9.2 package. The volcano plot was generated by first performing differential expression analysis of LPS-treated Stat3−/− versus Stat3+/+ cDC1s and plotting log fold changes and P values of genes from the STAT5 pathway curated in the Hallmark pathway Molecular Signature Database (MSigDB).
Chromatin immunoprecipitation was performed using the SimpleChIP Enzymatic Chromatin IP Kit (Cell Signaling Technology, 9003s). Sheared chromatin was then immunoprecipitated with STAT5 (Cell Signaling Technology, 94205s) and IgG (Cell Signaling Technology, 2729) antibodies. SYBR green master mix (Applied Biosystems) was used to measure amplification of DNA using QuantStudio 3 Fast Real-Time PCR system (Applied Biosystems). The promoters of gene were quantified using the specific primers (Extended Data Table 3). After normalization to the Input DNA, the amount of output DNA of each target protein was calculated by subtracting that of the IgG control.
Single-cell suspensions were prepared from fresh mouse tumour tissues or spleen, and lymphocytes were enriched by density gradient centrifugation. To assess intracellular cytokine production, cells were cultured for 4 h in the presence of phorbol myristate acetate (5 ng ml−1; Sigma-Aldrich), ionomycin (500 ng ml−1; Sigma-Aldrich) and brefeldin A (1: 1000, BD Biosciences). Cells were fixed and permeabilized with the Transcription factor staining buffer set (Invitrogen, 00-5523-00). Cellular phenotypes were assessed multi-parameter flow cytometry panels. Data were acquired on a BD LSRFortessa. Antibodies against the following mouse antigens were used: CD45 (30-F11, HI30), CD90 (53-2.1, 30-H12), CD3 (17A2), CD45R/B220 (RA3-6B2), CD4 (RM4-5, GK1.5), CD8 (53−6.7), IFNγ (XMG1.2), granzyme B (GB11), IL-2 (JES6-5H4), Ki-67 (B56), I-A/I-E (M5/114.15.2), CD80 (16-10A1), CD86 (GL1), H-2Kb (AF6-88.5.5.3), H-2 (M1/42), XCR1 (ZET), TNF (MP6-XT22), CD11c (HL3), phospho-Tyr694-STAT5 (SRBCZX), phospho-Tyr705-STAT3 (13A3-1). Additionally, antibodies against the following human antigens were used: CD8 (RPA-T8), IFNγ (B27) and TNF (MAb11). The strategies for DC gating and in vitro cultures and tissues are shown in Extended Data Figs. 2c and 3e, respectively. The strategy for T cell gating is presented in Extended Data Fig. 3k.
Sample sizes were determined based on previously published studies to ensure appropriate statistical power. In vitro experiments were performed in at least two independent replicates. For in vivo studies, each group consisted of a minimum of five mice, which was considered sufficient to detect meaningful biological differences with good reproducibility, and mice were randomized into treatment groups at the start of the experiment. Experiments were not performed in a blinded manner, as knowledge of the treatment groups were necessary to carry out the study. t-tests were used to assess differences between two independent experimental groups, and one-way analysis of variance (ANOVA) was used to compare three or more groups. Two-way ANOVA was applied to compare tumour growth curves. Data are presented as mean ± s.e.m., and statistical significance was defined as P < 0.05 for all tests. All statistical analyses related to these experiments were performed using GraphPad Prism software v.10.2.2.
Kaplan–Meier analysis was conducted to estimate overall survival, with differences between groups assessed using log-rank tests. Cox proportional hazards models were used for multivariate survival analysis. Pearson's correlation coefficient was applied to evaluate linear correlations between variables, and the Wilcoxon rank-sum test was performed to assess group differences. All P values are two-sided and not adjusted for multiple comparisons. The statistical analyses were conducted using R packages.
All human studies were conducted under the oversight and approval of the Institutional Review Board at the University of Michigan Medical School.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Clinical sequencing data are publicly available with raw data available upon request from dbGaP phs000673.v5.p1 (refs. 39,47). RNA-seq data that were newly generated in this study for in vitro analysis have been deposited at the Gene Expression Omnibus (GEO) at NCBI under accession GSE289764. Single-cell RNA-seq data that support the findings of this study were downloaded from GEO accession GSE169246. The two original melanoma RNA-seq datasets were deposited in the European Nucleotide Archive (ENA) under accession PRJEB23709 and in dbGaP under accession phs000452.v2.p1. The processed data for these two melanoma datasets can be found at https://ngdc.cncb.ac.cn/icb/resources. All materials are available from the corresponding authors upon reasonable request. Source data are provided with this paper.
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The authors thank J. Deng for providing Stat1–/– C57BL/6J mice (originally from The Jackson Laboratory); M. Wang, B. Wen and D. Sun for the pharmacokinetics study; and our laboratory members for their intellectual input. This work was supported in part by research grants from the Breast Cancer Research Foundation, NIH/NCI R01 grants (CA217648, CA123088, CA099985, CA193136, CA152470 and CA244509), and the NIH/NCI through the University of Michigan Rogel Cancer Center Grant (CA46592). J.-X.L. and W.J.L. are supported by the Division of Intramural Research, the National Heart, Lung and Blood Institute, the National Institutes of Health.
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
Jiajia Zhou, Kole Tison, Michael Pitter, Linda Vatan, Peng Liao, Jiali Yu, Heng Lin, Shuang Wei, Xue Gao, Sara Grove, Ilona Kryczek & Weiping Zou
Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
Jiajia Zhou, Kole Tison, Michael Pitter, Linda Vatan, Peng Liao, Jiali Yu, Heng Lin, Long Jiang, Shuang Wei, Xue Gao, Sara Grove, Ilona Kryczek, Michael D. Green & Weiping Zou
Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA
Kole Tison & Weiping Zou
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
Kole Tison, Long Jiang & Marcin Cieslik
Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Haibin Zhou, Longchuan Bai, Ranjan Kumar Acharyya, Donna McEachern, Hoda Metwally, Yu Wang & Shaomeng Wang
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
Jae Eun Choi, Abhijit Parolia, Marcin Cieslik, Arul M. Chinnaiyan & Weiping Zou
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
Jae Eun Choi, Abhijit Parolia, Marcin Cieslik, Arul M. Chinnaiyan & Shaomeng Wang
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA
Michael D. Green
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Jian-Xin Lin & Warren J. Leonard
Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA
Arul M. Chinnaiyan
University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
Arul M. Chinnaiyan, Shaomeng Wang & Weiping Zou
Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA
Arul M. Chinnaiyan & Weiping Zou
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
Shaomeng Wang
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
Shaomeng Wang
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J.Z. conceived the study, designed experiments, conducted experiments and wrote and revised the manuscript. K.T. performed human bioinformatic analyses and wrote and revised the manuscript. H.Z. developed SD-36. L.B. developed SD-36 and SD-2301 and conducted in vitro human PBMC studies with SD-2301. R.K.A. developed SD-2301. D.M. assisted with in vivo experiments and supervised the use of SD-36 and SD-2301. H.M. provided assistance with in vivo experiments. Y.W. conducted the pharmacokinetics study. M.P. performed mouse bioinformatic analyses. J.E.C. assisted with human bioinformatic analyses. L.V. performed flow cytometry sorting of samples. P.L. designed ChIP–qPCR primers. J.Y. assisted in preparing single-cell suspensions from mouse tumour tissues. H.L. assisted with antigen presentation assays. L.J. assisted with the identification of Stat3+/+ and Stat3−/− mice. S. Wei identified and generated Stat3+/+ and Stat3−/− mice and guided the protocol for experimental animals. X.G. assisted with phospho-kinase array. S.G. generated Stat3+/+ and Stat3−/− mice. A.P. supervised bioinformatic analyses. M.C. assisted in acquiring human tumour samples and provided bioinformatic support. I.K. conducted in vitro human studies, assisted with the analysis of flow cytometry data, provided scientific input, engaged in discussions, revised the manuscript and supervised the study. M.D.G. contributed to the acquisition of human tumour samples and oversaw bioinformatic support. J.-X.L. provided Stat5b−/− mice. A.M.C. had a role in acquiring of clinical samples and supervised bioinformatic support. W.J.L. provided Stat5b−/− mice, provided scientific input, participated in discussions and revised the manuscript. S. Wang conceived the study, developed SD-36 and SD-2301, designed experiments, provided scientific input, participated in discussions, revised the manuscript, supervised the study and acquired funding. W.Z. conceived the study, designed experiments, composed the manuscript, provided scientific input, participated in discussions, wrote and revised the manuscript, supervised the study and acquired funding.
Correspondence to
Shaomeng Wang or Weiping Zou.
W.Z. serves as a scientific advisor or consultant for Cstone, Hanchor Bio and NextCure and was a consultant for Oncopia. S. Wang was a co-founder and a paid consultant for Oncopia Therapeutics and owned equity in Oncopia, which was acquired by Roivant Sciences and Proteovant Therapeutics. S. Wang was a paid consultant for Proteovant Therapeutics and Roivant Sciences and owned stock in Roivant Sciences. S. Wang was the principal investigator for a research contract between Oncopia/Proteovant and the University of Michigan. S. Wang is a co-founder, paid consultant, and member of the board of directors of Ascentage Pharma Group International and owns stock in Ascentage. A.M.C. was a co-founder and a paid consultant for Oncopia and owned equity in Oncopia and was a paid consultant for Proteovant Therapeutics. The University of Michigan owned stock in Oncopia and Ascentage. The University of Michigan has filed multiple patents on STAT3 degraders, which have been licensed by Oncopia/Proteovant (now SK Life Science Labs) for clinical development. S. Wang, H.Z., L.B., R.K.A., D.M. and H.M. are inventors on SD-36 and/or SD-2301 and have received royalty payments from the University of Michigan. All other authors declare no competing interests.
Nature thanks David Frank, Ignacio Melero and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a. The Kaplan Meier (KM) survival curve was plotted to visualize the difference in survival probability between patient stratifications. Cohort 1 patients with ICB unresponsive tumors (sarcoma, lymphoma, prostate cancer, and others) were excluded for analysis. n = 69, p = 0.0374, the CoxPH model calculates the effect of the STAT5 pathway/STAT3 DC maturation (high/high group) on survival outcome relative to STAT5 pathway/STAT3 DC maturation (high/low group) when tumor type is controlled. b-c. KM curves of OS in melanoma patients (cohort 2) treated with ICB, by low or high DC score and the ratio of STAT5 versus STAT3 (DC1HiSTAT5/STAT3Hi, DCHiSTAT5/STAT3Lo, DCLoSTAT5/STAT3Hi, DCLoSTAT5/STAT3Lo). n = 72 (b), n = 42 (c), p = 0.038 (b), p = 0.051 (c) by log-rank test. d. High and low STAT3 gene signaling scores in patients with TNBC (cohort 3). Based on the STAT3 ssGSEA score, two distinct clusters were resolved. e-f. STAT5 and STAT3 gene signatures in DCs in non-responders (cohort 3). STAT5 (e) and STAT3 (f) gene signatures were analyzed in DCs in the post-ICB samples of non-responders compared to their pre-ICB samples. NS, not significant, Wilcoxon Rank-sum test. g. UMAP representations were used to identify different DC subtypes from the integrated scRNA-seq datasets of TNBC (cohort 3). The cells were then color-coded according to their respective DC subtypes. h-s. STAT5 and STAT3 gene signatures in cDCs and moDCs during ICB treatment (cohort 3). STAT5 (h, j, l, m, p, and r) and STAT3 (i, k, n, o, q, and s) gene signatures in cDCs and moDCs were compared between responders and non-responders after ICB treatment in TNBC. *p = 0.036 (m), *p = 0.034 (p), ****p < 0.0001 (h, i, l, q), Wilcoxon Rank-sum test. the central line represents the median. The lower and upper hinges of the box correspond to the 25th and 75th percentiles. The whiskers extend to the smallest and largest values no further than 1.5 * IQR from the hinges. Outliers are plotted as individual points.
a-b. Xcr1 Cre knock-in mice express an mCherry fluorescent protein under the control of the Xcr1 promoter in cDC1s. mCherry expression and XCR1-APC-Cy7 staining in DCs from Stat3+/+ and Stat3−/− mice were analyzed by FACS (a). mCherry expression and XCR1-APC-Cy7 staining in DCs (CD11c), B cells (B220), T cells (CD3 and CD90), macrophages (F4/80) from Stat3−/− mice were analyzed by FACS (b). One of four mice is shown. c. Gating strategy for cDC1s (CD11c+XCR1+) in BMDCs. d-g. Phenotype of Stat3−/− mice. The representative images show mouse body size (d), lymphoid organs (e), and T cell subset distribution (f-g) in Stat3+/+ and Stat3−/− mice. h. Western blotting shows CD80 and CD86 expression in Stat3+/+ and Stat3−/− cDC1s. One of three experiments is shown. i. Real time qPCR shows the expression of cytokine receptor mRNAs in mouse cDC1s. mean ± SEM, n = 4, ****p < 0.0001, one-way ANOVA. j. Effect of GMRβ knockdown on the JAK-STAT signaling pathway. JAWSII cells were transfected with shRNAs against Gmrβ or control shRNA and cultured with GM-CSF. Cell lysates were subjected to analysis by immunoblots. One of three experiments is shown. k. Effect of GM-CSF on JAWSII cells. The immunoblots show the expression levels of JAK family members in JAWSII cells. One of three experiments is shown. l-m. Effect of STAT3 deletion on GM-CSF and GMRβ expression in cDC1s. GM-CSF was detected by ELISA in culture supernatants in Stat3+/+ and Stat3−/− cDC1s on day 5 (l). n = 3, NS, not significant, unpaired two-tailed t-test. GMRβ was determined by Western blotting (m). One of three experiments is shown. n. The fractions of IL-6+ DCs (in red) and non-DCs are depicted in the TNBC patient dataset30. o. RNA-seq analysis (from Fig. 2n) shows the expression of Il6 by TPM (Transcripts Per Million) in mouse Stat3+/+ and Stat3−/− cDC1s. n = 4, NS, not significant, unpaired two-tailed t-test. p. Effect of STAT3 deletion on IL-6 expression in cDC1s. IL-6 was detected by ELISA in culture supernatants in Stat3+/+ and Stat3−/− cDC1s on day 4. n = 3, NS, not significant, unpaired two-tailed t-test. q-r. RNA-seq analysis (from Fig. 2n) shows the expression of IL-6 receptors (Il6ra, Il6st) by TPM (Transcripts Per Million) in mouse Stat3+/+ and Stat3−/− cDC1s. n = 4, NS, not significant, unpaired two-tailed t-test. s. Western blot shows expression of IL-6Rα and GP130 in Stat3+/+ and Stat3−/− cDC1s. One of three experiments is shown. t-x. Effect of FLLL32 on STAT5 activation and DC maturation in vivo. Stat3+/+ and Stat3−/− mice bearing peritoneal B16F10 (t) and MC38 (u-x) tumors were treated with FLLL32 on day 9 for 24 h. FACS shows expression of pSTAT5 (t, u), MHC-I (v), MHC-II (w), and CD80 (x) in peritoneal cDC1s. MFI, mean fluorescence intensity. mean ± SEM, n = 3. ****p < 0.0001 (t-w), ***p = 0.0001 (x), one-way ANOVA. y-z. GSEA analysis reveals significant differences in the CCR chemokine receptor binding (y) and interferon gamma production (z) between Stat3+/+ and Stat3−/− cDC1s. Source data contained unprocessed WB.
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a-d. Effect of STAT3 deletion on DC-mediated T cell activation. OT- I cells were cultured with Stat3+/+ or Stat3−/− cDC1s without loading SIINFEKL peptides. FACS shows the percentage of Ki67+ (a), IFNγ+ (b), TNFα+ (c), and GZMB+ (d) OT- I cells. e. Gating strategy for cDC1s (CD11c+XCR1+) in MC38 tumor bearing mouse model. f. Effect of STAT3 deficiency on the interaction between JAK2, STAT3, and STAT5 in DCs in vivo. Lin− CD11c+XCR1+ cDC1s were enriched and sorted from the TME in Stat3+/+ and Stat3−/− mice bearing peritoneal MC38 tumors. Co-immunoprecipitation (IP) was performed with anti-JAK2 in DC lysates. One of two experiments with repeats is shown. g-j. MC38 tumors were inoculated into Stat3+/+ and Stat3−/− mice. MHC-II (g, h), and CD86 (i, j) expression in cDC1 from MC38 tumor-draining lymph nodes (TDLNs) were analyzed by FACS. mean ± SEM, n = 4, **p = 0.0062 (h), *p = 0.0335 (j), unpaired two-tailed t-test. k. Gating strategy for CD8+ T cells in MC38 tumor bearing mouse model. l-q. Effect of STAT3 deletion on MC38 tumor progression. FACS shows the percentages of MC38 tumor infiltrating IL-2+CD8+ T cells (l, m), and the percentages of TDLN IL-2+ (n, o), and IFNγ+ (p, q) CD8+ T cells. For l, n, and p, one representative dot plot is shown in each panel. mean ± SEM, n = 3 (m), n = 4 (o, q), *p = 0.0141 (m), **p = 0.006 (o), **p = 0.0021 (q), unpaired two-tailed t-test. r-y. Effect of STAT3 deletion on the phenotype of DCs and T cells in B16F10 bearing mice. FACS shows the expression of MHC-I (r, s) and CD80 (t, u) in tumor-infiltrating cDC1s, and the percentages of tumor infiltrating IL-2+ (v, w) and TNFα+ (x, y) CD8+ T cells. For r, t, v, and x, one representative dot plot is shown in each panel. MFI, mean fluorescence intensity. mean ± SEM, n = 3 (s, u), n = 4 (w, y), *p = 0.038 (s), *p = 0.0363 (u), *p = 0.0109 (w), *p = 0.0172 (y), unpaired two-tailed t-test. Source data contained unprocessed WB.
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a. SD-36 structure is shown. b. Immunoblotting shows STAT1 in shStat1 JAWSII cells. c-e. Effect of STAT1 on SD-36-regulated DC phenotype. FACS shows the expression of MHC-I (c), MHC-II (d), and CD80 (e) in shStat1 JAWSII cells treated with SD-36. MFI, mean fluorescence intensity. means ± SEM, n = 3, *p = 0.0117 (c), *p = 0.0195 (d), ***p = 0.0006 (e), one-way ANOVA. f. Immunoblotting shows STAT1 in bone marrow derived DC1s from Stat1+/+ and Stat1−/− mice. One of three experiments is shown. g. Effect of STAT1 on STAT5 activation in cDC1s. FACS shows the expression of pSTAT5 in bone marrow derived Stat1+/+ and Stat1−/− cDC1s. n = 3, NS, not significant, unpaired two-tailed t-test. h-j. Effect of STAT1 on SD-36-regulated DC maturation. Stat1+/+ and Stat1−/− DCs were treated with SD-36 for 12 h. FACS shows the expression of MHC-I (h), MHC-II (i), and CD80 (j) in cDC1s. MFI, mean fluorescence intensity. means ± SEM, n = 3, *p = 0.0314 (i), *p = 0.0138 (j), **p = 0.0059 (h), one-way ANOVA. k. Effect of SD-36 on B16F10 tumor progression. B16F10 tumor bearing C57/B6 mice were treated with 10 mg/kg SD-36. Tumor volumes were shown. mean ± SEM, n = 7, *p = 0.0114, two-way ANOVA. l-m. Effect of SD-36 on MC38 tumor progression. MC38 tumor bearing C57/B6 mice were treated with SD-36. Tumor weight (l) and image (m) were shown. mean ± SEM, n = 5, ***p = 0.0004, unpaired two-tailed t-test. n-s. Effect of SD-36 on tumor progression (n-p) and mouse body weights (q-s). Mice bearing B16F10 (n, q), CT26 (o, r), and EMT6 (p, s) were treated with SD-36 (100 mg/kg) three times a week when tumor volume reached 100 mm³. Tumor volumes and mouse body weights were monitored. means ± SEM are shown, n = 8 (n, q), n = 10 (o, p, r, s), ***p = 0.0005 (n), ****p < 0.0001(o, p), two-way ANOVA. t-u. Effect of SD-36 on large tumor progression. Mice bearing CT26 tumors (500 mm3/tumor) were treated with vehicle (t) or SD-36 (u). Tumor volumes were monitored. Source data contained unprocessed WB.
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a. Effect of SD-36 on tumor growth in NSG mice. MC38 tumor-bearing NSG mice were treated with SD-36 (100 mg/kg) or vehicle. Tumor volume was monitored. mean ± SEM, *p = 0.0326, two-way ANOVA. b. Efficacy of anti-CD8 mAb in CD8+ T cell depletion. MC38 bearing were treated with anti-CD8 mAb. FACS shows CD8+ T cells in the tumor draining lymph node (TDLN). One of 5 is shown. c-f. Role of SD-36 in CD8+ T cells in 4T1 tumor draining lymph nodes (TDLN). 4T1 tumor bearing mice were treated with SD-36. FACS shows the percentages of TDLN TNFα+ (c, d), and IFNγ+ (e, f) CD8+ T cells. For c, e, one representative dot plot is shown in each panel. mean ± SEM, n = 4, *p = 0.0184 (f), **p = 0.0063 (d), unpaired two-tailed t-test. g-r. Role of SD-36 in CD8+ T cells in LLC tumor bearing mice. FACS shows the percentages of TNFα+ (g, h), IFNγ+ (i, j), and GZMB+ (k, l) CD8+ T cells from tumors (g-l) and tumor-draining lymph nodes (m-r). For g, i, k, m, o, and q, one representative dot plot is shown in each panel. mean ± SEM, n = 6 (h, j, l), n = 4 (n, p, r), *p = 0.0224 (p), *p = 0.0294 (r), **p = 0.0072 (h), **p = 0.0071 (n), ***p = 0.0007(j), ***p = 0.0008 (l), unpaired two-tailed t-test. s. Effect of SD-36 on tumor growth in Batf3−/− mice. Batf3−/− mice were inoculated with LLC cells and with SD-36 (n = 8) or vehicle (n = 11). Tumor volumes were monitored. t. Effect of SD-36 on STAT3 protein in DCs and LLC tumor cells. Immune blotting shows the levels of STAT3 in DCs and LLC tumor cells treated with SD-36 for 12 h, and the ratio of STAT3 to actin expression. u. DCs and LLC tumor cells were treated with 1 μM SD-36 for 12 h. Intracellular SD-36 was quantified by LC-MS/MS. mean ± SEM, n = 4, **p = 0.0011, unpaired two-tailed t-test. v. Role of SD-36 in DCs. MC38 tumor-bearing mice were treated with SD-36 or vehicle. Immune blotting shows key transcriptional factors in DCs isolated from spleens. One of three experiments is shown. w. Effect of cDC1 STAT3 in SD-36-regulated tumor progression. MC38 tumor bearing Stat3+/+ and Stat3−/− mice were treated with SD-36 or vehicle. Tumor volume was determined. mean ± SEM, n = 7, **p = 0.0056, two-way ANOVA. x. Role of cDC1 STAT3 in SD-36-regulated anti-tumor immunity. Stat3+/+ and Stat3−/− cDC1s were transferred into MC38-bearing Batf3−/− mice. These mice were treated with SD-36. Tumor volume was monitored. mean ± SEM, n = 5, **p = 0.002, two-way ANOVA. Source data contained unprocessed WB.
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a-b. Effect of SD-36 on ICB efficacy in humans in vitro. DCs from human ovarian cancer tissues were pretreated with SD-36, washed, and co-cultured with T cells in the presence of anti-human PD-L1 for 3 days. FACS shows the percentage of GZMB+IFNγ+ (a) and IL-2+TNFα+ (b) CD8+ T cells, mean ± SEM, n = 4, *p = 0.0237 (a, control vs. SD-36), *p = 0.0135 (a, control vs. Anti-PD-L1), *p = 0.0302 (b), ****p < 0.0001 (a), one-way ANOVA. c. Chemical structure of SD-2301 structure. d. Effect of SD-2301 on STAT3 expression in DCs in vitro. DCs were treated with SD-2301 (50 nM) for 24 h. Immune blotting shows STAT3 protein. One of 3 is shown. e. Effect of SD-2301 on STAT3 expression in DCs in vivo. Wild type mice bearing peritoneal B16F10 tumors were treated SD-2301 (5 mg/kg). Immune blotting shows STAT3 expression in peritoneal DCs. n = 3/group. f. Comparison of the effect of SD-2301 and SD-36 on STAT3 degradation in mouse DCs. DCs were treated with SD-2301 and SD-36 for 24 h. Immune blotting shows STAT3 expression in DCs. One of three experiments is shown. g-n. Comparison of the anti-tumor effect of SD-2301 and SD-36. B16F10 bearing mice were treated with SD-2301 (5 mg/kg) or SD-36 (20 mg/kg) every 3 days. Tumor volume was monitored (g). FACS shows the expression of IFNγ (h, i) and GZMB (j, k) in B16F10 infiltrating CD8+ T cells, and the expression of MHC-I (l), MHC-II (m), and CD80 (n) in tumor infiltrating cDC1s. MFI, mean fluorescence intensity. means ± SEM, n = 7 (g), n = 4 (i, k, l, m, n), **p = 0.0023 (g), ***p = 0.0003 (g), two-way ANOVA (g); **p = 0.0014 (i), **p = 0.0015 (l), **p = 0.0046 (n), ***p = 0.0001 (k), ***p = 0.0001 (m), unpaired two-tailed t-test (i, k, l, m, n). o-p. Effect of SD-2301 on blood vessels in tumors. B16-F10 and MC38 bearing mice were treated with SD-2301. CD31+ vessel density was quantified in B16-F10 (o) and MC38 (p) tumors. Representative immunohistochemical staining images and the quantification of CD31+ vessel densities are shown. n = 4 tumors, NS, not significant, unpaired two-tailed t-test. q. Effect of SD-2301 on mouse body weights. B16F10 bearing mice were treated with SD-2301 (5 mg/kg) every 3 days for 18 days. Mouse body weights were monitored. r-s. Effect of SD-2301 on ICB efficacy in vivo. B16F10 (r) or MC38 (s) bearing mice were treated with SD-2301, anti-PD-L1, and their combination. The group of B16F10 bearing mice (r) treated with SD-2301 is identical to that shown in Extended Data Fig. 6g. Tumor volumes were monitored. mean ± SEM, n = 7, *p = 0.0106, ***p = 0.0009, ****p < 0.0001, two-way ANOVA. t-u. Effect of SD-2301 on neoantigen specific CD8+ T cell response. MC38 bearing mice were treated with SD-2301 or vehicle. FACS shows the percentage of tumor infiltrating KSPWFTTL tetramer+CD8+ T cells. means ± SEM, n = 6, *p = 0.0216, unpaired two-tailed t-test. v. Effect of SD-2301 on the role of STAT3 in DC-regulated tumor progression. B16F10 tumor bearing Stat3+/+ and Stat3−/− mice were treated with SD-2301 or vehicle. Tumor volumes were monitored. mean ± SEM, n = 7, ****p < 0.0001, Two-way ANOVA. w. Effect of SD-2301 on cDC1-regulated tumor progression. MC38 bearing Batf3+/+ and Batf3−/− mice were treated with SD-2301 or vehicle. The group of control mice treated with SD-2301 is identical to that shown in Extended Data Fig. 6s. Tumor volumes were monitored. mean ± SEM, n = 7, ****p < 0.0001, Two-way ANOVA. x. Pharmacokinetics (PK) of SD-2301 in mice. Female CD-1 mice (n = 3) were administered with SD-2301 (5 mg/kg). Blood samples were collected for PK analysis. Cl, clearance; Vss, volume of distribution at steady state; T1/2, elimination half-life; Cmax, maximum drug concentration; AUC, area-under-the-curve. y. Effect of SD-2301 on STAT3 expression in human immune cells. Human peripheral blood mononuclear cells were treated with different concentrations of SD-2301 for 14 h. The immunoblots show the expression levels of STATs. One of two repeats. z. The schematic diagram shows that STAT3 restrains the JAK2-STAT5 signaling pathway, thereby reducing STAT5-dependent DC maturation and lessening T cell immunity and immunotherapy effectiveness. Source data contained unprocessed WB.
Source data
This file contains experimental procedure for SD-2301, and Supplementary Figs. 1–4. Supplementary Fig. 1: Synthesis of SD-2301. Supplementary Fig. 2: UPLC spectrum of SD-2301. Supplementary Fig. 3: 1H-NMR Spectrum of SD-2301 (400 MHz, Methanol-d4). Supplementary Fig. 4: 13C-NMR Spectrum for SD-2301 (101 MHz, Methanol-d4).
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Zhou, J., Tison, K., Zhou, H. et al. STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity.
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Choice behaviour of animals is characterized by two main tendencies: taking actions that led to rewards and repeating past actions1,2. Theory suggests that these strategies may be reinforced by different types of dopaminergic teaching signals: reward prediction error to reinforce value-based associations and movement-based action prediction errors to reinforce value-free repetitive associations3,4,5,6. Here we use an auditory discrimination task in mice to show that movement-related dopamine activity in the tail of the striatum encodes the hypothesized action prediction error signal. Causal manipulations reveal that this prediction error serves as a value-free teaching signal that supports learning by reinforcing repeated associations. Computational modelling and experiments demonstrate that action prediction errors alone cannot support reward-guided learning, but when paired with the reward prediction error circuitry they serve to consolidate stable sound–action associations in a value-free manner. Together we show that there are two types of dopaminergic prediction errors that work in tandem to support learning, each reinforcing different types of association in different striatal areas.
When animals and humans make choices, they exhibit two key tendencies: pursuing rewarding actions and repeating past actions1,2. Dopamine neurons that encode reward prediction error (RPE)3 provide a critical teaching signal for value-based learning, reinforcing actions that lead to reward. Recently it has been proposed that repetitive ‘habitual' choices may instead be updated by a movement-based teaching signal4,5,6.
The hypothesized teaching signal encodes an action prediction error (APE), the difference between the action that is taken and the extent to which the action was predicted. Although experimental evidence is lacking, theoretical models suggest that this value-free learning system could operate alongside canonical value-based learning in the basal ganglia5,6. These models predict two types of dopaminergic teaching signals: RPE, which reinforces reward-driven actions, and APE, which reinforces repeated actions4,6. Notably, dopaminergic neurons located in the ventral tegmental area (VTA) and medial parts of the substantia nigra pars compacta (SNc) encode RPE7,8, whereas those in the lateral SNc and substantia nigra pars lateralis (SNl), which project to the tail of striatum (TS), prominently respond to movement9,10,11,12.
Here we investigated whether movement-related dopaminergic activity encodes an APE, providing a value-free teaching signal to reinforce repeated state–action associations. To address this, we examine the role of dopamine in the TS as mice learn an auditory discrimination, cloud-of-tones (COT)13 task. We show that dopaminergic input to this region is important for learning, and that dopaminergic activity during the task is movement-related. We go on to show that this movement-related dopaminergic activity encodes an APE. Causal manipulations show that this value-free teaching signal can reinforce state–action associations, essentially biasing mice to repeat the actions that they have taken in the past. We propose a model where this movement-based teaching signal works in conjunction with canonical RPE signalling to boost and stabilize learning about consistent state–action associations.
In the COT task, mice initiate trials by nose-poking a central port, triggering auditory stimuli composed of a short train of overlapping pure tones (5–40 kHz). They selected a left or right reward port on the basis of whether the stimulus contained primarily low (5–10 kHz) or high (20–40 kHz) frequencies (Fig. 1a and Extended Data Fig. 1a). In line with previous reports14, bilateral inactivation of the TS with muscimol (a GABAA (γ-aminobutyric acid type A) receptor agonist), but not the dorsomedial striatum (DMS), impaired task performance (Fig. 1b,c) in expert mice. Unilateral optogenetic inactivation of either type of striatal projection neurons (SPNs) in the TS also had an opposing and significant effect on choices of mice (Fig. 1d–f and Extended Data Fig. 1b,c). These results demonstrate that the TS is needed to execute the learned behaviour and that both populations of SPNs exert opposing contributions to the auditory-guided choices.
a, Schematic of the task. Frequencies (freq.) represent auditory stimuli, volumes represent reward. b, Muscimol injection locations, indicated by the co-injection of fluorescent cholera toxin B. Scale bar, 2 mm. c, Psychometric task performance of mice, saline in TS (2 mice; 4 sessions), DMS (3 mice; 11 sessions) and TS (5 mice; 15 sessions). Lines represent logistic fits of the means. d, Schematic for inhibition of D1 SPNs or D2 SPNs. e, Psychometric task performance for opto-stimulated trials for the D1 (Drd1-cre) archaeorhodopsin (Arch) (8 mice; 15 sessions) and A2A (Adora2a-cre) Arch (8 mice; 12 sessions) mice. Lines represent logistic fits of the means. Stim, stimulation. f, Quantification of the bias for each session shown in e. Scatter dots represent the mean for each session, and error bars illustrate the variation of shuffled data (Methods). Colour-filled dots indicate P < 0.05. D1-Arch: P = 2.27 × 10−5, Cohen's d = −1.40; A2A-Arch: P = 2 × 10−7, Cohen's d = 2.33; Kruskal–Wallis test. g, Example lesion and control mice histology. h, Learning rate of the lesioned TS (n = 11 mice) and control (n = 10 mice) groups (lines represents group means). i,j, Maximum performance (i; P = 0.0023, Kruskal–Wallis test; Cohen's d = −1.70) and maximum learning rate (j; P = 0.0006, Kruskal–Wallis test; Cohen's d = −2.04) between the groups (same mice as in h). k, Example TH staining in the TS for control and lesion mice. l, Learning rate of the TS dopamine-ablated (n = 9 mice) and control (n = 5 mice) groups. m,n, Differences on the maximum performance (m; P = 0.006, Kruskal–Wallis test; Cohen's d = −2.39) and maximum learning rate (n; P = 0.014, Kruskal–Wallis test; Cohen's d = −1.71) between the groups (same mice as l). Error bars indicate s.d. in c,e,h,l. In box plots, boxes represent quartiles 2 and 3, the centre line shows the median and whiskers extend to the furthest data point within 1.5 times the inter-quartile range from the box.
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To test whether the TS was also needed to learn the task, we ablated the TS prior to training using a viral-mediated caspase-based strategy (Fig. 1g and Extended Data Fig. 2a,b). Lesions of the TS caused a deficit in learning (Fig. 1h–j and Extended Data Fig. 2c–f), reducing both the learning rate and the maximum performance reached on the task (Fig. 1i,j). To confirm that the deficits in learning are not due to an inability of the mice to act upon the learned sound–action association we infused an N-methyl-d-aspartate (NMDA) receptor antagonist, d-2-amino-5-phosphonovalerate (d-AP5) in the TS (Extended Data Fig. 3a,b). d-AP5 infusions did not affect performance in expert mice (Extended Data Fig. 3c) but significantly impaired learning when infused during training (Extended Data Fig. 3d–g). In addition, ablation of the TS-projecting dopamine neurons also recapitulated the general TS lesions effects. TS dopamine-ablated mice had deficits in learning (Fig. 1k–n and Extended Data Fig. 3h–p), without influencing the time taken to move from the centre port to the choice ports (Extended Data Fig. 3k), or the time taken between trials (Extended Data Fig. 3l). Together, these results confirm that both the TS and its dopaminergic innervation are required to facilitate learning and execute the auditory discrimination task.
To understand the role of TS dopamine in the task, we measured its dynamics with dLight1.1, a genetically encoded fluorescent dopamine sensor15. TS dopamine responses correlated in time with contralateral movements from the centre port, in sharp contrast to the large reward responses in ventral striatum (VS) (Fig. 2a–e and Extended Data Fig. 4).
a, Schematic of the experimental approach for recording dopamine activity in the VS and TS. The anterior–posterior distance between the VS and TS are not to scale. b, Fluorescent images showing optical fibre locations and dLight expression in the TS and the VS. Scale bar, 1 mm. c, Recording fibre locations from the VS and TS matched to the reference atlas. d, Example of a TS and a VS recording session aligned to time of leaving the centre port to make a contralateral (contra) choice or an ipsilateral (ipsi) choice. White dot shows time of entering contralateral or ipsilateral choice port. e, Average photometry traces in TS (n = 10 mice) and VS (n = 7 mice) aligned to task events. Shaded time windows show significant differences between the two trace types in each subplot, calculated by performing two-sample t-tests on 0.1-s bins and a P value threshold for significance of 0.01. f, Average response kernels to behavioural events for recordings in the TS and VS. Shaded time windows are calculated as in e. Coeff., coefficient. g, Percentage explained variance (var.) of the whole recording session (VS median = 31.3; TS median = 5.50) and for different behavioural kernels for linear regression models fitted on VS (n = 7 mice) and TS (n = 10 mice) recordings. Error bars represent s.e.m. in e,f. In box plots, boxes represent quartiles 2 and 3, the centre line shows the median and whiskers extend to the furthest data point within 1.5 times the inter-quartile range from the box.
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To separate dopamine responses associated with overlapping behavioural events, we applied a linear regression model to photometry data obtained early in training. The model included three event types: cue (centre port entry), choice (centre port exit) and outcome (side port entry). VS responses were best explained by the outcome kernel, capturing the large responses to rewards and dips for unrewarded trials (Fig. 2e–g and Extended Data Fig. 4c–f). By contrast, TS showed minimal outcome-related dopamine activity (Fig. 2e–g and Extended Data Fig. 4c–f). In line with other studies16,17,18, we observed dopaminergic reward responses when we recorded in the posterior region of the dorsolateral striatum (pDLS), which is located just rostral to the TS and is not prominently innervated by the primary auditory cortex19 (Extended Data Fig. 4a,b,n,o). The largest TS dopaminergic response was contralateral movement-locked activity (Fig. 2e–g), which was also seen when mice made contralateral movements to return from the side ports to the centre port (Extended Data Fig. 4j–m). VS movement-related activity was smaller, with no significant difference between contralateral and ipsilateral actions (Extended Data Fig. 4g–i). These results show that VS dopamine activity significantly encodes reward outcome, consistent with RPE, whereas the TS dopamine activity encodes movement information.
To confirm that TS dopamine activity was unrelated to sound, we omitted the cue on some trials (Extended Data Fig. 5a–g) and found no significant difference in response. To assess task dependence, we recorded TS dopamine activity as mice explored an open arena. As in-task recordings, TS dopamine increased during contralateral movements (Extended Data Fig. 5h–j), and its signal scaled with movement amplitude (Extended Data Fig. 5k–n). Turn angle significantly correlated with TS dopamine (Extended Data Fig. 5n), a correlation that was absent in VS. These results confirm that TS dopamine encodes information about movement.
To determine whether there was any additional sensory response to the sound stimuli, we trained mice on a version of the task in which sounds were played when the mice left the side ports and returned to the centre port to initiate the next trial (Extended Data Fig. 5o). There was no significant response to the sound in this version of the task but the response to contralateral orienting movement from the centre port remained (Extended Data Fig. 5p–t). In addition, there was no significant response when the sound cues were played as the mice freely explored an open arena (Extended Data Fig. 5u–y), confirming that the recorded TS dopamine signal correlated with movement and not sound.
Our results indicate that TS dopamine is crucial for learning the auditory frequency discrimination task and encodes information about movement rather than reward or sound. Although dopamine RPEs are known to drive cortico-striatal plasticity and learning3,20,21,22, the role of movement-related dopamine remains unclear. Habit-formation models predict that movement-related dopamine could encode a value-free APE, representing the discrepancy between an executed action and its predicted occurrence in a given state4,6.
If the movement-related dopaminergic activity in the TS encodes an APE, then dopamine activity in the TS should decrease over time as mice learn to predict the action that they will take in response to the sound. To test this prediction, we recorded TS and VS dopamine signals over the course of learning and compared these signals to values of RPE and APE from a dual value-based/value-free reinforcement learning model (Extended Data Fig. 6). Characteristic of an RPE signal, cue-related dopamine activity in the VS grew over time (Fig. 3a–d) after an initial fall in the response that might be due to changes in stimulus salience or alternative interpretation of VS dopamine signal23,24,25. In line with encoding an APE signal, the movement-related dopamine activity in the TS decreased as mice learned the task (Fig. 3e–h). This decrease resembled the exponential decay of the value-free system of the model (Fig. 3g).
a, dLight recording in the VS. Each trace is the average of 200 trials. b, Example VS dopamine response size to contralateral cue binned every 40 trials. c, Average change in contralateral cue-aligned VS dopamine response. The solid orange represents the mean (n = 7 mice). The light orange trace is the mean predicted RPE response from 100 model agents. a.u., arbitrary units. d, Size of contralateral cue-aligned dopamine response in VS in the first and last session of training (n = 7 mice), P = 0.016 (paired two-sided t-test), Cohen's d = −1.25. e–g, As a–c but for TS recordings (n = 6 mice). h, As d but for the TS (n = 9 mice), P = 0.006 (paired two-sided t-test). Cohen's d = 1.19. i, Modelled responses for APE at the time of correct contralateral choice if the previous choice for that stimulus was ipsilateral or contralateral. j, As i but for an example average (mean) TS dopamine response. k, Regression coefficients. One-sided t-test against zero, corrected using the Bonferroni method for multiple comparisons. VS: n = 7 mice, P = 0.005, 1.0, 1.0, 1.0, 1.0 (left to right), (Cohen's d = 2.23, 0.37, 0.23, 0.17, 0.13 (left to right)). TS: n = 6 mice, P = 0.04, 0.20, 0.20, 0.47, 0.63 (left to right), (Cohen's d = −1.72, −1.13, −1.13, −0.84, −0.75 (left to right)). l,m, As i,j but for the VS response. n, Task design. WN, white noise. o, Modelled APE and RPE signals following the state change. p, Example TS dopamine responses to the contralateral choice in response to the normal or the white noise cue. q, TS dopamine response to the contralateral action before and after the introduction of the novel state (P = 0.01, paired two-sided t-test) (n = 6 mice), Cohen's d = −1.81. r, As p but for a VS recording aligned to cue. s, As q but for VS recording aligned to cue. (P = 0.02, Wilcoxon signed-rank test) (n = 7 mice), Cohen's d = 1.04. Error bars represent s.e.m.
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To confirm that this decay in the signal was not due to changes in the way that mice were moving and performing the task, we tracked changes in speed and kinematics over the course of learning. Fitting a linear regression model that considered the log trial number, speed and turn angle in each mouse revealed that the change in TS dopamine signal that is predicted by log trial number persisted even once the proportion of the signal that could be predicted by movement alone was accounted for (Extended Data Fig. 6c–l). The majority of the explained variance in a full model with movement and log trial number was captured by changes in the trial number rather than changes in speed or turn angle (Extended Data Fig. 6m).
If the movement-related dopaminergic activity in the TS encodes an APE, then changes in the dopamine activity in the TS should also reflect the recent history of sound–action pairings that have been experienced. Therefore, the size of the dopamine signal should be smaller when the same action is taken in response to the same sound on subsequent trials (Fig. 3i). In agreement with this, the TS dopamine response was on average significantly smaller when mice repeated the same action in response to the same stimulus in the past trial (Fig. 3j,k). By contrast, the size of the cue response in the VS was larger when the correct sound–action pairing was repeated on subsequent trials (Fig. 3l,m), consistent with an RPE signal as the sound–action pairing would have a larger predicted value on the subsequent trial (Fig. 3l). Together these results show that the movement-related dopamine activity in the TS does not reflect a pure movement signal that is invariably linked to action characteristics, rather the size of the signal changes on a trial-by-trial basis depending on how predictable the sound–action association is, as expected from an APE signal.
The learning-associated changes in movement-related TS dopamine suggests that responses are modulated by how predictably an action follows a given state (auditory cue). Therefore, if trained mice were to make a familiar movement in response to an unfamiliar sound, the action would not be predicted by the stimulus and consequently the resulting APE should be larger. To examine this hypothesis, we replaced the auditory cue associated with the contralateral action with a novel cue (white noise) (Fig. 3n,o). The novel stimulus decreased the accuracy of mice (Extended Data Fig. 6o–t) and significantly increased the movement-related TS dopamine signal (Fig. 3p,q), as expected from an APE signal (Fig. 3o). There was no significant TS dopamine response to the unfamiliar white noise stimulus when it was played as mice freely explored an open arena (Extended Data Fig. 5x,y). As predicted by the RPE model, the VS dopamine cue response to the novel sound was smaller (Fig. 3r,s), as there is less value predicted by the novel cue (Fig. 3o).
a, Experimental approach. Slc6a3 encodes the dopamine transporter (DAT). b, Stimulation protocol. c, Average performance (mean) of mice. Left hemisphere n = 6 mice, right hemisphere n = 7 mice. Pre-stimulation data are pooled across all 13 recording sessions (n = 7 mice, 13 hemispheres). Error bars represent s.d. d, Distribution of session biases for the TS (4 mW n = 10 mice, n = 15 hemispheres, 8 mW n = 7 mice, n = 13 hemispheres) and the VS (4 mW n = 8 mice, n = 11 hemispheres, 8 mW n = 5 mice, n = 8 hemispheres) stimulations of the state–action experiment. TS: 4 mW P = 0.018, Cohen's d = 1.46; 8 mW P < 0.001, Cohen's d = 2.07. VS: 4 mW P = 0.57, Cohen's d = −0.19; 8 mW P = 0.742, Cohen's d = 0.19; Wilcoxon signed-rank test relative to zero (two-sided). e, Stimulation protocol. f, Same as d for the state–outcome TS-stimulation experiment (TS: 4 mW n = 10 mice, 8 mW n = 6 mice; TS: 4 mW P = 0.625, Cohen's d = 0.40; 8 mW, P = 0.909, Cohen's d = 0.05; VS: 4 mW P = 0.84, Cohen's d = −0.21; 8 mW P = 0.461, Cohen's d = 0.27; Wilcoxon signed-rank test relative to zero (two-sided)). g, Experimental approach. h, Average change in the bias for trials preceded by small or large dopamine choice movement responses (DA) in TS (n = 4, mice), error bars represent 68% confidence interval. i, Regression coefficients from a logistic regression (n = 4 mice) (log uncertainty: P = 0.006, Cohen's d = 3.31; dopamine: P = 0.03, Cohen's d = 2.01; one-sample t-test against zero, two-sided t-test). Filled circles represent significant correlations. Error bars represent s.d. j, As h but for VS dopamine responses (n = 5 mice). Error bars represent 68% confidence interval. k, As i but for VS dopamine at time of choice. n = 5 mice. log uncertainty: P = 0.03, Cohen's d = 1.44; dopamine (at time of cue): P = 0.29, Cohen's d = −0.54; one-sample t-test against zero, two-sided t-test. Error bars represent s.d. l, Example trajectories with smallest or largest Fréchet distances. m, Regression coefficients. Filled circles represent significant correlations for individual mice (n = 6 mice). One-sample t-test against zero, P = 0.03, Cohen's d = −1.24. Error bars represent 95% confidence interval. In box plots, boxes represent quartiles 2 and 3, the centre line shows the median and whiskers extend to the furthest data point within 1.5 times the inter-quartile range from the box.
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Another hallmark of an APE is that it should be value-free and should not be modulated by either the outcome or the predicted value of an action. In agreement with this, the dopamine signal in the TS did not significantly respond to a larger or smaller than predicted reward (Extended Data Fig. 7a–d). By contrast, the VS dopamine signal was altered in a manner consistent with RPE (Extended Data Fig. 7b,e,f). The size of the TS dopamine signal was also not modulated by changes in the predicted value of an action (Extended Data Fig. 7g–i), in contrast to the RPE-consistent VS signal (Extended Data Fig. 7h,k,l).
Finally, we compared our data to other theoretical models of dopamine activity, movement per se, novelty or salience (Methods). Unlike the models for APE and RPE, none of the models consistently matched the pattern of modulation across conditions that we observed in our recordings (Extended Data Fig. 8). Together, our results reveal that the movement-related TS dopamine signal is consistent with encoding APE.
To determine whether the TS dopamine signal can act as a teaching signal, we optogenetically stimulated TS dopamine release at different task epochs. To mimic the endogenous movement-related TS dopamine signal, we stimulated unilaterally at the centre choice port, in trials where there was more sensory evidence for a contralateral choice (Fig. 4a,b and Extended Data Fig. 9a,b). Within sessions, stimulation induced a significant contralateral choice bias (Fig. 4c,d and Extended Data Fig. 9c). This bias developed over the course of the session as would be expected if it influenced learning (Extended Data Fig. 9d) and could be replicated in a model where we artificially stimulated APE (Extended Data Fig. 9e). Optogenetic stimulation did not bias action directly as there was no choice bias on individually stimulated trials (Extended Data Fig. 9f). Stimulating dopamine release in the VS at the time of choice had no significant effect (Fig. 4d), nor did stimulation of dopamine release in the TS or the VS at the time of choice outcome (Fig. 4e,f). In a free choice paradigm TS dopamine stimulation did not induce a choice bias but there was a significant bias towards the stimulated port when we stimulated dopamine release in the VS (Extended Data Fig. 9g–j). Finally, there were no appetitive or aversive effects of the stimulation in a real-time place-preference assay when we stimulated dopamine release in the TS (Extended Data Fig. 10a,b). Together these results show that TS dopamine release can, as predicted by the computational models, reinforce state–action but not state–outcome associations.
Other theories suggest that movement-related dopamine facilitates movement initiation or modulates ongoing action9,26,27. However, closed-loop optogenetic stimulation of TS dopamine release in an open-field arena did not influence movement likelihood or alter movement parameters when mice did move (Extended Data Fig. 10c–i). These findings suggest TS dopamine activity reinforces state–action associations rather than influencing ongoing action.
Since TS dopamine stimulation reinforced state–action associations, we investigated whether endogenous TS dopamine release functioned similarly. A logistic regression model predicting choice repetition from the previous trial's dopamine response and current log uncertainty showed significant positive correlations for both factors (Fig. 4g–i), indicating that mice were more likely to repeat their previous choice when the TS dopamine response was larger and sensory uncertainty was higher. By contrast, dopamine reward response size in the VS did not correlate with choice bias (Fig. 4j,k). These results suggest that movement-related dopamine at choice timing serves as a value-free teaching signal, reinforcing stimulus–action associations in the TS so that mice learn to repeat the action that they have taken in the past when they hear the auditory stimulus.
If the TS dopamine response encodes an APE on the current trial, it should not only bias mice toward repeating stimulus–action associations but also influence trial kinematics, making subsequent actions more similar. To test this, we performed a linear regression between the current trial TS dopamine response at time of choice and the Fréchet distance between current and subsequent trial trajectories (which provides a measure of the similarities between the two trajectories) (Fig. 4l). The analysis revealed a significant negative correlation between TS dopamine response size and Fréchet distance, indicating that a larger TS dopamine response in a given trial led to a more similar subsequent trajectory (Fig. 4m and Extended Data Fig. 10j). These findings show that larger TS dopamine signals bias mice to repeat prior state–action associations with more similar movement trajectories.
To examine interactions between striatal regions receiving RPEs or APEs, we built a basal ganglia model that simulated learning with these prediction errors (Fig. 5a). Our dual value-based/value-free model had an actor and critic, updated by RPE, that learned to control actions and generate reward predictions. The value-free control system, updated by APE, learned to control action and generate action predictions. A model with only a value-free controller was unable to learn the task, as the model continues to repeat what it has done in the past, which is to randomly choose left or right in equal proportion (Fig. 5a). By contrast, a model with only the value-based controller was able to independently learn the task (Fig. 5b). Notably, a model with both controllers learned faster than the value-based system alone (Fig. 5b). Initially, there was no difference between the learning rate of these two models, because early learning is exclusively driven by RPE updates. However, as the dual model begins to consistently choose a particular action in response to a particular sound, APE updates started to reinforce specific stimulus–action associations, boosting performance and learning rate. This divergence between the value-based and dual-controller model recapitulates the learning deficits observed when we lesioned the TS or removed dopamine innervation to this region (Extended Data Fig. 11a). Our model shows that the value-free controller alone cannot support learning but when paired with the value-based controller, it acts to boost learning and store stable associations.
a, Schematic of the network model. b, Top, task performance across learning for the full dual-controller model (combined), the value-based controller, or the value-free controller. Bottom, differences in performance between the combined model and the value-based model (12 random agents selected for each). c, Change of the model weights for a reward association (high tone→left action), as means for 100 agents. Vertical lines indicate inactivation time points in d. d, Performance levels before and after (as the mean after ten trials) model inactivations of the TS or the actor networks. e, Schematic of the experimental approach for acute inhibition of D1 SPNs or D2 SPNs in the TS. f, Quantification of the contralateral bias on opto-stimulated trials (Methods) for each session as a function of session's performance. Error bars represent 95% confidence intervals. Lines show the mean and s.d. of linear fits for each mouse in each dataset. D1-Arch P = 0.004; A2A-Arch P = 7.6 × 10−4; Methods; n = 8 mice. g, Proportion of significantly biased sessions in f as a function of performance. h, Final weights in the TS for each sound–action association.
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Although both the value-based and value-free controllers can control behaviour, our muscimol inactivation data (Fig. 1c) highlights that in well-trained mice, behavioural performance relies on the TS (value-free controller). Since the value-free controller cannot learn the task alone, the task must first be learned by the value-based controller and then control must transfer over time to the value-free controller. In other dual-controller models, this transfer is achieved by an external arbiter4,6. We examined if a similar transfer would occur if the actor's weights decayed over time when RPE was low, consistent with striatal literature28,29,30,31. When the value-based actor's weights decayed, there was indeed a transfer of control in our model. Initial performance was controlled by the value-based controller, and over time, the value-free controller took over (Fig. 5c,d). In the expert condition, the dual-controller model retains the predicted value of each state–outcome association in the critic and the state–action association in the value-free controller (TS) (Fig. 5c and Extended Data Fig. 11b). The differential retention of the state value information in the critic and the decay of the state–action associations in the actor, validated the selection of an actor–critic architecture for our value-based controller.
To test whether the TS also slowly takes over control of performance like the value-free controller in our model, we optogenetically inactivated either type of TS projection neuron throughout learning (Fig. 5e). Early in training optogenetic inactivation of neither type of TS-SPNs had a significant effect on behaviour (Fig. 5f). However, as training progressed the inactivation began to have a significant effect on choices and these effects grew larger as the mice became experts at the task. These behavioural effects began to consistently increase after the mice were performing above 65% (Fig. 5f,g). This is a comparable training stage to where the control and lesion groups diverged when the TS was lesioned experimentally or in the model (Extended Data Fig. 11a). Taken together, this data shows that the TS only begins to contribute to task performance and learning once mice are already preferentially choosing a specific action in response to the auditory cues.
In the COT task, frequency-specific cortico-striatal plasticity supporting appropriate sound–action associations develops in each hemisphere of the TS throughout learning32,33. The same appropriate sound–action associations also form in our value-free controller, showing that APEs could be used to drive the frequency-specific changes in cortical striatal plasticity as mice learn the task (Fig. 5h). Together, our behavioural results, chronic lesions, acute inactivation, dopamine recordings, optogenetic perturbations and previous synaptic plasticity results32 are consistent with the TS forming the value-free part of a dual value-based/value-free learning system (Extended Data Fig. 11c).
Here we show that movement-related dopaminergic activity in the TS acts as a teaching signal to reinforce state–action associations. TS dopamine activity encodes an APE, the difference between the action taken and the predicted action in a given state. This value-free signal teaches mice to repeat past actions. Alone the value-free system (APE→TS) is not able to support reward-guided learning but in conjunction with the canonical RPE system it learns to mimic and store the value-guided state–action associations. Together we show that there are two types of dopaminergic prediction errors that work in tandem to support learning, each reinforcing different types of association in different areas of the striatum.
The identification of dopamine transients prior to movement initiation led to the idea that movement-related dopamine release may act to trigger the initiation of movement9,11,20,26. However, more recent experiments that used optogenetic stimulation parameters that were calibrated to mimic physiological levels of SNc dopamine release did not trigger body movement or lead to an invigoration of ongoing action34,35. The calibrated stimulation was however, as we observe, able to act as a teaching signal to drive conditioned place-preference learning and reinforce the use of particular behavioural syllables. This suggests that, as we have seen in the TS and consistent with APE, movement-related dopamine activity in other striatal areas may also act as a value-free teaching signal rather than as a trigger or modulator of ongoing movement. Notably, learning rules that incorporate terms similar to APE have been used to describe how mice learn to adjust the gain of specific kinematic features28. Yttri & Dudman36 showed that the changes were dependent on the DMS, suggesting that there may be common learning rules and computations across the striatum.
This raises the possibility that movement-related dopaminergic responses throughout the striatum9,10,11,12,20,26,37 may reflect APE. In line with this SNc movement-related dopamine activity also decreases with practice in a lever-pressing task9, as it should if the activity reflects an APE5. Furthermore, dopamine transients in the dorsolateral striatum (DLS) occur when sub-second action modules are initiated even in the absence of rewards or task structure35. The size of these transients is proportional to how predictable the upcoming action is with respect to the action that was just taken. This pattern of activity is what would be expected if these dopamine transients reflected an APE that compared the action that is taken (or soon to be taken) to the action that was predicted given the preceding behaviour. Together, the current data on movement-related dopamine activity are consistent with APE, suggesting that all movement-related dopamine activity throughout the striatum may reflect APEs that serve as value-free teaching signals.
The caudate tail (CDt)—the primate homologue of the TS—is also innervated by an anatomically distinct population of dopamine neurons38 that are not activated by differences in reward outcome39. Rather, as we observe here, these neurons are preferentially active prior to contralateral orienting eye movement or when stimuli that predict contralateral orienting responses are presented39, as would be expected if they also encode an APE. The contralateral nature of the response in primates was interpreted as a unilaterally processed visual response39. Our results now show that, at least in our task, the TS dopamine responses in mice are related to contralateral movement initiation and not auditory cues. The response to movement rather than sensory cues is also consistent with TS-projecting dopaminergic neurons receiving input from the deeper motor-related layers of the superior colliculus rather than from the superficial sensory-related layers40,41. Whether APE signals are driven by the preparation or execution of action will need to be determined in future work and may help resolve the difference in explanation. While the interpretation of the signal was different, the proposed function of the CDt-projecting dopamine neurons is entirely consistent with what we show here, in that it serves to reinforce stable sensory–motor associations in the CDt in an outcome-independent manner42,43. This suggests that the TS is unique across species in that it exclusively receives a value-free movement-based teaching signal to update stable sensory–motor associations.
Other laboratories have also shown that dopaminergic activity in the TS is not activated by reward44,45 but by threatening stimuli, such as an air puff or loud sounds. In addition, large TS dopaminergic transients are active when mice initiate avoidance behaviour, and these responses decrease as mice stop performing avoidance responses44. These observations led to the proposal that TS dopaminergic activity encodes a threat prediction error (TPE)44,46. In agreement with these results, we can also observe threat responses in the same region (and same mice) where we observe APE responses (Extended Data Fig. 12). However, whereas optogenetic stimulation of dopamine release in the TS was able to reinforce state–action associations, we could not detect any aversive effect of this stimulation even when we used higher power than was needed to influence associations in our task. Although our TS dopamine stimulation was not able to induce avoidance behaviour, it does appear clear that TS dopamine release is critical for maintaining innate aversive associations40,44. How TPE and APE work in the TS to support their different functions at different timescales will need to be determined in the future. One option is that threat- and movement-related activity are encoded by separate dopaminergic subpopulations. In support of this, it has recently been reported that threat and acceleration-related dopamine responses are encoded in separate genetic subpopulations that both project to the TS, expressing Slc17a6 (also known as Vglut2) and Anxa1, respectively37,47,48,49. These populations may respectively encode TPE and APE.
APE was first conceived as a teaching signal that could update habitual value-free state–action associations4,6. These models offer a parsimonious account for hallmarks of habitual behaviour, such as slower adaptation to contingency degradation or reversal and an insensitivity to outcome devaluation. This is because the stable associations in these models are driven by APE so are stored in an outcome-independent manner and are therefore insensitive to changes in outcome value. Our results show that dopamine neurons that project to the TS encode this type of movement-based prediction error. Interestingly the CDt is where habitual stimulus–action associations are stored29,39,50. Typically for instrumental learning the posterior DMS and the DLS have been shown to be critical for goal-directed and habitual learning respectively31,51,52,53,54,55. Recently the pDMS has been shown to receive reward-related dopaminergic teaching signals30,56. By contrast, movement-related dopamine signals, that could reflect APEs, are prominent in the DLS11,37. Taken together, we propose that RPE and APEs may be used as different teaching signals to drive goal-directed (value-based) and habitual (value-free) learning in different regions of the striatum.
The value-free system updated by APEs learns to repeat the actions that have been taken in the past. This does not seem like an advantageous strategy, but this system must exist for a reason. The first thing to note is that although APE is a value-free teaching signal, this does not mean that the associations that are formed in the TS will be insensitive to value. Rather, the ‘value-free' associations form through repetition of actions that were initially taken in pursuit of value. In this way, the associations that form in the TS can be thought of as storing the long-term ‘value' of an association even though they were never reinforced in value-based manner per se. Sustaining these associations in an outcome-independent manner makes them more stable to short-term fluctuations. Indeed, stimulus–action associations in the CDt system are incredibly stable—once formed they are retained for >100 days in the absence of reinforcement50. Another advantage of the value-free system is that from a normative perspective learning from terms such as APE will bias control systems to repeat stable associations, this can help in learning to act upon regular structure in the environment and forming a compressed default policy—that is, acting the same way in response to the same regular structure irrespective of situational differences57,58,59. Overall, the value-free system could ensure that consistent associations are stored in a more stable and efficient manner that enables them to be acted upon quickly and reliably.
Another idea is that stimulus–action associations in the value-free system form a prior for Bayesian inference of action that encodes the policy that has worked in the past6,58,59. During inference this prior would be useful in biasing decisions when there is a high degree of uncertainty regarding the value of the action computed in the value-based controller. Finally, recent theoretical work has also predicted that if dopamine neurons encoded an APE, then it would allow the basal ganglia to implement off-policy learning algorithms5. Future work will be important in establishing the exact nature of the interaction between the value-based and value-free basal ganglia systems and to elucidate the contribution of APEs to habits, priors and off-policy learning.
Male and female adult mice, aged between 2 and 7 months old, from the following mouse lines were used: C57BL/6 J wild-type (Charles River), Drd1-Cre (Gensat: EY262), Adora2a-cre (Gensat: KG139), Slc6a3-cre (JAX: 006660), Ai14 (tdTomato, JAX: 007914), Ai35 (Arch-GFP, JAX: 012735) and Ai32 (channelrhodopsin-2/EYFP, JAX: 024109).
Mice were housed in HVC cages with free access to chow and water on a 12 h:12 h inverted light:dark cycle and tested during the dark phase. The ambient temperature of the rooms was kept between 20–24 °C and the humidity was maintained between 45–65%. Mice used in the COT task were water deprived. Mice had access to water during each training session, and otherwise 1 ml water per mouse was administered. Water was supplemented as needed if the weight of the mouse was below 85%. All experiments were performed in accordance with the UK Home Office regulations Animal (Scientific Procedures) Act 1986 and the Animal Welfare and Ethical Review Body (AWERB). Mice in test and control groups were littermates and randomly selected.
All viruses were made in house except for pAAV5-CAG-dLight1.1 (Addgene, 111067), which was used for the photometry recordings. dLight1.1 expression was induced by injecting 30–100 nl of pAAV5-CAG-dLight1.1 in the TS and 90 nl in the VS. Chronic lesions of the TS were achieved by injecting a 1:1 mix of AAV2/1-hSyn-Cre at 1014 viral genomes (vg) per ml and AAV2/5-EF1a-DIO-taCasp3-T2A-TEVp at 1014 vg ml−1. The mix was diluted five times in saline buffer prior to injection. The same surgical procedure, using the virus AAV2/5-CAG-EGFP (3 × 1012 vg ml−1), was used for the control group. For all chronic lesion experiments, 4 injections (30 nl each) were made in each hemisphere at 4 or 5 different depths to distribute the viruses as evenly as possible and to provide enough coverage.
Mice were anaesthetized with isoflurane (0.5–2.5% in oxygen, 1 l/min), also used to maintain anaesthesia. Carpofen (5 mg kg−1) was administered subcutaneously before the procedure. Craniotomies were made using a 1-mm dental drill (Meisinger, HP310104001001004). Coordinates are measured from the extrapolated intersection of the straight segments of the coronal sutures between the parietal and the frontal bones. This point usually lies slightly frontal to bregma and is more stereotypic than bregma itself with respect to the brain. The following coordinates were used: TS: 1.8 posterior, 3.45–3.55 lateral, 3.4–3.5 depth; VS: 1.0-1.1 anterior, 1.65 lateral, 4.4–4.5 depth; DMS: 0.5 posterior, 1.45 lateral, −2.0 depth. Viral injections were delivered using pulled glass pipettes (Drummond, 3.5 inch) in an injection system coupled to a hydraulic micromanipulator (Drummond, Nanoject III) on a stereotaxic frame (Leica, Angle Two), at approximately 10 nl min−1. For optogenetic experiments, we used flat optical fibres of 200 μm diameter (Newdoon: FOC-C-200-1.25-0.37-7) and tapered optical fibres (Optogenix, Lambda Fiber Stubs) of 200 μm diameter with 1.5 mm active length, 4 mm implant length. For photometry experiments, flat fibres (Doric Lenses 0.57NA, 200 or 400 μm diameter, 4 to 7 mm long) were implanted vertically, 0.1 to 0.15 mm dorsal of the injection site of dLight1.1. Eight mice that were targeted for TS recordings were not used in any experiments as initial investigation revealed they had reward responses which have not been observed in the TS44,45. To confirm these fibres were outside the TS in six out of eight of these mice we performed serial two-photon microscopy and confirmed that in all cases the fibres were located outside of the TS. For chronic d-AP5 cannulation experiments, we used 26-gauge guide cannulas (Plastics One, C200GS-5), that were cut to 5 mm below the pedestal. We implanted the guide cannulas in the TS (coordinates: 1.82 posterior, 3.55 lateral, 3.0 depth) and then fit them with a dummy cannula with no projection (Plastics One, C200DCS). All implants were affixed using light-cured dental cement (3 m Espe Relyx U200), which was also used to attach a headbar. In mice that received only injections the wound was either sutured (6-0, Vicryl Rapide) or glued (Vetbond). For photometry experiments a subset of mice had fibres implanted in both the TS and the VS to compare how the signals in these regions developed throughout learning.
For muscimol injections, bilateral cranial openings were performed over the DMS and the TS, and a headbar was positioned stereotactically. A landmark that aligned to bregma allowed for future injections in stereotactic positions. Closures of cranial openings were prevented by covering the exposed brain with Duragel (Cambridge Neurotech). Skull was covered with Kwiksil (World Precision Instruments), which was removed before every injection. Before each training session, mice were head-fixed while awake and 30 nl of either muscimol (Sigma-Aldrich) at 0.2 mg ml−1 or saline were injected for experimental and control sessions, respectively, co-injected with cholera toxin B (Cambridge bioscience) of different colours to trace injection sites during histology. After a 15-min period, mice started the training session.
For chronic d-AP5 infusion experiments, we head-fixed the mice for 6 min and then habituated them in the training boxes for the first two days using the protocol described above. Starting from day 3, we administered either saline or 20 mM d-AP5 (Tocris, 0106) bilaterally in the TS using internal cannulas (Plastics One, C200IS) with 0.6 mm projection using a custom-built set up. The mice were awake and head-fixed during the infusion and received an infusion of 500 nl of 20 mM d-AP5 per hemisphere in 3 min, which was followed by a 3 min wait time before internal cannulas were retracted to be replaced by dummy cannulas again. The mice were then immediately put in the behavioural boxes to train in the auditory protocol. After the mice completed ≥3,000 trials, we administered saline in both groups in the following session. For acute d-AP5 infusion experiments, we let these mice train without infusion till they reached expert-level performance. We then infused either saline and d-AP5 in different sessions using the same method described above and measured their performance in the perceptual auditory two-alternative forced choice task.
For dopamine neuron ablations we followed the protocol in ref. 44. In brief, we first injected intraperitoneally (10 mg kg−1), a solution made of 28.5 mg desipramine (Sigma-Aldrich, D3900-1G), 6.2 mg pargyline (Sigma-Aldrich, P8013-500MG), 10 ml water and NaOH to pH 7.4. Subsequently, mice underwent surgery, and a solution of 10 mg ml−1 6-hydroxydopamine (6-OHDA; Sigma-Aldrich, H116-5MG), dissolved in saline buffer was injected. Once prepared, we kept the solution on ice covered from light and injected it within 3 h. If the solution turned brown, it was discarded. For controls we only injected saline buffer. For all manipulation experiments cage mates were assigned to either control or manipulation groups prior to surgery, this was not done through an explicit randomization procedure. Power calculations were not used to define the size of the groups prior to experiments. Experimenters were not blinded to whether mice were in the control or manipulation groups.
Mice received a lethal intraperitoneal injection of pentobarbital (0.1 ml per 10 g) inducing unconsciousness and death. Once unresponsive, mice were first perfused with phosphate-buffered saline (PBS) followed by 4% paraformaldehyde (PFA). The mice were decapitated, and the brains were extracted and fixed in 4% PFA for 24 to 48 h at 4 °C. Subsequently, brains were stored in PBS until further processing.
Mouse training was carried out in a sound-isolated box containing the behavioural chamber, which consists of a closed arena of 19 cm × 15 cm with 3 ports located in a wall (1.95 cm from the floor, each port 3 cm from the next). To better separate cues and actions and to increase variability in movement times, the three ports were spaced further apart for photometry experiments. The centre port was located in the middle of one of the long sides of the arena and the choice ports were located in the centre of the shorter sides. The ports are equipped with LEDs so they can be illuminated, and photovoltaic infrared sensors to detect poke events. Water can be delivered through each of the side ports. Ports were purchased from Sanworks or constructed in house to the same standards. Controlling chips were purchased from Sanworks. The chamber was illuminated exclusively with infrared light. Mice were monitored through standard webcams without the infrared filter. Sounds were delivered through one central speaker (DigiKey: HPD-40N16PET00-32-ND) and amplifiers (DigiKey: 668-1621-ND). Bpod (Sanworks) was used to control the state machine, and the software was run using Matlab.
The COT task is a self-initiated two-alternative-choice paradigm. For behavioural experiments the possibility to start a new trial is signalled by turning on the centre port LED. This LED cue was not present for mice that were used for photometry. Mice start a trial by poking in the centre port and holding their position for 100 to 300 ms. The centre port LED is turned off after that required time has elapsed. In between 0 and 50 ms after poking in the centre port, sound is triggered, lasting for 500 ms. Following poking out from the centre port, mice were trained to poke in either of the two side ports. Two microlitres of water was delivered in only one of the two ports, contingent on the stimulus.
Depending on the training stage, pokes in the wrong port abort the trial. During the first day of training, mice were habituated to the box and the poking sequence by doing a visual version of the task in which both side ports delivered water in every trial. Water amounts were decreased from 5 μl to 2 μl during the first 3 days of training. All photometry recordings started after the initial habituation day and after the reward amount was decreased, but before the performance of the mice improved beyond chance.
For the simple version of the task (not the psychometric), we included an anti-bias protocol to force the mouse to sample from the two ports. The protocol samples every ten trials for the proportion of error trials and calculates the percentages of port choices on those trials, adjusting the target port on the next ten trials to overcome any potential bias, proportionally to the errors and the bias. Therefore, this protocol engages progressively more as the mouse becomes more biased and disengages if the mouse becomes unbiased. This protocol was only active during the initial phases of learning as it uses the proportion of error trials for engagement and calibration. All the experiments using the psychometric version of the task were performed once mice were experts (>85% performance on the simple task). The simple version of the task delivered only the easiest possible trial types, with 98% of tones being from one of the two octaves. For the psychometric experiments, seven equally spaced ratios of high or low tones were used. From the beginning of training, the trial types were randomly interleaved, affected by the anti-bias protocol described above.
Several variations of the COT task were used during photometry recordings. In the outcome value change experiment, unexpected large rewards (6 μl) and omissions were introduced randomly on both sides with a probability of 0.1 each. Mice experience multiple sessions of this protocol to get enough trials of each type.
In the predicted value change experiment, the value of one port was changed 100 trials into a session. This port delivered 6 μl rather than 2 μl, whilst the other port still delivered 2 μl. Mice did multiple sessions of this protocol and experienced both sides becoming the large reward size.
The state change experiment was performed only once per mouse. 150 trials into a training session, the sound that had previously corresponded to the contralateral choice to the recording fibre was changed for a white noise stimulus. This new white noise stimulus overlapped with the original COT frequencies. This white noise was louder than the background white noise and was clearly detectable. The mice were required to make a contralateral response to the white noise to receive a reward.
To test whether the dopamine signals were dependent on an auditory stimulus being present, the sound indicating contralateral turns was omitted in expert mice (silence trials).
In the sound-on-return task, the sound indicating a contralateral turn was played during the return from either side port instead of at the centre port. The sound lasted until the mouse returned and poked into the centre port or at most for 2.5 s. If the mouse did not return to the centre port within 5 s, the subsequent trial would be a classic COT task trial with the sound being played upon poke in into the centre port.
The response to passive sounds was always tested at the end of a classic COT or a sound on return session. Mice were left inside the training box for an additional 10 min while all three ports were covered with custom made lids. During that time both high and low frequency sounds or white noise lasting 500 ms were presented at random time intervals (mean interval 5 s) and in a random sequence.
Sounds consist of a stream of 30 ms pure tones presented at 100 Hz (each tone was introduced 10 ms after the previous one). One of two octaves (5 to 10 kHz, or 20–40 kHz) was selected as the target octave to indicate the side port where water was available on that trial. Each 30 ms tone was randomly drawn from 16 logarithmically spaced frequencies on each octave. The difficulty of the trial was controlled by varying the proportion of 30 ms tones from each octave. For example, in a trial catalogued as 82% of high tones, for each 30 ms tone there are 82% chances of playing a tone from the 20–40 kHz octave, and 18% (100% − 82%) chances of playing a tone from the 5–10 kHz octave. These probabilities are independently computed, so two tones from different octaves can sound simultaneously. The overall amplitude of the sound is randomly selected between 60 and 80 dB. The amplitude of the sound during the passive exposure experiments was also 60–80 dB and the sound duration was 0.5 s.
Water was delivered into the two side ports for correct choices using a solenoid valve that was carefully calibrated. As previous studies have suggested that the neurons in the TS are responsive to valve click noises45, for the photometry experiments we placed valves outside the training boxes and muffled them using sound insulation foam. In addition, we played quiet white noise constantly inside the training box. We confirmed with a microphone that the valve clicks could not be detected with these precautions.
Fluorophores were stimulated using 465 nm and 405 nm LEDs (Thorlabs) of max power 0.2 mW. The 465 nm and 405 nm LED amplitudes were modulated using a sinusoid of 211 and 531 Hz respectively. The 405 nm light falls at the isosbestic point for fluorophores of the type used in this study60. This enabled separation of signal from movement artefacts and bleaching as done by ref. 61. Light was passed from the LED source through optical fibres with NA 0.57, through a commutator (Doric Lenses, FRJ 1 × 1 PT 0.15) to a patch cord (Doric Lenses, FC-ZF1.25 LAF). A mini cube and photodetector (Doric Lenses) were used to collect the signal. The signal was then passed to a NIDAQ (National Instruments) and recorded and analysed using custom Python scripts as described in ‘Statistical analysis'. Behaviour was controlled with a Bpod which sent TTL pulses to the NIDAQ at the start of each trial.
Mice were filmed from above during training and recording sessions using a Basler acA640-750um USB 3.0 camera. Videos were acquired at 30 Hz and synchronized with the photometry acquisition using the NIDAQ. For ease of analysis, mice were always trained in the same box and cameras were never moved.
For this experiment we used a 40 cm × 40 cm square arena, and experiments were conducted with ambient light. Sessions lasted for 30 min. See ‘Optogenetic manipulations' for specifics about the triggered stimulations.
For this experiment we used a 50 cm × 20 cm × 28 cm (L × W × H) arena. Mice were allowed to explore the setup for 20 min, during which video footage and photometry recordings were acquired.
For opto-inhibition of either the D1 or the D2 SPNs, in 15–25% of trials, randomly selected, a sustained pulse of green (532 nm) light was delivered after mice initiated the trial, always preceding the onset of sound delivery by at least 50 ms and lasting longer than the sound duration. Light intensity was calibrated to 12 mW at the fibre tip.
For dopamine opto-excitation, during the COT task, the first 150 trials of each session were done without stimulation to get a baseline behaviour, and subsequently, stimulated trials were introduced with these parameters: blue (473 nm) light delivered starting at the time of poking and lasting 150 ms in 5 ms pulses at 33 Hz of 4 or 8 mW intensity measured at the fibre tip. For the state–action experiment, stimulation was delivered unilaterally in the centre port for trials in which the state predicted a movement contralateral to the stimulated hemisphere. For the state–outcome experiment, stimulation was delivered bilaterally on one of the two side ports (for the whole duration of the session) every time the mice chose that port (correct and incorrect trials), coupled with water during correct trials. No anti-bias protocol was employed during these experiments. To test for effects on movement initiation, we performed an experiment similar to the one in ref. 9. We placed mice in an open field where mice received a blue (473 nm) light stimulation (5 ms pulses at 33 Hz during 500 ms of 4 or 8 mW intensity measured at the fibre tip) if they were immobile for at least one second. For each of these events, there was a 50% chance of triggering the laser. Trials in which light was not delivered were used as within-animal control.
All mice used in the threat experiment were individually housed in the three to four weeks preceding the experiment62. Mice were placed in an arena (50 cm × 20 cm × 28 cm, L × W × H) with a white opaque floor allowing reliable tracking of the dark coated mice. At one end, the arena contained a rectangular shelter (10 cm × 20 cm) made of red Perspex. The other end of the arena constituted the threat zone (20 cm × 20 cm), in which visual stimuli were presented on a computer monitor (51 cm × 33 cm) that was centred above the arena at a height of 30 cm. IR LEDs provided diffuse illumination of the arena. Mice were allowed to explore the entire arena including the shelter for at least 7 min before any looming stimuli were triggered upon their next entry into the threat zone. Visual stimuli were generated using PsychToolBox and MATLAB. A single looming stimulus consisted of five high contrast expanding spots, which expanded linearly from 3°–50° over 0.2 s (235° s−1) and remained at maximum radius for 0.25 s. The inter-spot-interval was 0.4 s. Each mouse was presented with three looming stimuli in one session. All looming stimuli trials were manually triggered for these mice. Minimum inter-trial interval was 90 s.
Data acquisition was controlled using custom scripts in MATLAB or Python and a NIDAQ (National Instruments). Fluorophores were stimulated as described above. Videos were acquired at 30 frames per second using an IR sensitive camera (Basler acA460-750 um USB 3.0) positioned 70 cm away from the arena and 70 cm above its floor. Frame acquisition was triggered using a NIDAQ generated TTL that was also recorded and used for post-hoc synchronization. Real-time stimulus presentation onsets were determined post-hoc using a photodiode (Thorlabs APD430C) and the TTL trigger acquired at 10 kHz.
We imaged the fixed brains using serial section63 two-photon64 microscopy. Our microscope was controlled by ScanImage Basic (Vidrio Technologies) using BakingTray, a custom software wrapper for setting up the imaging parameters (https://github.com/SainsburyWellcomeCentre/BakingTray, https://doi.org/10.5281/zenodo.3631609). Images were assembled using StitchIt (https://github.com/SainsburyWellcomeCentre/StitchIt, https://zenodo.org/badge/latestdoi/57851444). The 3D coordinates of the injections and fibre placements were determined by aligning the brains to the Allen Reference Atlas–Mouse Brain (available from https://atlas.brain-map.org) using brainreg65 and visualized using custom functions and brainrender66.
Brain slices were all stained following the same procedure: Blocking was performed in staining solution (PBS + 1% BSA + 0.5% Triton X-100) for 15 min. Primary antibodies (1:1,000 in staining solution) were incubated for 2–4 h at room temperature or overnight at 4 °C with rocking. Washes were performed for 15 min with a staining solution. Secondary antibodies (1:500 in staining solution) and DAPI were incubated for 2 h at room temperature while rocking. Slices were then washed in PBS and mounted using Mount Medium. Primary antibodies used were NeuN (abcam, ab104225), tyrosine hydroxylase (TH) (Sigma-Aldrich, AB152) and GFP (Aves labs, GFP-1020) (to reveal dLight-expressing cells). Secondary antibodies used were Alexa-488 anti-mouse (Invitrogen, AB_2534069), Alexa-567 anti-chicken (Invitrogen, AB_2535858), and Alexa-647 anti-rabbit (Invitrogen, AB_2535813).
Brains were sliced using a cryotome at a thickness of 30 μm. Fifteen to 20 slices covering the entire striatum at regular intervals were selected for NeuN staining. Slices were mounted in standard glass slides using standard mounting medium and subsequently imaged in the Slide Scanner (Zeiss) using a 20× objective. Individual slices were registered to the Allen Reference Atlas–Mouse Brain (https://atlas.brain-map.org) using ABBA (https://github.com/BIOP/ijp-imagetoatlas), and the NeuN channel was thresholded automatically, per slice, based on the intensity levels in the cortex. The coverage of NeuN staining in the striatum was determined for each slice, and the inverse was determined as lesioned area.
Brains were sectioned and mounted as described for the chronic lesions but stained for TH to specifically label dopamine cell processes. Slices were imaged using the Axio Scan (Zeiss). Manual regions of interest were drawn for the striatum, the cortex, and the background in each slice. For each slice, the mean intensity in the striatum was normalized to the cortex following background subtraction, and the relative intensity between the striatum and cortex was calculated. For the analysis of the correlation with the performance, data was normalized within each mouse (posterior striatum ratio/anterior striatum ratio). One mouse was removed from the analysis owing to lack of ablation (except in Extended Data Fig. 3j).
Sessions with less than 60 trials were omitted, the first 5 trials of each session were discarded, and trials in which the mouse was not engaged (defined as having an inter-trial interval longer than 3 times the median value of that session) were not considered for analysis. Together, this amounts to less than 2% of data discarded. The remainder of the trials were ordered chronologically. Mice that did not learn the task (end performance less than 55%) were discarded from the analysis. This amounts to a total of three mice in the whole study.
The LogisticRegressionCV from scikit-learn package in Python was used to fit the data from the psychometric version of the task. This was only used for visualization purposes.
The first 5,000 trials for each mouse were used for analysis. To calculate individual learning parameters, per mouse, we modelled the performance of every mouse using a modified Weibull function67,68: \({\rm{performance}}=50+a(1-{2}^{{(\frac{-{\rm{trials}}}{l})}^{s}})\). The maximum performance was defined as the maximum of the median of the trials, binned using a window of size 200. Parameters were fitted using the scipy package in Python (optimize.minimize function). Statistical differences between the groups for these parameters were calculated using the non-parametric test Kruskal–Wallis from scipy.stats.kruskal. Significance of the behavioural correlation with the lesion size was performed using the scipy.stats.linregress function. To calculate the differences in performance at different times in learning, we first removed those trials in which mice were extremely biased towards one of the two ports. Bias was determined as described in ‘Behavioural procedures', and extremely biased trials were defined as those having a value larger than twice the standard deviation for the whole dataset. This correction was not applied to calculate the significance of the observed differences. Two mice (one experimental and one control) were removed for the chronic lesions experiment as they did not learn the task at all, and we suspected that they were deaf. Additionally, the two last sessions of one control and one experimental mouse were removed as the performance dropped to chance. One experimental mouse was excluded from the dopamine cell ablation experiment as the lesion quantification showed no ablation (this mouse performance was comparable to controls). At each point in training, performance was defined as the performance of the past 100 trials. To assess the significance of the differences between the two groups, the data were binned using a window of 100 trials, and the differences between the means of each group were calculated. To generate a shuffled dataset, experimental labels (for example, lesion or control) were randomly assigned to each mouse, always maintaining the proportion of labels on the original dataset, and differences between groups were calculated the same way. We did this 10,000 times. The same procedure was used to analyse the data from the dual-controller model comparisons. The global significance of the dataset was assessed as the likelihood of the cohorts being different at any time, in comparison to the shuffled groups. Mixed ANOVA was used from the pingouin package.
Each individual session contains a few hundred trials, seven trial types, and between 15 and 25% of stimulated trials. A session of 300 trials can have as few as 6 (300 × 1/7 × 0.15) stimulated trials for a particular type. This can generate a large variability when calculating the proportion of binary choices, as each individual trial will have a large influence (17% in our example). To assess the significance of the biases caused by the optogenetic manipulations, we generated, for every session, a baseline distribution (1,000 shuffles) of port choice proportions for every unstimulated trial type (proportion of high versus low tones), using the same number of trials that were stimulated for that trial type. This generated the natural variability in the potential choices for each trial type and was used to assess the significance of the biases for individual sessions. The total bias for each session was defined as the average difference between opto-stimulated and unstimulated trials for all trial types. Only sessions with more than 150 trials in total were selected for analysis. For mice in which more than data for more than one session and stimulation type was available, we selected the one with the best performance, which is a good indicator of how well a mouse was doing on the task and we reasoned would offer the most stable control to compare the effect of the stimulation to. This resulted in only 3 sessions removed from the dataset, from a total of 30. Including all sessions or changing the session selection method did not alter the significance of the results. The statistical significance for each group was calculated using the non-parametric test Kruskal–Wallis from scipy.stats.kruskal, comparing the observed biased values of every session against a randomly-sampled counterpart, per session, using the variance described above. Only sessions in which the mice did the psychometric version of the task were included in this analysis.
The raw data were demodulated offline using custom Python scripts to produce traces that corresponded to the signal (465 nm) and background (405 nm) channels61. Then the data were processed according to the methods described in ref. 69. In brief, the demodulated traces were denoised using a median filter and a low-pass Butterworth filter (10 Hz cut off). The resulting signal and background channel traces were high-pass filtered at 0.001 Hz to correct for photo-bleaching. To correct for motion artefacts, the background channel data were fitted to the signal channel data using a linear regression. The proportion of signal that was explained by the background channel was then subtracted from the signal channel component, such that only the signal specific to the 465 nm excitation frequency remained. Finally, dF/F was calculated by dividing this signal by the baseline fluorescence (the signal channel trace filtered using a low-pass filter with a cut off at 0.001 Hz). All traces were z-scored to allow better comparison across mice and sessions.
Peak dopamine responses were calculated using the Python package PeakUtils or by taking the maximum value of the trace if no peak was found in a given window. For cue responses, the window was between the cue onset and entry into the choice port. For action (APE) responses, the window was between the time of exiting the centre port and entry into the choice port. For outcome responses (used in the outcome value manipulation experiment) the window was between the time entry into the choice port and 200 ms later. As VS dopamine clearly dips to omitted rewards, instead of calculating peaks, the mean of the dopamine response within this window was used as an estimate of the response.
Following ref. 12, we built a linear regression model to predict the photometry signal at each time point from the behavioural events around this time. In this model, the predicted dLight response is calculated as the convolution of a time series a,b, etc., representing different behavioural events as series of 0 s and 1 s, where 1 s represent the occurrence of the behavioural event. This means that at time t, the predicted dLight response g(t) is given by the weighted sum of the different behavioural events shifted in time within a set window. The model can be expressed as follows:
where \([{\tau }_{x}^{-},{\tau }_{x}^{+}]\) gives the shifted time window in which behavioural event x is allowed to influence the predicted photometry signal. ka, kb, etc. are the kernels for the behavioural events, or equivalently, the linear regression weights for the events at each different time shift. When plotted as a time series, these regression weights form the estimated response profile for the dLight signal due to a given behavioural event. These regression coefficients were estimated using the linear regression function of the Python package scikit-learn.
Behavioural events were selected from trials in which the mouse did not repeat events (for example, did not repeatedly poke their head in the centre port). The model was fitted for each mouse for each session as the signal in the TS and VS evolved over learning. As the choice movement initiation time is unclear and may start prior to the withdrawal of the head from the centre port is detected, the movement kernels were allowed to extend 0.5 s prior to the event. As the movement duration was longer than the cue and outcome responses, the movement kernel was allowed to extend 1.5 s after the event, whereas the cue and outcome kernel windows were limited to 1 s after the event.
The calculation of the percentage variance explained by the full model was performed per session per mouse and then averaged across sessions. To calculate the percentage variance explained by each regressor, the predicted dLight signal was recalculated without that particular regressor, inspired by ref. 70. The explained variance of the new prediction compared to the true signal was then calculated. Finally, the percentage variance explained by the removed regressor was calculated by comparing the explained variance of the full model, vfull, to the explained variance when that regressor is removed from the prediction calculation vpartial, using the following equation:
Although this method does give a decent comparative measure of the contribution of each regressor to the explained variance of the data by the prediction, it can result in percentages larger than 100 if the predicted dLight signal without that regressor performs worse than the intercept at explaining the data. This can be seen for some of the VS recordings without the outcome regressor.
In Fig. 2g the full photometry trace was used to estimate the percentage variance explained, both for the full model and the individual regressors. This includes extended periods with no behavioural events as the task is self-paced. This may lead to an underestimate of the percentage of the photometry signal that is explained by the task. To account for this the percentage variance explained was recalculated solely on the portions of the photometry trace for which there were behavioural events, a process we refer to as ‘trimming'. This trimming was only done in Extended Data Fig. 4m.
Additionally, we explored including return to centre movements as behavioural events for the kernel regression model. These events were taken from the time of the mouse leaving the choice port and taking a ‘direct' route back to the centre port. To assess how direct the path taken by the mouse to the centre port was, we used the tracking data (see below) and computed the cosine similarity between the optimal path from the side port to the centre and the path taken by the mouse. Return vectors with a cosine similarity ≥0.9 to the optimal vector (within the first 10 s of leaving the choice port, or when the mouse entered the centre port) were included in Extended Data Fig. 4j,k and were considered for inclusion in the regression. Return event kernels had a window from 0.2 s prior to and 1.5 s after leaving the side port. This was chosen to be conservative so as to avoid crossover with the next trial/prior choice movement and to be comparable to choice movements within the task, which had a mean duration of 0.68 ± 0.53 s (ipsi) and 0.68 ± −0.61 s (contra), for which the kernel window also extended 1.5 s after leaving the port.
For ease of visualization and alignment, only short return movements (≤1 s) were included for the averages in Extended Data Fig. 4j,k.
We performed a linear regression (using statsmodels.api.OLS) predicting the size of the dopamine response (TS dopamine at time of choice, VS dopamine at time of cue) on correct contralateral trials from previous choices for the same stimulus. We included data from throughout training for this analysis. A positive regression coefficient means there is a larger dopamine signal on the current trial when the side chosen on the current trial was chosen in response to the same stimulus in the past (how far in the past is given by the x axis). A negative regression coefficient means that the dopamine response is smaller when the chosen side had been chosen in response to the same stimulus in the past. Separate regressions were performed for each ‘lag' (number of trials back value).
The position of the mouse was tracked using DeepLabCut71 and variables such as speed, acceleration, angular velocity and angular acceleration were calculated using custom scripts in Python. As the videos for the freely moving experiment were taken at a slight angle, the coordinates were transformed into standard space using custom Python scripts. Videos taken during the COT task were taken from above so there was no need for such a transform. Speed and acceleration were calculated using the nose as a marker. For angular velocity and acceleration, a triangle was formed using the nose and the two ears and a line was drawn from nose to the line between the two ear markers. This line from the nose to the back of the head was taken as the heading direction of the mouse. Turn angles were calculated using the cumulative angular velocity. In the task, 0° was defined as the angle when the mouse leaves the centre port. To calculate the maximum turn angle in the task, a sigmoid curve was fitted to the cumulative angular velocity for each trial between the sound onset and entering the choice port. The upper plateau of the sigmoid (maximum fitted cumulative angular velocity) was then taken to be the turn angle for the trial.
To determine the coarse relationship between the turn angle and the size of the dopamine response, trials were divided into four quantiles based on the size of the dopamine response between the mouse leaving the centre port and entering the choice port for contralateral choices. Turn angles were divided into using the quantiles that were created from the size of the dopamine response. A regression slope was fitted (using the function stats.linregress from the Python package SciPy) between the average quantile turn angle and average quantile dopamine response for each mouse for each session. The fit slope was then compared to the fit slope if the x and y quantile labels were shuffled in. The data were shuffled 100 times and the distribution of the fit slopes from the actual data were compared to the shuffled distribution.
In the freely moving experiment, turns were defined as the moment when the angular velocity crossed a threshold of ±0.5 s.d. Turns were required to last at least 0.06 s and were only included for analysis if no other turns occurred in the preceding or subsequent 0.5 s. The head angle at the times of turn onset was then used to define 0° turn angle and turn angles were determined using the cumulative angular velocity from this time point.
To investigate whether changes in turn angle and speed could account for the decrease in TS dopamine response size with trial number seen in Fig. 3, for each mouse we built a linear regression model predicting dopamine response size for all trials from speed and turn angle. The resulting predicted signal was subtracted from the actual signal per trial, before regressing the residuals against log trial number. To calculate the relative contributions of speed, turn angle and trial number, we also built a regression model with all three predictors to estimate the respective variance explained.
To quantify the bias for each session, we calculated the choice differences between the first 150 trials (pre-stimulation), and the subsequent trials, as long as there were more than 100 trials. Sessions in which the initial bias of the mouse to either of the ports was larger than 2:1 were removed from the analysis. We averaged the biases if several sessions existed for the same mouse on the same stimulation conditions, so that we had only one observation per condition. We used the non-parametric two-sided Wilcoxon sign-rank statistic (scipy.stats.wilcoxon) to calculate the significance of the observed biases.
For the open-field stimulation, we calculated the speed of the mouse as the difference between the position of the mouse in each frame, convolved with a kernel of size 5 for smoothing purposes. The overall threshold to consider that the mouse was moving was determined empirically, but the results presented were invariant across a large range of values tested. Instant speed was calculated as the average speed from movement initiation to 300 ms after. Average movement was calculated from stimulation to 5 s later. We used the t-test on two related samples (as above) to assess the significance of every parameter.
Data analysis was inspired by ref. 72. Dopamine responses considered in this analysis were reward responses for the VS and movement-aligned responses for the TS. Dopamine responses were categorized as large or small based on whether they were larger than or smaller than the 65th percentile respectively. The average change in percentage of contralateral choices was calculated for large and small dopamine responses on the preceding trial for each level of sensory uncertainty on the current trial (which correspond to the different percentage mixtures of tone clouds described in ‘Behavioural procedures'). A logistic regression was performed (using statsmodels.api.Logit) to investigate the relationship between dopamine response size on the previous trial, perceptual uncertainty and the choice (repeat or switch) on the current trial.
For this analysis, we used data from the psychometric version of the task. Mice were required to meet certain behavioural criteria in order for their data to be included: the slope of the psychometric curve at the Point of Subjective Equality to measure sensitivity and bias at the edges (the ‘easy' trials). Bias was calculated by taking the difference in percentage correct at the two easy trial types. Mice were required to have a slope ≥1 and a bias ≤0.09 to be included, acting as a measure how well the mice had learned the task. This ensured that all mice in the analysis had similar behaviour, with little bias and strong discrimination between stimuli.
For this analysis, following Lak et al.72, only trials where mice made a correct choice were included. Note that, as the tail dopamine response is taken between movement onset and reward delivery, for the ambiguous trials (50% high and low) the mouse would have no information as to the outcome of their choice at this time point. Therefore, all trials of this type were included.
For the VS mice, the dopamine reward responses were used so only correct trials could be used. For the TS, correct trials were used for all stimuli other than the ambiguous stimulus. For the ambiguous stimulus, both correct and incorrect trials were used. The TS dopamine responses are taken aligned to movement, prior to reward being delivered.
We performed a linear regression (using statsmodels.api.OLS) between the current trial TS dopamine response at time of choice and the Fréchet distance73 between trajectories on the current and subsequent trial (which provides a measure of the similarities between the two trajectories that takes into account the location and ordering of the points along a curve, with a low value indicating high similarity between the two trajectories). Fréchet distances were computed recursively.
For the experiment in which opto-inhibition was done at different points in learning, mice only did the simplest version of the task (stimuli were either 98% of high tones or 98% of low tones). The initial 20 trials of every session were discarded, and the baseline distributions of choice proportions and the session bias were calculated as indicated above. Because mice performed close to perfection in this version of the task, we only included in the analysis the choices to the port where biases were expected to happen, in agreement with our previous results (it is not possible to measure any positive contralateral bias in a trial in which the mouse chooses the contralateral port all the time in unstimulated trials). Mice were all implanted bilaterally, and the stimulated implant was alternated every day of training. We only included in the analysis those implant sites which resulted in at least one significantly biased session (P < 0.05, calculated as indicated above). This removed 4 implants from the analysis out of 17. The regression models were done for each individual implant, and the average slope for each genotype was calculated. The significance of the global results were assessed against random datasets, generated by shuffles of the performance values associated with every session. P values were calculated as the proportion of ‘random slopes' being larger (expecting negative and positive contralateral biases for D1-Arch and A2A-Arch, respectively).
The RL model used an actor–critic framework with soft-max (inverse temperature = 5.0) policy selection. The model used a semi-Markov state representation, previously introduced by74 to capture the time-course variability of dopamine commonly seen in experimental tasks. In the semi-Markov formalism, the agent keeps track of its current state as well as a representation of ‘dwell time' within that state. Actor, critic and stimulus–action strengths are then updated only when a state transition takes place. It has the added advantage that the states in the model directly correspond to the within-trial behavioural stages of the task, while allowing for representation of time. This formalism has been previously used in prior work modelling dopamine signals in tasks with variable timing75,76 and it allows us to model the time course of dopamine in a more realistic manner than other previous studies, which have often assumed that each time point within a behavioural stage of the task is an independent state (see ref. 77 for a review).
The states consisted of Start, High tone, Low tone, Outcome, as well as an action state associated with each of the time of action for each sound and action pairing (in order to align to the time of action to match the data). Actions consisted of Left, Right, Centre and Idle to represent the movement to enter left, right and centre ports (and not taking an action). A state transition happened when the agent moved between one of the above states, for example the start state to the high tone state. The behaviour is self-paced for the mice, with sometimes multiple seconds of variability in timing between trials. The critic had dimension 1 × n states. The actor had dimension n states × n actions. The non-value dependent model had dimensions n states × n actions.
The RPE was scaled according to dwell time in the state to approximate temporal discounting74 as is necessary for the semi-Markov representation. RPE was calculated at each state transition k as
where \({r}_{k+1}\) is the reward received in the new state, \({\rho }_{k}\) is the average reward per time step and \({d}_{k}\) is the time spent in the last state before transitioning. \({\rho }_{k}\) was calculated by looking at average reward per time step in the last n (n = 500 in our model) state transitions:
The critic value function was then updated using the RPE \({\delta }_{k}\) signal:
and the actor stimulus–action value function was updated in a similar manner:
where α and β are both learning rates that were set to 0.005.
As in ref. 74, the RPE signal was then taken to be \(\sigma ({\delta }_{k}+\psi )\), where \(\sigma (x)=0\) if \(x\le 0\) and \(\sigma (x)=x\) if \(x > 0\). \(\psi \) was set to be 0.2 to represent a baseline level of dopamine.
The non-value dependent model calculated APE, \({\delta }_{{a}_{k}}\), at state transitions (see Extended Data Fig. 6b to see full set of actions and states in the modelled task) as the difference between the action taken, ak, and the stimulus action strengths given the stimulus \(A(s)\), according to the equation
APEs were rectified, resulting in only one component of the APE vector being non-zero, essentially providing a scalar update signal. This rectification also matched the data better as dips in TS dopamine were never observed at time of action. Importantly, this rectification did not change the general properties of the algorithm. Stimulus–action pairing strengths were then updated using APE:
where ε is the rate at which the stimulus–action association was formed, which was set to 0.01 for all simulations apart from the predicted value change experiment simulation, where it was set to 0.001 to mimic how a value-free controller should update slowly. For other simulations this was less relevant as we aimed to show the direction of change of APE and RPE signals rather than their relative rates of updating (Extended Data Fig. 8).
Every time the mouse revisited a state it had visited before, a counter \(I(s)\) was increased to keep track of how many times that state had been visited:
This was used to compute novelty N, which decayed exponentially with exposure to a state, according to
Salience L was computed as a weighted combination of value and novelty of the state:
In the above equations, \(\gamma \) and \(\mu \) were set to 0.01 and 0.5, respectively.
In all simulations except for the simulation of the effect of previous choice on subsequent dopamine response (Fig. 3i,l), the inverse temperature term of the soft-max was set to 5.0. For Fig. 3i,l it was set to 0.5, to better capture the more exploratory nature of the behaviour of the mouse and to ensure there were enough trials throughout learning with both ipsi- and contralateral previous choices.
The movement model of dopamine comprised a vector with length equal to the number of actions available. When an action was taken, the corresponding element in the vector was set to 1. All other elements were 0.
In all candidate models of dopamine photometry signals, learning rates and constants were not fitted to match the numbers of trials taken to learn the task seen in the experimental data, so trends should be interpreted as approximations of general patterns rather than models of the exact behaviour.
We simulated a task with two states (the first element, s = 1, corresponds to low tone, the second element, s = 2, corresponds to high tone) and two actions (first element corresponding to right and the second corresponding to left, a = 1 or a = 2). We modelled two parallel systems, one for the value-based controller that is updated by RPE, this had two components, an actor and a critic. The second system had a value-free controller that was updated by APE. The actor in the value-based controller and the value-free controller were modelled as a weight matrix (dimension 2 × 2) that projected from the sensory states to the two possible actions that could be taken, the weights within these matrices are notated as \({W}_{{\rm{actor}}}\) and \({W}_{{\rm{tail}}}\). The critic in the value-based controller was modelled as a 2 × 1 matrix, \({W}_{{\rm{critic}}}\), with each sensory state projecting to one of the cells in the matrix. The output for the \({W}_{{\rm{actor}}}\) and the \({W}_{{\rm{tail}}}\) on each trial was computed as the weight matrix × the state input—that is, \({A(s)}_{{\rm{actor}}}={W}_{{\rm{actor}}}s\) and \({A(s)}_{{\rm{tail}}}={W}_{{\rm{tail}}}\,s\).
To calculate the actual action taken by the model, we first calculate the action predicted by the sum of the outputs of the two controllers. An additional noise term was added, \({A(s)}_{{\rm{noise}}}\) (drawn from a uniform distribution between 0 and 1):
The action associated with the maximal value of \({A(s)}_{{\rm{total}}}\) was the action a that the model took (corresponding to the choice of the mouse)—that is, \(a={\rm{argmax}}({A(s)}_{{\rm{total}}})\).
The model received a reward, r = 1, if the index of the action taken, a, corresponded to the action rewarded (here r = 1 if: s = 1 and a = 1 or s = 2 and a = 2).
We then computed the RPE and APE signals. For the RPE signal, we first calculated the predicted value from the critic as \(V={W}_{{\rm{critic}}}\,s\). We then calculated the reward prediction error as
To calculate APE and represent it as a scalar value we first binarized the instantaneous predicted action vector: \({A}_{{\rm{tail}}}^{{\rm{binary}}}\), such that the index corresponding to the maximum \({A}_{{\rm{tail}}}\) was 1 and 0 everywhere else. Then we computed the predicted action \({p}_{a}\) (initialized at 0) as a low-pass filter of this binary choice vector:
with a time constant \({\tau }_{{\rm{tail}}}=100\). The APE was then calculated as \({\delta }_{{\rm{APE}}}=a-{p}_{a}\) for the action taken.
Finally, we updated the \({W}_{{\rm{actor}}}\) and \({W}_{{\rm{tail}}}\) weights as a function of a three-factor learning rule that included the sensory state, the action taken (that is, both the value-based actor and the value-free controllers receive an efference copy of the action taken) and the APE/RPE signal on the current trial:
where β = 0.02 is a learning rate;
where α = 0.04 is a learning rate.
The \({W}_{{\rm{critic}}}\) weights were updated by a two-factor learning rule that included the sensory state and the RPE signal on the current trial:
The RPE weights of the actor also decayed to its steady-state value of 1 with a time constant of \({\tau }_{{\rm{decay}}}=100\):
The \({W}_{{\rm{tail}}}\) and \({W}_{{\rm{actor}}}\) weights were bounded to be positive and were initialized to 1. The \({W}_{{\rm{critic}}}\) values were initialized as 0 and were also bounded to be positive.
We simulated 100 trials. A trial lasted 1,000 timesteps (2,000 for the inactivations). For plotting the performance, we low-pass filtered the reward with a time constant of 10 a.u., starting from 0.5. The inactivations were conducted at time 30, 100 and 1,000 after which either the \({W}_{{\rm{actor}}}\) (for the RPE system) or the \({W}_{{\rm{tail}}}\) (for the APE system) were set to 0 and weights were not plastic anymore. For the psychometric curve, we varied the difficulty level d from 0 to 1 and set the first element of \(s=1-d\) and the second element of \(s=d\). For the TS dopamine stimulation simulations, we doubled the APE signal.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
The data that support the findings of this study are available at https://rdr.ucl.ac.uk/projects/Dopaminergic_action_prediction_errors_serve_as_a_value-free_teaching_signal/240596. In addition, Allen Brain Atlas connectivity (https://connectivity.brain-map.org/) data were used to demarcate the cortico-striatal projection patterns from AUDp (experiments 100149109, 116903230, 120491896 and 146858006) and S1(SSp) (experiments 112882565, 114290938 and 126908007). Source data are provided with this paper.
The analysis code is available at https://doi.org/10.5281/zenodo.15119142.
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The authors thank the Advanced Microscopy Facility and Viral Vector Core in the SWC for assistance with histology, imaging and custom production of viral vectors, especially J. Broni-Tabi, R. Campbell, G. Estrada Girona and M. Strom; F. Claudi for advice on analysis; M. Watabe-Uchida, T. Mrsic-Flogel, S. Hofer, T. Branco and A. McAskill for their comments on the manuscript; and all members of the Stephenson-Jones laboratory for their contributions to this project, particularly F. Marbach. This work was supported by an EMBO Long-Term Fellowship (ALTF 827-2018) (H.M.V.), a Ramon y Cajal Fellowship (RYC2022-035145-I) (H.M.V.), a Swedish Research Council International Postdoc Grant (2020-06365) (Y.J.), the Sainsbury Wellcome Centre Core Grant from the Gatsby Charitable Foundation and Wellcome (219627/Z/19/Z) (M.S.-J.), the Sainsbury Wellcome Centre PhD Programme (F.G.) and a European Research Council grant (starting no. 557533) (M.S.-J.). Mouse silhouettes were obtained from https://scidraw.io/ and https://doi.org/10.5281/zenodo.3925917 (Figs. 1a, 3n, 4b,e and Extended Data Figs. 3k,l, 7a,g, 9g,i, 12b,e) and https://doi.org/10.5281/zenodo.3925901 (Extended Data Figs. 5h,u, 10c).
These authors contributed equally: Francesca Greenstreet, Hernando Martinez Vergara, Yvonne Johansson
Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, UK
Francesca Greenstreet, Hernando Martinez Vergara, Yvonne Johansson, Sthitapranjya Pati, Laura Schwarz, Stephen C. Lenzi, Jesse P. Geerts, Matthew Wisdom, Alina Gubanova, Lars B. Rollik, Jasvin Kaur, Joseph Cohen, Emmett Thompson, Troy W. Margrie, Claudia Clopath & Marcus Stephenson-Jones
Institut d′Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Hernando Martinez Vergara
Bioengineering Department, Imperial College London, London, UK
Jesse P. Geerts & Claudia Clopath
Gatsby Computational Neuroscience Unit, University College London, London, UK
Theodore Moskovitz
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M.S.-J., F.G. and H.M.V. conceived and designed the study. H.M.V., F.G., Y.J., S.P., M.W., L.S., S.C.L., M.S.-J., A.G., J.C. and J.K. performed the experiments. H.M.V., F.G., Y.J., S.C.L. and L.B.R. wrote the software for data analysis. F.G., H.M.V., Y.J., S.P., C.C., L.S., T.M., E.T., L.B.R. and J.P.G. analysed the data. H.M.V., F.G., Y.J., S.P. and M.S.-J. made the figures. M.S.-J., F.G., H.M.V. and Y.J. wrote the manuscript. M.S.-J., T.W.M. and C.C. provided resources. All work was supervised by M.S.-J. H.M.V., F.G. and C.C.
Correspondence to
Marcus Stephenson-Jones.
The authors declare no competing interests.
Nature thanks Elliot Ludvig, Eric Yttri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer review reports are available.
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a, Schematic of the task, left. Example spectrograms showing low (left plot) and high (right plot) “cloud of tone” stimuli. b, Coronal sections along the striatum indicating fiber placement positions (tip of the fiber). Note that fibers were inserted in both hemispheres and are mirrored here for illustration purposes. Primary auditory cortex (AUDp) projections (yellow) and primary somatosensory cortex (SSp) projections (blue) are shown in the other hemisphere. c, Horizontal (top) and side view (bottom) of the same histological data. For the horizontal section the recording location depths are collapsed onto a single horizontal atlas image for illustrative purposes. On the side view, the striatum is outlined and the AUDp projections are indicated in grayscale. All error bars represent the standard deviation.
a, Representative image of a lesioned brain illustrating the image analysis used to quantify the proportion of lesioned striatum. Slices were registered to the atlas and the area with remaining neurons (as stained by NeuN) was defined. The rest of the striatum was considered as lesioned. b, Quantification of the lesion area for the 11 mice in the caspase dataset, across several coronal slices of the posterior striatum, that include the entire TS. c, Learning rate (performance vs. trial number) of individual mice in the lesion in TS and the control groups. Light blue and light gray traces are from mice that had an initial bias. d, Differences of means in performance between control and lesion groups. Dotted lines indicate the 95% confidence interval for the shuffled data (see methods). e, Learning rate for trials with the low tone stimulus (performance vs. trial number) of lesion TS and the control groups (shaded area indicates standard deviation). f, Same as F but for high tone stimulus trials (shaded area indicates standard deviation).
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a, Representative image showing the location of an infusion cannula implanted over the TS. b, Coronal sections along the striatum indicating cannula placement positions (center tip of the cannula). Note that cannulas were inserted in both hemispheres and are mirrored here for illustration purposes. Primary auditory cortex projections are also shown (yellow). c, Behavioral effect of acute D-AP5 infusion in expert mice (>5000 trials). n = 4 mice. d, Learning rate (performance vs. trial number) of D-AP5 and saline infusion groups (shaded area indicates standard deviation). D-AP5 n = 7 mice, Control n = 5 mice. e, Differences in performance between the groups. Dotted lines indicate the 95% confidence interval for the shuffled data (see methods). f, Same as D but showing the data from individual mice. g, Behavioral performance of mice in the last session of chronic D-AP5 infusion (brown), or when saline was infused in the first session after reaching 3000 trials, D-AP5 group (yellow) or the control group (gray). h, Quantification of the TH staining fluorescence ratio between the striatum and the cortex after background subtraction, at different levels in the allen reference (ARA) anterior-posterior axis. The data is shown as the fluorescence relative to controls. Primary auditory cortex projections are shown. i, Example TH-stained (dopamine axons) coronal slices at the level of the dorsal striatum (DS) for control and lesion mice. j, Correlation between the maximum performance achieved for each mouse and the lesion size (p = 0.049, two-sided Wald test). k, Time elapsed between center port poke and side port pokes, as medians for each animal, for the 6-OHDA and control groups (p = 0.31, Kruskal-Wallis test). l, Time elapsed between trials, as medians for each animal, for the 6-OHDA and control groups (p = 0.73, Kruskal-Wallis test). m, Differences of means in performance between control and lesion groups (6-OHDA n = 9 mice, Control n = 5 mice. Dotted lines indicate the 95% confidence interval for the shuffled data (see methods). n, Learning rate (performance vs. trial number) of individual mice in the 6-OHDA and the control groups (same mice as panel m). o, Learning rate for trials with the low tone stimulus (performance vs. trial number) of 6-OHDA and the control groups (same mice as panel m, shaded area indicates standard deviation). p, Same as O but for high tone stimulus trials. All boxplots show the range from quartile (Q1 - Q3), the median and the whiskers extend to the farthest data point lying within 1.5x the inter-quartile range (IQR) from the box.
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a, Coronal sections along the striatum indicating fiber placement positions (center tip of the fiber). Note that fibers were inserted in both hemispheres and are mirrored here for illustration purposes. Primary auditory cortex projections are shown in the other hemisphere. b, Horizontal (top) and side view (bottom) of the same histological data. For the horizontal section the recording location depths are collapsed onto a single horizontal atlas image for illustrative purposes. On the side view, the striatum is outlined and the AUDp projections are indicated in grayscale. c, Average photometry traces from TS (blue, n=10mice) and VS (orange, n = 7 mice) aligned to cue early in training (first three recorded sessions). Performance in these sessions was between 52.8% to 75.8% with an average performance of 64.0%. For TS mice it was comparable to VS mice (TS: min: 51.4%, max: 80.0%, avg: 64.5%; VS: min: 55.8%, max: 70.1%, avg: 63.3%). d, Same as C but aligned to contralateral choice. Movement initiation for choice (leaving the center port) occurs on average (0.19 s +/- 0.05 s) after cue onset. e, Same as C but aligned to reward delivery. f, Example of a TS (blue) and VS (orange) recording session aligned to cues predicting a contralateral choice. g, Comparison of rise time for dopamine response from onset of the cue in the VS (n = 7) and TS (n = 10) early in training (first three recorded sessions). Rise time onset is determined by the time taken for the dopamine trace to reach more than one standard deviation above a baseline period (1.5 s prior to cue onset) (p = 0.002 two-sided independent samples t-test), Cohen's d = 1.90. h, TS dopamine responses for contralateral and ipsilateral choices aligned to movement onset early in training (first three recorded sessions). Shown separately for mice for whom contra-choice corresponded to high frequencies (n = 6) or mice for whom the contra choice corresponded to the low frequencies (n = 4). i, Same as H but for VS recordings aligned to cue onset. Shown separately for mice for whom contra-choice corresponded to high frequencies (n = 2) or mice for whom the contra choice corresponded to the low frequencies (n = 5). (n = 7 mice). j, Average photometry trace across the first 3 recorded sessions early in training, for an example mouse aligned to leaving to the side ports to return to the center port. k, Same as J but an average of all mice (n = 10). l, Average regression kernels across mice (n = 10) for the return to center behavioral events. m, Percentage explained variance for different kernel regression models of TS dopamine. Original kernel regression model with only choice (center port exit): median = 5.1, original model including the return to center (ipsi and contra) behavioral events median = 7.1, original model only allowing photometry data for which there are behavioral events to be included in the explained variance calculation “+ trimming” median = 8.5, model with return events and trimming median = 10.3. For one session in the original regression there was no video recording, so this is why the ‘original' explained variance is slightly different to that reported in the main figure, as this session was not included in this analysis. n, Average photometry traces from cDLS (n = 3 mice) aligned to choice. o, Same as N but aligned to reward. All error bars represent SEM. All boxplots show the range from quartile (Q1 - Q3), the median and the whiskers extend to the farthest data point lying within 1.5x the inter-quartile range (IQR) from the box.
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a, Change in percentage of completed trials (where animals made a left or right choice after leaving the center port) in trials with a normal stimulus (tone) or silence trials (p = 0.23, paired two-sided t-test, Cohen's d = 1.15). b, Average photometry traces of one mouse aligned to contralateral choice. c, As for B but an average across mice (n = 3 mice). d, Change in peak response to the contralateral choice if the associated cloud of tones is replaced with silence (p = 0.31, paired two-sided t-test, Cohen's d = 0.79). e, The number of tone-contralateral action pairings or silence-contralateral action pairings that the mice experienced prior to the recordings in B-D, (p = 0.07, paired two-sided t-test, Cohen's d = 2.10). f, Difference in average speed for tone and silence trials for TS mice (n = 3), (p = 0.28, paired t-test, Cohen's d = 0.84). g, Difference in average turn angle for tone and silence trials for TS mice (n = 3), (p = 0.75, paired two-sided t-test, Cohen's d = 0.21). h, Animals were allowed to move freely in a different arena to the training box whilst dLight signals were recorded from the TS. Inset: Head angle during a detected turn in the freely moving arena. Dark blue line represents the orientation of the head at the beginning of the turn. Light blue line shows head orientation 0.5 s later. i, Example photometry response in the TS to contralateral and ipsilateral turn onsets in the freely moving arena. j, As in I but averaged across animals (n = 3 mice). k, Example traces from a TS recording session in the frequency discrimination task separated by size of the response. l, Average turn angle for these quartiles plotted against quartile midpoint (example session). m, The plateau of the sigmoid for each trial turn angle vs the average peak size of the TS photometry signal per quartile based on the photometry signal (example session). n, Data from early in training (first three recorded sessions) is analyzed as shown in O and a regression slope fitted (TS: n = 18 (6 mice, 3 sessions), VS: n = 21 (7 mice, 3 sessions). The slopes of the regressions (averaged per mouse) were tested against zero (one sample two-sided t-test). The TS slopes were significantly greater than zero (p = 0.03, Cohen's d = 1.20), whereas the VS slopes were not (p = 0.87, Cohen's d = −0.06). o, Schematic of the task structure when sound indicating an upcoming contralateral trial was played as mice return to the center port in 51.66 +/− 0.04 % of trials. p, Average dopamine response aligned to sound played while mice returned to the center during early training (n = 6 mice). q, Same as p but aligned to contralateral choice. r, Average amplitude of dopamine response aligned to the sound and choice across mice (p = 0.0047, Cohen's d = 1.97). Size of the sound response is significantly smaller than zero (p = 0.008793, one-sample one-sided t-test against zero). s, Same as P but ipsi- and contralateral returns are plotted separately and returns without concomitant cue are also shown. t, Difference in response size of returns shown in S (circles, p = 0.2945, one way ANOVA, n = 6 mice) and response sizes of mice when the cue is novel during the first training session (crosses, p = 0.2815, Kruskal Wallis test, n = 3 mice). u, Schematic of the arena where the high and low tone task sounds were played passively as the mice explored. Passive sounds responses were tested in mice that were at an early stage of training on the CoT task (average performance 60.6 +/− 6.4 % in n = 5 mice). v, Average dopamine response in the TS during contralateral movement in the 2AC task (dark blue) and during passive sound presentation in subsequent exploration (pale blue) (n = 5 mice). w, Average amplitude of choice aligned response in the task and of passive sound response during exploration across mice (p = 0.0092, paired t-test, Cohen's d = 2.11). There is no significant response to the sound (p = 0.45, one-sample two-sided t-test against zero). x, Average dopamine response in the TS during contralateral movement in the 2AC task (dark blue) and during passive presentation of white noise in subsequent exploration (pale blue) (n = 3 mice). Mice had on average experienced 93 presentations +/- 3.30 of white noise as a task cue before these recordings, this is less than half than during the CoT state-change experiment (195 + /−35 trials). y, Average amplitude of choice aligned response in the task and of white noise response during exploration across mice (p = 0.02, paired t-test, Cohen's d = 3.87). There is no significant response to the sound (p = 0.84, one-sample two-sided t-test against zero). All error bars represent SEM.
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a, The model comprises an actor that learns stimulus-action values and guides action choices, a critic that learns a value function that is used to calculate RPE. The RPE signal is broadcast to the actor and critic to update their respective value functions. A value-free system learns to predict actions from those taken in the past and updates its prediction using the difference between its prediction and the action taken (APE). APE and RPE equations are written with respect to time (t), as is common, for illustrative purposes. For the model equations we use dwell time in the state (k) to approximate temporal discounting, see methods. b, The Markov decision process used to model the task. c, Correlation between the turn angle and the size of the dopamine response in the TS for all trials in all sessions of an example mouse. d, Correlation between the average speed of an example mouse and the TS dopamine response for all trials in all sessions. e, Linear regression coefficients for speed and turn angle on single trial TS (n = 6 mice) dopamine responses for the first three sessions of training. Stats: one-sample two-sided t-test against zero, speed: (p = 0.448, Cohen's d = −0.34), turn angle: (p = 0.033, Cohen's d = 1.20). Filled circles represent significant correlations for individual mice. Error bars represent 95% confidence interval. f, Turn angle of an example mouse over the course of training, binned per 40 trials. g, Average speed during a choice of an example mouse over the course of training, binned per 40 trials. h, Linear regression coefficients for the effect of trial number on speed or turn angle at a single trial level (n = 6 mice). Stats: one-sample two-sided t-test against zero, speed: (p = 0.154, Cohen's d = 0.68), turn angle: (p = 0.340, Cohen's d = −0.43). Filled circles represent significant correlations for individual mice. Error bars represent 95% confidence interval. i, TS dopamine response, binned per 40 trials of an example mouse over the course of training (blue). A linear regression model was built using average speed and turn angle to predict the TS dopamine signal. The model prediction from just the movement parameters over the course of training is shown in gold (binned per 40 trials). j, The movement model used in panel I was subtracted per trial from the TS dopamine responses to give the remaining signal that was not explained by speed or turn angle (residuals in blue). A new linear regression model was built using log trial number to account for the remaining TS dopamine signal (purple). Both are shown binned per 40 trials. k, The correlation between the individual trial residual dopamine responses and log trial number for an example mouse. l, Regression coefficients for the effect of log trial number on the residual dopamine response (n = 6 mice) (filled circles show significant correlations for individual mice). One-sample two-sided t-test against 0, p = 0.003, Cohen's d = −2.14. Error bars represent 95% confidence interval. m, Total model variance explained by each parameter in a model where speed, turn angle and trial number are used to predict the size of the TS (n = 6 mice) dopamine response throughout learning. n, Difference between TS dopamine response in the last 40 trials of a previous session and next 40 trials of a session (between sessions) and first 40 trials of a session and last 40 trials of the same session (within session) (n = 6, between sessions: p = 0.27 one-sample two-sided t-test against 0, two-sided t-test Cohen's d = 0.51, turn angle p = 0.05 one sample t-test against 0 two-sided t-test, Cohen's d = −1.07). Error bars represent 95% confidence interval. o, Performance in the 50 trials before and after the state change (n = 13 mice, p = 1.98×10-4 paired two-sided t-test, Cohen's d = 1.46). p, Changes in turn angle before and after the state change (n = 13 mice, p = 0.85 two paired two-sided t-test, Cohen's d =−0.08). q, Changes in average speed before and after the state change (n = 13 mice, p = 0.02 paired two-sided t-test, Cohen's d = 1.42). r, Performance before and after state change at trial 150 (black dashed line) binned per 20 trials (n = 13). Green lines show mean, error bars represent sem, grey lines represent data from individual mice. s, Same as R but showing the response time following the state change. t, Same as R but showing the bias towards ipsilateral choices following the state change. u, behavioral bias towards the large reward port before and after the change in value. The last 50 trials from each block are used for analysis with blocks being a minimum of 70 trials (n = 10 mice, p = 0.002 paired two-sided t-test, Cohen's d = 1.39). v, Percentage of trials where mice did not make a choice before and after the value change is introduced at trial 100 (black dashed line) binned per 20 trials (n = 10 mice). Green lines show mean, error bars represent sem, grey lines represent data from individual mice. w, Same as V but showing the change in performance. x, Same as V but showing the change in response time. y, Same as V but showing the change in choice bias over the course of the session. All boxplots show the range from quartile (Q1 - Q3), the median and the whiskers extend to the farthest data point lying within 1.5x the inter-quartile range (IQR) from the box.
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a, Schematic of the outcome manipulation task design. b, Modelled responses for how APE and RPE signals would respond to changes in reward outcome. c, Example TS response to omissions, normal sized and large rewards. d, Group data (n = 6 mice) for TS dopamine response size to omission, normal and large reward (p = 0.84, p = 0.54, paired two-sided t-test, adjusted using Bonferroni correction), (Cohen's d: large > normal 0.40, normal > omission 0.57). e, Same as c but for a VS recording. f, Same as d but for VS recording (n = 7 mice, p = 3.16×10-6, p = 8.87×10-6, paired two-sided t-test, adjusted using Bonferroni correction), (Cohen's d: large > normal 7.01, normal > omission 5.89). g, Schematic of the predicted value manipulation task design. h, Model predictions for changes in predicted outcome value. i, Example movement-aligned TS response when the relative value of the cues changed. j, Summary data showing the change in movement-aligned response in the TS for relative value changes (p = 0.26, paired two-sided t-test) (n = 5 mice), Cohen's d = 0.58. k, Same as i but for the VS response aligned to cue. l, Same as j but for the VS response aligned to cue (p = 2.41×10-4, paired two-sided t-test) (n = 5 mice), Cohen's d = 5.56. All error bars represent SEM.
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a, Model predictions for how the different models of dopamine respond in the state change experiment. b, Model predictions for how the different models of dopamine respond in the cue value change experiment. c, Salience model dopamine signal aligned to time of high cue, low cue, and reward. Size of response to cues shown for 100 agents over training. d, Novelty model dopamine signal aligned to time of high cue, low cue, and reward. Size of response to cues shown for 100 agents over training. e, Movement model dopamine aligned to time of contralateral choice, ipsilateral choice, and reward. Size of response to contralateral choice shown for 100 agents over training.
a, Coronal sections along the striatum indicating fiber placement positions (center tip of the fiber). Note that fibers were inserted in both hemispheres and are mirrored here for illustration purposes. Primary auditory cortex projections are shown in the other hemisphere. b, Horizontal (top) and side view (bottom) of the same histological data. For the horizontal section the recording location depths are collapsed onto a single horizontal atlas image for illustrative purposes. On the side view, the striatum is outlined and the AUDp projections are indicated in grayscale. c, Psychometric curves for all 8 mW sessions where dopamine release was optogenetically stimulated in the TS at the time of choice (center port). d, Scatterplot showing that the stimulation choice bias develops over the course of a session (8 mW, p = 0.035; 4 mW, p = 0.006, linear regression). e, Model simulation of the state-action optogenetic experiment. The APE was unilaterally stimulated when the cue predicted a contralateral action. f, Quantification of the contralateral choice bias on stimulated trials when optogenetic stimulation in the TS was delivered on 15% of trials at the center port. session (4 mW, p = 0.67; 8 mW, p = 0.28, Kruskal-Wallis test); 4 mW: n = 9 mice, 18 hemispheres mice, 8 mW n = 7 mice, 13 hemispheres g, Experimental design: animals enter a central port (gray) to initiate trials and then choose between water and water + optogenetic stimulation of dopamine release in the TS by entering one of two side ports. h, Choice bias (n = 5 mice) for 4 Hz optogenetic stimulation (p = 0.99, t-test) or 20 Hz optogenetic stimulation (p = 0.49, t-test). Solid dots indicate mean ± SEM and transparent dots indicate single sessions from individual animals. i, Same as g but with a 50% probability of receiving a water reward at the choice ports. j, Same as h but with the probability of receiving a water reward at the choice ports reduced to 50%. (TS, p = 0.11; VS, p = 0.002 Cohen's d = 1.80, t-test). All boxplots show the range from quartile (Q1 - Q3), the median and the whiskers extend to the farthest data point lying within 1.5x the inter-quartile range (IQR) from the box.
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a, Heatmaps showing the occupancy for different sides of an arena during a real-time place-preference experiment where each side of the arena is paired with optogenetic stimulation of dopamine release in the TS. b, Bar graphs (mean) showing the percentage occupancy during control, stimulation in the left or in the right chamber. error bars represent SEM. c, Schematic showing the experimental closed-loop setup for detecting immobility and triggering dopamine release. d, Speed heatmap of trials sorted by movement onset for stimulated and control trials (n = 9 biologically independent animals). e, Speed histogram, same data as in n; error bars: SEM. f, g, h, i, Distribution, as means per mouse, of different movement parameters (see methods) (p:4 mW p = 0.21, 8 mW p = 0.42; q: 4 mW p = 0.67, 8 mW p = 0.78; r: 4 mW p = 0.87, 8 mW p = 0.80; s: 4 mW p = 0.93, 8 mW p = 0.50; paired two-sided t-test); same animals as in n. j, Regression coefficients for effect of TS dopamine response on the current trial on difference between turn angle on current and subsequent trial. Filled circles represent significant correlations for individual mice (n = 6 mice). Stats: one-sample t-test against zero, p = 0.07, Cohen's d = −0.94. Error bars represent 95% confidence interval.
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a, Moment in learning in which differences in between groups become significant, for the behavioral data and the network model. Dotted lines indicate the 95% confidence interval for the shuffled data (see methods). b, Change of the model weights during learning, as means for 100 agents, for the Critic, Actor, and TS networks. c, Summary schematic of the anatomical representation for the dual-controller model. Dotted arrow indicates the proposed, but as yet unverified, broadcast of APEs to the dorsal striatum.
Source data
a, Schematic of the experimental approach for recording dopamine activity in TS. b, Schematic of the experimental arena containing a threat zone (indicated by a dashed line) above which a looming stimulus can be displayed and a shelter (blue shaded area). c, Schematic of a single trial of the looming stimulus, consisting of 5 consecutive expanding spots. Black line illustrates how the looming spot radius changes over time. d, The dlight1.1 photometry traces for all three trials for each mouse (gray lines) and the average (blue line) in response to the five looming stimuli (top). The position tracks for each trial of the mice along the long axis of the behavioral arena (bottom). Looming spot onsets (black, dashed lines) and their durations (black circles) are shown. (n = 4 mice). e, Schematic of the frequency discrimination task. f, Average photometry response of the same mice as shown in (D) in the frequency discrimination task aligned to choice (n = 4 mice). g, Same as F aligned to reward. All error bars represent SEM.
Source data
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Greenstreet, F., Vergara, H.M., Johansson, Y. et al. Dopaminergic action prediction errors serve as a value-free teaching signal.
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Discover new clues about how our ancient relatives disappeared from time.
“There is nothing like looking, if you want to find something,” says Thorin Oakenshield in J.R.R. Tolkien's beloved fantasy novel The Hobbit. “You certainly usually find something, if you look, but it is not always quite the something you were after.”
For example, in 2015, paleoanthropologist Ludovic Slimak made a remarkable discovery at Grotte Mandrin, a cave in Rhône Valley, France. He and his team had been working the area since 1998 to find remnants of humanity's prehistoric forbearers, and after 17 years, they certainly found something: a piece of a jaw belonging to a Neanderthal.
As the years went on, more and more remains of this Neanderthal were discovered. “I began to find {remnants of the Neanderthal's jaw} in 2015,” Slimak told the New Statesman in 2022, “but each year we find one tooth, or one fragment of bone.” Slimak determined that this particular Neanderthal lived 42,000 years ago, towards the end of that species' time on this planet.
As such, he named the Neanderthal Thorin after the Tolkien character. “Thorin in the Hobbit is one of the last dwarf kings under the mountain and the last of its lineage,” Slimak told the website IFLScience. “Thorin the Neanderthal is also an end of lineage. An end of a way to be human.”
To confirm his suspicions about Thorin's age and attempt to glean more information about not just when but how this particular specimen lived, Slimak and his colleagues had Thorin's genome analyzed. The results, published in the journal Cell Genomics, show that Thorin's lineage managed to stay isolated from the rest of the Neanderthal population, “in spite of the fact that other groups lived nearby.”
Nearly a decade before ever finding Thorin, Slimak had already theorized that any Neanderthals who had resided in the Rhône Valley would have been different from those in the surrounding areas. His assessment, at that point, was based on the stone tools found at various sites, noting that those in the Rhône Valley didn't reflect the newer tool-making style found at other locations.
“It turns out that what I proposed 20 years ago was predictive,” Slimak told the publication Live Science. “The population of Thorin had spent 50 millennia without exchanging a single gene with the classical Neanderthal populations.” The analysis showed that Thorin had “high genetic homozygosity,” which indicates inbreeding in the lineage's recent past. It also offers no evidence of interbreeding with modern humans of the time.
“Everything must be rewritten about the greatest extinction in humanity and our understanding of this incredible process that will lead Homo sapiens to remain the only survival of humanity,” Slimak said in assessing what this discovery means. “How can we imagine populations that lived for 50 millennia in isolation while they are only two weeks' walk from each other? All processes need to be rethought.”
Michale Natale is a News Editor for the Hearst Enthusiast Group. As a writer and researcher, he has produced written and audio-visual content for more than fifteen years, spanning historical periods from the dawn of early man to the Golden Age of Hollywood. His stories for the Enthusiast Group have involved coordinating with organizations like the National Parks Service and the Secret Service, and travelling to notable historical sites and archaeological digs, from excavations of America' earliest colonies to the former homes of Edgar Allan Poe.
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It's giving “fur mom” a whole new meaning.
Gear-obsessed editors choose every product we review. We may earn commission if you buy from a link. Why Trust Us?
Cats or dogs? Dogs or cats? Whether you're a feline fanatic or with the canine crowd, maybe you've noticed your cat has an eerie resemblance to a popular purebred pug on social media, or that your dog is starting to look like a lot of Instagram cats.
This phenomenon isn't a trick of the imagination. Some breeds of dogs and cats really are starting to look uncannily similar, and it's all because of the human aesthetic preferences that go into breeding them. After analyzing the shapes of about 2,800 skulls of cats, dogs and their wild brethren, evolutionary biologists Abby Drake (from Cornell University) and Jonathan Losos (from Washington University) found that there was more variation in the skulls of domesticated animals than wild ones because of artificial selection by breeders. They did a double take, however, after comparing the shapes of dog and cat skulls.
“The skulls of a pug or a Pekingese and a Persian cat are more similar to each other than either is to their ancestors, the wolf and the North African wildcat,” Losos said in a recent press release. “I don't think anyone would have expected that.”
Regardless of whether they happen to be dog or cat lovers, humans tend to prefer flat faces and huge eyes, most likely because these features closely mirror infants of our own species and trigger parental instincts. Homo Sapiens is one of the most altricial species on Earth, meaning that our offspring are helpless and depend on caregivers for one of the longest periods in the animal kingdom. Seeing these features automatically puts many of us into nurturing mode—so much so, in fact, that caring for pets is also sometimes referred to as alloparenting (which refers to parenting anything other than direct offspring).
Puppies and kittens are not helpless for long. As precocial animals, they are walking, leaping, pawing at the carpet, and knocking over houseplants just weeks after they open their eyes. Human infants don't even begin crawling until about 7 months. Despite a puppy being anything but helpless, features that make a breed appear like a human infant (which needs our constant attention) up the cuteness factor.
The merging of dog and cat features is an example of convergent evolution, which happens when unrelated organisms (which may even live far apart for each other) evolve similar characteristics because of the environmental pressures they face. This has been going on since there was life on Earth—for example, when fossils from what appeared to be a saber-tooth cat emerged in Argentina, scientists examining the bones realized that the creature was actually a monstrous marsupial that had developed fangs to tear through leftover carcasses.
Divergent evolution, which results in speciation, is the opposite. Canids (dogs) and felids (cats) diverged from each other 50 million years ago.
“If you read the breed standards for the Pekingese and the Persian, the language is very similar in terms of how they want the nose to be up between the eyes and the face to form a vertical plane with no protrusion of the muzzle,” Drake said in the press release.
There are still those of us (including this author) who love creatures that don't even look remotely human as our own. But, in general, people tend to melt at anything that looks human-ish. Problems with this arise when an animal's health is compromised for its looks. For instance, flat-faced dogs like pugs and Boston Terriers cannot fly because of a high (and potentially lethal) nosebleed risk. And pugs did not evolve these characteristics on their own—they used to be almost unrecognizable by today's standards, with longer faces and legs. It is because humans bred the individuals with the flattest faces that they developed into what they are now.
Your neighbor's very expensive designer dog went and had puppies with a stray of indeterminate breed? Scandalous, but in the end, it's probably better for the puppies.
Elizabeth Rayne is a creature who writes. Her work has appeared in Popular Mechanics, Ars Technica, SYFY WIRE, Space.com, Live Science, Den of Geek, Forbidden Futures and Collective Tales. She lurks right outside New York City with her parrot, Lestat. When not writing, she can be found drawing, playing the piano or shapeshifting.
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Based on seminal work in placental species (eutherians)1,2,3,4,5,6,7,8,9,10, a paradigm of mammalian development has emerged wherein the genome-wide erasure of parental DNA methylation is required for embryogenesis. Whether such DNA methylation reprogramming is, in fact, conserved in other mammals is unknown. Here, to resolve this point, we generated base-resolution DNA methylation maps in gametes, embryos and adult tissues of a marsupial, the opossum Monodelphis domestica, revealing variations from the eutherian-derived model. The difference in DNA methylation level between oocytes and sperm is less pronounced than that in eutherians. Furthermore, unlike the genome of eutherians, that of the opossum remains hypermethylated during the cleavage stages. In the blastocyst, DNA demethylation is transient and modest in the epiblast. However, it is sustained in the trophectoderm, suggesting an evolutionarily conserved function for DNA hypomethylation in the mammalian placenta. Furthermore, unlike that in eutherians, the inactive X chromosome becomes globally DNA hypomethylated during embryogenesis. We identify gamete differentially methylated regions that exhibit distinct fates in the embryo, with some transient, and others retained and that represent candidate imprinted loci. We also reveal a possible mechanism for imprinted X inactivation, through maternal DNA methylation of the Xist-like noncoding RNA RSX11. We conclude that the evolutionarily divergent eutherians and marsupials use DNA demethylation differently during embryogenesis.
Marsupials diverged from eutherians 160 million years ago, and provide unique insight into mammalian embryology12. Relative to that of eutherians, formation of the placenta occurs late, and implantation is transient. By contrast, pups are born early and complete development outside the uterus. Like eutherians, marsupials undergo X chromosome inactivation (XCI). However, they lack the eutherian XCI-initiating noncoding RNA Xist. Instead, the alternative noncoding RNA, RSX, is implicated in marsupial XCI11. Furthermore, in eutherians, XCI in the soma is random, but in marsupials, it is imprinted, with the paternal X always chosen for silencing13.
Epigenomic profiling has not been performed in preimplantation marsupial embryos. DNA methylation, which in eutherians is globally reprogrammed and linked to key events in embryo development, is of particular interest14. In eutherians, the paternal genome undergoes active demethylation after fertilization. Subsequently, the paternal and maternal genomes undergo passive demethylation, resulting in global hypomethylation in the early blastocyst1,2,3,4,5,6. Global erasure of DNA methylation is not observed in non-mammalian vertebrates15,16, and is thought to serve a mammal-specific function (for example, to permit early embryonic genome activation (EGA), erasure of paternal methylation and epimutations, formation of the trophectoderm, establishment of pluripotency or expression of transposons regulating embryo development)7,8,9,10. These embryonic milestones occur over a more protracted period in the marsupial, making it a useful alternative model to investigate the role of DNA demethylation in mammalian embryogenesis. Marsupials possess the core vertebrate DNA methylation machinery, including de novo methyltransferase genes (DNMT3A and DNMT3B), DNMT3L, TET1–3, UHRF1 and two maintenance methyltransferase genes (DNMT1A and DNMT1B)17. However, the status of DNA methylation in gametes and during preimplantation development has not been explored.
To examine global methylation during marsupial embryogenesis, we generated low-input bisulfite sequencing (BS-seq) libraries from opossum sperm, oocytes and male and female preimplantation embryos, collected daily from embryonic day (E) 1.5 to E7.5, as well as triplicate adult somatic tissues representing the three germ layers (Fig. 1a and Supplementary Table 1). Our embryo series included the time points of EGA (E3.5), XCI (E3.5), blastocyst formation (E5.5) and lineage divergence to form the trophectoderm and epiblast (EPI; E6.5 and E7.5; Supplementary Table 1). Control BS-seq on mice recapitulated published results3, with sperm and brain exhibiting hypermethylation and a bimodal methylation pattern, and blastocysts showed global hypomethylation (mean methylation 76% in sperm, 71% in brain and 16% in blastocysts; Extended Data Fig. 1a).
a, Light microscopy images of gametes, E1.5–E7.5 opossum embryos and brain. ED, embryonic disc; TE, trophectoderm. Scale bars, 10 μm (sperm), 100 μm (embryos) and 0.5 cm (brain). The black arrowhead marks the zona pellucida; the asterisk marks the mucoid coat; the white arrowheads mark blastomeres. Sample numbers are provided in Supplementary Table 1. b, Histograms of DNA methylation distribution at CpG sites captured at ≥5× coverage (note different scales on y axes). c, Mean DNA methylation level across developmental time. d, Micrographs: pronuclear-stage embryos (29.5 h post coitum) immunostained for histone H3 (n = 7), 5mC (n = 8) or 5hmC (n = 3) and co-immunostained for H3K9me3. The two pronuclei (Pat, paternal; Mat, maternal) are of equivalent size (unlike in mice), but the paternal pronucleus is often marked by proximity to the sperm tail (arrowhead in first panel). Scale bars, 20 μm. Plots: quantification of the data. The centre line indicates the median, the bounds indicate the first and third quartiles, and the whiskers indicate 1.5× interquartile range (IQR). The more granular appearance of H3K9me3 in the middle and bottom panel is due to acid treatment of these samples, which is required for 5mC and 5hmC visualization.
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In our opossum experiments, we obtained between 47 million and 337 million reads per library, with mapping rates between 15.7% and 71% (Supplementary Table 1). Principal component analysis separated sperm from other samples, with further separation by time point along principal component 2 (Extended Data Fig. 1b). After in silico pooling per time point, we captured between 49% and 91% of CpGs at 1× coverage, and 4.2% and 83% of CpG sites at 5× coverage (Extended Data Fig. 1c and Supplementary Table 1). As genomic coverage did not reach saturation in lower-input time points, we examined the proportion of genomic regions captured in each sample, and found that they were broadly similar between time points (Extended Data Fig. 1d). We therefore interpreted the global methylation distributions of each time point as representative of the overall genome.
Examination of the opossum methylation data revealed similarities to and differences from eutherians (Fig. 1b,c and Extended Data Fig. 2a). In opossums, like eutherians3,4,5,6, the sperm genome was hypermethylated relative to the oocyte. However, in opossums, the magnitude of the difference was smaller (mean methylation 77% in sperm and 65% in oocyte). As a result, the methylation level in oocytes was similar to that in somatic tissues (mean methylation 72%, 69% and 55% in brain, liver and spleen, respectively). Furthermore, following fertilization in the opossum, the genome remained relatively hypermethylated (mean methylation 62.5%). The E1.5 methylome was more similar to that of the oocyte, suggesting that some sites in the sperm are demethylated and reprogrammed to an oocyte-like state (Fig. 1b,c and Extended Data Fig. 1b). Nevertheless, the high levels of methylation in the early embryo demonstrated that the global loss of DNA methylation typical of eutherians did not occur in the opossum. To support this conclusion, we immunostained for 5-methylcytosine (5mC) and its derivative 5-hydroxymethylcytosine (5hmC) in opossum zygotes (Fig. 1d). In eutherians, demethylation of the paternal genome after fertilization results in lower 5mC and higher 5hmC levels in the paternal than in the maternal pronucleus1,2,18,19. We reproduced these findings in mice (Extended Data Fig. 2b). In the opossum, the paternal and maternal pronucleus contained equal levels of histone H3 but could be distinguished by histone 3 Lys9 tri-methylation (H3K9me3) staining, the level of which was lower in the paternal pronucleus (see Fig. 1d caption for details). In contrast to those of eutherians, 5mC and 5hmC levels in the opossum were similar between the paternal and maternal pronucleus. DNA methylation dynamics in the paternal pronucleus therefore differ between opossums and eutherians.
We next tracked DNA methylation levels during cleavage and blastocyst formation. The hypermethylated state persisted up to and including E4.5, when the mean methylation was 64% (Fig. 1b,c). Subsequently, in the blastocyst, methylation initially decreased to 54% at E5.5 and 45% at E6.5, before rising to 49% at E7.5. Differential methylation testing of CpG sites between paired samples revealed that more than 90% of captured sites did not undergo significant changes in methylation level (Extended Data Fig. 2c). The stability in methylation was observed at all specific genomic features, including genes, intergenic regions and transposons (Extended Data Figs. 2d and 3a). In the last case, we nevertheless observed expression of multiple transposable element families at EGA (Extended Data Fig. 3b). This may be because expression derives from individual subfamily loci for which we did not capture sufficient BS-seq coverage to reveal locus-specific patterns. Alternatively, expression may be triggered independently of DNA demethylation. As observed in eutherians20, promoters and CpG islands (CGIs) were largely hypomethylated across developmental time (Extended Data Fig. 2d). We conclude that, in contrast to the case in eutherians, in opposums, EGA and the cleavage divisions take place in the context of a hypermethylated genome.
In the opossum, lineage divergence initiates at E6.5. To establish whether the decrease in methylation levels revealed by bulk analysis affected all cells or specific lineages, we performed BS-seq on isolated E7.5 embryonic disc (comprising EPI and primitive endoderm) and trophectoderm. The level of methylation was higher in the embryonic disc (63%) than in the trophectoderm (47%; Fig. 1b,c). This observation was consistent with the results of previous methylation-sensitive enzyme assays21. One explanation for this finding is that DNA methylation is retained in the EPI but reduced in the trophectoderm. An alternative is that methylation is reduced in both cell types and is then rapidly re-established in the EPI. To distinguish these possibilities, we performed single-cell multi-omics on embryos collected before lineage divergence (E5.5) and after lineage divergence (E6.5 and E7.5; Fig. 2a). As embryos transitioned from E5.5 to E6.5, a decrease in methylation was observed in both the EPI and the trophectoderm. Subsequently, at E7.5, the level of methylation increased in the EPI but continued to decrease in the trophectoderm. The level of methylation in the trophectoderm was similar to that described for eutherian post-implantation extraembryonic tissues22. Partially methylated domains, a characteristic of the eutherian trophectoderm, were also present in the opossum (Fig. 2b). Thus, relative to that in eutherians, DNA demethylation in opossums occurs late, is transient and modest in the EPI, and is sustained in the trophectoderm. Furthermore, a lower level of methylation and formation of partially methylated domains in the extraembryonic tissue is a conserved feature of therian mammals.
a, Mean methylation level in blastocyst single cells before and after lineage segregation. nE5.5 = 58, nE6.5 EPI = 19, nE6.5 TE = 19, nE7.5 EPI = 24, nE7.5 TE = 14. The centre line indicates the median, the bounds indicate the first and third quartiles, and the whiskers indicate 1.5× IQR. b, Segmentation of the genome into contiguous regions with similar methylation levels (segments 1–3) according to embryonic disc (ED) and trophectoderm (TE) methylation patterns. Presence of long segments with an intermediate level of methylation in the trophectoderm is indicative of partially methylated domains in this tissue. c, Mean expression of DNA methylation machinery derived from previous RNA-seq data23. Error bars represent 1.96 × s.e.m. noocyte = 6, nE1.5 = 7, nE2.5 = 21, nE3.5 = 62, nE4.5 = 55, nE5.5 = 140, nE6.5 = 201, nE7.5 EPI = 108, nE7.5 TE = 55.
Source data
To investigate the mechanisms behind DNA methylation changes during blastocyst development, we examined the mRNA expression of DNA methylation enzymes in our published opossum embryo single-cell RNA sequencing (RNA-seq)23 data (Fig. 2c) and new multi-omics dataset (Extended Data Fig. 4a), which showed good coherence. Expression of the maintenance methyltransferases DNMT1A, DNMT1B and the DNMT1 binding partner UHRF1 was high during cleavage and then declined before blastocyst formation. Notably, between E6.5 and E7.5, the expression of these factors, and of the establishment methyltransferases DNMT3A and DNMT3B, increased in the EPI concomitant with increased DNA methylation. Conversely, mRNA expression of these enzymes fell in the trophectoderm, concomitant with reduced DNA methylation. The DNMT cofactor DNMT3L was not expressed. Expression of the ten-eleven translocation methylcytosine dioxygenase TET1 was observed; notably, however, levels of expression of TET2 and TET3, the latter of which influences methylation in eutherian embryos18,24,25,26,27,28, were very low. Our findings suggest that differences in DNMT enzyme expression could drive the distinct DNA methylation profiles in the EPI and trophectoderm.
We next identified differentially methylated regions (DMRs) in opossum oocytes and sperm. We found 20,800 sperm-specific and 22,921 oocyte-specific DMRs. As in eutherians, oocyte DMRs were relatively enriched in intragenic regions and CGIs, whereas sperm DMRs were enriched in intergenic regions (Fig. 3a). To identify transient and long-term autosomal imprints, we searched for DMRs that exhibited intermediate levels of methylation (40–60%) at E3.5, and tracked their fate in E7.5 embryonic disc and trophectoderm, and adult brain, liver and spleen. We found 12,096 intermediately methylated regions at E3.5 (Fig. 3b). Around half of these were retained at E7.5, some in a trophectoderm- or embryonic disc-specific manner, and 85 persisted in all 3 adult tissues. As in eutherians, most retained DMRs were of maternal origin (Supplementary Table 2). In adult tissues, we identified 78 DMR-proximal genes, 3 of which are known to be imprinted29 (NKRFL2, ZFP68 and RWDD2A; example locus in Fig. 3c), and the remainder of which are imprinting candidates (Supplementary Table 2).
a, Genomic distribution of gamete DMRs. b, Fate of gamete DMRs during embryogenesis. c, DNA methylation levels at individual CpG sites at a representative region of the imprinted NKRFL2 locus. d, DNA methylation profiles in eutherian and opossum oocytes at genes transcribed in oocytes (active), genes not transcribed in oocytes (inactive) and intergenic regions. The centre line indicates the median, the grey circle indicates the mean, the bounds indicate the first and third quartiles, and the whiskers indicate 1.5× IQR.
Source data
Eutherian oocytes exhibit divergent DNA methylation patterns, with methylation restricted to the bodies of expressed genes in rodents and extending into non-transcribed regions in other species3,4,5,30. To understand the relationship between oocyte transcription and methylation in opossums, we integrated our methylation datasets with previously published RNA-seq data, and compared our findings with those in other eutherians23,31,32,33,34,35,36 (Fig. 3d and Supplementary Table 3). Transcribed genes were heavily methylated across the gene body in eutherians and opossum. Non-transcribed regions (inactive genes and intergenic regions) were methylated at low levels in mice and rats, moderately methylated in humans, and more highly methylated in cows, consistent with previous findings. Opossums exhibited an extreme scenario, with non-transcribed regions exhibiting a very high level of methylation. DNMT3L was not expressed in oocytes, indicating that, as in humans37, de novo DNA methylation in opossum oocytes is DNMT3L independent. We also found that non-CpG methylation is relatively enriched in opossum oocytes, as in eutherian oocytes, indicating that this feature is conserved in therians (Extended Data Fig. 4b).
The active X and inactive X (Xi) exhibit distinct DNA methylation patterns in eutherians. At a chromosome-wide level, the Xi is slightly less methylated than its active counterpart, but the Xi exhibits hypermethylation at CGI promoters38,39,40,41,42. We confirmed these findings in adult mouse somatic tissues using a model exhibiting skewed XCI (Extended Data Fig. 5a,b). By contrast, in marsupials, the Xi is hypomethylated at CGIs and transcription start sites43,44,45,46,47,48. However, patterns of DNA methylation on the X chromosome have not been examined in preimplantation embryos.
We found that in adult opossum tissues, the level of X-chromosome DNA methylation in female animals was approximately half of that in male animals, in agreement with findings in another marsupial, the koala48 (Fig. 4a and Extended Data Fig. 5c). Allele-specific analysis shows that this was due to hypomethylation of the silenced paternal X chromosome (Extended Data Fig. 5d). Hypomethylation was observed at all genomic features on the Xi, except at XCI escapees45, where methylation levels were equivalent to those on the active allele (Extended Data Fig. 5e,f). To examine when Xi hypomethylation is established, we assessed X-chromosome DNA methylation levels in embryos (Fig. 4b), which we sexed by quantification of X- and Y-mapping reads (Extended Data Fig. 5g). In the sperm and oocyte, X-chromosome DNA methylation levels were equivalent, demonstrating that the Xi is not inherited from the sperm in a hypomethylated state. Loss of methylation on the Xi occurred gradually during the cleavage stages, with hypomethylation clear from the blastocyst stage (Fig. 4b). Methylation levels therefore differ between chromosomes, being retained on the active X and the autosomes, but lost on the Xi during embryo development.
a, Methylation distribution of the autosomes and X chromosome in adult male and female brain represented as density plots showing the distribution of the data and the probability of a variable being a certain value. b, Methylation distribution of the autosomes and X chromosome in male and female gametes and embryos. c, Methylation at the RSX locus in gametes, embryos and adult tissues. d, Quantitative PCR analysis in DNMT1-knockout (KO) immortalized male fibroblasts. ncontrol = 3, nDNMT1 KO = 3. Unpaired t-test. Each point represents the mean of the replicates. Error bars represent s.e.m. e, RSX RNA fluorescence in situ hybridization in wild-type and DMNT1-KO day-8 immortalized male fibroblasts. DAPI, 4′,6-diamidino-2-phenylindole. Scale bars, 20 μm. f, Quantification of RSX clouds in RNA fluorescence in situ hybridization at 4 and 8 days after DNMT1 deletion. g, X/A gene expression ratios at 4 and 8 days after DNMT1 deletion. ncontrol = 3, nDNMT1 KO = 3. Unpaired t-test. Error bars represent s.d. Each point represents the median X/A ratio per replicate. h, Schematic of DNA methylation status in eutherian (left) and opossum (right) embryos.
Source data
In most eutherians, XCI in the early embryo is random49,50. The mouse is an important exception, with random XCI preceded by silencing of the paternal X imprinted in the preimplantation embryo51,52. Imprinted XCI in mice is independent of DNA methylation53, relying instead on H3K27me3-mediated silencing of the maternal Xist allele54. The contribution of DNA methylation to XCI imprinting in marsupials is unclear. Methylation of the maternal RSX promoter has been observed in fetal opossum tissue45, but whether this epigenetic mark is inherited from the gamete is unknown. We identified a DMR encompassing the RSX promoter that was highly methylated in the oocyte and hypomethylated in sperm (Fig. 4c). Intermediate methylation of this region in female embryos and adult tissues suggests that this pattern is retained, consistent with an instructive role in imprinted XCI.
To assess its role in RSX regulation, we ablated DNA methylation in bulk immortalized male opossum fibroblasts using CRISPR-mediated deletion of DNMT1A and DNMT1B (hereafter DNMT1). Loss of DNMT1 reduced methylation genome wide, including at the RSX promoter (Extended Data Fig. 6a,b). It also caused ectopic expression of the normally silent RSX allele in male cells, as assayed by quantitative PCR (Fig. 4d). This ectopic expression was accompanied by formation of RSX clouds in male cells (Fig. 4e,f).
Ectopic expression of RSX in male fibroblasts was associated with suppression of X-gene activity, with X genes over-represented among all downregulated genes (Extended Data Fig. 6c) and the X-to-autosome (X/A) ratio mildly but significantly decreased (Fig. 4g). Loss of DNMT1 also led to a decrease in the level of DNA methylation and an increased level of expression of multiple transposable element families (Extended Data Fig. 6d). We also examined expression of the autosomal H19 locus, which is imprinted in marsupials55 (H19 is not present in the opossum assembly and was therefore not recovered in our earlier imprinted screen). The level of H19 expression increased following DNMT1 deletion (Extended Data Fig. 6e), suggesting that DNA methylation may be a general mechanism regulating imprinting in opossums.
Here we define the DNA methylation landscape of early development in a marsupial. We demonstrate that opossums do not undergo a eutherian-like global demethylation phase during cleavage (Fig. 4f). DNA demethylation is mild and transient in the EPI but sustained in the trophectoderm. On the basis of our findings, we suggest that in therian mammals, DNA demethylation may play an especially important role in trophectoderm formation. Differences in DNA methylation between the EPI and trophectoderm are presumably achieved through cell-autonomous mechanisms, because the marsupial blastocyst is unilaminar. We propose that this is regulated by differential expression of the DNA methylation machinery. DNA demethylation is also proposed to erase germline-acquired epimutations7. This model would predict that epimutations are more stably maintained in marsupials than in eutherians.
We also identify new candidate marsupial imprinted genes that will be useful for investigating conservation and evolution of imprints in therians. In eutherians, imprints are maintained in embryos through the Krüppel-associated box zinc-finger proteins ZFP57 and ZFP445. Of the two, only ZFP445 is conserved in marsupials56 and may contribute to imprint maintenance in these mammals. We offer a mechanism for marsupial imprinted XCI, mediated by differential methylation of RSX. Once methods to epigenetically edit the marsupial genome become available, it would be possible to further test this mechanism by targeted ablation of DNA methylation at the RSX promoter. This DNA methylation-mediated mechanism of imprinted XCI differs to that in mice, which achieve imprinted XCI using H3K27me3. We previously identified XSR, an RSX antisense RNA expressed in oocytes and from the maternal X chromosome in embryos23. Although its contribution to imprinted XCI is not established, XSR may help establish RSX promoter methylation through a mechanism reminiscent of Tsix-mediated Xist promoter methylation23.
Our work highlights the strength of the marsupial model to understand evolutionary epigenetics. Given that post-fertilization global DNA methylation erasure is absent in the opossum, and zebrafish15,16, we propose that this process evolved after the marsupial–eutherian split. In this context, it is noteworthy that Dppa3 (also known as Stella or Pgc7) evolved after the marsupial–eutherian divergence57. In eutherians, Dppa3 is important for preimplantation development58,59,60, and has been implicated in both passive demethylation and protection against demethylation57,61,62,63,64,65,66,67,68. Our current findings are consistent with the hypothesis that evolutionary acquisition of Dppa3 accompanied the development of oocyte and embryonic DNA demethylation9,57.
Opossums and mice (C57BL/6J and Mus spretus) were maintained in the Francis Crick Institute Biological Research Facility in accordance with UK Animal Scientific Procedures Act 1986 regulations (project licence P8ECF28D9) and subject to Francis Crick Institute's internal ethical review. Additional opossums were housed at the University of Texas Rio Grande Valley under Institutional Animal Care and Use Committee protocol AUP-19-31. No randomization or blinding was performed and no statistical methods were used to predetermine sample size. Mice were housed in individually ventilated cages (GM500, Tecniplast) with a 12:12-h light/dark cycle, a temperature of 20–24 °C and humidity of 55% ± 10%. Adults (8 weeks–6 months) were housed in groups of 3–4 animals, with the different sexes housed separately. Mice had free access to water and food and were provided enrichment activities including rodent balls and nesting boxes. Matings for timed collection of embryos were conducted by placing female mice into the cage of male mice at approximately 17:00. Observation of a vaginal plug the following morning was taken to indicate that mating had occurred.
Opossums were individually housed in Double Decker cages (GR1800, Tecniplast), with male and female animals housed in separate rooms except during mating periods. The temperature of the housing was maintained between 24 °C and 28 °C, and humidity was maintained between 55% and 75%, with a 14 h/10 h light/dark cycle. Opossums had free access to dried food and water, supplemented every second day with live mealworms, and weekly by fresh fruit. To induce oestrous before mating, adult male and female (≥6 months) mice were placed in single-storey rat cages immediately adjacent to each other for 2 days, and then swapped into each other's cages for an additional 2 days. Subsequently, pairs were placed into the same cage and kept together for 10 days, during which period animals were monitored by infrared CCTV camera for mating behaviour69.
Mouse E0.5 (11 h post coitum (hpc)) and E3.5 (82–84 hpc) embryos were recovered by flushing the uteri with PBS (Gibco number 14190-094) from a blunt-ended needle under a Leica MC80 dissecting microscope, aspirated using a Stripper pipette with a 275-μm tip (MXL3-STR and MXL3-275, Cooper Surgical), and washed three times through drops of clean PBS. For immunofluorescence, zygotes were fixed in 4% PFA in PBS with 0.2% Triton X-100 for 60 min at room temperature and washed three times in 0.2% Triton X-100 in PBS with 0.01% polyvinyl alcohol (PVA; number P8136, Sigma). For sequencing of blastocysts, the zona pellucida was removed by incubation in acid Tyrode's solution (T1788, Sigma-Aldrich), and then the embryo was washed three times in PBS, snap-frozen on dry ice and stored at −80 °C until processing. Picking-buffer-only negative controls were collected in parallel, and processed through the library preparation procedure to verify the absence of contamination.
Opossum embryos were recovered from the uteri in PBS under a Leica MC80 dissecting microscope at E0.5 (29 hpc), E1.5 (36 hpc), E2.5 (60 hpc), E3.5 (84 hpc), E4.5 (108 hpc), E5.5 (132 hpc), E6.5 (156 hpc) and E7.5 (180 hpc). In the case of oocyte collection, the female animal was mated to a vasectomized male animal, and oocytes were recovered from the uterus at 36 hpc. Embryos were aspirated using a Stripper pipette with a 600-µm tip (MXL3-600, Cooper Surgical), or a micropipette fitted with a 200-µl tip for large E7.5 embryos, and washed three times in PBS. Samples were imaged using a Leica DMIL LED microscope with a 20× objective and then further processed for sequencing or immunofluorescence. The shell coat was perforated with 1-μm dissecting needles (10130-20, FST) and incubated in 5 mg ml−1 protease in PBS (P8811-100MG, Sigma) at 32 °C for between 2 and 7 min. The sample was transferred into fresh PBS, and any remaining mucoid coat was removed by disaggregation with dissecting needles.
For sequencing, the oocytes and E0.5–7.5 embryos were washed through three drops of fresh PBS, dispensed to 0.2 µl tubes, and snap-frozen on dry ice and stored at −80 °C until further processing. We collected multiple single embryos for each time point, and in addition collected pooled litters of oocyte, E2.5 and E3.5 samples (Supplementary Table 1). For E7.5 embryonic disc and trophectoderm samples, after removal of the shell coat, the embryonic disc was isolated from the trophectodermT by dissection with 1-μm needles, washed through three drops of PBS, and snap-frozen as above. For single-cell sequencing, embryos were washed through three drops of fresh PBS with BSA, and incubated in TrypLE (12604013, ThermoFisher) diluted to 0.5× in PBS for 2–8 min at 35 °C. Following TrypLE incubation, embryos were moved to PBS with BSA and disaggregated to single cells by repeated pipetting through a narrow-bore pipette, before nucleosome, methylome and transcriptome (NMT)-sequencing processing. Picking-buffer controls were included as described above. For immunofluorescence, E0.5 zygotes were fixed and washed as above for mouse embryos.
For collection of sperm from mouse and opossum adult male animals, epididymides were dissected from the testes and rinsed in PBS. Cauda epididymides were transferred to 2 ml Bigger–Whitten–Whittingham buffer (opossums) or TYH buffer (mice). Several small incisions were made, followed by incubation at 37 °C for 30 min to facilitate sperm swim out. The swim-out was diluted approximately 1:10 in PBS, and visualized on a dissecting microscope using a dark field. Individual sperm were aspirated using a Stripper pipette with a 100-µl tip (MXL3-100, Cooper Surgical) and washed three times in PBS before collection in 5 µl RLT Plus (1053393, Qiagen) containing 2% β-mercaptoethanol. For collection of pools of sperm, multiple sperm cells were picked in one pipette and processed together through washing, collection and freezing as for single sperm cells. Picking-buffer controls were included as described above.
For collection of genomic DNA from adult mice, and genomic DNA and RNA samples from adult opossums, brain, liver and spleen tissues were dissected into ≈10-mm pieces, snap-frozen in liquid nitrogen, and stored at −80 °C. To facilitate allele-specific analyses, a cross was set up with parent animals from the LL2 opossum stock, and tissue samples were collected from the parents for whole-genome sequencing (WGS) and genomic variant identification, and from three male and three female littermates for BS-seq and RNA-seq. Mouse tissue samples were collected from a model exhibiting skewed XCI through a targeted Xist deletion70 (that is, C57BL/6J Xisttm1Jae × Mus spretus F1 hybrid cross). We collected three heterozygous female offspring in which XCI is completely skewed, and three male littermates with Xist deleted. Frozen tissue was pulverized using a pestle and mortar pre-cooled on dry ice, and used for genomic DNA extraction with the PureLink Genomic DNA Mini kit (K18290-02, Invitrogen) or RNA extraction using the Ambion RNAqueous-Micro Kit (AM1931, ThermoFisher). Samples were then processed for WGS, BS-seq or RNA-seq library preparation.
Library preparation was performed with oligonucleotides compatible with the NEBNext library preparation kit (E7535S) following an established method71 and described briefly here. For gamete and embryo samples, samples were lysed in 2.5 µl RLT Plus and processed following the low-input library method71. For brain, liver, spleen and fibroblast samples, 6 ng of genomic DNA was used to prepare libraries following the bulk method71. Samples were spiked with 6 fg of Lambda DNA (D152A, Promega) and bisulfite-converted using the EZ Methylation Kit (D5020, Zymo). Bisulfite-converted DNA was purified using the PureLink PCR Purification Column Kit (K310050, Invitrogen) with an additional treatment with M-desulfonation buffer (EZ Methylation Kit, Zymo). Samples were eluted into a mixture containing 0.4 µM Preamp primer (5′-CTACACGACGCTCTTCCGATCTNNNNNN-3′) and submitted to one (brain, liver and spleen samples) or five (gamete and embryo samples) rounds of pre-amplification with Klenow exo− (M0212M, NEB). Unused oligonucleotides were degraded by incubation with exonuclease I (M0293L, NEB), and samples were purified with Ampure XP beads (A63881, Beckman Coulter). Samples were resuspended in a mixture containing 0.4 µM Adaptor 2 Oligo for NEB indices (5′-CAGACGTGTGCTCTTCCGATCTNNNNNN-3′) and adaptor-tagged by incubation with Klenow exo−. Samples were purified using Ampure XP beads and resuspended in a mixture containing 0.2 μM NEBNext Universal Adaptor and 0.2 μM NEBNext Index Adaptor (E7535S, NEB), and library amplification was performed using KAPI Hifi HotStart polymerase (KK2502, KAPA Biosystems). Varying numbers of PCR cycles were performed depending on input amount (opossum oocytes and E1.5–E5.5 embryos: 19 cycles; mouse E3.5 embryos and opossum E6.5 and E7.5 embryos: 10–14 cycles; sperm: 10–18 cycles; brain, liver and spleen: 10 cycles). Library sequencing was carried out by the Francis Crick Institute Advanced Sequencing Facility (ASF). Gamete and embryo libraries were sequenced (100-base-pair (bp) paired end) on an Illumina HiSeq 4000, yielding between 47 million and 337 million reads per library. Brain, liver and spleen libraries were sequenced (150-bp paired end) on an Illumina HiSeq 4000, yielding between 198 million and 363 million reads per library.
Purified RNA was submitted to the Francis Crick Institute ASF for preparation of cDNA using the SMART-Seq v4 Ultra Low Input RNA Kit (634894, Takara), followed by library preparation using the Nextera XT DNA Library Preparation Kit (FC-131-1096, Illumina). Sequencing (100-bp paired end) was performed on an Illumina HiSeq 4000, generating between 54 million and 156 million reads per library.
Disaggregated single cells were deposited into individual wells of a 96-well plate, and NMT-seq libraries were prepared as previously described71. In brief, cells were incubated with M.CviPI for 15 min, followed by separation of mRNA and genomic DNA using Oligo-dT beads, and subsequent preparation of RNA-seq and BS-seq libraries. Sequencing (100-bp paired end) was performed on an Illumina HiSeq 4000.
Primary opossum fibroblasts were derived from a newborn male animal and immortalized using SV40-tag virus infection. Single-cell clonal selection was performed to identify an euploid cell line. Opossum fibroblasts were maintained in DMEM (Gibco) supplemented with 20% fetal bovine serum, 1% GlutaMax (Gibco), 1% sodium pyruvate (Gibco) and 1% penicillin–streptomycin (Gibco, 10,000 U ml−1) and were routinely tested and found to be negative for mycoplasma. Single-guide RNAs (sgRNAs) targeting all opossum DNMT1 paralogues (DNMT1A, DNMT1B and DNMT1Ψ) were designed using the online tool CRISPRdirect (https://crispr.dbcls.jp/): DNMT1 gRNA 1: 5′-TCTGAAGGCTTTCATCAAGC-3′; DNMT1 gRNA 2: 5′-CATTGTGGGCCATTGAAATG-3′. sgRNAs were annealed and ligated into the targeting plasmid px333-puro. The plasmid px333-puro was obtained after cloning a puromycin-resistance cassette isolated from px459v2 (gift from F. Zhang, Addgene number 62988) into the px333 vector (gift from A. Ventura, Addgene number 64073)72.
Immortalized opossum fibroblasts were seeded onto gelatin-coated wells of 6-well plates. The following day, fibroblasts were transfected using PEI MAX (49553-93-7). A 2 µg quantity of plasmid (with sgRNAs or empty plasmid for negative control) was added to 200 µl of Opti-MEM (Gibco) and 8 µl of PEI MAX (1 mg ml−1). One day after transfection, puromycin (2.5 µg ml−1) was added for 48 h to select successfully transfected cells. Control and DNMT1-knockout cells were fixed for RNA fluorescence in situ hybridization (RNA FISH) or frozen down for quantitative PCR with reverse transcription (qRT–PCR) at specific time points.
Cells were washed in cold PBS and treated with ice-cold permeabilizing solution (0.5% Triton X-100, 2 mM vanadyl ribonucleoside complex in PBS) for 10 min. After fixation using ice-cold 4% PFA in PBS for 10 min, cells were rinsed in ice-cold PBS twice, dehydrated through ice-cold 70%, 80%, 95% and 100% ethanol for 3 min each, and air-dried. BAC VM-18-303M7 (CHORI) was used for RSX RNA FISH. BAC DNA was labelled using Nick Translation Kit (Abbott) with fluorescent nucleotides (spectrum orange-dUTP; 02N33-050, Abott), and cells were hybridized with a denatured mix of probes along with 1 µg salmon sperm DNA in hybridization buffer (50% formamide, 10% dextran sulfate, 1 mg ml−1 PVP, 0.05% Triton X-100, 0.5 mg ml−1 BSA, 1 mM vanadyl ribonucleoside complex in 2× SSC) at 37 °C overnight in a humid chamber. Stringency washes were performed on a hot plate, three times for 5 min in 50% formamide in 1× SSC (pH 7.2–7.4) preheated to 45 °C, and three times for 5 min in 2× SSC (pH 7–7.2) preheated to 45 °C. Cells were mounted in antifade containing DAPI (Vector) with a coverslip and stored at −20 °C.
RNA from control and DNMT1-knockout male opossum fibroblasts across three different time points and three replicates was purified using RNAqueous-Micro Total RNA Isolation kit (Invitrogen, AM1931). Purified RNA was retrotranscribed using the Maxima First Strand cDNA synthesis kit (Thermo Scientific, K1641). The following primers were used to assess gene expression in RT–PCR assays using PowerUp SYBR Green (Applied Biosystems, A25780): RSX (5′-AGAAGGGACCCCAAGACAC-3′, 5′-TGGGTCACTTCCACTTCCTC-3′); DNMT1 (5′-GACGCAGTAACACTGGAGCA-3′, 5′-ATCCCATTCCAACCTTCCAT-3′); H19 (5′-TCCAGCAGCAGTCAGTGAAC-3′, 5′-TCATCCATCCATGAGCAGAG-3′); ABCD4 (5′-ATCGATAATCCGGACCAGCG-3′, 5′-ATGATCAGCTTGCTGGCCAT-3′), GAPDH (5′-TAAATGGGGAGATGCTGGAG-3′, 5′-ATGCCGAAGTTGTCGTGAA-3′).
Libraries from control and DNMT1-knockout RNA samples from day 4 and 8 were prepared with the NEBNext Ultra II Directional PolyA mRNA kit according to the manufacturer's instructions. Libraries were sequenced on the Illumina NovaSeq 6000 system (paired end, 100-bp read length). Raw RNA-seq reads were processed using the RNA-seq nf-core pipeline (v3.2); star_rsem was used to generate raw reads counts. The read counts were processed in R using the DESeq2 package (v1.36). Genes expressed at very low levels were filtered out by applying a rowSums filter of ≥5 to the raw counts table. Raw counts were normalized using the DESeq() function, specifying ~genotype_day in the design formula. log2[fold change] and adjusted P values between DNMT1 knockout and control were calculated using the lfcShrink() function in DESeq2, specifying type = ‘ashr', analysing day 4 and day 8 separately.
X/A ratios were calculated using the median expression of X and autosomal genes in each sample after filtering out genes expressed at low levels (transcripts per million (TPM) of <1). X/A ratios between control and DNMT1-knockout samples were compared by Student's t-test. Repetitive element expression was analysed as above for opossum embryos.
Samples of 3 μg of genomic DNA prepared from ear snips from one male and one female opossum from the LL2 stock were submitted to the Francis Crick Institute ASF for library construction (KAPA HyperPlus). Libraries were sequenced (150-bp paired end) on a HiSeq 4000, producing 256,834,288 reads (99.23% mapped) for the female animal and 122,371,579 reads (99.27% mapped) for the male animal. Data were used for identification of genomic variants, described below.
We modified the MonDom5 reference genome to include a gap-filling long-read sequence of the RSX locus73. We prepared modified gene, repeat and CGI annotation files with corrected coordinates on the gap-filled X chromosome. We also included annotation for both opossum DNMT1 paralogues17 in our modified gene annotation file.
Opossum embryo RNA-seq data23 and DNMT1-knockout RNA-seq data were mapped to the modified MonDom5 reference genome and ASM229v1 reference genome, respectively, using HISAT2 (ref. 74) with the command hisat2 -3 0 -5 9 --fr --no-mixed --no-discordant, and read summarization at genes was performed using the Rsubread package75, excluding multi-mapping reads. Fragments per kilobase of transcript per million mapped read (FPKM) values were calculated using the scater package76. Read summarization at repetitive elements and calculation of counts per million were performed using Telescope77. Line plots showing mean and standard error of gene and repeat expression were generated using ggplot2.
To generate a bigwig file per time point, the filtered methylKit csv files were converted from csv to bedGraph using awk and then converted to bigwig using the UCSC bedGraphToBigWig utility. Genomic coordinates of the transposable elements, specifically L1, MIR and ERV1, were obtained from the mondom5 RepeatMasker GTF file, selecting for those in the ‘forward' orientation. Using deepTools78, the computeMatrix function in scale-regions mode was used to calculate the methylation score, using the parameters --binSize 50 --averageTypeBins mean -a 1000 -b 1000. The plotProfile function was used to generate the profile plot for each transposable element, using the parameters --perGroup --yMin 0 --yMax 1.
The methSeg function from the R package MethylKit79 was used to divide the genome into contiguous stretches of similar methylation level in E7.5 embryonic disc and trophectoderm samples. Parameters used were minSeg = 5, G = 1:3, join.neighbours = TRUE. Individual CpG sites with a minimum coverage of five reads in both samples were used for the analysis. The length and average methylation level of each segment were plotted using ggplot2.
Single-cell RNA-seq data were aligned to the opossum ASM229v1 genome, using the nf-core rnaseq pipeline (3.2), using the parameters –aligner star_rsem –bam-csi-index. Raw counts were loaded into Seurat (4.3.0)80 for analysis in R (4.2.2). In total, there were 74 E5.5 samples, 142 E6.5 samples and 42 E7.5 samples. Each dataset was normalized using NormalizeData, and then datasets were integrated together using the functions SelectIntegrationFeatures, FindIntegrationAnchors and then IntegrateData. The integrated dataset was scaled used ScaleData. Principal component analysis was applied using RunPCA. Uniform manifold approximation and projection was estimated for the integrated dataset using RunUMAP. Module scores for EPI and trophectoderm were calculated using the AddModuleScore function, with the following genes used as markers for each cell lineage. EPI: NANOG, PRDM14, POU5F1 and POU5F3; trophectoderm: GATA2, GATA3, TEAD4, AQP3 and KLF4.
Single-cell BS-seq data were trimmed using the TrimGalore!81 command trim_galore --clip_R1 6 --three_prime_clip_r1 6, mapped using Bismark82 with the command bismark --non_directional --un --ambiguous --multicore 2 and deduplicated using the command deduplicate_bismark. Methylation information was extracted with the command bismark_methylation_extractor --comprehensive --multicore 2 --bedGraph --CX --cytosine_report --nome-seq. Average CpG methylation was calculated per cell and plotted according to the cell lineage determined for the corresponding RNA-seq library (module score, above).
Raw RNA-seq and BS-seq data were processed using the nf-core rnaseq (3.12) and methylseq (2.5.0) pipelines, respectively. Gene bodies and intergenic regions for each organism were identified using the GenomicFeatures83 R package. Following a methodology similar to that in ref. 34, genes were classified as active if their TPM was >5 and inactive if their TPM was ≤1, and Bismark CpG methylation calls were imported into R using the methylKit79 R package, then destranded, pooled by sample condition and filtered for CpG sites with a minimum coverage of three reads. The regionCounts function was used to calculate the methylation level across active genes, inactive genes and intergenic regions. These were visualized as violin plots used ggplot2 (ref. 84).
WGS data from LL2 parent opossums were used to identify genomic variants. WGS reads were trimmed using TrimGalore!81 with the command trim_galore --cores 4 -- paired --fastqc --gzip --retain_unpaired --clip_R1 10 --clip_R2 10 -- three_prime_clip_R1 5 --three_prime_clip_R2 5. Libraries were mapped to the MonDom5 reference genome using BWA-MEM85 with the command bwa mem -t 32 -M -R. Paired and unpaired mapped reads were then merged, sorted and indexed using SAMTools86. Variants were called using the GATK best practices pipeline87. For the base recalibration step, known variants were not available for opossums. Therefore, variants were initially called independently with three pipelines: BCFtools88, Varscan89 and GATK87. Variants identified by all three pipelines were considered high-confidence variants and were used for GATK base recalibration. Subsequently, variants were called for each opossum, and then combined, and genotypes were annotated to produce a variant call file. BEDtools maskfasta was used to create an N-masked version of the MonDom5 reference genome from the complete set of 25 million variants. Using a custom R script, variants were filtered to include only hemizygous and heterozygous single nucleotide polymorphisms (SNPs). The resultant 2 million SNPs were used in the SNPsplit pipeline90.
For mice, genomic variant data (41,668,158 SNPs) were derived from the C57BL/6J and M. spretus genomes (Mouse Genomes Project91), and the program SNPsplit90 was used to generate an mm10 reference genome in which parental genomic variants were N-masked.
BS-seq reads were trimmed using the TrimGalore!81 command trim_galore --clip_R1 6 --three_prime_clip_r1 6. Reads were mapped to the mm10 (mouse) or MonDom5 (opossum) reference genome using Bismark82 on single-end mode with the command bismark --non_directional --un – ambiguous. For adult libraries, reads were mapped to the N-masked genomes, and bam files were generated for all mapped reads as well as for allele-specific reads using SNPsplit90 with the command SNPsplit --bisulfite –conflicting. Library statistics (Supplementary Table 1) were extracted from TrimGalore! and Bismark output reports. Bam files were deduplicated and methylation calls were extracted using Bismark. CpG methylation calls were imported into R92 using the package methylKit79, and principal component analysis was performed using all CpG methylation calls for each individual sample. Data were destranded and pooled by sample condition, and the number of CpG sites captured at different coverage thresholds was calculated. For subsequent analyses, data were filtered for CpG sites with a minimum coverage of five reads. Methylation distribution histograms, mean methylation plot and genomic coverage plots were generated using ggplot2 (ref. 84). This workflow was independently reproduced to ensure that the results were accurate and robust.
DMRs between gametes were identified as follows: 100-bp non-overlapping tiles covered by a minimum of three reads in both oocyte and sperm samples and containing a minimum of one CpG in a tile were identified. The methylation level of each tile was compared between oocyte and sperm using the diffMeth function from the R package methylKit79, with the parameters difference = 80 and qvalue = 0.01. Gamete DMRs with putative transient or life-long retention of differential methylation were defined as tiles with intermediate methylation levels (40−60% methylated), in either E3.5 and E7.5 embryonic disc or trophectoderm (transient embryonic or trophectoderm DMRs), or in E3.5, E7.5 embryonic disc, and all three of brain, liver and spleen (life-long DMRs). The gene nearest to each life-long DMR was identified using the nearest function from the R package GenomicRanges83, and this list was manually checked for previously reported marsupial imprinted genes29,93. To retain maximum read coverage in low-input embryo samples, all libraries per time point were in silico-pooled for this analysis. The dataset therefore included male and female embryos, precluding analysis of sex differences or the X chromosome.
CpG methylation calls were destranded, pooled by sample condition (sex and tissue) and filtered for minimum coverage of five reads in all conditions. For embryo samples, sex was inferred from the ratio of reads mapping to chromosome X and pseudo-Y (coding sequence of 19 known opossum Y-chromosome genes)94,95. Autosomes and X-chromosome allelic methylation distributions were represented as ridgeline plots using the R package ggridges96.
Allele-specific CpG methylation calls were destranded, pooled by sample condition (sex, tissue and parental genome) and filtered for minimum coverage of five reads in all conditions. To avoid loss of X-linked sites in female samples due to low coverage of the X chromosome in male files, data import and filtering for X chromosomes was performed separately with the coverage parameters as for autosomes, but excluding paternal genome files from male samples. Ridgeline plots were generated using ggridges96 as above.
To generate a list of genes expressed in each tissue, RNA-seq reads were trimmed using TrimGalore!81 with the command trim_galore --paired -- clip_R1 10 --clip_R2 10. Trimmed reads were aligned to the N-masked MonDom5 reference genome using HISAT2 (ref. 8) with the command hisat2 --no-softclip --no-mixed --no-discordant. Mapped files were converted to bam files and merged by sample using SAMtools86. Reads overlapping annotated genes were quantified using the command featureCounts from the R package Rsubread75, excluding multi-mapping reads. Files were merged by biological replicate, and FPKM values were calculated using the R package DESeq2 (ref. 97) using the robust median ratio method. Gene models annotated as pseudogenes were excluded, and a threshold of FPKM > 1 was imposed. Expressed genes were categorized as escaping or subject to XCI on the basis of published work45. Methylation level at genes was calculated using the methylKit functions regionCounts and percMethylation, and represented as violin plots for each category using ggplot2 (ref. 84).
Embryos were permeabilized in 0.5% Triton X-100 in PBS at 4 °C overnight, followed by three washes in 0.2% Triton X-100 in PBS with 0.1% PVA (0.2% TX–PBS–PVA). After 3.5 M HCl treatment for 30 min at room temperature, embryos were washed three times in 0.2% TX–PBS–PVA, blocked for 1–4 h at room temperature in 3% BSA in 0.2% TX–PBS–PVA (0.22-µM-filtered, blocking solution) and incubated overnight at 4 °C in primary antibody in blocking solution. Antibodies used were 5mC (BI-MECY-0100, Eurogentec) at 1:100, 5hmC (75-268, NeuroMab) at 1:1,000, H3K9me3 (07-442, MerckMillipore) at 1:200, H3 (ab1791, Abcam) at 1:100. Embryos were washed three times in 0.2% TX–PBS–PVA and incubated in Alexa Fluor-conjugated secondary antibodies at 1:250 in blocking solution for 2 h at room temperature. Three further 0.2% TX–PBS–PVA washes were performed, and DNA was counterstained with 10 µg ml−1 propidium iodide (P4170, Sigma) for 1–2 h at room temperature. Samples were washed three times with PBS with 0.1% PVA and mounted in Vectashield (H-1000-10, Vector Laboratories). Samples were imaged using an LSM710 confocal microscope with 1-µm z-sections. Images were processed and fluorescence intensity was measured using Fiji98.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
BS-seq and RNA-seq data have been deposited at the Gene Expression Omnibus (GEO) under the accession number GSE206499. WGS data have been deposited at the Sequence Read Archive under the accession number PRJNA819000. Publicly available datasets analysed in this study are accessible via the Gene Expression Omnibus under the accession numbers GSE163620, GSE71434, GSE101571, GSE163620 and GSE71985; DDBJ under the accession numbers DRA006642 and DRA000570; and ArrayExpress under the accession number E-MTAB-7515. Source data are provided with this paper.
Code used in preparation and analysis of data and the generation of figures is available via GitHub at https://github.com/bleeke/opossum-methylation.
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We thank the Francis Crick Institute Biological Research Facility, Advanced Sequencing Facility, Bioinformatics and Biostatistics Facility and High-Performance Computing team, M. Sangrithi, N. Fogarty, S. Clark, W. Reik, S. Smallwood, G. Kelsey, P. Skoglund and K. Niakan for advice on the project, and D. Odom and members of the laboratory of J.M.A.T. for comments and discussion on the manuscript. Work in the laboratory of J.M.A.T. is supported by the European Research Council (CoG 647971) and the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001193), the UK Medical Research Council (FC001193) and the Wellcome Trust (FC001193). Some of the work at the University of Texas Rio Grande Valley was conducted in facilities constructed with support from the NIH grant C06 RR020547. Research in the laboratory of R.J.O. is supported by grants from the Bernice Bibby Research Trust and The Paradifference Foundation, the Wellcome Trust through the research equipment grant (212917/Z/18/Z), the NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, the MRC (MR/V038664/1) and the King's College London Innovation Fund. A.T. is supported by funding from the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement number 101098236 ERC-2022-AdG). For the purpose of open access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission.
Open Access funding provided by The Francis Crick Institute.
These authors contributed equally: Bryony J. Leeke, Wazeer Varsally
Sex Chromosome Biology Laboratory, The Francis Crick Institute, London, UK
Bryony J. Leeke, Wazeer Varsally, Sugako Ogushi, Jasmin Zohren, Sergio Menchero, Aurélien Courtois, Daniel M. Snell, Obah Ojarikre, Shantha K. Mahadevaiah & James M. A. Turner
MRC Laboratory of Medical Sciences, London, UK
Bryony J. Leeke
Institute of Clinical Sciences, Imperial College London, London, UK
Bryony J. Leeke
Advanced Sequencing Facility, The Francis Crick Institute, London, UK
Daniel M. Snell
INSERM U934, CNRS UMR3215, Institut Curie, PSL Research University, Paris, France
Aurélie Teissandier
Comparative Medicine, Novartis, Basel, Switzerland
Fanny Decarpentrie
Department of Medical and Molecular Genetics, King's College London, London, UK
Rebecca J. Oakey
Division of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA
John L. VandeBerg
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B.J.L. and W.V. are equal first authors, and S.O. and J.Z. are equal second authors. B.J.L. and J.M.A.T. conceived and designed the project and wrote the manuscript. B.J.L. performed gamete, embryo, single-cell and adult tissue collections, BS-seq, RNA-seq, WGS and computational analyses. W.V. performed computational analyses. J.Z. performed adult tissue collections, WGS and computational analyses. S.O. performed embryo immunostaining and fibroblast RNA FISH. S.O. generated DNMT1-knockout fibroblasts. S.M. performed single-cell collections, DNMT1-knockout experiments and analyses. A.C. imaged and quantified RNA FISH experiments. S.K.M. performed gamete collections. D.M.S. processed NMT-seq libraries. F.D. made initial findings of the RSX DMR. J.L.V. provided additional opossum material. O.O. managed the animal colonies. A.T. performed computational analyses. J.M.A.T., J.L.V. and R.J.O. acquired funding.
Correspondence to
Bryony J. Leeke or James M. A. Turner.
The authors declare no competing interests.
Nature thanks Déborah Bourc'his, Takashi Sado and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a. Histograms of methylation distribution at CpG sites captured at ≥ 5x coverage in mouse sperm (n = 2 libraries of ~100 sperm, in silico pooled), E3.5 embryos (n = 3, in silico pooled), and adult brain (n = 2, in silico pooled) (please note variable scales on y-axes). b. Principal component analysis of opossum methylation in all samples. c. Percentage of CpG sites captured at different coverage thresholds. d. Percentage of captured CpG sites for different chromosomes and genomic features.
Source data
a. Histograms of methylation distribution at CpG sites captured at ≥ 5x coverage in opossum adult liver and spleen. b. Pronuclear stage mouse embryos immunostained for 5-methylcytosine (5mC; n = 51), or 5-hydroxymethylcytosine (5hmC; n = 6), each co-immunostained for H3K9me3. mat = maternal, pat = paternal, pb = polar body. Scale bar = 10μm. c. Pairwise comparisons of percentage significantly differentially methylated sites (Fisher's exact test, q-value <= 0.01, methylation difference 0.25) across entire developmental time course. For each comparison, “higher” and “lower” refers to the status of the second sample listed on the x-axis relative to the first sample d. Histograms of DNA methylation distribution at CpG sites captured at ≥ 5x coverage for each genomic feature (please note variable scale on y-axes).
Source data
a. Metaplots of methylation across L1, MIR, and ERV1 loci in opossum embryos. b. Expression of LINE, SINE and LTR repetitive elements in opossum embryos. Repetitive element subfamilies are labelled according to Repeatmasker nomenclature, including ‘?' notation for presumptive subfamily. Noocyte = 12, NE1.5 = 14, NE2.5 = 42, NE3.5 = 124, NE4.5 = 110, NE5.5 = 280, NE6.5 = 402, NE7.5 EPI = 216, NE7.5 TE = 110. Error bars = 1.96*SE. Each point represents the mean of the replicates.
Source data
A. Expression of methylation enzymes in EPI and TE using the multi-omics dataset. NE5.5 = 58, NE6.5 EPI = 19, NE6.5 TE = 19, NE7.5 EPI = 24, NE7.5 TE = 14. Error bars = 1.96*SE. Each point represents the mean of the replicates. b. Levels of non-CpG methylation (CHH and CHG sites) in opossum gametes and embryos.
Source data
a Allele-specific methylation distribution of the autosomes and X chromosome in adult mouse male and female brain and liver, represented as density plots showing the distribution of the data and the probability of a variable being a certain value. b. CGI methylation on the inactive and active X for data in a. c. Methylation distribution of the autosomes and X chromosome in adult opossum male and female liver. d. Allele-specific methylation analysis of the paternal and maternal alleles for data in c. e. Methylation at specific genomic features on the inactive and active X in adult opossum brain, liver and spleen. f. Gene body methylation on the inactive and active X for genes subject to or escaping XCI for female samples in e. g. Sexing of gamete and embryo samples via read mapping to the X and Y chromosome.
Source data
a. Metaplot of 100,000 randomly selected 1000 nucleotide regions demonstrating global decrease in DNA methylation in DNMT1-deleted fibroblasts at day 4. b. Mosaic loss of DNA methylation at the RSX promoter post-DNMT1 deletion at day 4. c. Proportion of upregulated and downregulated genes by chromosome in DNMT1-deleted fibroblasts at day 8. d. Methylation and expression of repetitive elements following DNMT1-deletion. Above, metaplots showing decreased DNA methylation at L1, MIR and ERV1 repetitive elements 4 days after DNMT1-deletion. Below, line graphs showing transcriptional de-repression of L1, MIR, ERV1 and ERVK elements by day 8 after DNMT1-deletion. Ncontrol = 3, NDNMT1 KO = 3. Error bars = 1.96*SE. Each point represents the mean of the replicates. e. qPCR analysis of H19 in DNMT1 deletant fibroblasts. Ncontrol = 3, NDNMT1 KO = 3. Unpaired t-test. Error bars = SEM. Each point represents the mean of the replicate.
Source data
BS-seq library information including sample descriptions, numbers of samples per time point, and sequencing, mapping and coverage statistics. Tab 1 contains information for each individual sequencing library. Tab 2 contains information for in silico-pooled data (per sample and time point).
Information about gamete DMRs identified as potential imprinted regions. Tab 1 contains information including genomic position, methylation level at different time points, and nearest annotated gene. Tab 2 contains information about the number of gamete DMRs retaining intermediate methylation levels in different time points, broken down by gamete of origin.
Sources of publicly available sequencing data used in this study. Tab 1 contains information for BS-seq datasets. Tab 2 contains information for RNA-seq datasets
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Leeke, B.J., Varsally, W., Ogushi, S. et al. Divergent DNA methylation dynamics in marsupial and eutherian embryos.
Nature (2025). https://doi.org/10.1038/s41586-025-08992-2
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Here we report on the nearly complete and uncrushed 14th specimen of Archaeopteryx. Exceptional preservation and preparation guided by micro-computed tomographic data make this one of the best exemplars of this iconic taxon, preserving important data regarding skeletal transformation and plumage evolution in relation to the acquisition of flight during early avian evolution. The ventrolaterally exposed skull reveals a palatal morphology intermediate between troodontids1 and crownward Cretaceous birds2,3. Modifications of the skull reflect the shift towards a less rigid cranial architecture in archaeopterygids from non-avian theropods. The complete vertebral column reveals paired proatlases and a tail longer than previously recognized. Skin traces on the right major digit of the hand suggest that the minor digit was free and mobile distally, contrary to previous interpretations4. The morphology of the foot pads indicates that they were adapted for non-raptorial terrestrial locomotion. Specialized inner secondary feathers called tertials5,6 are observed on both wings. Humeral tertials are absent in non-avian dinosaurs closely related to birds, suggesting that these feathers evolved for flight, creating a continuous aerodynamic surface. These new findings clarify the mosaic of traits present in Archaeopteryx, refine ecological predictions and elucidate the unique evolutionary history of the Archaeopterygidae, providing clues regarding the ancestral avian condition.
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Raw CT data and segmented models relevant to this manuscript are available via Morphosource (Media ID 000702228; Media ID 000702231).
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We thank T. Lumbsch, B. Lauer and R. Lauer for facilitating the specimen acquisition; A. Stroup for assisting with figures; M. Colbert, J. Maisano and D. Edey for scanning the main slab; C. Wang and X. Zhang for segmentation assistance; S. Selzer for aiding preparation; D. Drummond and J. Stierberger for photographing the specimen; and B. Marks for access to extant bird specimens. M.W. is supported by the National Natural Science Foundation of China (42225201).
Negaunee Integrative Research Center, Field Museum of Natural History, Chicago, IL, USA
Jingmai O'Connor, Alexander Clark, Pei-Chen Kuo, Akiko Shinya & Constance Van Beek
Committee on Evolutionary Biology, University of Chicago, Chicago, IL, USA
Alexander Clark
School of Zoology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
Yosef Kiat
Steinhardt Museum of Natural History, Tel Aviv University, Tel Aviv, Israel
Yosef Kiat
Center for Functional Anatomy and Evolution, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Matteo Fabbri
Key Laboratory of Vertebrate Evolution and Human Origins, Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences, Beijing, China
Jing Lu, Min Wang & Han Hu
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J.O'C. led the research and wrote the manuscript; H.H. led the segmentation; M.F., P.-C.K. and J.L. assisted with segmentation; A.C., P.-C.K., M.F., H.H., Y.K. and M.W. assisted with research and manuscript preparation; A.S. and C.V.B. prepared the specimen.
Correspondence to
Jingmai O'Connor or Han Hu.
The authors declare no competing interests.
Nature thanks Jessie Atterholt, Daniel Field, Johan Lindgren, Patrick O'Connor and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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a-c, premaxillae in right lateral, ventral, and caudal view; d-f, vomer in dorsal, left lateral, and ventral view; g-i, right maxilla in lateral, medial and ventromedial view; j-l, right postorbital in medial, rostral, and medial view; m-p, left ectopterygoid in ventral, dorsal, lateral, and medial view; q-v, left pterygoid in ventral, dorsal, cranial, caudal, lateral, and medial view; w-aa, left palatine in rostral, dorsal, ventral, lateral, and medial view. Scale bar equals five millimeters. cf, caudal fork; cp, choanal process; fp, frontal process; jp, jugal process; lp, lateral process; mf, maxillary fenestra; mp, maxillary process; np, nasal process; pf, pterygoid flange; pr, promaxillary fenestra; pp, premaxillary process; pt, pterygoid process; qw, quadrate wing; rp, rostral process; sp, squamosal process.
a, modified from Elzanowski (2001); b, modified from Mayr et al.13; c, current reconstruction based on new data from the Chicago Archaeopteryx (FMNH PA 830). The palatal elements are color coded: orange, vomer; green, palatine; dark orange, ectopterygoid; pink, jugal; light blue, pterygoid; dark blue, quadrate; yellow, basicranium.
Elements, all figured in right lateral view, are to scale relative to each other but not between taxa. The proatlas is colored olive green; the atlas neurapophysis is pink; the atlas intercentrum is light green. Sinovenator is based on PMOL (Paleontology Museum of Liaoning) -AD00102; Tsaagan is based on IGM, Institute of Geology, Mongolian Academy of Sciences, 100/105; and Deinonychus is based on YPM, Yale Peabody Museum, 5210. Dashed lines indicate poor preservation. Fused atlas (only right neurapophysis could be reconstructed) in Archaeopteryx FMNH PA 830 in caudal (a) and cranial (b) view; right proatlas in lateral (c), medial (d), caudal (e), and cranial (f) view.
Scale bar equals 2 mm. Anatomical abbreviations not listed in Fig. 1 caption: sl, semilunate carpal. Grey indicates damaged bone. The carpals were identified based on 2D observations; the smallest carpals (scapholunare and distal carpal 3) could not be reconstructed from the CT data.
Extant arboreal taxa Hylocichla mustelina (a) and Cyanocitta cristata (b); terrestrial taxon Coturnix coturnix (c-d); raptorial taxon Buteo jamaicensis (e-f). Fossil taxa represented by (g-h) enantiornithine indet. HPG-15-1 (Xing et al., 2017); (i-j) Archaeopteryx FMNH PA 830; and (k) Microraptor STM5-109 (Pittman et al. 40). All extant specimens represent recently deceased individuals being prepared for the skeletonization at the Field Museum and thus lack catalog numbers. All extant bird photos by A. D. Clark.
Scale bar equals five centimeters.
a, scapulars and left humeral and ulnar tertials under UVABC; b, c, close up of the left tertials showing the preservation of barbs, rachises, and vane symmetry; d, open pennaceous body feathers preserved dorsal to the proximal caudal vertebrae and projecting off the left femur; e, close up of the open pennaceous feathers preserved in (d). Scale bar in (a) equals 2 cm, 5 mm in (b-c, e), and 1 cm in (d). Anatomical abbreviations not listed in Fig. 1 caption: ba, barbs; cv, wing coverts; op, open pennaceous body feathers; rh, rachis.
In many modern birds, the tertial feathers (black arrows; red feathers, inset) are morphologically distinct. These feathers function as protection for the remiges from abrasion when the bird is not flying and are particularly developed in species that feed on the ground, such as (a) wagtails (Motacillidae; pictured, Eastern Yellow Wagtail Motacilla tschutschensis; photo by Y. Kiat), and (b) many shorebirds (Charadriiformes; pictured, Buff-breasted Sandpiper Calidris subruficollis; photo by I. Davies, ML110171881, adapted with permission from Cornell Lab of Ornithology | Macaulay Library). These feathers may also help close the gap between the secondary feathers and the bird's body, thereby improving aerodynamic performance. Additionally, the tertials may be used for display and visual communication, as observed among some cranes (Gruiformes), such as the elongated tertials in the (c) Blue Crane (Anthropoides paradiseus; photo by M. McCloy, ML136331631, adapted with permission from Cornell Lab of Ornithology | Macaulay Library), or the prominent white tertials contrasting with the dark wing and body plumage in the (d) Pale-winged Trumpeter (Psophia leucoptera; photo by T. Palliser, ML62921801, adapted with permission from Cornell Lab of Ornithology | Macaulay Library).
The black and white pattern of the feathers is based on previous research that indicates the isolated wing covert was black and white (Carney et al., 2012). This Chicago specimen reveals the presence of the enlarged tertial tract.
Supplementary Methods, Discussion, Fig. 1, Tables 1–3 and References.
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O'Connor, J., Clark, A., Kuo, PC. et al. Chicago Archaeopteryx informs on the early evolution of the avian bauplan.
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The known fossil record of crown-group amniotes begins in the late Carboniferous with the sauropsid trackmaker Notalacerta1,2 and the sauropsid body fossil Hylonomus1,2,3,4. The earliest body fossils of crown-group tetrapods are mid-Carboniferous, and the oldest trackways are early Carboniferous5,6,7. This suggests that the tetrapod crown group originated in the earliest Carboniferous (early Tournaisian), with the amniote crown group appearing in the early part of the late Carboniferous. Here we present new trackway data from Australia that challenge this widely accepted timeline. A track-bearing slab from the Snowy Plains Formation of Victoria, Taungurung Country, securely dated to the early Tournaisian8,9, shows footprints from a crown-group amniote with clawed feet, most probably a primitive sauropsid. This pushes back the likely origin of crown-group amniotes by at least 35–40 million years. We also extend the range of Notalacerta into the early Carboniferous. The Australian tracks indicate that the amniote crown-group node cannot be much younger than the Devonian/Carboniferous boundary, and that the tetrapod crown-group node must be located deep within the Devonian; an estimate based on molecular-tree branch lengths suggests an approximate age of early Frasnian for the latter. The implications for the early evolution of tetrapods are profound; all stem-tetrapod and stem-amniote lineages must have originated during the Devonian. It seems that tetrapod evolution proceeded much faster, and the Devonian tetrapod record is much less complete, than has been thought.
The origin of tetrapods, understood as an evolutionary and ecological phenomenon, was not a single event but a process that began with the acquisition of incipient terrestrial locomotory competence in the tetrapod stem group and ended with the emergence of the major crown-group clades, amphibians and amniotes. Of particular importance for the future development of the global ecosystem was the origin of amniotes, the only tetrapod clade to achieve complete reproductive independence of water, and by far the most impactful in terms of both diversity and disparity.
An overall understanding of this phase of vertebrate evolution requires data on phenotypic change, the timing of evolutionary and cladogenetic events, and patterns of diversity, disparity and biogeography. Three principal data sources are available: body fossils, ichnofossils (footprints and other traces) and time-calibrated molecular phylogenetic divergence dates. Body fossils and ichnofossils are typically preserved in different sedimentation regimes, and can thus capture animals with different environmental preferences, but both require taphonomic settings with net sediment deposition rather than erosion, and will thus be biased towards lowland environments, although some upland depositional settings are also known10. Molecular divergence dates are unaffected by depositional environments, but are themselves partly dependent on fossil calibration of the phylogeny. Furthermore, they can date only phylogenetic nodes uniting living lineages, such as the tetrapod crown-group node (uniting the lissamphibian and amniote lineages) and the amniote crown-group node (uniting the mammal and reptile–bird lineages). Fossils, by contrast, can illuminate the details of morphological evolution within stem groups.
Molecular divergence dates for the amniote crown-group node from 30 recent studies (Supplementary Information Part 1), curated at the TimeTree website (https://www.timetree.org), form a tight cluster with a median age of 319 million years, which corresponds to early Bashkirian (mid-Carboniferous); the spread of the cluster is 308.5 to 334.7 million years, thus spanning from Moscovian (late Carboniferous) to Viséan (early Carboniferous). The corresponding date cluster of 32 dates for the tetrapod crown-group node has a much wider spread, ranging from 333.3 to 395.0 million years (that is, from the Viséan to the Eifelian (Middle Devonian)); the median age in this case is 352 million years, or Tournaisian (earliest Carboniferous). The preponderance of molecular evidence thus suggests an origin of the tetrapod crown group during the earliest Carboniferous, with crown amniotes appearing some 30–35 million years later. This places these events in the aftermath of the end-Devonian mass extinction, during and after the 20-million-year interval of poor fossil record known as Romer's gap11. The published fossil record is compatible with this time frame, showing the earliest crown-group amniote body fossils and trackways (Hylonomus and Notalacerta) in the Bashkirian1,2,3,4, the earliest crown-group tetrapod body fossils (for example, Balanerpeton) in the late Viséan5,6, and the earliest crown-group tetrapod trackways (for example, Batrachichnus and Palaeosauropus) in the mid-Tournaisian7 (Fig. 1a). However, this compatibility partly reflects the calibration of the molecular trees by known fossils, and is thus not a fully independent verification.
a, Stratigraphic timescale representation of the known early fossil record of crown-group tetrapods. Thin grey lines indicate phylogenetic branches; thick grey lines indicate the body-fossil record from the earliest occurrence; arrowhead and name in black on the right margin indicate the name of the earliest body fossil; blue rectangles indicate the earliest ichnofossil record when this is earlier than the body-fossil record; the dashed line of grey rectangles indicates the range extension between the earliest body fossil and the earliest ichnofossil; name in blue on the right margin indicates the name of the earliest ichnorecord. The amniote crown-group node (1) and tetrapod crown-group node (2) are given minimum ages compatible with the fossil record. All dates are from https://stratigraphy.org/chart. Ma, million years ago. b, Map of Australia showing the locality (blue asterisk). NSW, New South Wales; NT, Northern Territory; QLD, Queensland; SA, South Australia; TAS, Tasmania; VIC, Victoria; WA, Western Australia. c, Stratigraphy of the Mansfield Group.
We present here new trackway evidence from Taungurung Country, Victoria, Australia (Figs. 1b,c and 2), indicating that these dates are substantially too late. Crown amniotes were already present in northeast Gondwana by the early Tournaisian. This in turn implies that the crown tetrapod node must lie deep in the Devonian. New trackway data from Silesia in Poland show that the earliest records of crown amniotes in the equatorial regions of Euramerica are also earlier than previously thought, Serpukhovian rather than Bashkirian.
a, Photo of the slab, NMV P258240, as preserved. b, Same as in a, with footprints and trackways highlighted. Manus (front foot) prints are shown in yellow; pes (hind foot) prints are shown in blue. Am1–4, manus prints from trackway A; Ap1–4, pes prints from trackway A; Bm1–5, manus prints from trackway B; Bp1–4, pes prints from trackway B; Ip, isolated right pes print. c,d, Isolated right pes print Ip as a false-colour inverted scan image (c) and photo (d). e,f, Right manus print Am1 as a false-colour scan image (e) and photo (f). g, Photo of pes print Bp4 (above) and manus print Bm3 (below). In c–g, white arrows denote claw impressions or scratches, Roman numerals denote digit numbers. Scale bars, 50 mm (a) and 10 mm (c–g).
The Australian tracks are preserved on the upper surface of a loose but essentially in situ fine-grained silty sandstone block from the bank of the Broken River at Barjarg, Taungurung Country, Victoria (Museums Victoria specimen NMV P258240). In the Taungurung language, this section of the Broken River was referred to as Berrepit, meaning to flee or run away12. The block derives from the Home Station Sandstone member of the Snowy Plains Formation in the upper part of the Mansfield Group (Fig. 1b,c). Although aquatic invertebrate and fish trail trace fossils have previously been described from other locations within the Home Station Sandstone13, this is the first record of terrestrial vertebrate tracks. This new specimen was discovered by the two non-professional members of the author group (C.A.E. and J.E.), who brought it to the attention of the professional palaeontologists, in a demonstration of the value of citizen science. The locality lies within the Lachlan Fold Belt, a tectonically complex region with multiple sedimentary basins and several orogenic episodes during the Palaeozoic (Supplementary Information Part 2). The sedimentary deposits in the region are predominantly Devonian and include several important vertebrate localities8. However, the upper Mansfield Group9 contains a characteristic early Carboniferous vertebrate assemblage without Devonian index taxa such as placoderms, tristichopterids and porolepiforms14,15,16,17. An associated assemblage of vertebrate microremains has yielded a tooth of the chondrichthyan genus Ageleodus, which closely resembles teeth of this genus from the Famennian (latest Devonian) of the Catskill Formation in Pennsylvania, rather than examples from later Carboniferous localities14. Deposition in this region was terminated by the Kanimblan orogeny, which began in the latest Devonian and during which active folding seems to have come to an end by the late Tournaisian18,19 (Supplementary Information Part 2). The Snowy Plains Formation must thus belong to the early part of the Tournaisian; it probably falls within the age span 358.9 to 354 million years old.
The track surface, which is dense, fine-grained and very well preserved, carries three generations of subaerial original surface tracks, preserved in concave epirelief, which all seem to have been made by the same trackmaker taxon (Fig. 2a,b). The oldest is an isolated pes print (Ip). A brief rain shower after this footprint had been made left it, as well as the general surface, pockmarked with raindrop prints. Shortly after the rainfall, while the ground was still moist, a trackway (A) was made by an animal that left well-defined foot impressions. Sometime later, when the ground had begun to dry and harden, another trackway was made (B) that consists largely of well-preserved claw scratches with faint accompanying footprints. Neither trackway is associated with a body or tail drag. The spacing of manus and pes prints in trackway A implies a hip–shoulder distance of approximately 17 cm if the animal was trotting, slightly more if it was performing a sequential walking gait. The total body length is impossible to determine because neck plus head length and tail length are unknown, but applying the proportions of a modern water monitor (Varanus salvator), which has a broadly similar foot morphology, gives a suggested length in the region of 80 cm.
The tracks present a consistent foot morphology, well documented by the combined evidence of the different footprints (Supplementary Information Part 3). The manus is smaller than the pes (Fig. 2g). Both are pentadactyl, with five relatively long, slender digits splayed out into a fan shape, although digit V does not always leave a distinct impression. Digits I and V are the shortest, III and IV the longest. The digit impressions bulge distally into slightly swollen tips, but there are no distinct phalangeal pad impressions (Fig. 2e,f). The impression of the skin surface appears smooth without distinct scales, although this may be a preservation effect. Digits I–IV are associated with impressions of fairly large sharp claws, similar in relative size to those of a monitor lizard (Varanus), whereas digit V carries a very short claw. The claw prints are sometimes deflected medially at approximately 90° to the long axes of the digits, creating a characteristic inverted J shape (Fig. 2c,d). The claws are discrete structures, clearly distinct from the more proximal parts of the digits, as shown by the co-occurrence of softly rounded digit tips with sharp claw scratches in the same footprint (Fig. 2e,f).
This foot morphology carries a clear phylogenetic signal. Claws are a derived character of crown amniotes and are almost invariably present in this clade. Importantly, they are not present in known stem amniotes; seymouriamorphs, diadectids and limnoscelids all lack claws, as evidenced by their footprints7,20,21,22,23,24,25. As claws must have been present at the amniote crown-group node, it is probable that they originated at the very top of the stem group, but no unambiguous clawed stem amniotes have been discovered. Claws were apparently present in microsaurs10, which have an uncertain phylogenetic position but may be crown amniotes6. Outside the crown amniotes, claws or keratinized toe tips occur sporadically in modern anurans (Xenopus and Hymenochirus)26 and salamanders (for example, Onychodactylus), and may have been present in some temnospondyls judging by the shape of the terminal phalanges27. However, ichnotaxa such as Batrachichnus and Limnopus, which are attributed to temnospondyls, lack claw impressions7, and in any case, the presence of five digit-impressions on the manus prints of the Snowy Plains Formation slab rules out a temnospondyl identity for our trackmaker.
Within the amniote crown group, the deepest phylogenetic split is that between Synapsida (stem and crown mammals) and Sauropsida (stem and crown reptiles, including birds). The earliest known synapsid ichnogenus is Dimetropus, thought to represent ‘pelycosaur'-grade stem mammals, which is first recorded in the Bochum Formation (late Bashkirian) of Germany24. The earliest described sauropsid ichnotaxon is Notalacerta, which has been described from mid-Bashkirian localities. The broadly similar Varanopus and Dromopus are slightly younger2,25. These tracks have been ascribed to stem reptiles including captorhinids, protorothyrids and basal diapsids2,7,25,
Dimetropus prints are clearly different from those on the Snowy Plains Formation slab, notably in having longer soles with distinct ‘heels', less splayed toes and longer, straighter claws (Fig. 3h). By contrast, the Snowy Plains Formation tracks closely resemble Notalacerta, Dromopus and in particular Varanopus (Fig. 3a–c,e–g). All of these ichnotaxa have a short sole, which often leaves no impression, and digit impressions splayed into a fan shape. They are ectaxonic, meaning that the lateral digits are more strongly developed than the medial ones, and they all show claw impressions, which are not just distinctively sharp-pointed but are also commonly deflected medially (towards the body of the animal) from the long axis of the digit print to create J- or L-shaped digit impressions1,2. This exact effect is also seen in the Snowy Plains Formation tracks (Fig. 2); we conclude that the toes of all these trackmakers bore similar claws that were clearly offset from the more proximal part of the digit.
a–c, Three footprints of Notalacerta from the middle Serpukhovian to early Bashkirian Wałbrzych Formation of Silesia, Poland; each is shown as an optical scan (top) and photo (bottom). Holy Cross Branch of the Polish Geological Institute – National Research Institute in Kielce, Muz. PGI-OS 220/182 (a), 184 (b) and 185 (c). d, Isolated left pes print Ip from the Snowy Plains Formation slab NMV P258240 (Fig. 2c,d), reproduced here to facilitate comparison with other amniote footprints. e–g, Presumed sauropsid prints, manus (top) and pes (bottom), of Notalacerta (e), Varanopus (f) and Dromopus (g), all from ref. 2. h, Dimetropus manus or pes imprint, natural cast, IGWU-1, Geological Museum of the Institute of Geological Sciences, University of Wrocław, Wrocław. Labelling as in Fig. 2. Scale bars, 10 mm. Photos in e–g reproduced from ref. 2, Frontiers Media, under a Creative Commons licence CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
Notwithstanding these similarities, the Snowy Plains Formation tracks also bear some resemblance to another ichnotaxon, Hylopus hardingi, which is not attributed to crown amniotes. The presumed Hylopus trackmaker is often referred to as a reptiliomorph2, an imprecise term that is best interpreted as equivalent to stem amniote, although phylogenetic instability near the tetrapod crown-group node means that several groups of early tetrapods that have been considered as putative Hylopus trackmakers are retrieved either as stem amniotes or as stem tetrapods at present depending on the particular analysis2,6. Comparison between the Snowy Plains Formation tracks and Hylopus is made more complicated by the fact that the tracks attributed to Hylopus vary in morphology and include examples that appear to have claw impressions2, suggesting that some tracks have been misattributed to this ichnotaxon and could themselves represent early unrecognized sauropsids. However, typical and well-preserved H. hardingi footprints have distinctive, rounded (almost ball-shaped) toe-tip impressions without any trace of claw marks, and a very short digit V on the manus2. The Snowy Plains Formation footprints with their unambiguous discrete claw marks and long digit V on the manus cannot be attributed to H. hardingi.
This character distribution allows for two possible phylogenetic interpretations. There is general agreement that Notalacerta, Dromopus and Varanopus are sauropsid ichnotaxa, but whereas the foot morphology at the amniote crown-group node must have been pentadactyl and claw-bearing, the exact shape of the foot at this node is not known. The overall shape similarity between these ichnotaxa and H. hardingi may reflect a foot morphology conserved across the amniote crown-group node. The occurrence of some Hylopus-like traits in the Snowy Plains Formation tracks suggests either that the trackmaker was a very primitive sauropsid, phylogenetically basal to the Varanopus, Notalacerta and Dromopus trackmakers, or that it occupied a position close to the amniote crown-group node. In the first case, the crown-group node must predate this trackway slab; in the second, it could be contemporary with it. A substantially younger date for the crown-group node is ruled out, unless the crown amniote characters of the Snowy Plains Formation tracks are dismissed (with no evidential basis) as convergences.
The earliest crown amniote fossils acknowledged in the current literature are trackways of Notalacerta and associated body fossils of the stem reptile Hylonomus (which may have been the trackmaker) in the middle Bashkirian of Joggins, Nova Scotia, Canada1,2. However, during this study, tracks similar to those of Notalacerta have also been discovered in the Wałbrzych Formation of the Intra-Sudetic Basin of Silesia in Poland, which has been dated as mid-Serpukhovian to early Bashkirian (Namurian A) on the basis of palynostratigaphy28 (Fig. 3a–c). This pushes back the amniote record of Euramerica by approximately eight million years. The Carboniferous–Permian sites of the Intra-Sudetic Basin (Czech Republic and Poland) are historically important for the study of tetrapod tracks and have been studied for more than 150 years29. Rich material collected from the Carboniferous part of this succession provides a new guide for resolving the first appearance, diversification and environments of early amniotes in this part of Euramerica (Supplementary Information Part 4).
The implications of the Snowy Plains Formation trackways are profound and wide-ranging (Fig. 4). In terms of tetrapod evolution, the Devonian Period has, until now, been seen as the exclusive domain of the stem group. All recent palaeontological analyses place the lungfish–tetrapod node close to the Silurian/Devonian boundary30,31,32. The earliest known fish member of the tetrapod stem group, Tungsenia, is Pragian31. Limbed stem tetrapods appear in the ichnorecord in the Eifelian, and in the body-fossil record in the Frasnian33,34,35,36,37. The known tetrapod body-fossil record of the Frasnian and Famennian consists exclusively of stem-group forms. This fits with the idea of the crown-group radiation as a post-Devonian phenomenon following (and possibly impelled by) the end-Devonian extinction event10,37. However, the Snowy Plains Formation trackways challenge this interpretation.
Stratigraphic timescale representation of the Devonian and Carboniferous, showing the impact of the Snowy Plains Formation sauropsid tracks. The track record is shown as a pink rectangle, of double height to indicate possible age range. Other graphic conventions as in Fig. 1. The amniote crown-group node (1) and lungfish–tetrapod node (3) are given minimum ages compatible with the fossil record. The tetrapod crown-group node (2) is positioned in accordance with the branch-length proportions derived from TimeTree (https://www.timetree.org) as explained in the text; vertical blurring of the horizontal branch segment indicates that this date is uncertain and should be considered only as a general indicator, not a precise estimate.
A substantial time interval between the tetrapod and amniote crown-group nodes is a universal feature of recent molecular phylogenies in which both nodes are defined (Supplementary Information Part 1); the median age difference between these nodes in the calibrated phylogenies curated by TimeTree is 33 million years. These age differences are inferred from branch lengths that in turn reflect base substitutions recorded in the genomes of extant animals, and are thus not susceptible to the distorting effects of gaps in the fossil record. Even though the exact ages vary between phylogenies, depending both on the fossil calibrations and phylogenetic algorithms used, the substantial age separation between the amniote and tetrapod crown-group nodes is consistent and must be real; these cladogenetic events were separated by tens of millions of years.
As the Snowy Plains Formation is early Tournaisian in age, a sauropsid identification of the tracks implies that the amniote crown-group node can, at a minimum, be only marginally younger than the Devonian/Carboniferous boundary. This in turn means that the tetrapod crown-group node must lie much further back in the Devonian. To arrive at a rough age estimate for the tetrapod crown-group node, one avenue is to look at the lungfish–tetrapod node, which marks the bottom end of the tetrapod stem group. The median TimeTree age for this node is 408 million years. The corresponding ages of the amniote and tetrapod crown-group nodes are 319 and 352 million years; if the time distance from the amniote crown-group node to the lungfish–tetrapod node is given the unit value 1, the corresponding distance from the amniote crown-group node to the tetrapod crown-group node is 0.371, and that from the tetrapod crown-group node to the lungfish–tetrapod node is 0.629.
In fact, the earliest unambiguous stem lungfish, Diabolepis, is approximately 415 million years old (Xitun Formation, Lochkovian, China)38, so the inferred date for the lungfish–tetrapod node is slightly too young. If, as a thought experiment, the amniote crown-group node and the lungfish–tetrapod node are fixed, respectively, to the Devonian/Carboniferous boundary (358.9 million years) and the mid-Lochkovian (415 million years), and the aforementioned relative branch lengths are applied, they place the tetrapod crown-group node at a median age of 379.7 million years (early Frasnian). This should be understood only as the approximate mid-point of a wide zone of possibility (Fig. 4). However, a much younger age, at or close to the Devonian/Carboniferous boundary, can be rejected because the internode to the amniote crown-group node becomes implausibly short and incompatible with the substantial branch lengths consistently recovered by molecular phylogenies (Supplementary Information Part 1). Conversely, as neither the amniote crown-group node nor the lungfish–tetrapod node has a constrained maximum age, all three nodes could in fact be considerably older than indicated. The rapidly expanding number of sequenced vertebrate genomes creates potential for more robust future phylogenetic analyses that, with the inclusion of the Snowy Plains Formation tracks as a calibration point, can provide a more precise estimate of the tetrapod crown-group node date.
The earliest fossils of limbed tetrapods, the trackways from Zachełmie in Poland (Eifelian)29 and Valentia Island in Ireland (Givetian)30, are, respectively, about 390 and 385 million years old, and thus compatible with this new inferred timeline (Fig. 4). However, the widely accepted picture of Devonian tetrapods as a low-diversity array of primitive fish-like forms10,37 must be false. The cladogenetic event that gave rise to the tetrapod crown group was preceded by a series of others that gave off the various clades of limbed stem tetrapods, such as baphetids, colosteids and ichthyostegids, and before that the elpistostegalians and various tetrapodomorph fishes6,37. All of these cladogenetic events must now be fitted into, approximately, the first two-thirds of the Devonian period. The origins of stem amniote lineages such as seymouriamorphs and diadectomorphs must lie in the Late Devonian. Remarkably, the inferred age of the tetrapod crown-group node presented here is approximately contemporary with the elpistostegalians Elpistostege and Tiktaalik, often perceived as antecedents and potential ancestors of tetrapods39,40,41,42. This result strongly supports the much earlier origin of limbed tetrapods indicated by the Middle Devonian trackway record, and implies that tetrapods underwent a far faster process of cladogenesis and morphological evolution during the Devonian than has hitherto been recognized.
A series of body-fossil discoveries over the past four decades lend indirect support to this contention, by providing evidence for previously unsuspected diversity and morphological disparity among Devonian tetrapods43,44,45,46,47. Particularly noteworthy is the fact that each new tetrapod locality has yielded one or more new tetrapods, a marked contrast with the wide distribution of associated fishes such as Holoptychius and Bothriolepis, and a sign that our discoveries are sampling a high-diversity global tetrapod fauna with small geographic ranges for individual genera. Nevertheless, the complete absence so far in the Devonian body-fossil record of any crown-group tetrapods, or crownward stem-group clades such as colosteids and baphetids, indicates that this record markedly under-samples the living diversity.
The trackway record casts some additional light on this phenomenon. At present, the oldest records of amphibians, synapsids, sauropsids and limbed stem tetrapods are all ichnorecords7,24,33,34 (Fig. 4). It is well known from later parts of the vertebrate fossil record that trackway assemblages often capture taxa that are not seen in associated body-fossil assemblages48, and this also applies to the Devonian and Carboniferous record. The earliest known high-diversity tetrapod trackway assemblage, from the mid-Tournaisian of Blue Beach, Canada, contains taxa that are not represented among the associated body fossils (for example, temnospondyls)7. The Mansfield Group contains no known tetrapod body fossils14,15,16,17. This is also the case for the two Middle Devonian formations that contain published tetrapod tracks, the Givetian Valentia Slate Formation of Valentia Island, Ireland, and the Eifelian Wojciechowice Formation of Zachełmie, Poland; the former yields only fish49,50, the latter no body fossils at all. The trackway record thus provides direct evidence of the incompleteness of the body-fossil record, and in turn has a key part to play in fleshing out the picture of early tetrapod diversity, even though it is also quite meagre.
The poor fossil record hampers the search for temporal and spatial patterns of distribution. With the discovery of the Snowy Plains Formation tracks, the crown-group amniote record of northeastern Gondwana now predates that of Euramerica by about 30 million years, but we cannot rule out that earlier representatives may eventually be found in Euramerica as well. The mid- to late-Serpukhovian amniote tracks from Silesia are morphologically advanced, with pronounced claws and narrow, elongated digits, and some are quite large (Fig. 3c); this strongly suggests that the evolutionary history of this group is nested deeper in time but not yet recognized in this region (Supplementary Information Part 4). With regard to biogeography and living environments, recent palaeomagnetic reanalysis of the Devonian-Carboniferous pole path of Australia51,52 has revealed that the continent was located much further north during the Famennian to Viséan than had previously been thought. At the time of deposition of the Mansfield Group, the trackway locality lay at a latitude of approximately 17° south, at the southern edge of the tropics. This is quite similar to the equatorial latitude of the Euramerican Notalacerta localities, and does not present a strong case for a distinction between temperate and tropical faunas being a factor in early amniote distribution.
By contrast, the Snowy Plains Formation trackways do cast substantial new light on the effect of the end-Devonian mass extinction event on tetrapod evolution. Until recently53,54,55, the tetrapod fossil record showed a hiatus of approximately 20 million years, known as Romer's gap, between the end-Famennian and the late Viséan. The pre-gap and post-gap tetrapods appeared substantially different in character, with the post-gap forms showing much higher diversity and disparity, as well as being more advanced and including crown-group tetrapods in their ranks10,37. This gave rise to the idea that the extinction event had served as a reset for tetrapod evolution, allowing the emergence of more modern groups. It has also been linked to terrestrialization after a supposedly aquatic phase of tetrapod evolution in the Devonian10,37. This somewhat simplistic conception of Romer's gap and its relationship to tetrapod evolutionary history can now be replaced by a more nuanced interpretation. The presence of sauropsid tracks in the early Tournaisian implies that the tetrapod crown-group radiation was well under way in the Late Devonian, and that not only lineages such as temnospondyls, seymouriamorphs and diadectomorphs but also crownward stem tetrapods such as baphetids and colosteids crossed the Devonian/Carboniferous boundary. If this is correct, the mass extinction did not have a role in the emergence of these derived lineages, although it is still possible that the amniote crown group arose in its immediate aftermath. The impact of the extinction on diversity, and especially on the selective removal of archaic tetrapod lineages, is harder to assess but may have been substantial. With the exception of Tulerpeton56 and Brittagnathus47 in the Devonian, and some possible Devonian-grade tetrapods in the Tournaisian53,54,55, all known Devonian tetrapods seem to represent a less crownward segment of the tetrapod stem than any post-Devonian forms6. This suggests a selective extinction with appreciable effects on ecosystem structure.
The Snowy Plains Formation trackways have a disproportionate impact on our understanding of early tetrapod evolution because of their combination of diagnostic amniote characteristics and early, securely constrained date. They demonstrate, once more, the extraordinary importance of happenstance and serendipity in the study of severely under-sampled parts of the fossil record. Against this background, two things stand out: first, that the interpretation of such a fossil record is critically dependent on phylogenetic inferences and cannot be ‘read' as a literal account of the history of a group; and second, the fundamental, continuing importance of palaeontological fieldwork as a source of new knowledge.
Specimens were photographed under oblique lighting to emphasize the footprints. Optical scans were undertaken with a RangeVision Spectrum and the resulting STL files were rendered in RangeVision 3D studio 2022.1 for greyscale images or ParaView 5.10.1 for false-colour height maps.
This paper describes Australian and Polish fossil material, deposited with public museums in those countries (Museums Victoria; Holy Cross Branch of the Polish Geological Institute – National Research Institute in Kielce; Geological Museum of the Institute of Geological Sciences, University of Wrocław). The authors include Australian (J.A.L., J.G., A.M.C. and A.B.C.) and Polish (G.N.) researchers, as well as the two discoverers of the Australian trackway slab (C.A.E. and J.E.). As the Australian specimen comes from Taungurung Country, we have consulted with Taungurung Elder and language specialist Aunty L. Padgham about the project; she gave us permission to use the Taungurung name for the section of the river where this fossil was located (see also Acknowledgements).
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Optical surface scans of the footprints shown in Figs. 2c,e and 3a–d can be downloaded via figshare at https://doi.org/10.6084/m9.figshare.25869367 (ref. 57).
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We acknowledge that NMV P258240 comes from Taungurung Country, and pay our respects to Taungurung Elders past and present, and all of the Taungurung community. We thank Aunty L. Padgham, Taungurung Elder and language specialist, for providing the Taungurung name for the section of the river where this fossil was located; and A. Gołasa, A. Miziołek and P. Menducki for full access to material collected by them from the Sudetic area in Poland, and also for permission to document of the most important specimens from these collections. P.E.A. acknowledges the support of ERC Advanced Grant ERC-2020-ADG 10101963 “Tetrapod Origin”. J.A.L. and A.M.C. receive funding from the Australian Research Council, grants DP 220100825 and DP 200103398.
Open access funding provided by Uppsala University.
College of Science and Engineering, Flinders University, Adelaide, South Australia, Australia
John A. Long, Alice M. Clement & Aaron B. Camens
Department of Organismal Biology, Uppsala University, Uppsala, Sweden
Grzegorz Niedźwiedzki & Per E. Ahlberg
Polish Geological Institute – National Research Institute, Warsaw, Poland
Grzegorz Niedźwiedzki
Department of Archaeology and History, La Trobe University, Bundoora, Victoria, Australia
Jillian Garvey
DJANDAK, Dja Dja Wurrung Enterprises, Bendigo, Victoria, Australia
Jillian Garvey
Independent researcher, Jamieson, Victoria, Australia
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C.A.E. and J.E. discovered specimen NMV P258240. J.A.L. provided overall project leadership and wrote most of the first draft manuscript. A.M.C. and A.B.C. made early interpretations of the specimen and contributed to the first draft manuscript. G.N. made the final interpretation of NMV P258240, identified the Notalacerta footprints from the Wałbrzych Formation, and made all photographs and scan images. J.G. contributed expertise on the Mansfield Group ichnofossils and liaised with the Taungurung community. A.B.C. made footprint and track measurements on NMV P258240 for Supplementary Information Part 3, which he wrote together with J.A.L. and A.M.C. P.E.A. composed all figures and wrote the final draft manuscript excluding Supplementary Information Part 3. All authors commented on the final draft and made modifications to it.
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Per E. Ahlberg.
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Supplementary Notes 1–4, Figs. 1 and 2, Table 1 and References.
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Long, J.A., Niedźwiedzki, G., Garvey, J. et al. Earliest amniote tracks recalibrate the timeline of tetrapod evolution.
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When two massive objects (black holes, neutron stars or stars) in our universe fly past each other, their gravitational interactions deflect their trajectories1,2. The gravitational waves emitted in the related bound-orbit system—the binary inspiral—are now routinely detected by gravitational-wave observatories3. Theoretical physics needs to provide high-precision templates to make use of unprecedented sensitivity and precision of the data from upcoming gravitational-wave observatories4. Motivated by this challenge, several analytical and numerical techniques have been developed to approximately solve this gravitational two-body problem. Although numerical relativity is accurate5,6,7, it is too time-consuming to rapidly produce large numbers of gravitational-wave templates. For this, approximate analytical results are also required8,9,10,11,12,13,14,15. Here we report on a new, highest-precision analytical result for the scattering angle, radiated energy and recoil of a black hole or neutron star scattering encounter at the fifth order in Newton's gravitational coupling G, assuming a hierarchy in the two masses. This is achieved by modifying state-of-the-art techniques for the scattering of elementary particles in colliders to this classical physics problem in our universe. Our results show that mathematical functions related to Calabi–Yau (CY) manifolds, 2n-dimensional generalizations of tori, appear in the solution to the radiated energy in these scatterings. We anticipate that our analytical results will allow the development of a new generation of gravitational-wave models, for which the transition to the bound-state problem through analytic continuation and strong-field resummation will need to be performed.
Shortly after writing down his theory of general relativity, Einstein postulated the existence of gravitational waves1. Just as accelerated charges give rise to electromagnetic waves, so too do accelerated masses generate gravitational radiation. It took one hundred years to reach the technical ability to first detect gravitational waves16 as they emerge from binary inspirals and mergers of black holes and neutron stars—the highest mass density objects in our universe. Today, more than one hundred such events have been observed by the LIGO, Virgo and KAGRA detectors3. The planned third generation of ground-based and space-based gravitational-wave observatories17,18,19, including the recently approved LISA mission, will reach an experimental accuracy enabling unprecedented insights into gravitational, astrophysical, nuclear and fundamental physics.
To benefit from the increased sensitivity of gravitational-wave detectors, corresponding increases in precision are required in our ability to solve the gravitational two-body problem4, described by the highly nonlinear Einstein field equations, and thus predict the gravitational waves produced in a binary encounter. Although numerical relativity, which discretizes spacetime and solves the resulting equations numerically on supercomputers, provides a good option5,6,7, it is slow and computationally expensive (a run for a single configuration can take weeks). As tens of millions of waveform templates are needed for gravitational-wave data analysis, fast approximate analytical results to the two-body problem are therefore also required. These can be generated using perturbation theory, picking one or more small parameters and solving the equations order by order in a series expansion. For the binary inspiral, this includes a slow-velocity and weak-gravitational-field expansion (post-Newtonian)8,9,10, as well as the semi-analytical self-force expansion20,21,22 in a small mass ratio (m1/m2 ≪ 1).
Here we describe a black hole (or neutron star) scattering encounter, which—although asymptotically unbounded—also yields physical data concerning the bound two-body problem, relevant for binary inspirals23,24. In the scattering regime, we may advantageously make use of a weak-gravitational-field expansion, in powers of Newton's constant G, valid as long as the two bodies are well separated but moving at arbitrary velocities11,12,13,14,15,25 (Fig. 1). The first non-trivial order for such a black-hole scattering was found in 1979 (ref. 26), namely, the sub-leading G2 order27. Rapid progress has been made since then by synergistically porting techniques from quantum field theory (QFT)12,13,14,28, the mathematical framework for elementary particle scattering, to this classical physics problem. The third order (G3) was established in 2019 (refs. 29,30,31,32) and the fourth order (G4) was completed in 2023 (refs. 33,34,35,36,37). At least the fifth order (G5) precision will be needed to prepare for the third generation of gravitational-wave detectors4.
Two black holes (or neutron stars) with masses mi and incoming velocities vi, impact parameter b and resulting relative scattering angle θ, radiated gravitational-wave energy Erad and recoil (shown in blue).
Being characterized by three fundamental properties—their mass, spin and charge—black holes are, in a sense, the astrophysical equivalents of elementary particles. QFT is a highly mature subject and precise analytic predictions for particle scattering events, used at colliders, such as CERN's Large Hadron Collider, are commonplace. We benefit from this progress in gravity through the close theoretical link between hyperbolic motion (unbound scattering) and elliptic motion (bound orbits). State-of-the-art technologies for performing the multi-loop Feynman integrals involved in scattering cross-sections have enabled some remarkable predictions in elementary particle physics38,39,40,41 and uncovered surprising connections to algebraic geometry42,43,44,45.
The link to algebraic geometry arises through the function spaces that are needed to express the observables at growing perturbative orders. We typically find generalizations of logarithms, known as multiple polylogarithms, which are well understood. At higher orders, elliptic integrals make their appearance46. Geometrically, these are period integrals over the two non-trivial closed cycles of a family of elliptic curves (also known as tori) (Fig. 2). The physical parameters determine the shape of the latter. Yet, this is just the tip of the iceberg.
The elliptic curve (topologically a torus) and two-dimensional projections of the K3 surface and CY3 reflecting their symmetries. Red and blue lines are (projections of) the real n-dimensional cycles Γn. The corresponding periods over the n-form Ωn(x), that is, \({\int }_{{\varGamma }_{n}}{\varOmega }_{n}(x)\), depend on the so-called modulus x (related to the relative velocity v of the black holes \(1/\sqrt{1-{(v/c)}^{2}}\) = v1 · v2/c2 = (x + x−1)/2) parametrizing the shape of CY manifolds and yield master integrals in our problem.
Recently, it has become evident43,44,45,47,48 that CY manifolds emerge in generalizations of the aforementioned function spaces, which encode Feynman integrals in higher-order perturbation theory. These are complex n-dimensional manifolds whose metric obeys Einstein's vacuum equations in 2n-spacetime dimensions49. Geometrically, these higher-dimensional CY n-folds represent a beautiful series of critical geometries generalizing the elliptic curve (n = 1) and may be thought of as 2n-dimensional generalizations of the torus. To motivate this, consider the Legendre family of elliptic curves Y2 = X(X − 1)(X − x) with X and Y complex variables. The one-form Ω1 = dX/Y yields the elliptic periods \({\varpi }_{0}=2{\int }_{1}^{\infty }{\rm{d}}X/Y\) and \({\varpi }_{1}=-2{\rm{i}}{\int }_{-\infty }^{0}{\rm{d}}X/Y\), which are expressible through standard elliptic integrals. These satisfy a second-order differential equation \((1+4(2x-1){\partial }_{x}+4x(x-1){\partial }_{x}^{2}){\varpi }_{k}=0\) for k = 0, 1, known as a Picard–Fuchs equation. In turn, CY n-folds exhibit an n-form Ωn, whose periods—integrals over higher-dimensional integration cycles (Fig. 2)—generalize the elliptic integrals. These n-fold periods obey Picard–Fuchs equations of order (n + 1). Although CY twofolds—known as K3 surfaces50—have a unique topology, the topological types of CY (n > 2)-fold are not classified but believed to be finite. CY threefolds (CY3) are of particular interest in string theory, in which they are used to curl up the six extra spacetime dimensions to arrive at the four observable spacetime dimensions51.
Although specific higher-loop Feynman integrals are known to be expressed in terms of CY periods43,44,45,47,48, physical observables tend to be much simpler than the multitude of contributing Feynman integrals. For example, the Feynman integrals occurring in black-hole scattering at orders G4 (refs. 33,34) and G5 (ref. 52) encode K3 periods, but these contributions strongly cancel in the physical observable within the conservative sector at G5 (ref. 53). Similar intriguing cancellations occur in QFT computations54,55. Furthermore, CY n-fold periods have a transcendentality degree45,56 increasing with their dimension n. This leads to the important question of what classes of transcendental functions appear in physical observables in perturbation theory. Before our work, no physical observables were known that feature CY n-fold periods for n ≥ 3. We expect that our findings and the methods described below will have substantial implications for high-precision predictions in particle physics as well.
In this article, we report on a new landmark result of the QFT-based classical general relativity programme by providing complete scattering observables of a binary black hole (or neutron star) encounter up to the fifth order in the weak-field expansion (G5) and sub-leading order in the symmetric mass ratio ν = m1m2/(m1 + m2)2. This encounter is depicted in Fig. 1 and involves two black holes scattering with a deflection angle θ and radiating gravitational waves with total energy Erad. We describe the black holes as point particles, an approximation valid as long as their separation b is large compared with their intrinsic sizes, that is, their Schwarzschild radii 2Gmi/c2—the weak-gravitational-field region. Consequently, the G expansion is really an expansion in the dimensionless quantity GM/bc2 with total mass M = m1 + m2. The two scattering observables θ and Erad, the latter depending on CY3 periods, can be used to calibrate gravitational-waveform models.
The gravitationally interacting two-body system is governed by an action consisting of two worldlines, coupled to the gravitational Einstein–Hilbert term:
Variation of this action gives rise to the Einstein and geodesic equations. To explain our notation, the proper time intervals \({\rm{d}}{s}_{i}=\sqrt{{g}_{\mu \nu }{\dot{x}}_{i}^{\mu }{\dot{x}}_{i}^{\nu }}{\rm{d}}\tau \) give rise to the followed trajectories \({x}_{i}^{\mu }(\tau )\) (μ = 0, 1, 2, 3) of the ith black hole, parametrized by a time parameter τ (a dot symbolizes a τ derivative). The spacetime metric gμν(x) yields the curvature scalar R[g] and \(g=\det ({g}_{\mu \nu })\).
We calculate the change in four-momentum of each body over the course of scattering, \(\Delta {p}_{i}^{\mu }\), known as the impulse. With the momentum of each body given by \({p}_{i}^{\mu }={m}_{i}{\dot{x}}_{i}^{\mu }\), the impulse is simply the difference between the momentum at late and early times:
The initial momentum of each black hole is given by its mass times initial velocity, \({p}_{i}^{\mu }(\tau \to -\infty )={m}_{i}{v}_{i}^{\mu }\). Working in a weak-gravitational-field region, we have series-expanded order by order in Newton's constant. With results up to G4 already determined33,35,36, and the conservative (non-radiating) part of G5 derived by some of the present authors53, here we extract the subleading-in-ν G5 component from which we will also derive the scattering angle θ and radiated energy flux Erad. Note that ν tends to zero for m1 ≪ m2 and vice versa.
Our calculation is performed using Worldline Quantum Field Theory (WQFT)11,57, in which a Worldline Effective Field Theory action is used to represent the black holes as point particles25,28. This allows us to reinterpret this classical physics problem as one of drawing and calculating perturbative Feynman diagrams (Extended Data Fig. 1). The main benefit of WQFT for classical physics computations is a clean separation between classical and quantum effects. In this language, gravitons (wavy lines) and deflection modes (solid lines) are the quantized excitations of the metric gμν and trajectories \({x}_{i}^{\mu }\). The momenta and energies of these particles are unfixed and must be integrated over. The key principle being exploited here is that tree-level one-point functions, given by a sum of diagrams with a single outgoing line and no internally closed loops, solve the classical equations of motion58. We recursively generated the graphs to be computed at the fifth order in G, yielding a total of 426 diagrams. These diagrams directly translate to mathematical expressions, Feynman integrals, by way of Feynman rules derived from the action in equation (1) (Extended Data Fig. 2).
The resulting Feynman integrals are a staple of perturbative QFT. Individual Feynman integrals, which may diverge in four spacetime dimensions, are treated by working in D dimensions so that divergences appear as (D − 4)−1 poles. Finiteness of our results in the limit D → 4, that is, the cancellation of all intermediate divergences, then provides a useful consistency check. Our calculation of the impulse calls for the evaluation of millions of Feynman integrals, which may have at most 13 propagators of the kinds seen in Extended Data Fig. 2. To evaluate them, we generate linear integration-by-parts (IBP) identities, which reduces the problem to one solving a large system of linear equations. The task was nevertheless enormous and consumed around 300,000 core hours on high-performance computing clusters.
Our task is ultimately to determine expressions for a basis of 236 + 232 master integrals, which split under parity (\({v}_{i}^{\mu }\to -{v}_{i}^{\mu }\)) into two distinct sectors. From these, all other integrals may be expressed as linear combinations using the IBP identities. To do so, we exploit the integrals' non-trivial dependence on only a single variable x: it derives from the relativistic boost factor \(\gamma =1/\sqrt{1-{(v/c)}^{2}}={v}_{1}\cdot {v}_{2}/{c}^{2}\) for the initial relative velocity v of the two black holes, through γ = (x + x−1)/2. Rather than attempt a direct integration, we may therefore set up two systems of differential equations in x (even and odd parity) as:
The integrals to be computed are grouped into vectors I and the matrices \(\widehat{M}\) take a lower block triangular form (Fig. 3). To obtain this system, derivatives of the master integrals with respect to x are re-expressed as linear combinations of the masters themselves using the IBP identities. We solve the system order by order in a series expansion close to D = 4, with higher-order terms given by repeated integrals (with respect to x) of lower-order terms. Boundary conditions on the integrals are fixed in the non-relativistic (low-velocity) limit x → 1.
The blocks on the diagonals determine the function spaces of the multiple sub-sectors. The unmagnified diagonal sectors give rise to multiple polylogarithms.
Repeated integrations with respect to the kinematic parameter x produce the mathematical functions \({\mathcal{I}}\) appearing in our final result for the impulse:
with the base case \({\mathcal{I}}(;x)=1\). The nature of the integration kernels ϕi determines the types of function and are associated with underlying geometries. In the simplest case, the kernels ϕi are rational functions with single poles, for example, x−1, (x + 1)−1 or (x − 1)−1, and iterated integrations produce the function class of multiple polylogarithms—including the ordinary logarithm \({\mathcal{I}}({x}^{-1};x)=\log \,x\). Geometrically, we can interpret these integration kernels as periods of a zero-dimensional CY space, given by two points on a sphere. In more complicated scenarios, usually related to higher-loop computations, the ϕi are connected to periods of higher-dimensional algebraic varieties. A key challenge is to understand the kernels and the associated class of iterated integrals occurring in a physical problem. In a G4 calculation of the impulse, squares of elliptic integrals arise, which are geometrically interpreted as periods of a one-parameter K3 surface (Fig. 2). In the odd-parity sector of integrals at the present fifth order in G, the kernels also depend on CY3 periods and we express physical quantities in terms of the corresponding class of iterated functions.
To see the origin of the CY3 periods, and to clarify their precise nature, we examine the differential equation matrix \(\widehat{M}(x,D)\) (see Fig. 3) in the limit D → 4. The diagonal blocks of this matrix are associated with specific Feynman graphs appearing in the impulse, of which the CY3 geometry is isolated to a single 4 × 4 diagonal sub-block. We can decouple these four first-order differential equations such that we obtain a single fourth-order differential equation, which is the Picard–Fuchs equation of the CY threefold:
The latter is solved by the four CY threefold periods \({\varpi }_{k}(x)={\int }_{{\varGamma }_{3}^{k}}{\varOmega }_{3}(x)\), in which the three-form Ω3(x) is integrated over the real three-dimensional cycles \({\varGamma }_{3}^{k}\), k = 0, 1, 2, 3. For an algebraic definition of the CY family together with an explicit expression of Ω3, we refer to refs. 52,59. These integrals appear within the integration kernels ϕi of the iterated integrals (equation (4)).
Our final expression for the fifth-order impulse is involved and described in Methods, in which we also elaborate on the function space. From the impulse, we can derive the scattering angle θ, which measures the angle of deflection between the ingoing and outgoing momenta in the initial centre-of-mass inertial frame (Fig. 1). As the system dissipates energy, it recoils, and so the initial frame choice is not preserved over the course of a scattering event. Like the impulse (equation (2)), the scattering angle is expanded in the weak-field limit with the Gn component, denoted θ(n). These components are also expanded in powers of the symmetric mass ratio ν and at order G5, we have
with M and Γ = E/M the total mass and mass-rescaled energy of the initial system, respectively. A central result of our work is the computation of all contributions except for θ(5,2). The function space of the angle θ(5) arises from integrals only in the even-parity sector and is simpler than that of the complete impulse. We compare our result with available numerical relativity simulations60 in Fig. 4.
Scattering angle θ is plotted as a function of the impact parameter in units of the Schwarzschild radius, bc2/GM, up to order G5 for an equal-mass scenario with initial relative velocity v = 0.5125c. The black dots are existing numerical relativity (NR) simulations60. The G5 curve follows from equation (6) (excluding the unknown ν2θ(5,2) contribution). The dashed line is the exact in G (ν = 0) probe limit result for geodesic motion in a Schwarzschild background. The inset plot depicts the relative differences to the numerical relativity data. Larger values of bc2/GM correspond to the perturbative regime. We find agreement with NR within the error for bc2/GM > 12.5. The monotonically falling corrections to the consecutive Gn orders yield an intrinsic error estimate of our G5 results: they are more precise than the NR data for bc2/GM > 14.
Source Data
Our other main result is the total radiated energy and momentum from the system over the course of the scattering. Using the principle of four-dimensional momentum conservation, which includes conservation of energy, the total loss of momentum through gravitational-wave emission must balance the change in momenta of the two individual black holes (or neutron stars):
The impulse of the second black hole, \(\Delta {p}_{2}^{\mu }\), can straightforwardly be inferred from that of the first using symmetry. The radiated energy, then, is given simply by the zeroth component of the radiated four-momentum in the centre-of-mass frame \({E}_{{\rm{rad}}}={P}_{{\rm{rad}}}^{0}=-\Delta {p}_{1}^{0}-\Delta {p}_{2}^{0}\), whereas the recoil Precoil derives from its spatial components. Unlike the scattering angle, it includes integrals from the odd-parity sector and so contains CY periods. These terms contribute to the repeated backscattering of radiative gravitons off the potential background—known as the ‘tail-of-tail' effect.
Summarizing, in this work, we have extended the state of the art of the gravitational two-body problem to a new perturbative order (G5) to the sub-leading mass ratio level ν. Our analytical findings require the use of a new class of functions, CY threefold periods, in the radiative sector. These methodological advances will also benefit particle phenomenology, in which CY periods appear in higher-loop-order diagrams43,44,45,47,48. By comparing with numerical relativity data, we demonstrated percent-level agreement in the perturbative domain. These results provide input data for high-precision waveform models using effective-one-body resummation techniques24,60,61,62 that can now be developed. For the comparable-mass case, we foresee the need to also incorporate next-to-next-to-leading-order mass ratio (ν2) contributions, in which new CY threefolds are expected to make their appearance52. This we leave for future studies.
We use the WQFT formalism11,57,63 that quantizes the worldline deflections \({z}_{i}^{\mu }(\tau )\) and graviton field hμν(x) arising in the background field expansions \({x}_{i}^{\mu }(\tau )={b}_{i}^{\mu }+{v}_{i}^{\mu }\tau +{z}_{i}^{\mu }(\tau )\) and \({g}_{\mu \nu }={\eta }_{\mu \nu }+\sqrt{32{\rm{\pi }}G}{h}_{\mu \nu }\), respectively (now setting c = 1). In the gravitational sector, we use a nonlinearly extended de Donder gauge that simplifies the three-graviton and four-graviton vertices (see Supplementary Information). The worldline actions (equation (1)) are improved by making use of the proper time gauge \({\dot{x}}_{i}^{2}=1\) for the ith black hole:
This ensures a linear coupling to the graviton hμν. At the present four-loop (G5 or 5PM) order, we require up to six-graviton vertices that derive from the Einstein–Hilbert action plus gauge-fixing term—taken in D = 4 − 2ϵ dimensions. We also require the single-graviton emission plus (0,…, 5)-deflection vertices derived from equation (8). We provide the explicit vertices and graviton gauge-fixing function in a Zenodo repository submission64 accompanying this article; an analytic expression for the n-deflection worldline vertex was given in refs. 11,63.
The full 5PM integrand is generated using the Berends–Giele-type recursion relation discussed in ref. 65 and sorted into five self-force (SF) sectors according to their scaling with the masses m1 and m2:
The powers of the masses follow from the number of times a worldline is touched in a given graph. Here we compute the sub-leading self-force (1SF) contributions \(\Delta {p}_{{\rm{1SF}}}^{(5)\mu }\) and \(\Delta {p}_{\overline{1{\rm{S}}{\rm{F}}}}^{(5)\mu }\), as well as reproducing the 0SF contributions \(\Delta {p}_{{\rm{0SF}}}^{(5)\mu }\) and \(\Delta {p}_{\overline{0{\rm{S}}{\rm{F}}}}^{(5)\mu }\) that follow from the geodesic motion in a Schwarzschild background. The resulting integrand is reduced to scalar integrals by means of tensor reduction and ‘planarized' using partial fraction (eikonal) identities as described in ref. 53. In summary, all integrals are mapped to the 5PM-1SF planar family \({\int }_{{\ell }}:=\int {d}^{D}{\ell }/(2\pi {)}^{D}\), \(\bar{\delta }(x)\,:=\,2\pi \delta (x)\)
in which {σ} and {n} denote causal i0+ prescriptions and integer powers of propagators, respectively. The four worldline propagators Di(σi) appearing are (i = 2, 3, 4)
and the 14 gravitons propagators DIJ with I = (0, 1, i, q) are
There are at most three bulk graviton propagators D1i that may go on-shell at 5PM order.
IBP identities66,67,68 are used to reduce to master integrals. We use a future release of KIRA 3.0 (refs. 69,70) adapted to our needs that uses the FireFly71,72 library for reconstructing rational functions through finite-field sampling. We have 45 top-level sectors in the 5PM-1SF family that have been described in ref. 53. The integrals encountered in the planar family (equations (10a)–(10c)) have propagator powers in the range ni/IJ ∈ [−9, 8]. The strategies applied to reduce the runtime of the IBP reduction are comparable with the conservative case53. The final set of needed IBP replacement rules to master integrals generated comprises about 30 GB of data and can be made available on request.
The method of differential equations73,74,75 is used, in which the matrices in equation (3) depend on the parameters x and the dimensional regulator ϵ = (4 − D)/2. We take the physical limit ϵ → 0 to compute our observables. Therefore, we need the solutions of the integrals expanded in ϵ. To systematically compute this expansion, we transform equation (3) into canonical form75 such that the ϵ dependence is factored out of the differential equation matrix:
with J(x, ϵ) = \(\widehat{{\bf{T}}}(x,{\epsilon })\)I(x, ϵ) and \({\epsilon }\widehat{A}(x)=(\widehat{T}(x,{\epsilon })\widehat{M}(x,{\epsilon })+d\widehat{T}(x,{\epsilon })/dx)T{(x,{\epsilon })}^{-1}\). The solution is then a path-ordered matrix exponential:
in which j encodes the boundary values of our integrals at x = 1.
We take a bottom-up approach to determine the required transformation \(\widehat{T}(x,{\epsilon })\). For this, we sort our integrals into groups sharing the same set of propagators. These so-called sectors are ordered from lower (fewer propagators) to higher (more propagators), resulting in the block diagonal matrix in Fig. 3. We begin by ϵ-factorizing the lower sectors and then move on to the higher sectors. First, we transform the diagonal blocks, which are identified with the maximal cuts76, into ϵ-form and then proceed to the off-diagonal contributions. The IBP reductions were fully completed for all integrals before the diagonal blocks were identified. Particularly for handling sectors coupled to the CY3 diagonal sector, it is important to choose a good initial basis of integrals such that the relevant couplings are as simple as possible. As we proceed to canonicalize, we adapt and improve our choice of initial basis accordingly.
The simplest diagonal blocks to canonicalize are those containing only multiple polylogarithms77,78,79, depicted in lilac in Fig. 3. The algorithm CANONICA80 finds the necessary transformation to ϵ-form for these blocks by making a suitable ansatz. It is noteworthy that the complexity of this transformation, as well as the runtime, depends highly on the choice of initial integrals. In general, we pick our initial basis integrals so that the regulator ϵ does not appear non-trivially in the denominators of the differential equation (3).
Diagonal blocks containing a K3 surface, depicted in purple in Fig. 3, are handled using INITIAL81. The INITIAL algorithm requires a pure seed integral to construct an ϵ-factorized differential equation through an ansatz tailored to the specific seed integral. Note that, in this context, a pure integral is given as a linear combination of iterated integrals (equation (4)) having no non-trivial pre-factors in x. For non-pure integrals, these pre-factors are non-trivial functions and are known as leading singularities. For each K3 sector, we find an appropriate seed integral by analysing the diagonal block at ϵ = 0. We decouple each diagonal K3 block by switching to a derivative basis: \({{\bf{I}}}_{{\rm{K3}}}=({I}_{1},{I}_{2},{I}_{3})\to ({I}_{1},{I}_{1}^{{\prime} },{I}_{1}^{{\prime\prime} })\) or \({{\bf{I}}}_{{\rm{K3}}}=({I}_{1},{I}_{2},{I}_{3},{I}_{4})\to ({I}_{1},{I}_{1}^{{\prime} },{I}_{1}^{{\prime\prime} },{I}_{4})\), depending on the size of the block, in which Ii are the master integrals of this sector—I4 is chosen so that it decouples from I1 and its derivatives as much as possible. The choice of I1 ensures that its third-order differential (Picard–Fuchs) equation (\(\widehat{\theta }=x\frac{{\rm{d}}}{{\rm{d}}x}\)),
has the explicit solution \({{I}_{1}| }_{{\epsilon }=0}\propto {\varpi }_{{\rm{K3}}}={\left(\frac{2}{\pi }\right)}^{2}{K}^{2}(1-{x}^{2})\), that is, it is proportional to a K3 period. Unlike the polylogarithmic case, this third-order differential equation is not factorizable into first-order equations. Using the normalized integral I1/ϖK3 as the seed, INITIAL may then construct an ϵ-form for the diagonal parts of our K3 sectors (similar to the 4PM case).
To canonicalize the single diagonal CY3 block, depicted in red in Fig. 3, we follow the discussion in ref. 52. Similar to K3, we first pick a suitable starting integral and make a basis change \({{\bf{I}}}_{{\rm{CY3}}}=({I}_{1},{I}_{2},{I}_{3},{I}_{4})\to ({I}_{1},{I}_{1}^{{\prime} },{I}_{1}^{{\prime\prime} },{I}_{1}^{\prime\prime\prime })\). The starting integral I1 is chosen so that, when ϵ = 0, it satisfies the Picard–Fuchs equation (5), which is a hypergeometric system. This implies that the periods of our CY3 geometry are given in terms of hypergeometric functions, for example, \({x}_{4}{F}_{3}\left[\frac{1}{2},\frac{1}{2},\frac{1}{2},\frac{1}{2};1,1,1;{x}^{4}\right]\). Moreover, this also gives rise to intriguing arithmetic properties discussed in ref. 59. From this equation and its four fundamental solutions ϖ0,…, ϖ3, which we collect in the Wronskian matrix W(x) = (∂jϖi) with 0 ≤ i, j ≤ 3, we construct in several steps the rotation matrix into ϵ-form. This approach was invented in ref. 82 and further developed in ref. 83, and, in the K3 case, it is equivalent to the INITIAL algorithm. The process involves the following three steps:
We split the Wronskian matrix into a semi-simple and unipotent part \(\widehat{W}={\widehat{W}}^{{\rm{ss}}}\times {\widehat{W}}^{{\rm{u}}}\). Naively, we can understand this splitting as a decomposition of the maximal cuts of the CY3 sector into their leading singularities and pure parts. The unipotent part is named after the unipotent differential equation it fulfils:
in which Au(x) is nilpotent. The matrix Au(x) can generally be written in terms of invariants, known as Y-invariants, of the CY variety and was explicitly given for our CY3 in ref. 52.
We rotate our integrals with the inverse of Wss, which strips them of their leading singularities. (The analogous operation for K3 is normalizing I1 with the K3 period ϖK3, leaving only the pure part.) To parametrize all degrees of freedom in Wss of a CY3, we need the holomorphic solution ϖ0, an extra function
called the structure series, and their derivatives. The appearance of α1 is new compared with the K3 case and shows the increased complexity in structure of a CY3. In ref. 84, the structure series α1 (and more generally the Y-invariants) are generally defined and used to construct a normal form of a CY differential equation; more specifically, for our CY3, they were derived in ref. 52. For ϵ-factorizing our differential equations, it is important that this normal form of the CY differential equation is in a factorized form with respect to its derivatives. To eliminate all redundancies in this step, we must use Griffiths transversality—an essential property of CY geometries that yields quadratic relations between their periods—to simplify the form of \({\widehat{W}}^{{\rm{ss}}}\).
After completing these steps and appropriately rescaling in ϵ to arrange the weights of the integrals, the diagonal block of our CY3 looks like:
We find an ϵ-form by acting with a suitable set of transformation matrices on \({\widetilde{{\bf{I}}}}_{{\rm{CY3}}}\), working order by order in ϵ starting from ϵ−2. The process requires us to introduce four new functions Gi(x) (i = 1,…, 4), which obey a first-order differential equation containing ϖ0, α1, their derivatives and Gj(x) functions with j < i. For example,
Because of this structure, the functions Gi(x) are all expressible as iterated integrals of CY periods and associated functions. These functions were previously introduced in terms of a different variable in ref. 52 and are listed for our conventions in the Supplementary Information of this article.
We now have the ϵ-form of the diagonal part of the CY3 sector and, thus, a canonical form of all diagonal blocks. We refer to this intermediate basis, in which all diagonal blocks are in ϵ-form, as \({\mathfrak{J}}\). The next stage in canonicalization involves tackling the off-diagonal blocks. To do so, we distinguish between off-diagonal blocks coupled to the CY3 sector, which require special care, and the rest.
We have developed our own algorithm to transform the off-diagonal entries of our differential equation that do not couple to the CY3 sector but can depend on K3 functions. This algorithm uses FINITEFLOW85 and MultivariateApart86 and provides suitable ansätze also including elliptic contributions for the required transformations. It is similar to algorithms used for polylogarithmic off-diagonals, such as those found in CANONICA or Libra87.
For sectors polylogarithmic or K3 on their diagonal blocks, yet also coupled to the CY3 sector, a good initial basis of integrals is essential to minimize these couplings. One possibility to identify such candidates is to perform an integrand analysis, usually done in the Baikov representation88,89 of the integrals. However, we instead found it simpler to use the diagonals themselves to derive constraints on the initial choice of integrals, expanding on the ideas of ref. 90. Having now found canonical masters on the diagonals, that is, the maximal cuts, our strategy is to choose initial candidate integrals that are related as closely as possible to these canonical masters within their respective diagonal blocks. More precisely, we search for candidates that, on their diagonal blocks, are given by a linear combination of the canonical maximal cut integrals and overall functions of ϵ and x:
in which the ck are constant numbers.
We expect that such a ‘good' choice of candidate integrals only requires minimal corrections to form a canonical basis. For certain sectors that are polylogarithmic on their corresponding diagonal block, we need to enlarge these types of constraint by combining different polylogarithmic sectors and requiring equation (18) to hold beyond a single diagonal block. Thus, we obtain further conditions resulting from off-diagonal couplings between separate polylogarithmic blocks. In some instances, we can also relax the condition in equation (18) by considering the ck(x) as functions of x and still find easy transformations. The use of IBPs makes this procedure efficient and allows us to find all transformations for the coupling to the CY3 manually, proceeding similarly as for the diagonal of the CY3 sector. We build successive transformations, removing iteratively all nonlinear-in-ϵ contributions, starting with the highest negative power of ϵ. By doing so, for some integrals, we need to introduce 16 new functions G5(x),…, G20(x), which again satisfy first-order differential equations listed in the Supplementary Information. More specifically, for the mixings between K3 and CY3 sectors, we introduce new functions whose first-order differential equations contain the periods of both the K3 and the CY3. For example,
This concludes the canonicalization process of the whole differential equation system.
Having converted our matrix into its canonical form, \(\widehat{A}(x)\) provides all integration kernels needed to express the master integrals as iterated integrals (equation (4)). We selected a set of linearly independent kernels by examining their small velocity expansion. Our observables consist of iterated integrals that include K3, CY3 and mixed integration kernels, functions from the rotation matrix \(\widehat{T}(x,{\epsilon })\) and algebraic functions from the decomposition in terms of initial master integrals. We need at most four-times-iterated integrals; all multiple polylogarithms are constructed from the kernels \(\{\frac{1}{x},\frac{1}{1\pm x},\frac{x}{1+{x}^{2}}\}\) and have a maximum transcendental weight of 3. Let us also note that the K3 and CY3 periods occurring above are related to those of the Legendre curve by a symmetric and a Hadamard product, respectively52,59.
A complete solution to the differential equation (3) requires the determination of integration constants in the form of boundary integrals, that is, master integrals in the static limit x → 1 (v → 0), which are functions only of ϵ. As the integration and x → 1 limit do not commute, we use the method of regions91,92,93 to isolate contributions with definite (ϵ-dependent) scalings in the velocity v and series-expand integrals at the level of the integrand. These so-called regions are associated with different velocity scalings of the bulk graviton momenta ℓi, which can be either potential (P) or radiative (R):
There are three propagators {D12, D13, D14} that may enter both regions; the rest are kinematically restricted to P (including the velocity-suppressed P: (v2, v)) by the presence of energy-conserving delta functions δ(ℓi · vj). We thus denote the four possible regions as (PPP), (PPR), (PRR) and (RRR). We needed to evaluate 14 + 14 (even + odd) boundary integrals in the (PPR), 5 + 5 in the (PRR) and 4 + 4 in the (RRR) sectors, as well as the 28 + 18 (PPP) boundary integrals that were already determined in the conservative case53 (here there is no distinction between Feynman and retarded bulk propagators). We perform all integrals analytically and check them numerically using pySecDec94,95,96,97,98,99 and AMPred100,101,102,103.
All new boundary integrals for us to evaluate, as compared with ref. 53, contain radiative graviton propagators. Our main strategy is to perform them by means of Schwinger parametrization, in which we also benefit by explicitly integrating out loops involving only gravitons, leaving lower-loop integrals. In doing so, we evaluate at most two-loop integrals in all but two cases. These two cases are genuine three-loop integrals for which we did not manage the integration over Schwinger parameters and therefore moved over to the time domain to establish identities at the level of the series coefficients. In general, our integrations yield generalized hypergeometric functions pFq, which can be series-expanded in ϵ by numerically expanding them to high precision and reconstructing analytic expressions using an ansatz and an integer relation algorithm. Expressions for all boundary integrals, and our methodology for deriving them, are elaborated in the Supplementary Information.
Our main results are full expressions—including dissipation—for the 1SF and \(\overline{1{\rm{S}}{\rm{F}}}\) parts of the momentum impulse, \(\Delta {p}_{{\rm{1SF}}}^{(5)\mu }\) and \(\Delta {p}_{\overline{1{\rm{S}}{\rm{F}}}}^{(5)\mu }\) (equation (9)). They are expanded on basis vectors:
also pulling out an overall factor of the impact parameter b. This decomposition constitutes a split into parts originating from integrals of even and odd parity in \({v}_{i}^{\mu }\). The basis vectors are the impact parameter \({\widehat{b}}^{\mu }=({b}_{2}^{\mu }-{b}_{1}^{\mu })/b\) and dual velocity vectors \({\check{v}}_{1}^{\mu }=(\gamma {v}_{2}^{\mu }-{v}_{1}^{\mu })/({\gamma }^{2}-1)\) and \({\check{v}}_{2}^{\mu }=(\gamma {v}_{1}^{\mu }-{v}_{2}^{\mu })/({\gamma }^{2}-1)\). The main coefficients of interest here are \(\{{c}_{b},{\bar{c}}_{b}\}\) and \(\{{c}_{v},{\bar{c}}_{v}\}\), because the set \(\{{c}_{v}^{{\prime} },{\bar{c}}_{v}^{{\prime} }\}\) being determined by lower-PM results from using preservation of mass \({p}_{1}^{2}={({p}_{1}+\Delta {p}_{1})}^{2}\). The coefficients are further decomposed into those with an even or odd number of radiative gravitons in the boundary fixing:
with w ∈ {b, v}. The even part is defined from (PPP) + (PRR) and the odd part from (PPR) + (RRR). The two parts have distinctive parities under flipping the sign of the relative velocity v → −v. Even and odd sectors then give rise to integer and half-integer post-Newtonian (PN) orders, respectively.
The 1SF and \(\overline{1{\rm{S}}{\rm{F}}}\) parts of the impulse therefore each consist of four non-trivial coefficients, labelled by b or v, each having an even or odd number of radiative gravitons R. We expand each of these in sets of basis functions F(γ) with coefficient functions d(γ), being polynomial up to factors of (γ2 − 1),
barred coefficients being expanded in the same way. Here z ∈ {even, odd} counts the parity of radiative gravitons. The second line with a logarithm produced from the cancellation of 1/ϵ poles between the different boundary regions is associated with tails. It is relevant for all coefficients except cb,odd, \({\bar{c}}_{b,{\rm{odd}}}\) and cv,even. The b-type basis functions are all multiple polylogarithms of maximum weight three and, thus, relatively simple. By contrast, the v-type basis functions are much more complex. They generally have the structure of equation (4) with kernels depending on the CY periods. All basis functions and polynomial coefficients are provided in the ancillary file in our repository submission64.
The total loss of four-momentum at 5PM order, using equation (7), is given schematically by (see, for example, ref. 104):
Our \(1{\rm{SF}}/\overline{1{\rm{S}}{\rm{F}}}\) result fixes all coefficients except r4(γ). Similarly, we may derive the relative scattering angle105,106 \(\theta =\arccos ({{\bf{p}}}_{{\rm{in}}}\cdot {{\bf{p}}}_{{\rm{out}}}/| {{\bf{p}}}_{{\rm{in}}}| | {{\bf{p}}}_{{\rm{out}}}| )\). Here pin = p1 = −p2 is the incoming momentum in the centre-of-mass frame and
is the (relative) outgoing momentum. We expand the scattering angle in G:
Both the angle and \({P}_{{\rm{rad}}}^{(5)\mu }\) expansion coefficients are separated into parts even and odd under v → −v and expanded on suitable basis functions. All of these results can be found in the observables.m ancillary file in our repository submission64.
Our result for the impulse has been checked internally by the cancellation of 1/ϵ poles and obeying the mass condition \({p}_{1}^{2}={({p}_{1}+\Delta {p}_{1})}^{2}\)—verifying the \(\{{c}_{v}^{{\prime} },{\bar{c}}_{v}^{{\prime} }\}\) coefficients (equations (21a) and (21b)). We have also checked that the (PPP) 1SF contribution is related to its \(\overline{1{\rm{S}}{\rm{F}}}\) counterpart by symmetry. Furthermore, we have performed several checks using the non-relativistic (v → 0) limit. First, PN results for the relative scattering angle at 5PM and to first order in self-force are known to 5.5PN order104,105,107. These include conservative terms at integer PN orders, starting from 0PN order, which were already matched in ref. 53, plus dissipative terms appearing at 2.5PN, 3.5PN, 4PN, 4.5PN, 5PN and 5.5PN orders, which we reproduce. Furthermore, and in the same works104,105,107, dissipative PN results for the radiation of energy and recoil of the two-body system were reported at a relative 3PN order to their leading order. These allow us to perform non-trivial checks on r1(γ), r2(γ) and r3(γ) of equation (24) to relative 3PN order.
As an example of our results, we print explicitly the series expansion in v of the G5 component of Erad:
The terms in the square brackets up to v6 reproduce the known PN results of Erad, with the remaining three lines providing further hitherto unknown terms. Naturally, this series expansion can be extended to any order in v using our present results. Explicit results relevant for the PN checks of the relative scattering angle and recoil are given in the Supplementary Information.
The complete set of observables up to the 5PM-1SF order of our work, the scattering angle, radiated energy and impulse four-vector are available in the Zenodo open repository submission https://doi.org/10.5281/zenodo.14604438 (ref. 64) accompanying this article. They are provided in the form of Mathematica computational notebooks. Source data are provided with this paper.
The analytical results of our work used the commercial computer algebra system Wolfram Mathematica108, as well as the freely available computer algebra system Form99. The publicly available programs for reconstructing rational functions through finite-field sampling, FireFly71,72 and FiniteFlow85, were used. Furthermore, programs designed for the analytical treatment of differential equations, including MultivariateApart86, CANONICA80 and INITIAL81, were used as described in Methods. Crucially, the IBP software package KIRA 3.0 (refs. 69,70) was used for the reduction to master integrals in its beta version that can be made accessible by J.U. on reasonable request. For the numerical checks of the boundary integrals, the public software pySecDec94,95,96,97,98,99 and AMPred100,101,102,103 was used. All of our code and observables are provided in Mathematica computational notebooks: the WQFT Feynman rules necessary to perform the 5PM computation, the explicit form of the boundary integrals, as well as the 20 transcendental Gi functions necessary to derive the canonical form of the differential equations. These computational notebooks are freely available in the Zenodo repository submission https://doi.org/10.5281/zenodo.14604438 (ref. 64). The set of IBP replacement rules to the master integrals (30 GB of code) generated using KIRA 3.0 can be made available on reasonable request to the corresponding author.
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We thank M. Beneke, W. Chen, C. Dlapa, R. Morales, R. Porto, N. Syrrakos, L. Tancredi, D. van Straten and M. Wilhelm for insightful discussions and J. Kleinmond for providing the waveform visualization of Fig. 1. This work was financed by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Projektnummer 417533893/GRK2575 ‘Rethinking Quantum Field Theory' (G.U.J., G.M., B.S., J.P., J.U.) and 508889767/FOR5372/1 ‘Modern Foundations of Scattering Amplitudes' (A.K., J.P.) and in part by the Excellence Cluster ORIGINS (C.N.) under Germany's Excellence Strategy – EXC-2094-390783311; the UK Royal Society under grant URF\R1\231578 ‘Gravitational Waves from Worldline Quantum Field Theory' (G.M.); the European Union through the European Research Council under grant ERC Advanced Grant 101097219 (GraWFTy) (M.D., J.P.); and ERC Starting Grant 949279 (HighPHun) (C.N.). The views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. This research was supported by the Munich Institute for Astro-, Particle and BioPhysics (MIAPbP), which is financed by the DFG under Germany's Excellence Strategy – EXC-2094-390783311 (G.U.J., G.M., J.P., B.S.). The authors gratefully acknowledge the computing time made available to them on the high-performance computer Lise at the NHR Center Zuse-Institut Berlin (ZIB). This centre is jointly supported by the Federal Ministry of Education and Research and the state governments participating in the National High-Performance Computing (NHR) joint funding programme (http://www.nhr-verein.de/en/our-partners).
Open access funding provided by Humboldt-Universität zu Berlin.
Institut für Physik, Humboldt-Universität zu Berlin, Berlin, Germany
Mathias Driesse, Gustav Uhre Jakobsen, Gustav Mogull, Jan Plefka, Benjamin Sauer & Johann Usovitsch
Max-Planck-Institut für Gravitationsphysik (Albert-Einstein-Institut), Max Planck Society, Potsdam, Germany
Gustav Uhre Jakobsen & Gustav Mogull
Bethe Center for Theoretical Physics, Universität Bonn, Bonn, Germany
Albrecht Klemm
Hausdorff Center for Mathematics, Universität Bonn, Bonn, Germany
Albrecht Klemm
Centre for Theoretical Physics, Department of Physics and Astronomy, Queen Mary University of London, London, UK
Gustav Mogull
Physik-Department, TUM School of Natural Sciences, Technische Universität München, Garching, Germany
Christoph Nega
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As is customary in high-energy physics, the authors and their contributions are listed in alphabetical order. M.D., G.U.J., G.M., J.P. and B.S. performed the integrand generation and planarization; M.D., B.S. and J.U. conducted the integration-by-parts reduction; C.N. and B.S. canonicalized the differential equations; A.K., C.N. and B.S. identified the underlying Calabi–Yau structures; M.D., G.U.J., G.M., J.P., B.S. and J.U. contributed to the boundary integrals and boundary matching; G.U.J., G.M. and B.S. performed the checks with the existing post-Newtonian results; M.D., G.U.J., C.N. and B.S. simplified the final results and implemented them numerically; G.M. and J.P. secured the funding and provided leadership of the project. All authors contributed to the writing of the manuscript.
Correspondence to
Jan Plefka.
The authors declare no competing interests.
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Organized order by order in Newton's constant G. The dotted lines represent the worldlines of the two black holes, exchanging gravitons (wavy lines) and propagating deflection modes (solid lines).
Retarded graviton, retarded worldline and cut worldline propagators, the relevant worldline and bulk vertices and a sample G2 Feynman diagram. Here ℓ is the loop momentum and q the momentum transfer.
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4 min read
Science Tells Us the U.S. Is Heading toward a Dictatorship
The red flags abound—political research tells us the U.S. is becoming an autocracy
By Dan Vergano
In a split image on television, President Donald Trump delivers address to a joint session of Congress on March 4, 2025.
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As president, Donald Trump pretty much checks all the warning boxes for an autocrat. Last September Scientific American warned of Trump's “nonsensical conspiracy fantasies,” that he “ignores the climate crisis” and has fondness for “unqualified ideologues,” whom he would appoint should he become president again. It's now May and sadly, that all checks out.
The U.S. is in a bad place and, scholars warn, looks to be headed for worse.
Worse even than Trump's relentless attacks on science have been his administration's assaults on the law. His officials have illegally fired federal workers, impounded congressional appropriations and seized people off the street for deportations to foreign prisons, threatening the same for all U.S. citizens. “The depth and breadth of this administration's disregard for civil liberties, political pluralism, the separation of powers and legal constraints of all kinds mark it as an authoritarian regime,” law professor David Pozen of the Columbia University School of Law told the New York Times in April.
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We should all be worried that the U.S. is headed toward an autocracy—government by one person—even without political science offering a warning. But scholarship on how nations descend into this unfortunate state, seen in places like Turkey and Hungary, might not surprise you with what it suggests about the U.S.
“Since Donald Trump's inauguration, the country has embarked on the slippery slope toward autocracy,” concludes political scientist Daniel Stockemer of the University of Ottawa, in a May report in Politics & Policy. Rather than a coup, Trump's attacks on law firms, universities, immigrants and others constitute “a more incremental form of democratic erosion,” he writes, one that follows a six-step theory of incremental autocratization based on research on the democratic backsliding seen worldwide in recent decades. The model arose in major part from the work of political scientist Marianne Kneuer of the Dresden University of Technology. She looked at the last quarter-century's collapse in Venezuela, examining how states turn from democratic to autocratic in stages, as opposed to a sudden coup.
The U.S. has already breached the first three steps of Stockemer's theory. The first step is one of social turmoil; this originated with the Tea Party movement during the Obama administration. Marked by angry politics, backlash against minorities and immigrants, and distrust in institutions, the U.S. has in the last two decades changed from a “full” to a “flawed” democracy, according to the Economist's global democracy index.
The second step requires a “project of radical change,” like the populist movement of Venezuela's Hugo Chavez in the 1990s, or in the U.S. case Trump's MAGA movement, which defends white, male privileges and holds prime loyalty for many Republicans.
The third step is a “decisive electoral victory,” applicable to Chavez in 1999 or Trump in 2024, the latter a vote that also brought Trump control of a subservient Congress.
That leaves us at the edge of the fourth step, the dismantling of checks and balances on executive power.
“If my theory is correct, the U.S. is still in this transition phase between democracy and autocracy,” says Stockemer, by e-mail. “If they move more in the direction of autocracy, we would see that the administration tries to defy more court orders.” One key part of the fourth step is the declaration of fabricated emergencies, such as the “red scare” of the McCarthy era, to trample checks and balances, such as the judiciary's control of the legal system. In May, for example, the White House deputy chief of staff suggested Trump could unilaterally suspend habeas corpus, a legal remedy for unlawful detention that dates at least to the Magna Carta and is in the U.S. Constitution, to summarily round up immigrants. He cited an imaginary “invasion”—even though border crossings are at their lowest point in U.S, history, according to Trump's U.S. Customs and Border Protection agency—as a reason. The courts would likely resist such a move, as the Supreme Court did under the Bush administration in 2008, and whether the Trump administration abides by judicial decisions will determine whether the fourth step has occurred.
Warnings of the fifth step on the road to autocracy, securing long-term power, come in Trump's musing of seeking an unconstitutional third term as president. The final step, the infringement of basic rights and freedoms, also is flashing warning signs, says Stockemer. These are already evident in executive orders that disengage the U.S. from the United Nations Human Rights Council, remove transgender service members from the military and privilege Christianity. He predicts that attacks on minority voting rights in 2026 and 2028 would be an expected outcome of this step.
A simpler “competitive authoritarianism” yardstick for measuring democratic collapse comes from political scientists Steven Levitsky, Lucan Way and Daniel Ziblatt earlier this month. “We propose a simple metric: the cost of opposing the government,” they write in the New York Times. By that measure, they add, the U.S. has already crossed that line, ordering Department of Justice investigations into perceived political enemies, donors to the Democratic Party and news outlets ranging from CBS News to the Des Moines Register. “The administration's authoritarian offensive has had a clear impact. It has changed how Americans behave, forcing them to think twice,” they added.
The good news is that the slide into autocracy isn't inevitable for the U.S. The courts may hold, Congress may start listening to protestors as Trump's approval rating slides, and the Republican coalition, described as “Big Tech on one side, white nationalists on the other,” in the Boston Review, may fracture.
Even so, the damage already done is real: “It is very easy to destroy something such as USAID, but it takes a long time to rebuild it both physically and also in a trust sense, both in America and abroad,” says Stockemer, noting the rapid plummet of Canadian attitudes toward the U.S., from positive to sharply negative. “I can tear down a house in a day, but it will take a year or longer to rebuild it.”
This is an opinion and analysis article, and the views expressed by the author or authors are not necessarily those of Scientific American.
Dan Vergano is senior opinion editor at Scientific American, where he writes the weekly column Argonaut. He has previously written for Grid News, BuzzFeed News, National Geographic and USA Today. He is chair of the New Horizons committee for the Council for the Advancement of Science Writing and a journalism award judge for both the American Association for the Advancement of Science and the U.S. National Academies of Sciences, Engineering, and Medicine.
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Human milk is the ideal source of nutrition for infants. Most health organizations recommend direct breastfeeding from the first hour of life, extending throughout the first and second year. However, uncertainties regarding the volumes of milk ingested by the infant contribute to suboptimal rates of breastfeeding. Here we introduce a compact and unobtrusive device that gently interfaces to the breast via four electrodes and accurately measures expressed milk volume during breastfeeding through changes in the alternating current impedance. The data pass wirelessly to a smartphone continuously throughout each breastfeeding session for real-time graphical display. Comprehensive experimental and computational results establish the operating principles and guide engineering choices for optimized performance. Evaluations with 12 breastfeeding mothers over periods of as long as 17 weeks in the neonatal intensive care unit and in home settings illustrate the practical utility of this technology in addressing a critically important unmet need in maternal and neonatal care.
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The data supporting the results in this study are available within the paper and its Supplementary Information. The data used in the study are not publicly available because they contain information that could compromise research participant privacy. Anonymized data can be made available from the corresponding authors on request for academic purposes. Sample data are available on GitHub at https://github.com/JH127/Sample-data (ref. 35).
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This work was supported by the Querrey Simpson Institute for Bioelectronics at Northwestern University. S.O. acknowledges funding from a National Research Foundation of Korea (NRF) grant (2021R1C1C2010180) funded by the Korea government (MSIT), and the DHA SBIR Phase II award (W81XWH22C0106). R.A. acknowledges support from the ASME—Applied Mechanics Division Haythornthwaite Foundation Research Initiation Grant. J.-Y.Y. acknowledges funding from the Basic Research Laboratory (BRL) Project of National Research Foundation (RS-2024-00406674) funded by the Ministry of Science and ICT of Korea, as well as the Technology Innovation Program (RS-2024-00443121) funded by the Ministry of Trade Industry and Energy (MOTIE, Korea).
These authors contributed equally: Jihye Kim, Seyong Oh, Raudel Avila.
Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
Jihye Kim
Advanced College of Bio-convergence Engineering, Ajou University, Suwon, Republic of Korea
Jihye Kim
Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA
Seyong Oh, Hee-Sup Shin, Anthony R. Banks, Yonggang Huang & John A. Rogers
Division of Electrical Engineering, Hanyang University ERICA, Ansan, Republic of Korea
Seyong Oh
Department of Mechanical Engineering, William Marsh Rice University, Houston, TX, USA
Raudel Avila
School of Science and Engineering, University of Missouri, Kansas City, MO, USA
Hee-Sup Shin
Haku Technology, San Diego, CA, USA
Matthew Banet
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Jennifer Wicks, Daniel T. Robinson & Craig F. Garfield
Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
Jennifer Wicks, Daniel T. Robinson & Craig F. Garfield
Department of Mechanical Engineering, Northwestern University, Evanston, IL, USA
Yonggang Huang
Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL, USA
Yonggang Huang
Department of Material Science and Engineering, Northwestern University, Evanston, IL, USA
Yonggang Huang & John A. Rogers
Department of Semiconductor Convergence Engineering, Sungkyunkwan University, Suwon, Republic of Korea
Jae-Young Yoo & John A. Rogers
Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
John A. Rogers
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
John A. Rogers
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J.K., S.O., J.-Y.Y. and J.A.R. conceived of the idea and designed the research. J.K., S.O., H.-S.S., M.B., A.R.B., J.-Y.Y. and J.A.R. performed experiments and analysed data. R.A. and Y.H. performed electrical field modelling. J.K., J.W., D.T.R. and C.F.G. performed human clinical studies. J.K., S.O., R.A., J.W., J.-Y.Y., D.T.R., C.F.G. and J.A.R. wrote and edited the paper.
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Jae-Young Yoo, Daniel T. Robinson, Craig F. Garfield or John A. Rogers.
The authors declare no competing interests.
Nature Biomedical Engineering thanks Wei Gao, John Ho and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Kim, J., Oh, S., Avila, R. et al. A compact, wireless system for continuous monitoring of breast milk expressed during breastfeeding.
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May 13, 2025
Declining MMR Vaccination Rates Make West Texas Outbreak a Threat to Measles Elimination
High vaccination rates eliminated measles in the U.S. An outbreak that began in West Texas is threatening to overturn that status.
By Rachel Feltman, Lauren J. Young, Fonda Mwangi & Alex Sugiura
Anaissa Ruiz Tejada/Scientific American
Rachel Feltman: For Scientific American's Science Quickly, I'm Rachel Feltman.
More than 1,000 cases of measles have been confirmed in the U.S. since late January, including a cluster in West Texas that has caused one of the worst outbreaks in recent memory. These outbreaks are occurring even though measles was technically eliminated in the U.S. back in 2000. Here to explain what that means—and why that status could be at risk—is Lauren Young, associate editor for health and medicine at Scientific American.
Lauren, thanks so much for coming on to chat with us today.
If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.
Lauren Young: No, thank you for having me.
Feltman: So, to refresh our listeners' memories, could you give us a brief overview of the current measles outbreaks of concern?
Young: Sure, so the situation continues to worsen in the U.S.; measles cases are continuing to rise. The current case count as of May 1 of the [Centers for Disease Control and Prevention's] report says 935 confirmed cases, which is growing at a pretty alarming rate. The initial outbreak began in West Texas, and now it's in 29 states, and we're also seeing cases and outbreak spread in Mexico and Canada.
So it's important to note, too, that nearly 70 percent of the confirmed cases [in the U.S.] have been in younger people, ages 19 and below, and a large proportion of those cases are in unvaccinated people ...
Feltman: Mm.
Young: Which—and this is a concern 'cause measles is very highly contagious. It's known for, you know, spreading via cough. It's also known for creating a rash, which is pretty uncomfortable, coughing and runny nose, but it could also cause severe complications: it could open up people to pneumonia, organ failure and death. There've been three people who've died so far from these outbreaks, one adult and two children, and all three have been unvaccinated ...
Feltman: Mm.
Young: So it's definitely concerning. I know a lot of public health experts are keeping an eye on this and trying to understand, too, the public health response that's going on.
Feltman: Sure, and just how abnormal is this compared to recent years?
Young: Right, so every year we do see cases of measles, and this often happens primarily due to travel—so when someone goes abroad to a place where measles is more common, they'll come back and reintroduce, you know, some cases. But they're usually relatively contained. What we're seeing now is the highest number of cases since 2019, when we had a pretty large outbreak that started in New York.
But, you know, experts are pretty much in agreement that the case counts right now probably are also underestimations. When these cases started in West Texas, for instance, it was highly concentrated in Gaines County, which is known to have a pretty high population of homeschool children. And so it's hard to understand fully the vaccination rates in kids, since, again, these outbreaks and the, the cases are highly concentrated in children, so yeah, public health experts are definitely keeping an eye on this and are concerned about what's gonna happen in the next few months, yeah.
Feltman: Yeah, I think a lot of folks get confused about the statement that we hear a lot lately that measles has been “eliminated” in the United States. Could you explain what that status means and how we got it?
Young: Sure, so a disease gets “elimination” status when its incidence is reduced to zero in a specific region for a set time frame. It's a little bit of a jargony, like, public health status thing, but the CDC and the World Health Organization define the status for measles as a period of 12 months with zero endemic cases, so that means there needs to be no continuous transmission of the disease over a 12-month period of time—so you can't link one case from another case.
The United States achieved its elimination status of measles in 2000, and we've been able to keep that status primarily through prevention measures, particularly through vaccination. And, as we know, the measles, mumps and rubella vaccination, which is how you get vaccinated for measles, is pretty highly effective and very safe.
Feltman: Yeah, do experts think that that elimination status is at risk right now?
Young: Yeah, so there were a few prominent experts in the field of vaccine science who spoke out about this recently. Peter Marks, who was a former [Food and Drug Administration] official and he's a prominent vaccine expert, said he's worried that we're on the way to losing this status. Also Katherine Wells, who is the public health director in Texas, said in March during a news briefing that she's anticipating that this outbreak could go a year long ...
Feltman: Mm.
Young: So that would definitely be pushing into that 12-month window for achieving that elimination status.
Feltman: As you mentioned, this isn't our first big outbreak since 2000, so what factors are coming together to put our elimination status at risk after, you know, 25 years of success?
Young: Yeah, so there's a few things that seem to be, you know, folding into play based off of what I'm just hearing from the experts that I've talked to. One, for sure, is we've been seeing kind of this steady decline in vaccination rates, specifically in kids but, you know, just nationally as well, ever since the pandemic. A big part of that was: during the pandemic itself a lot of children missed their well appointments, where they would get their routine vaccinations. We did see, you know, some increase from that, but there's other things at play.
There's been a lot of antivaccine rhetoric that's been going on that's causing some of that increase to stagnate slightly, and, you know, experts are really highly concerned. We also have, you know, some public health officials in office right now who have a history of endorsing antivaccine rhetoric and are also endorsing studies to reevaluate things like autism and vaccines and that connection there.
So there's just this heightened concern around vaccines. And when we see things like a decline in vaccination rates it's very important for a disease like measles because it is so highly contagious. And for something like measles we need to see, as some experts have explained to me, very highly uniform vaccine coverage—in other words, high “herd immunity,” which is basically the level of either natural immunity or vaccination immunity you need to have in order to stop the spread of disease. So for measles you need about a 95 percent vaccination rate, and any sort of, you know, even slight decline in that can cause these severe outbreaks.
So that's what we're seeing here, where, you know, we have a small pocketed community that had a lower vaccination rate and is, you know, spurring this particular outbreak. But we're seeing that also, too, in other places in the country where there might be even just a small dip in vaccination and it causes a disease to spread. And measles is kind of, as some experts have said, a canary in a coal mine for vaccine-preventable diseases because it is so highly contagious, but if we continue to see this overall decrease in vaccinations for things like, you know, other eliminated diseases—like polio, for instance—that's also a little bit of concern for several experts.
We did a whole story about this—Tara Haelle, one of our contributors, did a really deep dive on what that exactly would look like. So this is on the forefront of a lot of people's minds, just the general interplay between vaccine recommendations from public health officials and also how that's playing out from, you know, past historical trends. It's all kind of coalescing together.
Feltman: Yeah, what do public health experts think we can do to keep measles from becoming endemic again?
Young: It seems maybe like a little bit beating a dead horse, but getting vaccinated, you know, I think is still an important thing to do. Listening to trusted health practitioners about treatment. Being active about, you know, going to the hospital or going and getting treatment if you're seeing any signs or symptoms—which, again, include the rash, coughing, and the runny nose and watery eyes.
Feltman: Lauren, thank you so much for coming on. Unfortunately, I'm sure this won't be the last time we talk to you about measles, but we really appreciate it.
Young: No, thank you for having me.
Feltman: That's all for today's episode. If you haven't already submitted your answers for the Science Quickly listener survey, go check it out at ScienceQuickly.com/survey. Your responses will help us steer the future of the show, and you might just win a fun prize for helping us out. We'll be back on Friday.
Science Quickly is produced by me, Rachel Feltman, along with Fonda Mwangi, Kelso Harper, Naeem Amarsy and Jeff DelViscio. This episode was edited by Alex Sugiura. Shayna Posses and Aaron Shattuck fact-check our show. Our theme music was composed by Dominic Smith. Subscribe to Scientific American for more up-to-date and in-depth science news.
For Scientific American, this is Rachel Feltman. See you next time!
Rachel Feltman is former executive editor of Popular Science and forever host of the podcast The Weirdest Thing I Learned This Week. She previously founded the blog Speaking of Science for the Washington Post.
Lauren J. Young is an associate editor for health and medicine at Scientific American. She has edited and written stories that tackle a wide range of subjects, including the COVID pandemic, emerging diseases, evolutionary biology and health inequities. Young has nearly a decade of newsroom and science journalism experience. Before joining Scientific American in 2023, she was an associate editor at Popular Science and a digital producer at public radio's Science Friday. She has appeared as a guest on radio shows, podcasts and stage events. Young has also spoken on panels for the Asian American Journalists Association, American Library Association, NOVA Science Studio and the New York Botanical Garden. Her work has appeared in Scholastic MATH, School Library Journal, IEEE Spectrum, Atlas Obscura and Smithsonian Magazine. Young studied biology at California Polytechnic State University, San Luis Obispo, before pursuing a master's at New York University's Science, Health & Environmental Reporting Program.
Fonda Mwangi is a multimedia editor at Scientific American. She previously worked as an audio producer at Axios, The Recount and WTOP News. She holds a master's degree in journalism and public affairs from American University in Washington, D.C.
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How much is the artificial intelligence (AI) revolution altering the process of communicating science? With generative AI tools such as ChatGPT improving so rapidly, attitudes about using them to write research papers are also evolving. The number of papers with signs of AI use is rising rapidly (D. Kobak et al. Preprint at arXiv https://doi.org/pkhp; 2024), raising questions around plagiarism and other ethical concerns.
To capture a sense of researchers' thinking on this topic, Nature posed a variety of scenarios to some 5,000 academics around the world, to understand which uses of AI are considered ethically acceptable.
Take Nature's AI research test: find out how your ethics compare
Take Nature's AI research test: find out how your ethics compare
The survey results suggest that researchers are sharply divided on what they feel are appropriate practices. Whereas academics generally feel it's acceptable to use AI chatbots to help to prepare manuscripts, relatively few report actually using AI for this purpose — and those who did often say they didn't disclose it.
Past surveys reveal that researchers also use generative AI tools to help them with coding, to brainstorm research ideas and for a host of other tasks. In some cases, most in the academic community already agree that such applications are either appropriate or, as in the case of generating AI images, unacceptable. Nature's latest poll focused on writing and reviewing manuscripts — areas in which the ethics aren't as clear-cut.
Nature's survey laid out several scenarios in which a fictional academic, named Dr Bloggs, had used AI without disclosing it — such as to generate the first draft of a paper, to edit their own draft, to craft specific sections of the paper and to translate a paper. Other scenarios involved using AI to write a peer review or to provide suggestions about a manuscript Dr Bloggs was reviewing (see Supplementary information for full survey, data and methodology, and you can also test yourself against some of the survey questions).
Survey participants were asked what they thought was acceptable and whether they had used AI in these situations, or would be willing to. They were not informed about journal policies, because the intent was to reveal researchers' underlying opinions. The survey was anonymous.
The 5,229 respondents were contacted in March, through e-mails sent to randomly chosen authors of research papers recently published worldwide and to some participants in Springer Nature's market-research panel of authors and reviewers, or through an invitation from Nature's daily briefing newsletter. They do not necessarily represent the views of researchers in general, because of inevitable response bias. However, they were drawn from all around the world — of those who stated a country, 21% were from the United States, 10% from India and 8% from Germany, for instance — and represent various career stages and fields. (Authors in China are under-represented, mainly because many didn't respond to e-mail invitations).
The survey suggests that current opinions on AI use vary among academics — sometimes widely. Most respondents (more than 90%) think it is acceptable to use generative AI to edit one's research paper or to translate it. But they differ on whether the AI use needs to be disclosed, and in what format: for instance, through a simple disclosure, or by giving details about the prompts given to an AI tool.
When it comes to generating text with AI —for instance, to write all or part of one's paper — views are more divided. In general, a majority (65%) think it is ethically acceptable, but about one-third are against it.
Asked about using AI to draft specific sections of a paper, most researchers felt it was acceptable to do this for the paper's abstract, but more were opposed to doing so for other sections.
Although publishers generally agree that substantive AI use in academic writing should be declared, the response from Nature's survey suggests that not all researchers have the same opinion, says Alex Glynn, a research literacy and communications instructor at the University of Louisville in Kentucky. “Does the disconnect reflect a lack of familiarity with the issue or a principled disagreement with the publishing community?”
Using AI to generate an initial peer-review report was more frowned upon — with more than 60% of respondents saying it was not appropriate (about one-quarter of these cited privacy concerns). But the majority (57%) felt it was acceptable to use AI to assist in peer review by answering questions about a manuscript.
“I'm glad to see people seem to think using AI to draft a peer-review report is not acceptable, but I'm more surprised by the number of people who seem to think AI assistance for human reviewers is also out of bounds,” says Chris Leonard, a scholarly-communications consultant who writes about developments in AI and peer review in his newsletter, Scalene. (Leonard also works as a director of product solutions at Cactus Communications, a multinational firm in Mumbai, India.) “That hybrid approach is perfect to catch things reviewers may have missed.”
In general, few academics said they had actually used AI for the scenarios Nature posed. The most popular category was using AI to edit one's research paper, but only around 28% said they had done this (another 43%, however, said they'd be willing to). Those numbers dropped to around 8% for writing a first draft, making summaries of other articles for use in one's own paper, translating a paper and supporting peer review.
A mere 4% of respondents said they'd used AI to conduct an initial peer review.
Overall, about 65% reported that they had never used AI in any of the scenarios given, with people earlier in their careers being more likely to have used AI at least for one case. But when respondents did say they had used AI, they more often than not said they hadn't disclosed it at the time.
“These results validate what we have also heard from researchers — that there's great enthusiasm but low adoption of AI to support the research process,” says Josh Jarrett, a senior vice-president at Wiley, the multinational scholarly publisher, which has also surveyed researchers about use of AI.
When given the opportunity to comment on their views, researchers' opinions varied drastically. On the one hand, some said that the broad adoption of generative AI tools made disclosure unnecessary. “AI will be, if not already is, a norm just like using a calculator,” says Aisawan Petchlorlian, a biomedical researcher at Chulalongkorn University in Bangkok. “‘Disclosure' will not be an important issue.”
On the other hand, some said that AI use would always be unacceptable. “I will never condone using generative AI for writing or reviewing papers, it is pathetic cheating and fraud,” said an Earth-sciences researcher in Canada.
AI is transforming peer review — and many scientists are worried
AI is transforming peer review — and many scientists are worried
Others were more ambivalent. Daniel Egan, who studies infectious diseases at the University of Cambridge, UK, says that although AI is a time-saver and excellent at synthesizing complex information from multiple sources, relying on it too heavily can feel like cheating oneself. “By using it, we rob ourselves of the opportunities to learn through engaging with these sometimes laborious processes.”
Respondents also raised a variety of concerns, from ethical questions around plagiarism and breaching trust and accountability in the publishing and peer-review process to worries about AI's environmental impact.
Some said that although they generally accepted that the use of these tools could be ethical, their own experience revealed that AI often produced sub-par results — false citations, inaccurate statements and, as one person described it, “well-formulated crap”. Respondents also noted that the quality of an AI response could vary widely depending on the specific tool that was used.
There were also some positives: many respondents pointed out that AI could help to level the playing field for academics for whom English was not a first language.
Several also explained why they supported certain uses, but found others unacceptable. “I use AI to self-translate from Spanish to English and vice versa, complemented with intensive editing of the text, but I would never use AI to generate work from scratch because I enjoy the process of writing, editing and reviewing,” says a humanities researcher from Spain. “And I would never use AI to review because I would be horrified to be reviewed by AI.”
Perhaps surprisingly, academics' opinions didn't generally seem to differ widely by their geographical location, research field or career stage. However, respondents' self-reported experience with AI for writing or reviewing papers did correlate strongly with having favourable opinions of the scenarios, as might be expected.
Career stage did seem to matter when it came to the most popular use of AI — to edit papers. Here, younger researchers were both more likely to think the practice acceptable, and more likely to say they had done it.
And respondents from countries where English is not a first language were generally more likely than those in English-speaking nations to have used AI in the scenarios. Their underlying opinions on the ethics of AI use, however, did not seem to differ greatly.
Various researchers and publishers have conducted surveys of AI use in the academic community, looking broadly at how AI might be used in the scientific process. In January, Jeremy Ng, a health researcher at the Ottawa Hospital Research Institute in Canada, and his colleagues published a survey of more than 2,000 medical researchers, in which 45% of respondents said they had previously used AI chatbots (J. Y. Ng et al. Lancet Dig. Health 7, e94–e102; 2025). Of those, more than two-thirds said they had used it for writing or editing manuscripts — meaning that, overall, around 31% of the people surveyed had used AI for this purpose. That is slightly more than in Nature's survey.
Science sleuths flag hundreds of papers that use AI without disclosing it
Science sleuths flag hundreds of papers that use AI without disclosing it
“Our findings revealed enthusiasm, but also hesitation,” Ng says. “They really reinforced the idea that there's not a lot of consensus around how, where or for what these chatbots should be used for scientific research.”
In February, Wiley published a survey examining AI use in academia by nearly 5,000 researchers around the world (see go.nature.com/438yngu). Among other findings, this revealed that researchers felt most uses of AI (such as writing up documentation and increasing the speed and ease of peer review) would be commonly accepted in the next few years. But less than half of the respondents said they had actually used AI for work, with 40% saying they'd used it for translation and 38% for proofreading or editing of papers.
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Nature 641, 574-578 (2025)
doi: https://doi.org/10.1038/d41586-025-01463-8
Richard Van Noorden co-designed, conducted and analysed the survey.
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The Kids Online Safety Act (KOSA) has been reintroduced into Congress. If passed into law, this bill could impose some of the most significant legislative changes that the internet has seen in the U.S. since the Children's Online Privacy Protection Act (COPPA) of 1998.
As it currently stands, KOSA would be able to hold social media platforms legally accountable if it's proven that these companies aren't doing enough to protect minors from harm. The bill includes a long list of possible harms, such as eating disorders, sexual exploitation, substance abuse, and suicide. Though it overwhelmingly passed through the Senate last year, the bill was stifled in the House.
KOSA has faced much backlash since its introduction in 2022.
Human rights groups like the ACLU raised concerns that the bill could be weaponized as a tool for censorship and surveillance. While amendments to KOSA have mitigated some of these concerns, groups like the Electronic Frontier Foundation and Fight for the Future have remained against the bill.
“The bill's authors have claimed over and over that this bill doesn't impact speech. But the Duty of Care is about speech: it's about blocking speech that the government believes is bad for kids,” Fight for the Future wrote in a statement. “And the people who will be determining what speech is harmful? They are the same ones using every tool to silence marginalized communities and attack those they perceive as enemies.”
However, KOSA has garnered support from companies like Microsoft, Snap, and X; X CEO Linda Yaccarino even worked with Senators Marsha Blackburn (R-TN) and Richard Blumenthal (D-CT) on the most recent draft of the bill. Google and Meta have remained opposed to the bill, but Apple announced today that it will support the legislation.
“Apple is pleased to offer our support for the Kids Online Safety Act (KOSA). Everyone has a part to play in keeping kids safe online, and we believe [this] legislation will have a meaningful impact on children's online safety,” Timothy Powderly, Apple's Senior Director of Government Affairs, said in a statement.
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Robert F. Kennedy Jr. faced Congress for the first time since taking over the Department of Health and Human Services.
Today, RFK Jr. appeared before both the House and Senate in two separate committee hearings. Though the main thrust of Kennedy's testimony concerned the upcoming HHS budget, the former environmental lawyer was also pressed to defend the administration's ongoing—and legally contested—budget and staffing cuts as well as his stances on a variety of issues, including vaccination and abortion.
This morning, Kennedy spoke in front of the House Appropriations Committee. RFK Jr. was repeatedly asked about decisions made by the Trump White House to unilaterally pause or cancel funding already allotted to the federal government by the previous Congress. Though he reiterated that he would follow the law and spend the money appropriated to HHS, Kennedy also attempted to justify Trump's cuts at times; other times, he promised that he has and would safeguard the most essential programs, such as Head Start and those related to tribal health, from current or future cuts.
True to his reputation, Kennedy also delivered some whoppers.
When asked about how he would further protect the health of Native Americans, RFK Jr. singled out ultra-processed food as a major factor behind their poorer health outcomes in particular. “Ultra-processed food is a genocide on the American Indian,” he stated.
In response to Representative Robert Aderholt (R-Ala.)'s question about how he would further the pro-life agenda, RFK Jr. said “every abortion is a tragedy.” Kennedy went on to boast that HHS has cut federal funding to programs overseas that fund, provide, or counsel people about abortions—a reinstatement of the so-called global gag rule.
Kennedy attempted to spin recent HHS funding and staffing cuts as a “rescaling” of the agency and its priorities. But Rep. Rosa DeLauro (D-Conn.) correctly noted that this rescaling has resulted in billions of dollars worth of cuts so far. According to a report released yesterday by the U.S. Senate Committee on Health, Education, Labor, and Pensions (HELP) Minority Staff, the Trump administration has terminated at least $13.5 billion in health funding since taking over, including 1,660 grants awarded by HHS.
Kennedy has also overseen the planned elimination of 20,000 jobs and over a dozen agencies within HHS, including the Substance Abuse and Mental Health Services Administration (SAMHSA). He and other officials have attempted to justify these cuts as part of a restructuring, with the responsibilities of SAMHSA and other shuttered agencies expected to be collapsed within a new organization called Administration for a Healthy America (AHA). This restructuring is currently on pause following a temporary restraining order placed by U.S. District Judge Susan Illston last week as part of an ongoing lawsuit filed against HHS by several union and public health organizations.
When asked by Rep. Watson Coleman (D-N.J.) how the elimination of agencies and programs related to minority health would improve the existing disparities among Americans, RFK Jr. argued that “Trump's vision for this country is the same as Martin Luther King Jr.'s.”
Kennedy also refused to answer whether he would vaccinate his children against polio and chickenpox, arguing that his personal opinion was irrelevant and that he didn't want to be seen as giving medical advice (he did state that he would probably vaccinate them against measles). Kennedy has infamously long misrepresented the safety of vaccines, particularly the measles, mumps, and rubella vaccine, for decades, and he has continued to state falsehoods about vaccines during his tenure at HHS.
Millions of Measles Cases Could Hit U.S. Over Next 25 Years If Vaccination Rates Drop
“We are doing a better job at CDC today than any nation in the world controlling this measles outbreak,” Kennedy said at one point. It is true that many parts of the world are facing a resurgence of measles. But these current outbreaks in the U.S., now over 1,000 cases, are the worst seen stateside since 2019. And experts caution that measles is on the brink of returning to the U.S. permanently.
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If you've ever tried to work remotely or travel with your laptop and wished for just a little more screen space, you're not alone. Sometimes, a singular display can be extremely limiting. A second monitor can do wonders for your productivity, and if you want to add one to your setup, you can get it for a pretty low price right now, especially if you're shopping at Amazon.
Head over there now to get the 15.6-inch KYY Portable Monitor for $70, down from its usual price of $130. That's $60 off and a discount of 46%.
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This screen is a 1080p Full HD display, which works great no matter whether you're gaming, writing up reports, or just checking out social media. It uses IPS technology, so every viewing angle is a good one, with no need to worry about the lighting where you are or positioning your screen just so to see everything that's going on.
Thanks to its USB-C and HDMI connections, you can just plug and play with this monitor as well. There's no special software you need to use to hook it up, so you can just get going as soon as you unbox the screen. It can sometimes be a bit of a hassle to get other laptops going, so that's kind of the beauty of this one. It feels ultra portable and something that you can just take down and put away when you're finished instead of retaining the heft that regular monitors often do.
It's also very lightweight and thin, making it super easy to slide into your laptop bag or backpack. It comes with a smart folding cover that doubles as a stand, so you can prop it up at a couple of different angles depending on your setup. Built-in speakers are included, too. They aren't studio quality, of course, but they're perfectly fine for calls, background music, or streaming. They'll also do just fine for handling meetings or anything like that you might need on a daily basis.
This monitor is awesome for just $70 (-46%), and it's honestly a great value any way you slice it. It's not trying to be a high-end display for graphic designers or hardcore gamers, but if you're looking for a simple, reliable second screen for travel, work, or everyday multitasking, this is an affordable and practical option that delivers more than you'd expect for the price.
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AI startup Stability AI has released Stable Audio Open Small, a “stereo” audio-generating AI model that the company claims is the fastest on the market — and efficient enough to run on smartphones.
Stable Audio Open Small is the fruit of a collaboration between Stability AI and Arm, the chipmaker that produces many of the processors inside tablets, phones, and other mobile devices. While a number of AI-powered apps can generate audio, like Suno and Udio, most rely on cloud processing, meaning that they can't be used offline.
Stability also claims that Stable Audio Open Small's training set is made up entirely of songs from the royalty-free audio libraries Free Music Archive and Freesound. That's as opposed to the training sets of the aforementioned Suno and Udio, which reportedly contain copyrighted content, posing an IP risk.
Stable Audio Open Small is 341 million parameters in size and optimized to run on Arm CPUs. (Parameters, sometimes referred to as “weights,” are the internal components of a model that guide its behavior.) Designed for quickly generating short audio samples and sound effects (e.g., drum and instrument riffs), Stable Audio Open Small can produce up to 11 seconds of audio on a smartphone in less than 8 seconds, claims Stability AI.
Here's a sample generated by Stable Audio Open Small:
And here's another one:
The model isn't without its limitations. Stable Audio Open Small only supports prompts written in English, and Stability notes in its documentation that the model can't generate realistic vocals or high-quality songs. The model also doesn't perform equally well across musical styles, Stability warns — a consequence of its Western-biased training data.
In another potential wrinkle for devs, Stable Audio Open Small has somewhat restrictive usage terms. It's free to use for researchers, hobbyists, and businesses with less than $1 million in annual revenue, but developers and organizations making over $1 million in revenue have to pay for Stability's enterprise license.
Stability, the beleaguered firm behind the popular image-generation model Stable Diffusion, raised new cash last year as investors, including Eric Schmidt and Napster founder Sean Parker, sought to turn the business around. Emad Mostaque, Stability's co-founder and ex-CEO, reportedly mismanaged Stability into financial ruin, leading staff to resign, a partnership with Canva to fall through, and investors to grow concerned about the company's prospects.
In the last few months, Stability has hired a new CEO, appointed filmmaker James Cameron to its board of directors, and released several new image-generation models.
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Add 10 USB Type-A ports to your system
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Have you ever experienced a lack of USB ports on your PC? Delock has introduced a new front-panel USB hub designed to enhance your case's connectivity by providing 10 additional USB Type-A ports for connecting peripherals and other devices.
Though we've progressed significantly from the bulky old PC cases, the number of USB ports on today's best PC cases hasn't changed much. Unless you opt for a specialized case, you're likely to find only two to four USB Type-A ports these days. The shift towards USB Type-C ports further complicates things. Over recent years, the availability of USB Type-A ports has declined, with some modern cases featuring just one. This is why front-panel hubs will remain relevant since some users will always require more traditional USB Type-A ports to be available at the front of their cases. Sometimes you may want to connect a card reader or something that doesn't require a lot of bandwidth, so it doesn't make sense to use up one of the faster USB interfaces on your motherboard.
Delock's front panel fits into a standard 3.5-inch bay inside your case. It provides 10 USB Type-A ports. The panel utilizes the VLI VL813 hub controller, so we're looking at USB 3.0 specifications with maximum transfer speeds up to 5 Gbps. The 5 Gbps USB Type-A ports are far from the fastest, but they'll do the job for everyday usage. Logically, they're backward compatible with older USB specifications. If you're transferring considerable data, you're better served with the speedy USB ports on your motherboard's rear panel.
The hub requires two connections. It communicates with your system's motherboard through a 19-pin USB header and draws its power from a 15-pin SATA power cable. The delivery scope is minimal. You receive the 3.5-inch hub, four Philips head screws to install it inside your case's 3.5-inch bay, and a user manual in case you have any questions about the product.
The Delock 3.5-inch hub can be found in several countries, though its availability in the U.S. is still unclear. It appears on Amazon U.K. but does not have pricing or stock information. In Germany, it can be purchased from a Delock retailer for €84.59 (~$94.76), suggesting a price of approximately $79.63 before the 19% VAT (value-added tax) is added.
Delock's hub is certainly expensive, especially since USB 3.0 front panel hubs begin around $13, with top-tier models nearing $30. Nevertheless, other brands typically don't provide as many USB Type-A ports as Delock does. While the maximum we've observed is eight ports, the Delock hub features an impressive ten.
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If you're still dragging a corded vacuum from room to room, or worse, avoiding vacuuming altogether because it's such a hassle, you might want to think about making a change. While it's true no one loves vacuuming, you've still got to do it. How else will you keep a clean house? It has to be done, so make sure you have an appliance you actually like to use while doing it.
Head to Amazon to get the Shark Pet Cordless Stick Vacuum for just $150, down from its usual price of $260. That's $110 off and a discount of 42%.
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This model is part of Shark's Rocket lineup and is built to move, so you can get around your house and finish up vacuuming fast. It's a 2-in-1 design, meaning you can use it as a full-length stick vacuum or convert it into a handheld unit when you need to clean upholstery, stairs, or even your car. Weighing just 7.5 pounds, it's light enough to carry up and down the stairs and can get around furniture super easily.
Performance-wise, it's definitely no slouch. The high-speed brushless motor gives it enough suction to pick up everything from pet hair to fine dust across both carpets and hard floors. It has a pretty big dust cup too, so you won't need to stop and empty it as often, and the CleanTouch system makes dumping debris super easy and hands-free.
One of the most useful features here is the built-in LED headlights on the nozzle, which help you spot crumbs, fur, and dust bunnies hiding under furniture or in low-light corners. It also comes with a crevice tool and pet multi-tool, which are great for tight spaces and picking up stubborn hair from couches or bedding.
Battery life is solid. You'll get up to 40 minutes of runtime on a full charge, which is usually plenty to get through a full clean if you work fast enough. And because it's cordless, you're not constantly switching outlets or getting tangled up in cords. That all makes for a much more efficient clean, so you'll be getting things done fast.
If you want a vacuum that actually feels substantial enough to use on a regular basis, this Shark pet-centric cordless should be your next buy. You'll actually like pushing it around, You can get this one for a surprising $150 (-42%), so make sure you get it's still up for grabs.
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AlphaEvolve finds new algorithms that outperform the best human-made solutions for data center management, chip design, and more.
Google DeepMind has once again used large language models to discover new solutions to long-standing problems in math and computer science. This time the firm has shown that its approach can not only tackle unsolved theoretical puzzles, but improve a range of important real-world processes as well.
Google DeepMind's new tool, called AlphaEvolve, uses the Gemini 2.0 family of large language models (LLMs) to produce code for a wide range of different tasks. LLMs are known to be hit and miss at coding. The twist here is that AlphaEvolve scores each of Gemini's suggestions, throwing out the bad and tweaking the good, in an iterative process, until it has produced the best algorithm it can. In many cases, the results are more efficient or more accurate than the best existing (human-written) solutions.
“You can see it as a sort of super coding agent,” says Pushmeet Kohli, a vice president at Google DeepMind who leads its AI for Science teams. “It doesn't just propose a piece of code or an edit, it actually produces a result that maybe nobody was aware of.”
In particular, AlphaEvolve came up with a way to improve the software Google uses to allocate jobs to its many millions of servers around the world. Google DeepMind claims the company has been using this new software across all of its data centers for more than a year, freeing up 0.7% of Google's total computing resources. That might not sound like much, but at Google's scale it's huge.
Jakob Moosbauer, a mathematician at the University of Warwick in the UK, is impressed. He says the way AlphaEvolve searches for algorithms that produce specific solutions—rather than searching for the solutions themselves—makes it especially powerful. “It makes the approach applicable to such a wide range of problems,” he says. “AI is becoming a tool that will be essential in mathematics and computer science.”
AlphaEvolve continues a line of work that Google DeepMind has been pursuing for years. Its vision is that AI can help to advance human knowledge across math and science. In 2022, it developed AlphaTensor, a model that found a faster way to solve matrix multiplications—a fundamental problem in computer science—beating a record that had stood for more than 50 years. In 2023, it revealed AlphaDev, which discovered faster ways to perform a number of basic calculations performed by computers trillions of times a day. AlphaTensor and AlphaDev both turn math problems into a kind of game, then search for a winning series of moves.
FunSearch, which arrived in late 2023, swapped out game-playing AI and replaced it with LLMs that can generate code. Because LLMs can carry out a range of tasks, FunSearch can take on a wider variety of problems than its predecessors, which were trained to play just one type of game. The tool was used to crack a famous unsolved problem in pure mathematics.
AlphaEvolve is the next generation of FunSearch. Instead of coming up with short snippets of code to solve a specific problem, as FunSearch did, it can produce programs that are hundreds of lines long. This makes it applicable to a much wider variety of problems.
In theory, AlphaEvolve could be applied to any problem that can be described in code and that has solutions that can be evaluated by a computer. “Algorithms run the world around us, so the impact of that is huge,” says Matej Balog, a researcher at Google DeepMind who leads the algorithm discovery team.
Here's how it works: AlphaEvolve can be prompted like any LLM. Give it a description of the problem and any extra hints you want, such as previous solutions, and AlphaEvolve will get Gemini 2.0 Flash (the smallest, fastest version of Google DeepMind's flagship LLM) to generate multiple blocks of code to solve the problem.
It then takes these candidate solutions, runs them to see how accurate or efficient they are, and scores them according to a range of relevant metrics. Does this code produce the correct result? Does it run faster than previous solutions? And so on.
AlphaEvolve then takes the best of the current batch of solutions and asks Gemini to improve them. Sometimes AlphaEvolve will throw a previous solution back into the mix to prevent Gemini from hitting a dead end.
When it gets stuck, AlphaEvolve can also call on Gemini 2.0 Pro, the most powerful of Google DeepMind's LLMs. The idea is to generate many solutions with the faster Flash but add solutions from the slower Pro when needed.
These rounds of generation, scoring, and regeneration continue until Gemini fails to come up with anything better than what it already has.
The team tested AlphaEvolve on a range of different problems. For example, they looked at matrix multiplication again to see how a general-purpose tool like AlphaEvolve compared to the specialized AlphaTensor. Matrices are grids of numbers. Matrix multiplication is a basic computation that underpins many applications, from AI to computer graphics, yet nobody knows the fastest way to do it. “It's kind of unbelievable that it's still an open question,” says Balog.
The team gave AlphaEvolve a description of the problem and an example of a standard algorithm for solving it. The tool not only produced new algorithms that could calculate 14 different sizes of matrix faster than any existing approach, it also improved on AlphaTensor's record-beating result for multipying two four-by-four matrices.
AlphaEvolve scored 16,000 candidates suggested by Gemini to find the winning solution, but that's still more efficient than AlphaTensor, says Balog. AlphaTensor's solution also only worked when a matrix was filled with 0s and 1s. AlphaEvolve solves the problem with other numbers too.
“The result on matrix multiplication is very impressive,” says Moosbauer. “This new algorithm has the potential to speed up computations in practice.”
Manuel Kauers, a mathematician at Johannes Kepler University in Linz, Austria, agrees: “The improvement for matrices is likely to have practical relevance.”
By coincidence, Kauers and a colleague have just used a different computational technique to find some of the speedups AlphaEvolve came up with. The pair posted a paper online reporting their results last week.
“It is great to see that we are moving forward with the understanding of matrix multiplication,” says Kauers. “Every technique that helps is a welcome contribution to this effort.”
Matrix multiplication was just one breakthrough. In total, Google DeepMind tested AlphaEvolve on more than 50 different types of well-known math puzzles, including problems in Fourier analysis (the math behind data compression, essential to applications such as video streaming), the minimum overlap problem (an open problem in number theory proposed by mathematician Paul Erdős in 1955), and kissing numbers (a problem introduced by Isaac Newton that has applications in materials science, chemistry, and cryptography). AlphaEvolve matched the best existing solutions in 75% of cases and found better solutions in 20% of cases.
Google DeepMind then applied AlphaEvolve to a handful of real-world problems. As well as coming up with a more efficient algorithm for managing computational resources across data centers, the tool found a way to reduce the power consumption of Google's specialized tensor processing unit chips.
AlphaEvolve even found a way to speed up the training of Gemini itself, by producing a more efficient algorithm for managing a certain type of computation used in the training process.
Google DeepMind plans to continue exploring potential applications of its tool. One limitation is that AlphaEvolve can't be used for problems with solutions that need to be scored by a person, such as lab experiments that are subject to interpretation.
Moosbauer also points out that while AlphaEvolve may produce impressive new results across a wide range of problems, it gives little theoretical insight into how it arrived at those solutions. That's a drawback when it comes to advancing human understanding.
Even so, tools like AlphaEvolve are set to change the way researchers work. “I don't think we are finished,” says Kohli. “There is much further that we can go in terms of how powerful this type of approach is.”
What the firm found challenges some basic assumptions about how this technology really works.
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A key question in artificial intelligence is how often models go beyond just regurgitating and remixing what they have learned and produce truly novel ideas or insights.
A new project from Google DeepMind shows that with a few clever tweaks these models can at least surpass human expertise designing certain types of algorithms—including ones that are useful for advancing AI itself.
The company's latest AI project, called AlphaEvolve, combines the coding skills of its Gemini AI model with a method for testing the effectiveness of new algorithms and an evolutionary method for producing new designs.
AlphaEvolve came up with more efficient algorithms for several kinds of computation, including a method for calculations involving matrices that betters an approach called the Strassen algorithm that has been relied upon for 56 years. The new approach improves the computational efficiency by reducing the number of calculations required to produce a result.
DeepMind also used AlphaEvolve to come up with better algorithms for several real-world problems including scheduling tasks inside datacenters, sketching out the design of computer chips, and optimizing the design of the algorithms used to build large language models like Gemini itself.
“These are three critical elements of the modern AI ecosystem,” says Pushmeet Kohli, head of AI for science at DeepMind. “This superhuman coding agent is able to take on certain tasks and go much beyond what is known in terms of solutions for them.”
Matej Balog, one of the research leads on AlphaEvolve, says that it is often difficult to know if a large language model has come up with a truly novel piece of writing or code, but it is possible to show that no person has come up with a better solution to certain problems. “We have shown very precisely that you can discover something that's provably new and provably correct,” Balog says. “You can be really certain that what you have found couldn't have been in the training data.”
Sanjeev Arora, a scientist at Princeton University specializing in algorithm design, says that the advancements made by AlphaEvolve are relatively small and only apply to algorithms that involve searching through a space of potential answers. But he adds, “Search is a pretty general idea applicable to many settings.”
AI-powered coding is starting to change the way developers and companies write software. The latest AI models make it trivial for novices to build simple apps and websites, and some experienced developers are using AI to automate more of their work.
AlphaEvolve demonstrates the potential for AI to come up with completely novel ideas through continual experimentation and evaluation. DeepMind and other AI companies hope that AI agents will gradually learn to exhibit more general ingenuity in many areas, perhaps eventually generating ingenious solutions to a business problem or novel insights when given a particular problem.
Josh Alman, an assistant professor at Columbia University who works on algorithm design, says that AlphaEvolve does appear to be generating novel ideas rather than remixing stuff it's learned during training. “It has to be doing something new and not just regurgitating,” he says.
The DeepMind researchers found that they could sometimes give an idea for an algorithm as a prompt and produce interesting new results. Alman says this raises the prospect that human scientists could collaborate with a system like AlphaZero. "That seems really exciting to me," he says.
AlphaEvolve is not the only DeepMind program to demonstrate real ingenuity. The company's famous board-game-playing program AlphaZero was able to devise original moves and strategies through its own form of experimentation. Balog says that the evolutionary approach used by his group could be coupled with the reinforcement learning method employed in AlphaZero—a process that lets a program learn through positive and negative feedback—to create something that explores new ideas in other areas.
Two previous DeepMind projects also used AI to push the boundaries of computer science. AlphaTensor, from 2022, used the reinforcement learning method to produce novel algorithms. Fun Search, from 2024, used an evolutionary method to generate more efficient code for a given problem.
Neil Thompson, a scientist at MIT who studies the way algorithms affect technological progress, says that a key question is not just whether AI algorithms can exhibit original ideas, but how generally this may apply to scientific research and innovation.
“If these capabilities can be used to tackle bigger, less tightly-scoped problems, it has the potential to accelerate innovation—and thus prosperity,” Thompson says.
What do you make of AlphaEvolve? What novel problems would you like to see AI take on? Let me know by emailing hello@wired.com or adding to the comments section below.
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AI-powered notetaking tool Granola has been on a roll. The startup's seen a steep uptick in usage since it launched a year ago, mostly thanks to word of mouth among VCs and founders, but a big driver seems to be the fact that people are using it for doing more than its core pitch — automated notetaking for meetings.
Granola's co-founder, Chris Pedregal, told TechCrunch that the company's users are increasingly using Granola for taking personal notes, which helps them make all their information, both from work and otherwise, available to the app's AI to parse and surface insights from. “[People] have Granola open all day because they have a lot of meetings, so it's like […] where they're starting to live,” he said.
Pedregal said Granola's organic popularity among the tech crowd and diversifying use cases has helped its user base grow 10% every week since its launch, though he didn't specify how many users it currently has.
Off the back of that rapid growth and popularity, Granola on Wednesday said it has raised $43 million in a Series B funding round led by Nat Friedman and Daniel Gross's venture firm, NFDG, at a valuation of $250 million.
The round also saw participation from existing investors Lightspeed and Spark, as well as angel investors including Vercel's Guillermo Rauch, Replit's Amjad Masad, Shopify's Tobias Lütke, and Linear's Karri Saarinen. The round brings the company's total funding raised to $67 million.
Alongside this funding, Granola is also extending its remit beyond its current single-user focus to make itself more useful for businesses: It's launching a new collaboration feature that lets users share transcripts and notes with teammates, and enable the app's AI take to advantage of a broader pool of notes and details to surface insights.
Users in an organization can create custom folders for various collaborative use cases like sales calls, customer feedback, and hiring. The app will also let users share meeting notes with people who don't use Granola to let them chat with its AI and ask it questions.
Other meeting transcription and notetaking apps, such as Read AI, Fireflies, and Otter, already offer similar shared-space features. Pedregal, though, says Granola is for more than notetaking. “I think how Granola differs from other notetakers is that it is very personal and you are in control all the time. You can edit notes at any point. It is not about just capturing a meeting, but it is a space where you can work, even post meetings,” he said.
Earlier this month, Granola updated its app to enable users to ask the AI bot questions about all meetings it had recorded. Building on that, the company will now allow users to ask questions about specific folders as well.
Granola's new collaborative focus is part of a broader trend — many AI-powered meeting transcription and notetaking tools are expanding their focus and building integrations with other tools as they try to become a hub that stores and lets users search through knowledge from various sources.
Meanwhile, productivity suites are introducing transcription tools to keep customers from having to use other apps for that purpose. For instance, Notion just yesterday launched an AI meeting notetaking tool.
Lightspeed's Mike Mignano believes that Granola has an edge in this space because of its interface and user experience.
“Since the start, the company has had the right mix of AI transcript and human control of taking notes. Now that they are building context across the meetings and making the notes shareable, the product has become stronger. With these features, Granola will have long-term context for users and teams, kicking off network effects for the startup,” he said.
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Color me impressed with this giant mouse pad deal
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Mouse pads are an often overlooked peripheral when it comes to your gaming setup. They can add comfort, styling, and color to your desk, from the material the pad uses, the print or design, and even lighting. Today's deal features a mouse pad from Razer that features the RGB-laden Chroma lighting tech, on top of a Halo Infinite-inspired design. This is the extended size, so it can easily accommodate both your keyboard and mouse.
With a massive discount, plus a money-off coupon code, you can pick up this excellent deal from Newegg, where the Razer Goliathus Extended Chroma mouse pad is just $24, reduced from the original list price of $79. This is the Halo Infinite version, and has been reduced firstly to $49, and if you enter the code LEESA855 at the checkout, the price lowers to just $24, thanks to the $25 coupon code.
The Razer Goliathus Extended mouse pad measures 920mm wide by 294mm tall (36.22x11.57-inches), meaning you can quite comfortably fit both your mouse and your keyboard on the thing without worry. A smooth surface means your mouse sensor will be more accurate when tracking headshots, and the rubber bottom will stop any slipping as it grips your desktop. Plastic tubing stitched around the edge of the mat contains the RGB lighting and difuses the light for a more delicate hue.
Razer Goliathus Extended Chroma Mouse Pad: now $24 (was $79)This flexible full-size soft mouse mat, complete with RGB lighting lining the edge, a non-slip rubber base, and a perfect finish for any optical mouse, is a fantastic solution for gamers looking to light up their desktop setup. Use code LEESA855 to save $25 and reach the $24 deal price.
Don't forget to look at our Newegg coupon codes for May 2025 and see if you can save on today's deal or other products at Newegg.
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Zhao Weiguo stepped down as chairman in 2022 after being placed under investigation.
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The former billionaire chairman of Tsinghua Unigroup, Zhao Weiguo, has been handed a suspended death sentence after being found guilty of corruption and embezzlement. Tsinghua Unigroup, founded in 1988, was once the darling of Chinese chip manufacturing and the owner of numerous Chinese semiconductor outfits, notably YMTC and Unisoc, but was plagued by corruption allegations and investigations.
As reported by the Wall Street Journal, state broadcaster China Central Television (CCTV) reported the sentence passed down by the Intermediate People's Court in the northeastern city of Jilin. According to the report, Zhao was sentenced to death, suspended for two years. The punishment in such cases is normally commuted to life imprisonment if he doesn't commit any further crimes during the suspension period.
Once thought to be worth nearly $2.8 billion, Zhao was accused of corruption and embezzlement by China's Central Commission for Discipline Inspection. The Commission alleged that Zhao, "as a manager of a state-owned enterprise, was blinded by greed, acted recklessly, betrayed his duties and mission, misused public resources for personal gain, turned public property into private property, and regarded the state-owned enterprises he managed as private territory." He was also accused of deliberately seizing state-owned assets, illegally giving profitable business to relatives and friends, purchasing goods from said businesses at inflated prices, and more.
According to the CCTV's report, the court said that Zhao's activities involved "extremely huge sums" and "caused especially severe losses to state interests." CCTV also claimed that Zhao admitted guilt, had shown remorse, and had tried to return misappropriated funds, which allegedly included state assets worth $65 million and company losses worth $124 million.
Tsinghua Unigroup was supposed to be an integral part of China's 'Made in China 2025' initiative, a plan to build a self-sufficient semiconductor industry, and was known for making high-profile and aggressive acquisitions funded by the state and bonds.
The company defaulted on $198 million in bonds in 2020 and by 2021 was facing bankruptcy, with debts to the tune of $31 billion. Zhao stepped down as chairman a year later, coinciding with reports of an investigation.
In March last year, YMTC claimed to have made a flash memory breakthrough in creating QLC NAND that matches the endurance of TLC NAND.
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The RTX 5090 isn't delivering the performance uplift we expected.
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New benchmarking figures appear to reveal that the NVIDIA RTX 5090 laptop GPU may not be all that it's cracked up to be, revealing some disappointing performance figures when compared to the 5090.
The RTX 5090 laptop GPU arrived in late March 2025, but its launch was plagued by several issues, including delayed review units. A few reviews were available soon after the GPU became available, like Tom's Hardware's review of the Razer Blade 16, but it took some time for us to see an RTX 4090 vs. RTX 5090 comparison on nearly identical units. Jarrod's Tech has released a video evaluating two XMG Neo 16 laptops that were equipped with both GPUs, and the results are interesting, to say the least.
The XMG Neo 16 (2024) used an Intel Core i9-14900HX paired with 32 GB of DDR5-5600 RAM and an RTX 4090, while the newer XMG Neo 16 (2025) is equipped with an Intel Core Ultra 9 275HX with 32 GB of DDR5-6400 RAM and an RTX 5090 GPU. Because of these specifications, one would expect the newer laptop to run faster, especially as it has a newer top-of-the-line laptop CPU, faster memory, and the RTX 5090. More than that, the newer GPU uses faster VRAM and has 50% more memory than the RTX 4090. Unfortunately, Jarrod's Tech's test results tell a different story.
Game Title
RTX 4090 Laptop - 4K - XMG Neo 16
RTX 5090 Laptop - 4K - XMG Neo 16
Difference Percentage
RTX 4090 Laptop - 1440p - XMG Neo 16
RTX 5090 Laptop - 1440p - XMG Neo 16
Difference Percentage
RTX 4090 Laptop - 1080p - XMG Neo 16
RTX 5090 Laptop - 1080p - XMG Neo 16
Difference Percentage
A Plague Tale: Requiem
50.98
52.61
3.20%
91.12
92
0.97%
122.57
121.96
-0.50%
Alan Wake 2, Ray Tracing Low + High Settings + Upscaling, No Frame Gen, DX12
59.38
59.03
-0.59%
89.10
88.58
-0.58%
108.29
109.44
1.06%
Apex Legends, Maximum Settings, DX12
216.97
219.81
1.31%
299.21
299.20
0.00%
299.27
299.50
0.08%
Assassin's Creed Shadows, Very High Settings, DX12
37.8
38.18
1.01%
56.98
56.73
-0.44%
66.91
65.88
-1.54%
Baldur's Gate 3, High Settings, DX11
81.01
85.03
4.96%
108.51
99.06
-8.71%
111.39
101.63
-8.76%
Black Myth: Wukong, Ray Tracing Very High + Cinematic Settings + Upscaling, DX12
39.42
40.87
3.68%
58.61
58.44
-0.29%
69.57
68.13
-2.07%
Cyberpunk 2077 v2.21, Ray Tracing Ultra Settings + Upscaling, No Frame Gen, DX12
62.95
62.99
0.06%
92.33
86.33
-6.50%
110.94
105.08
-5.28%
Dying Light 2, Ray Tracing High Quality Settings + Upscaling, DX12
71.81
76.12
6.00%
110.3
115.57
4.78%
136.02
144.79
6.45%
Forza Horizon 5, Extreme Settings, DX12
115.52
121.21
4.93%
153.64
170.22
10.79%
175.16
196.35
12.10%
Ghost of Tsushima, Very High Settings, DX12
55.48
54.63
-1.53%
95.3
97.47
2.28%
122.77
127.68
4.00%
God of War Ragnarok, Ultra Settings, DX12
77.33
82.2
6.30%
134.29
140.91
4.93%
171.02
175.72
2.75%
Hogwarts Legacy, Ultra Settings, DX12
56.95
53.54
-5.99%
94.9
95.11
0.22%
124.16
114.53
-7.76%
Horizon Forbidden West, Very High Settings, DX12
59.12
59.97
1.44%
100.96
100.37
-0.58%
126.96
127.66
0.55%
Kingdom Come: Deliverance II
49.34
50.75
2.86%
89.1
86.68
-2.72%
117.66
116.16
-1.27%
Marvel Rivals, Ultra Settings, DX12
57.66
59.54
3.26%
107.79
105.94
-1.72%
146.87
144.65
-1.51%
Marvel's Spider-Man 2, Ray Tracing Very High + Very High Settings + Upscaling, DX12
56.99
58.47
2.60%
75.13
80.71
7.43%
85.3
94.04
10.25%
Metro Exodus Enhanced, Extreme Settings + Ray Tracing Ultra, DX12
40.95
42.3
3.30%
71.53
73.28
2.45%
96.52
96.42
-0.10%
Microsoft Flight Simulator 2024, High-End Settings, DX12
41.72
42.66
2.25%
68.97
72.92
5.73%
88.67
95.53
7.74%
Red Dead Redemption 2, Ultra Settings, Vulkan
80.65
70.56
-12.51%
124.58
98.54
-20.90%
149.56
114.18
-23.66%
S.T.A.L.K.E.R. 2: Heart of Chernobyl
45.04
44.91
-0.29%
77.18
75.36
-2.36%
86.07
84.48
-1.85%
Shadow of the Tomb Raider, Highest Settings, DX12
106.00
115.00
8.49%
199.00
207.00
4.02%
242.00
242.00
0.00%
Starfield, Ultra Settings, DX12
57.95
55.32
-4.54%
87.90
81.61
-7.16%
100.25
99.70
-0.55%
The Last of US Part II, Very High Settings, DX12
62.97
69.48
10.34%
105.33
108.93
3.42%
132.98
140.83
5.90%
The Witcher 3, Ultra Settings, DX12
51.39
55.24
7.49%
108.78
111.51
2.51%
170.67
170.84
0.10%
Warhammer 40,000: Space Marine 2, Ultra Settings, DX12
43.54
51.61
18.53%
86.65
95.77
10.53%
125.35
119.79
-4.44%
Average
91.28
92.41
1.23%
134.10
134.13
0.02%
149.26
149.20
-0.04%
The YouTube channel tested 24 titles on both laptops and found that the average FPS results between the two GPUs were negligible. The RTX 5090 outperformed the 4090 by just 1.23% at 4K, with the performance gap dropping to just 0.02% at 1440p. And if you prioritize FPS over quality, the older GPU was found to hit a higher average FPS by 0.04% at 1080p gaming. The only silver lining the reviewer noticed is that the RTX 5090 ran cooler and at a lower GPU clock speed than the RTX 4090. This meant that it used less power and allowed gamers to play on battery for much longer.
Even though the MSI Titan 18 HX (another 5090 beast) is the best gaming laptop on the market right now, with the egregious pricing on laptops and GPUs, upgrading to an RTX 5090 is just not worth it yet. Unless you consider yourself an on-battery laptop gamer, need 24 GB of VRAM, or love Nvidia's Frame Gen tech, you're much better off getting the slightly older RTX 4090 when it comes to FPS per dollar.
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Jowi Morales is a tech enthusiast with years of experience working in the industry. He's been writing with several tech publications since 2021, where he's been interested in tech hardware and consumer electronics.
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Let's be honest. Your TV's built-in speakers probably aren't cutting it. And that's okay, because those types of speakers generally aren't very good. You get muffled dialogue, flat action scenes, and lackluster music. And for some people, setting up a full surround sound system can feel like too much. It's too many wires, too many speakers, too much money. If you still want decent sound but don't want complicated setup times and an extremely expensive entry price, a soundbar should be at the top of your list.
Right now, you can head to Amazon to grab the JBL Bar for just $200, which is $100 off its normal price of $300. That's a discount of 33%.
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This is a two-piece system. You get a soundbar that sits in front of your TV and a wireless subwoofer. Together, both serve up a punchy 300 watts of power, which is more than enough to fill a living room with crisp highs, clear dialogue, and deep, punchy bass. The sub makes a real difference and connects wirelessly to deliver targeted bass wherever you think you might need it most in the room.
It supports Dolby Digital and features JBL's Surround Sound processing, which simulates a wider, more immersive audio experience without needing extra rear speakers. You won't get true surround sound, but for most users, the effect feels cinematic enough, and it's way more convenient than setting up a whole surround system when you don't have the time or money. Or maybe it's the patience you don't have.
Setup is fairly quick. It uses HDMI ARC to connect to your TV, but it also has optical and Bluetooth options. You can stream from your phone directly to your soundbar as well. You can use Bluetooth to get it set up, and swap between connections from there if you want to use something else to listen or watch with.
This soundbar is super easy to set up right out of the box, and it won't cost you very much to invest in. Remember that it's just $200, saving you $100 off its normal price, and that's nothing to sneeze at. If you want a better sound setup at home and don't want to spend too much money, this really is the way to go. You'll have more space, you'll enjoy what you watch more, and your home will feel more like an entertainment epicenter.
See at Amazon
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The Anti-Defamation League is lobbying Alphabet, the parent company of Google, to vote down a shareholder proposal that would require the company to investigate whether its cloud services (specifically Project Nimbus, which is a contract with the Israeli government) are aiding human rights abuses in conflict zones (you know, like Gaza). Alphabet is expected to vote on the proposal at its next shareholder meeting on June 6th.
This week, the ADL sent a letter to Alphabet in which it described the proposal as a “ploy” by the Boycott, Divest, and Sanctions movement, which has long sought to curb American aid to the Israeli war machine. “Proposal 9 offers the pretense of concern for human rights when in fact it is a thinly disguised ploy to weaken Israel's national security — and to undermine its right to defend itself — by pressuring Alphabet to withhold vital technology that supports the country's self-defense capabilities,” said Jonathan Greenblatt, CEO and National Director of the Anti-Defamation League.
Nimbus is described by Google as “cloud services to digitally transform the State of Israel.” What Nimbus is actually used for is still somewhat unclear. It is a cloud and AI system, so ostensibly it could be used for a lot of different things. Human rights groups have repeatedly asked for more information about the project, to no avail. Google isn't the only large U.S. company involved in the project. Amazon is another major stakeholder that has provided cloud infrastructure.
Inside the company, concerns have swirled over whether Israel's increasingly genocidal policies against the Palestinians may lead to legal action against Google for its complicity in the carnage. In December, the New York Times reported that company lawyers were concerned that “Google Cloud services could be used for, or linked to, the facilitation of human rights violations, including Israeli activity in the West Bank.”
Over the past year, Israel has decimated the Palestinian population in Gaza, leading to widespread condemnations of “genocide” and to war crime charges filed by the International Criminal Court against the nation's leader, Benjamin Netanyahu. Some 50,000 Palestinians have reportedly been killed as a result of Israel's assault, the majority of whom have been women and children, according to one UN estimate. Amidst its blitzkrieg of the region, Israel has targeted journalists and healthcare workers with impunity and has openly targeted hospitals and other critical infrastructure. The government recently announced plans to permanently occupy and “flatten” all of Gaza.
Google's corporate kerfuffle over the Nimbus-related shareholder proposal also comes at the same time that The Intercept has revealed the degree to which the company intuited that Nimbus could prove problematic before it ever provided services to the Israeli government. The information is based on a confidential internal report from 2021 that showed executives' anxieties about the potential for the deal to spin out of the tech company's control. “Google Cloud Services could be used for, or linked to, the facilitation of human rights violations, including Israeli activity in the West Bank,” resulting in “reputation harm,” Google worried.
Even more problematically, Google worried that it would have a limited ability to control what Israel did with Nimbus. Due to the way in which the deal was structured, the project—once in Israel's hands—would largely be beyond Google's control. The report states that the company would “be constrained by the terms of the tender, as Customers are entitled to use services for any reason except violation of applicable law to the Customer.”
The Intercept article also makes clear the degree to which the Nimbus deal has wedded Google to the Israeli national security state. The article notes that the contract obligated the creation of a secret Israeli team within Google that was capable of handling the covert nature of the effort:
…Project Nimbus entails a deep collaboration between Google and the Israeli security state through the creation of a Classified Team within Google. This team is made up of Israeli nationals within the company with security clearances, designed to “receive information by [Israel] that cannot be shared with [Google].” Google's Classified Team “will participate in specialized training with government security agencies,” the first report states, as well as “joint drills and scenarios tailored to specific threats.”
Google has spent years attempting to tamp down criticism (both from inside its own ranks and from outside groups) over its ties to the Israeli government. Concerned Googlers have frequently lobbied for the tech giant to cut ties with Project Nimbus. Meanwhile, groups like No Tech for Apartheid have continually sought to condemn the project and its potential role in the ongoing atrocities being committed by the Israeli government. Publicly, Google has never expressed anything approaching concern, maintaining that Nimbus is a critical program for a key ally in the Middle East.
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But don't imagine you'll use Gemini in Android Auto to rehearse talking to your boss.
With Material 3 Expressive, Android is getting a more graphic design-y interface—the complete opposite of what is rumored for iOS 19.
Google's mobile OS is getting a bolder and more in-your-face visual refresh.
Big tech has an image problem. It's going to the people who make the images for help.
Google cofounder Sergey Brin recently said that employees should work 60 hours a week in-office to keep up in artificial intelligence race.
What red-blooded tech company wouldn't want a huge install base and the advantage of self-dealing?
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6/10
Escaping the screen isn't easy. When I tested the Light Phone III in March—a phone designed to strip away apps and focus on the basics—I quickly found how many little things I needed my smartphone for, from accessing my home's security cameras to authentication apps so I could sign in to web services on my laptop. Sometimes it's just not easy to go cold turkey. But that's where the Minimal Phone steps in.
This is an Android phone with a physical keyboard and an e-paper touchscreen. It looks like a Kindle had a baby with a BlackBerry. Unlike most anti-smartphone products that offer a curated suite of basic phone functions, the Minimal Phone lets you access any app through the Google Play Store like a normal Android phone. But the experience is hampered by the tiny, 4.3-inch e-paper screen that needs constant refreshing. The keyboard will also slow you down. This frustrating smartphone experience is sort of the point.
I got into bed one night, ready for my usual bedtime doomscrolling ritual. As my wife was zooming through TikTok, I looked at my phone and wailed to my wife, “I can't doomscroll!” I heaved a sigh, put my phone down, and went to bed. This is not to say that I magically woke up the next day with the best sleep of my life—using your phone before bed can affect sleep—but it did prove one thing: The Minimal Phone did its job of cutting my time spent on social media.
The difference in build quality between the Minimal Phone and the Light Phone III is stark. The latter mixes glass and metal, whereas the Minimal is almost entirely plastic. It feels lightweight, and I have to say, a little cheap. It doesn't help that immediately after unboxing it, the phone's back was already grubby with smudges, almost like I had just eaten a bag of Cheetos (I wish). Maybe that's why the company sells Dbrand skins to cover it up.
Minimal Phone
Rating: 6/10
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On the right edge is a power button with a fingerprint scanner baked in, and it's fairly reliable. The bottom houses the USB-C charging port and a headphone jack. On the left edge is the SIM tray, which supports microSD cards for storage expansion if 128 GB isn't enough. The volume buttons are divided by an “e-paper refresh” button, probably the button you'll press the most.
That brings us to the 4.3-inch touchscreen, which is … not great. This is largely because when you scroll or move through web pages and menus, there's a lot of ghosting—a faint image of the previous text you were staring at. Even one or two scrolls and you'll want to hit that e-paper refresh button liberally to remove these artifacts—that quickly becomes an annoying step.
It also doesn't help that the monochrome screen doesn't play well with lighter colors on select websites, though pages with mostly black and white text, like WIRED.com, look fine. Thankfully, I had no problems reading the matte screen in any lighting situation. You can adjust the screen's color temperature and brightness to suit your eyes, and there's no glare.
Moving throughout the Android 14 operating system can feel a little slow, but this is largely just the speed of the e-paper screen. From a performance standpoint, it seems to chug along fine with the MediaTek Helio G99 chipset inside. Granted, I do not recommend trying mobile games.
The home screen shows a list of shortcuts to core apps, like Phone, Messages, Camera, Calendar, and Calculator. There's a Notes app, and it defaults to opening Google Keep. (You can remove and add new ones by long-pressing the app name in the drawer.) I've used the phone like any other I test, even using Google Maps to navigate and Google Wallet for tap-to-pay at physical retailers, though you'll have a subpar experience with some apps more than others.
You won't want to do certain things on the Minimal Phone. Watching videos, playing games, and scrolling through social media do not mesh well with an e-paper screen and the slow refresh rate. YouTube videos and Instagram Reels alike feel like you're staring at a strobe light, with the screen flashing with every frame. Press and hold the e-paper refresh button, and you'll find an “ultra” refresh setting that makes this a little better, but the quality significantly diminishes, and everything looks like a blob. (I usually kept it at “hybrid," which switches to ultra when scrolling or when a video is playing.)
Minimal Phone
Rating: 6/10
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This plays nicely to the company's goal of giving you the modern-day essentials while stripping away distractions. And truly, it does work in this regard. I was barely on social media during my time with the Minimal Phone, and didn't miss it. The one thing to remember is that since you can install apps like Slack and connect your work email, I found myself still “online” and responding to colleagues even away from my desk. That's a decision to make in the app installation phase, and a test of self-control.
There are some overall quirks with the software. Most Android apps nowadays ask if you want to allow notifications, but I barely got this prompt on the Minimal Phone, which might be by design. Since I barely went on Instagram using this phone, I didn't realize I missed a few DMs from friends, so that's something to make sure you enable if you want. I also had trouble scanning QR codes in the camera app—it wouldn't register. So I took a picture and then used Google Lens to scan them, which worked as an alternative.
The physical keyboard is solid—not the best I've used but not the worst. The spacebar feels a bit mushy, and some buttons on occasion didn't register the keypress. I wish the Android navigation buttons above the keyboard were physical keys instead of touch buttons—I accidentally went to the home screen a few too many times when scrolling because it's right under the touchscreen.
The 16-megapixel camera is downright abysmal. All the photos look grainy, blurry, and overexposed or underexposed. I also don't know why the company stuffed the 5-MP selfie camera right next to the keyboard, where it's easy to block when holding the phone. There are huge bezels around the screen, so I'm unsure why the front camera couldn't sit at the top.
Minimal Phone
Rating: 6/10
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There's also no 5G support, but I didn't find this a problem. After all, it's not like I was streaming much. That said, I expected battery life to be better. With average use, the 3,000-mAh cell got down to roughly 50 percent at the end of a day, and it lasted me nearly two full days before needing a top-up. Considering all the sacrifices in screen quality and lack of social media, I expected several days of juice. At least there's wireless charging support, and you can even get a MagSafe case to connect it with MagSafe wireless chargers.
Minimal Phone
Rating: 6/10
All products featured on WIRED are independently selected by our editors. However, we may receive compensation from retailers and/or from purchases of products through these links.
The company claims it'll support the software for five years, but Minimal is a new company, and this is its first product. It could make good on its promise, but it could also close up shop—now you've sunk $399 on a device that won't get new Android versions, and it's already out of date.
The price is more stomachable than, say, the $599 Light Phone III. If you don't want to outright ditch your smartphone and swap your personal SIM, Minimal has cell plans (with call and text) starting at $15 per month, if you don't mind having a second number. That makes it more of a full-fledged distraction-free smartphone alternative. (The cell plan is through Gigs, which uses T-Mobile's and AT&T's networks.)
It comes down to what you want and knowing this phone's limitations. I didn't enjoy using the Minimal Phone, despite enjoying my time with the Light Phone III, which has fewer features. The plasticky and somewhat stale design is a turn-off, and the slow, ghosting screen gets old fast. If your goal is to limit screen time without sacrificing access to specific apps, the Minimal Phone does the job, or you could buy a cheap smartphone and be selective of what you install. I think the company will hit its stride in version two.
Minimal Phone
Rating: 6/10
All products featured on WIRED are independently selected by our editors. However, we may receive compensation from retailers and/or from purchases of products through these links.
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TensorWave, a data center provider building facilities primarily with AMD hardware, has raised $100 million as it seeks to further build out its data center infrastructure.
The funding round was led by Magnetar and AMD Ventures, and brings the company's total capital raised to $146.7 million, according to Crunchbase. Maverick Silicon, Nexus Venture Partners, and Prosperity7 also participated in the round.
It's a precarious time for data center projects. Tariff-related price hikes on components like server racks and chips could contribute to overall data center build costs increasing by 5% to 15%, per an analysis by TD Cowen.
Investors are also wary of such projects accumulating too much capacity, particularly as the number of cheap AI services continues to grow. Overcapacity is reportedly one of the factors delaying OpenAI's ambitious $500-billion Stargate data center project.
Las Vegas, Nevada-based TensorWave claims that it hasn't seen a slowdown in business, however. The company is on track to end the year with run-rate revenue of more than $100 million, which would mark a 20x increase from a year earlier, according to CEO Darrick Horton (pictured above, in the middle).
Nvidia is the favored hardware vendor for data centers that are used for training and running AI models. But TensorWave embraced AMD early on, aiming to provide cloud services at lower prices.
TensorWave recently deployed a “dedicated training” cluster of around 8,000 AMD Instinct MI325X GPUs. The new capital will enable the company to grow that cluster, as well as expand headcount and support “operational growth,” said Horton.
TensorWave has a team of around 40 people at present and expects headcount to reach over 100 by the end of the year.
“This $100 million funding propels TensorWave's mission to democratize access to cutting-edge AI compute,” Horton added. “Our 8,192 Instinct MI325X GPU cluster marks just the beginning as we establish ourselves as the emerging AMD-powered leader in the rapidly expanding AI infrastructure market.”
Other data center providers placing bets on AMD's AI chips range from startups like Lamini and Nscale to larger, more entrenched cloud providers such as Azure and Oracle.
Horton co-founded TensorWave with Jeff Tatarchuk (pictured above, on the left) and Piotr Tomasik (pictured above, on the right) in 2023. Tatarchuk had previously launched cloud vendor VMAccel with Horton and sold another startup, Lets Rolo, to digital identity firm Lifekey. Horton co-founded crypto mining company VaultMiner Technologies, VMAccel's corporate parent. As for Tomasik, he co-launched influencer marketer site Influential and is the second co-founder of Lets Rolo.
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A cybersecurity expert has created a proof of concept for CPU ransomware.
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Rapid7's Chrstiaan Beek has written proof-of-concept code for ransomware that can attack your CPU, and warns of future threats that could lock your drive until a ransom is paid. This attack would circumvent most traditional forms of ransomware detection.
In an interview with The Register, Beek, who is Rapid7's senior director of threat analytics, revealed that an AMD Zen chip bug gave him the idea that a highly skilled attacker could in theory "allow those intruders to load unapproved microcode into the processors, breaking encryption at the hardware level and modifying CPU behavior at will."
Google's Security Team has previously identified a security vulnerability in AMD's Zen 1 to Zen 4 CPUs that allows users to load unsigned microcode patches. It later emerged that AMD Zen 5 CPUs are also affected by the vulnerability. Thankfully, the issue can be fixed with new microcode, just like a previous Raptor Lake instability. However, Beek saw his opportunity. "Coming from a background in firmware security, I was like, woah, I think I can write some CPU ransomware," and that's exactly what he did.
According to the report, Beek has indeed written proof-of-concept code for ransomware that can hide in a CPU. Reassuringly, he promises they won't release it.
As per the report, Beek reckons this type of exploit could lead to a worst case scenario: "Ransomware at the CPU level, microcode alteration, and if you are in the CPU or the firmware, you will bypass every freaking traditional technology we have out there."
Beek also referenced leaked comments from the Conti ransomware gang, which surfaced in 2022. In a presentation given at RSAC, he highlighted chat logs from the group. "I am working on a PoC where the ransomware installs itself inside UEFI, so even after reinstalling Windows, the encryption stays," reads one. Another noted that with modified UEFI firmware, "we can trigger encryption before the OS even loads. No AV can detect this."
The upshot? "Imagine we control the BIOS and load our own bootloader that locks the drive until the ransom is paid," a hacker hypothesized.
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Beek warns that if bad actors were working on these exploits a few years ago, "you can bet some of them will get smart enough at some point and start creating this stuff."
To close his interview, Beek expressed his frustration that "We should not be talking about ransomware in 2025," and stated that everyone involved should be pulling together to fix the foundations of hardware security. He also bemoaned how many ransomware breaches were underpinned by high-risk vulnerabilities, weak passwords, lack of authentication, and more.
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There is no significant difference in the effectiveness of how autistic and non-autistic people communicate, according to a new study, challenging the stereotype that autistic people struggle to connect with others.
The findings suggest that social difficulties often faced by autistic people are more about differences in how autistic and non-autistic people communicate, rather than a lack of social ability in autistic individuals, experts say.
Researchers hope the results of the study will help reduce the stigma surrounding autism, and lead to more effective communication support for autistic people.
Autism is a lifelong neurodivergence and disability, and influences how people experience and interact with the world.
Autistic people often communicate more directly and may struggle with reading social cues and body language, leading to differences in how they engage in conversation compared to non-autistic people.
The study, led by experts from the University of Edinburgh, tested how effectively information was passed between 311 autistic and non-autistic people.
Participants were tested in groups where everyone was autistic, everyone was non-autistic, or a combination of both.
The first person in the group heard a story from the researcher, then passed it along to the next person. Each person had to remember and repeat the story, and the last person in the chain recalled the story aloud.
The amount of information passed on at each point in the chain was scored to discern how effective participants were at sharing the story. Researchers found there were no differences between autistic, non-autistic, and mixed groups.
After the task, participants rated how much they enjoyed the interaction with the other participants, based on how friendly, easy, or awkward the exchange was.
Researchers found that non-autistic people preferred interacting with others like themselves, and autistic people preferred learning from fellow autistic individuals. This is likely down to the different ways that autistic and non-autistic people communicate, experts say.
The findings confirm similar findings from a previous smaller study undertaken by the same researchers. They say the new evidence should lead to increased understanding of autistic communication styles as a difference, not a deficiency.
Autism has often been associated with social impairments, both colloquially and in clinical criteria. Researchers have spent a lot of time trying to 'fix' autistic communication, but this study shows that despite autistic and non-autistic people communicating differently it is just as successful. With opportunities for autistic people often limited by misconceptions and misunderstandings, this new research could lead the way to bridging the communication gap and create more inclusive spaces for all."
Dr. Catherine Crompton, Chancellor's Fellow, University of Edinburgh's Centre for Clinical Brain Sciences
The study is published in Nature Human Behaviour: https://www.nature.com/articles/s41562-025-02163-z [URL will become active after embargo lifts]. It was funded by the Templeton World Charity Foundation. It also involved researchers from the University of Texas at Dallas, the University of Nottingham, and the University of Glasgow.
University of Edinburgh
Crompton, C. J., et al. (2025). Information transfer within and between autistic and non-autistic people. Nature Human Behaviour. doi.org/10.1038/s41562-025-02163-z.
Posted in: Medical Research News | Medical Condition News
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A first-in-human study of an investigational once-daily oral treatment for obesity (SYNT-101) demonstrated positive preliminary data for the safe and effective redirection of nutrient absorption into the lower intestine, the weight loss and metabolic management mechanism behind gastric bypass surgery.
In the study, being presented at this year's European Congress on Obesity (ECO) in Malaga, Spain (11-14 May), participants were surveyed for adverse events, tolerability markers, as well as modulation of satiety hormones that influence hunger and weight loss. The results suggest a strong safety and tolerability profile, along with control of hunger and weight loss.
"These data validate the potential of SYNT-101 to induce metabolic changes that support glycaemic control, weight loss and energy balance," said Rahul Dhanda, chief executive officer of Syntis Bio, the Boston-based biopharmaceutical company developing SYNT-101.
"We believe that SYNT-101 will provide a convenient, more sustainable oral alternative and/or complement to systemic therapies such as GLP-1 drugs. The millions of people living with obesity need novel treatment options that are safe, effective and avoid the high costs and severe side effects that often accompany available treatment options."
Many obesity medications, like GLP-1 receptor agonists, are effective in aiding weight loss, but loss of lean muscle remains a common concern. There are also ongoing issues with these drugs around accessibility, gastrointestinal side effects and long-term maintenance.
SYNT-101 mimics the effects of gastric bypass by forming a temporary polydopamine coating in the duodenum, shifting nutrient exposure to the lower intestine to naturally promote satiety and support metabolic balance.
In addition, this "duodenal nutrient exclusion" effect improves satiety and metabolic regulation, and has been shown to better preserve lean muscle mass compared to GLP-1 drugs. The polydopamine lining is designed work for up to 24 hours, after which it is naturally cleared from the body. SYNT-101 will ultimately be delivered in a once-daily oral pill.
In preclinical studies, SYNT-101 has shown promising effects on glycaemic control and produced weight loss of 1% a week for six weeks while preserving 100% of lean muscle mass in rodent models.
In the human pilot study, nine healthy participants (2 male, 7 female, aged 24–53 years, BMI 19–29 kg/m2), received a single dose of SYNT-101 in liquid form, administered in three dose levels. Two participants were given 25% of the target dose, three received 50% and four received the full target dose.
Researchers conducted safety assessments and oral glucose tolerance tests to evaluate the tolerability and efficacy of SYNT-101, as well as endoscopic imaging to check whether the upper part of the small intestine was fully coated with the temporary polydopamine lining.
Blood tests were also conducted before and after treatment with SYNT-101 to assess the effects on satiety and metabolic hormone levels, including liver enzymes, leptin (a hormone that regulates appetite) and ghrelin (a hormone that causes hunger).
Endoscopic imaging confirmed that the polymer coating formed as expected across the upper small intestine, and tissue samples showed that SYNT-101 was safely eliminated within 24 hours of administration. No adverse or serious adverse events were reported in any dosage group.
During the 10 days following treatment, liver enzymes including aspartate transaminase (AST), alanine transaminase (ALT) and bilirubin remained stable for each participant, consistent with normal liver functioning.
Additionally, gastrointestinal tolerance was excellent, with no changes noted in the Gastrointestinal Symptom Rating Scale (GSRS), and all participants reported an average pain rating of 0.
Importantly, glucose tolerance tests revealed delayed uptake of glucose following SYNT-101 treatment. At 30 and 60 minutes, glucose absorption was far lower than in untreated patients, by roughly 35% and 21% respectively. This delay suggests that absorption occurs later in the intestine, as expected, rather than in the coated region of the duodenum.
Although the pilot study was not designed to measure weight loss, participants receiving a full dose of SYNT-101 also received blood tests, which showed elevated levels of leptin and lower levels of ghrelin, consistent with findings from preclinical in vivo models showing reduced food intake.
The authors note that larger trials are needed to fully assess the drug's efficacy and safety. Syntis Bio plans to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) during the second half of 2025.
We are eager to replicate these data in our upcoming Phase 1 clinical trial and further explore the ability of SYNT-101 to produce sustainable, safe, effective weight loss by reducing fat, preserving lean muscle and stimulating natural production of satiety hormones to prevent weight regain."
Rahul Dhanda, chief executive officer, Syntis Bio
European Association for the Study of Obesity
Posted in: Drug Trial News | Medical Condition News
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Approximately 1.4 million people will receive a diagnosis of diabetes this year, per the American Diabetes Association.
That means 1.4 million conversations with patients about what it means to have this chronic condition and how to manage it effectively. That means 1.4 million patients asking, “What do I do now?”
These conversations, which largely happen in primary care settings, give providers an opportunity to impress upon their patients the importance of keeping their blood glucose levels under control.
But these discussions must also be intentionally tailored to each individual patient's understanding of the disease and their role in caring for themselves.
Before diving into a discussion about treatment, the first step should be assessing your patient's existing knowledge about diabetes. Research suggests low levels of health literacy can be a barrier to good self-management and positive outcomes, which makes this assessment — followed by education — especially crucial.
“It's good to gauge their understanding of what this [disease] actually is,” said Absalon Gutierrez, MD, an endocrinologist with The University of Texas Health Science Center at Houston.
Learning some motivational interviewing skills can help with navigating this type of conversation, said Mohan Moreshwar Nadkarni, MD, an internist and chief of General Internal Medicine at University of Virginia Health in Charlottesville, Virginia.
Nadkarni uses these skills when seeing patients at a large primary care clinic where about 30% of the patients have diabetes. He often starts by asking patients what they know about the disease and if they have any relatives with diabetes and what that has meant for them.
Nadkarni asks questions to help gauge what might inspire patients to take charge of their health. The evidence-based approach improves patient engagement by encouraging patients to explore their own motivation to change their behaviors, rather than just listening to a set of instructions.
Bryan Cochran, MD, family medicine physician at MedStar Health Primary Care in Alexandria, Virginia, tailors each conversation to the individual patient because every patient has a different level of preparation for hearing such news.
“For some patients, they've been anticipating the diagnosis, and they may have been prediabetic or have a family history, so they are ready to hit the ground running with dietary changes or medications,” said Cochran. “For others, it can feel like a blind-sided diagnosis. They can feel shocked and overwhelmed to have to start a myriad of new lifestyle rules and restrictions, as well as potentially a whole host of new medications.”
Type 2 diabetes is associated with a wide range of possible comorbidities, including a higher risk for certain kinds of cancer, cardiovascular disease, obstructive sleep apnea, liver and kidney disease, and cognitive decline.
Neil Soskel, DO, primary care physician at Mount Sinai South Nassau in Lynbrook, New York, noted that some newly diagnosed patients don't quite grasp the seriousness of the diagnosis.
“I tell them that this is a lifetime disease,” Soskel said. “It's always going to be with them. They're just going to control it, and then I go into all the secondary complications.”
“You've kind of got to go with tough love,” he added.
Gutierrez said it can be useful to specifically tell patients that they likely won't feel a difference just from having elevated blood glucose levels.
But over time, uncontrolled diabetes can lead to several potential complications such as diabetic retinopathy, diabetic neuropathy, and even possibly amputation, as well as the increased risk for other comorbidities.
“You're trying to stop some things that are silent killers down the line,” Gutierrez said.
Brent Smith, MD, family physician in Greenville, Michigan, and member of the board of directors of the American Academy of Family Physicians, recommends approaching conversations that you have with patients with care.
“We have to couch it in a way that will make it have weight without being overly harsh,” said Smith.
Some patients may have struggled with their weight their entire adult lives, and suddenly they are finding out that they have diabetes.
“There's a lot of doubt and anger and all the bad emotions that go along with that,” said Smith. “If you approach that too casually or too negatively, it can immediately check them out of the process.”
Nadkarni agreed about the need for care, noting that his program holds seminars for residents to learn how to break bad news, including sharing with patients they have a chronic illness like diabetes.
“Because this is going to totally turn their lives topsy turvy, at least at first,” Nadkarni said.
A type 2 diabetes diagnosis may be particularly difficult for some younger adults (< 45 years) to receive, according to a 2021 study in Journal of General Internal Medicine.
Positive behavioral changes — including changes to physical activity levels, diet, and monitoring the effect of behaviors on blood glucose levels — lead to better management of diabetes and better outcomes, according to research.
In some cases, it also requires patient adherence to medication regimens that may change over time.
The primary care clinician can help newly diagnosed patients figure out what motivates them to change their behavior. “Do you want to be around for your grandchildren and to be a part of their life?” Smith might ask a patient. “If you do, we need to start making some changes.”
Primary care physicians can also encourage patients by emphasizing their ability to make positive changes and stick to their treatment plans.
“You can assure them that they can actually do well,” said Nadkarni. “They have it within their control to keep their diabetes at a safe level. That's something that I can't do for them. The locus of control has to be the patients themselves, being motivated to care for themselves.”
Send comments and news tips to news@medscape.net.
Carrying eagle feathers and chanting prayers, Western Apache runners hit the road on a roughly 80-mile journey this month to try to save their sacred land from being fast-tracked by President Donald Trump into a copper mine. This nationally watched battle, which hinges on religious freedom, awaits the U.S. Supreme Court.
The prayer run aimed to defend a 6-square-mile piece of land in rural Arizona outside of Phoenix called Chi'chil Biłdagoteel, or Oak Flat, where tribes have held ceremonies for centuries. The U.S. Forest Service, which owns the site, plans to trade a portion of it to a foreign-owned mining company, Resolution Copper, in exchange for other environmentally sensitive properties.
The battle over Oak Flat traces back 30 years, when prospectors found a massive copper deposit beneath the ground. The proposed land swap, which Congress approved in 2014 through a defense spending bill, has been stalled by three lawsuits.
But on April 17, the Trump administration pushed the project forward without waiting for the courts. The Forest Service announced it would issue an environmental review as soon as June 16, which would pave the way for the land transfer. Trump issued an executive order to expedite the Resolution Copper mine project, as part of a broader push to open more public lands to drilling and mining.
The copper mine would be the largest in North America, producing up to a quarter of U.S. copper demand, the company projects. But it also would destroy most of Oak Flat, leaving behind a sinkhole nearly 2 miles wide and as deep as the Eiffel Tower.
Apache Stronghold, a nonprofit that aims to protect sacred lands including Oak Flat, won a reprieve on May 9, when U.S. District Judge Steven Logan granted an injunction blocking the land swap while the Supreme Court considers its case. The high court is expected to decide whether to take it by early July.
"The federal government and Resolution Copper have put Oak Flat on death row — they are racing to destroy our spiritual lifeblood and erase our religious traditions forever," Wendsler Nosie Sr., founder of Apache Stronghold, said in a statement. "We are grateful the judge stopped this land grab in its tracks so that the Supreme Court has time to protect Oak Flat from destruction."
Apache Stronghold's temporary victory came after the four-day journey from Oak Flat to the federal courthouse in Phoenix ahead of the injunction hearing. The prayer run drew 60 runners, running in segments. Eighty-five faith groups and 44 tribal nations are supporting Apache Stronghold's Supreme Court appeal.
The fight over Oak Flat offers a glimpse into environmental, public health, and religious battles that may intensify as Trump prioritizes tapping into domestic sources of minerals such as copper, a key ingredient for electronics and renewable energy projects. The case also could set a legal precedent for whether religious freedom grants tribes the right to pray on ancestral lands outside of their reservations.
The Oak Flat case highlights some of the health concerns that arise when ancestral Native American lands owned by the federal government are opened to mining, from physical illness — due to water and air pollution — to psychological, spiritual, and existential distress.
In roadside prayers and rallies along the run, members of various tribes offered visceral accounts of the harm they've experienced after sacred lands were tapped for minerals, fossil fuels, and heavy metals. They described attacks on health, identity, religion, and culture that many referred to as ongoing genocide.
At Oak Flat Campground, Apache Stronghold supporters gathered for a ceremony before the prayer run began. Runners were blessed with ashes to protect them on a route that would traverse vast fields of cacti, narrow mountain passes, and even two combative drivers on city streets.
Among those lacing up running shoes was Nizhoni Pike, 24, one of Nosie's granddaughters. Pike has a deep connection to Oak Flat, where her family holds ceremonies and gathers medicinal plants and food. For Pike, her distress is visceral, immediate.
“This fight means so much,” she said.
Oak Flat is where Pike had her sunrise ceremony, a coming-of-age ritual, at age 13. During the ceremony, she built her own wickiup, a traditional Apache dome-shaped dwelling made of wood and thatch from the land. Her body was painted with white clay, embodying the White Painted Woman, a revered cultural figure. At the end of a four-day ceremony involving dancing from morning to night, Pike walked to a spring to wash off the clay and return it to the land. Butterflies filled the air, she recalled. Her family named the area Nizhoni's Butterfly Canyon.
The sunrise ceremony creates a cord by which women are forever connected to the land where they came of age, she said. Tribal elders have told her that women may suffer illness if the cords are cut.
“I'm really worried for me and the other girls that had their sunrise dances there,” she said.
She already had anxiety, she said, and it has grown worse because of the drying up and pending destruction of Oak Flat. Pike said when she returned to her butterfly canyon a few years after her sunrise ceremony, the spring was dry and a dead turtle floated in a nearby pool. She said she has seen large cracks in the earth there and old oak trees starting to die.
“I've never felt so much pain in my heart or spirit before,” she said.
She and other Apache members attribute the dryness to Resolution Copper, which has been pumping water out of a 7,000-foot-deep mining shaft on its adjacent property for years.
In a statement, company spokesperson Tyson Nansel denied that extracting water at that depth affects the surface water. He said the company treats the removed water then gives it away to farmers to grow crops so they can "pump less fresh groundwater themselves.” He said the company has made significant changes to its proposed mine to "reduce potential impacts on Tribal, social, and cultural interests."
Along the run, supporters gathered for blessings from various faith leaders, some of whom sprinkled them with holy water.
They first stopped in the nearby town of Superior, part of the Copper Triangle, which has a long history of mining. The mayor there supports the new mine, which the company has said will create 1,500 jobs during its projected 60-year lifespan. But opponents in Superior warned that mining has left the area with high cancer rates, toxic dumps, and ghost towns.
In the city of Mesa, runners stopped at an ancestral site of the O'odham people to receive support from two Native leaders with roots there.
Su:k Chu:vak Fulwilder, a council member of the Salt River Pima-Maricopa Indian Community, said loss of land and identity is taking a toll on her people. Fulwilder said her tribe suffers from high suicide rates, and her own son took his life in 2022.
“These sacred lands being disturbed — our spirits feel that pain and that anger,” she said.
Other supporters raised concerns about water quantity and quality in a time of long-term drought. Resolution Copper's plans to conduct block-cave mining would require nearly 250 billion gallons of water and the natural water systems would be "altered forever and, in many cases, destroyed in perpetuity," according to a federal environmental impact statement and hydrology report.
Henry Muñoz, 69, who worked in mines for nearly 24 years and is now chair of the Concerned Citizens and Retired Miners Coalition in Superior, noted that the mine would require scarce water to pipe away toxic waste and copper concentrate. The toxic slurry would be sent to a tailings site, he said, where it would require more water so that dust laden with arsenic and sulfur doesn't blow away. He noted that Resolution Copper is owned by foreign mining companies Rio Tinto and BHP, so much of the profit would go overseas.
With cuts to the Environmental Protection Agency and mine and worker safety agencies, Muñoz added, “the company is going to have free rein to do as they please with the environment, and the public won't have any recourse.”
The prayer run concluded in downtown Phoenix, merging into a march to the courthouse.
Cadence Hardy, 16, who is Diné, said she grew up in Black Mesa, Arizona, where intensive coal mining depleted an aquifer and its springs, deeply affecting Hopi and Diné communities. Her great-grandfather worked in a coal mine there and got lung disease and cancer, she said.
She said she's inspired to support Apache Stronghold “to stop what happened to my family from happening to their family.”
In the May 7 federal court hearing, Victoria Peacey, president of Resolution Copper, took the stand, facing a courtroom packed with Apache Stronghold supporters, and testified that it would be at least 16 years until Oak Flat would begin to sink.
Nizhoni Pike later said she felt overwhelmed. Sixteen years is a short time, and the consequence would be huge, she said. “My ancestors' history could literally be wiped.”
In the courtroom, Pike said, she looked Peacey in the eye.
“Look at me,” Pike recalled thinking. “You are going to destroy me if you destroy Oak Flat.”
If you or someone you know may be experiencing a mental health crisis, contact the 988 Suicide & Crisis Lifeline by dialing or texting "988.”
This article was reprinted from khn.org, a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF - the independent source for health policy research, polling, and journalism.
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Ada Carol Adkins lives with her two dogs in a trailer tucked into the timbers off Upper Mud River Road.
"I'm comfortable here, but I'm having health issues," said the 68-year-old, who retired from her job as a school cook several years ago after having a stroke. "Things are failing me."
Her trailer sits halfway up a ridge miles from town and the local health clinic. Her phone and internet are "wacky sometimes," she said. Adkins — who is fiercely independent and calls herself a "Mountain Momma" — worries she won't be able to call for help if service goes out, which happens often.
To Frontier Communications, the telecommunications company that owns the line to her home, Adkins says: "Please come and hook me right."
But she might be waiting years for better service, frustrated by her internet provider and left behind by troubled federal grant programs.
A quarter of West Virginia counties — including Lincoln, where the Mud River bends its way through hollows and past cattle farms — face two barriers to health care: They lack high-speed internet and have a shortage of primary care providers and behavioral health specialists, according to a KFF Health News analysis.
Years of Republican and Democratic administrations have tried to fix the nation's broadband woes, through flawed attempts. Bad mapping, weak standards, and flimsy oversight have left Adkins and nearly 3 million other rural Americans in dead zones — with eroded health care services and where telehealth doesn't reach.
Blair Levin, a former executive director of the Federal Communications Commission's National Broadband Plan, called one rural program rollout during the first Trump administration "a disaster."
It was launched before it was ready, he said, using unreliable federal maps and a reverse-auction process to select internet carriers. Locations went to the lowest bidder, but the agency failed to ensure winners had the knowledge and resources to build networks, said Levin, who is now an equity analyst with New Street Research.
The fund initially announced awards of $9.2 billion to build infrastructure in 49 states. By 2025, $3.3 billion of those awards were in default and, as a result, the program won't connect 1.9 million homes and businesses, according to a recent study.
A $42 billion Biden-era initiative still may not help Adkins and many others shortchanged by earlier federal broadband grants. The new wave of funding, the Broadband Equity, Access, and Deployment Program, or BEAD, has an anti-waste provision and won't provide service in places where previous grants were awarded — even if companies haven't delivered on their commitments.
The use of federal money to get people connected is "really essential" for rural areas, said Ross DeVol, CEO and chairman of the board of Heartland Forward, a nonpartisan think tank based in Bentonville, Arkansas, that specializes in state and local economic development.
"Internet service providers look at the economics of trying to go into some of these communities and there just isn't enough purchasing power in their minds," DeVol said, adding that broadband expansion is analogous to rural electrification. Without high-speed internet, "you're simply at a distinct disadvantage," he added. "I'll call it economic discrimination."
Adkins keeps spiral-bound notebooks and calendars filled with handwritten records of phone and internet outages.
In January, while bean soup warmed on the stove, she opened a notebook: "I got books full. Hang on."
Her finger traced the page as she recounted outages that occurred about once a month last year. Adkins said she lost connectivity twice in November, again in October, and in July, May, and March. Each time she went for days without service.
Adkins pays Frontier Communications $102.13 a month for a "bundle" that includes a connection for her house phone and wireless internet access on her cellphone. Frontier did not respond to requests for comment on Adkins' and other customers' service.
Adkins, a widow, spends most of her time at home and said she would do video calls with her doctors if she could. She said she still has numbness on one side of her body after the stroke. She also has high blood pressure and arthritis and uses over-the-counter pain patches when needed, such as after she carries 30-pound dog food bags into the house.
She does not own a four-wheel-drive truck and, for three weeks in January, the snow and ice were so severe she couldn't leave. "I'm stranded up here," she said, adding that neighbors check in: "'Do you have electric? Have you got water? Are you OK?'"
The neighbors have all seen Adkins' line. The pale-yellow cord was tied off with green plastic ties around a pole outside her trailer. As it ran down the hill, it was knotted around tree trunks and branches, frayed in places, and, finally, collapsed on the ground under gravel, snow, and ice at the bottom of the hill.
Adkins said a deer stepping on the line has interrupted her phone service.
David and Billi Belcher's double-wide modular home sits near the top of the ridge past Adkins' home. Inside, an old hunting dog sleeps on the floor. Belcher pointed out a window toward where he said Frontier's cable has remained unrepaired for years: "It's laying on the ground in the woods," he said.
Frontier is West Virginia's legacy carrier, controlling most of the state's old landlines since buying them from Verizon Communications in 2010. Twelve years later, the company won nearly $248 million to install high-speed internet to West Virginia through the Rural Digital Opportunity Fund, an initiative launched during President Donald Trump's first term.
"Big Daddy," as local transit driver Bruce Perry called Trump, is popular with the people of Lincoln County. About 80% of the county's voters picked the Republican in the last election.
The Trump administration awarded Frontier money to build high-speed internet to Upper Mud River Road residents, like Adkins, according to state mapping. Frontier has until Dec. 31, 2028, to build.
But the Belchers needed better internet access for work and could afford to pay $700 for a Starlink satellite internet kit and insurance, they said. Their monthly Starlink bill is $120 — a price many cannot manage, especially since Congress sunset an earlier program that helped offset the cost of high-speed plans for consumers.
Meanwhile, the latest broadband program to connect rural Americans is ensnared in Trump administration policy shifts.
The National Telecommunications and Information Administration, which administers the program, in April announced a 90-day extension for states to finalize their plans during a "comprehensive review" of the program.
West Viriginia Gov. Patrick Morrisey, a Republican, announced his state would take an extension. The move, though, doesn't make a lot of sense, said Evan Feinman, who left the agency in March after directing the broadband program for the past three years.
Calling the work already done in West Virginia an "incredible triumph," Feinman said the state had completed the planning, mapping, and the initial selection of companies. The plan that was in place would have brought high-speed fiber lines to homes ahead of schedule and under budget, he said.
"They could be building today, and it's just deeply disappointing that they're not," Feinman said.
When Feinman resigned in March, he sent a lengthy email stating that the new administration wants to take fiber away from homes and businesses and substitute it with satellite connections. The move, he said, would be more expensive for consumers and hurt rural and small-town America.
Morrisey, whose office declined to respond to requests for comment, said in his announcement that he wants to ensure West Virginia spends the money in a manner "consistent with program changes being proposed by the Trump Administration" and "evaluate a broader range of technology options."
Commissioners from Grant County responded with a letter supporting fiber-optic cables rather than satellite-based connections like those provided by Elon Musk's Starlink. Nationwide, 115 lawmakers from 28 states sent a letter to federal leaders stating that changes could "delay broadband deployment by a year or more."
For Adkins and others, the wait has been long enough.
While legislators in Washington and across the country bickered over the broadband program, Adkins went without phone and internet. By late March, she said, her 42-year-old son was increasingly worried, noting "you're getting up in age." He told her: "Mom, move out, get off of that hill."
A few miles from Upper Mud River Road, past the McDonald's and across the road from the local library, Brian Vance sat in his downtown Hamlin, West Virginia, office. He said his company has been trying to "build up there for a while."
Vance is a general manager for Armstrong Telephone and Cable, a regional telecommunications provider that competes with Frontier. He grew up in the community, and parents of a high school friend live off Upper Mud River. But he said "it's very difficult" to build fiber along the rocky terrain to homes where "you are hoping that people will hook up, and if they don't, well, you've lost a lot of money."
A 2022 countywide broadband assessment found that stringing fiber-optic lines along telephone poles would cost more than $5,000 per connection in some areas — work that would need big federal subsidies to be feasible.
Yet Vance said Armstrong cannot apply for the latest BEAD funding to help finance connections. And while he likes that the federal government is "being responsible" by not handing out two federal grants for the same area, Vance said, "we want to see people deliver on the grants they have."
If Frontier hadn't already gotten federal funds from the earlier Trump program, "we definitely would have applied to that area," Vance said.
The 2022 assessment noted the community's economy would not be sustainable without "ubiquitous broadband."
High-speed internet brings more jobs and less poverty, said Claudia Persico, an associate professor at American University. Persico, who is also a research associate with the National Bureau of Economic Research, co-authored a recent paper that found increased broadband internet leads to a reduction in the number of suicides as well as improvements in self-reported mental and physical health.
More than 30% of Lincoln County's population reports cases of depression, according to data from the Centers for Disease Control and Prevention. The rate of opioid prescriptions dispensed in Lincoln County is down about 60% from 2014 to 2024 — but still higher than the state average, according to the West Virginia Board of Pharmacy.
Twenty percent of the county's population lives below the poverty line, and residents are also more likely than the national average to experience heart disease, diabetes, and obesity.
Lincoln Primary Care Center offers telehealth services such as electronic medical records on a patient portal and a pharmacy app, said Jill Adkins, chief quality and risk officer at Southern West Virginia Health System, which operates the clinic.
But because of limited access, only about 7% of patients use telehealth, she said.
Della Vance was a patient at the clinic but said she has never used a patient portal. If she could, Vance said, she would check records on the baby she is expecting.
"You can't really get on if you don't have good service and no internet," she said. "It makes me angry, honestly."
Vance and her husband, Isaiah, live off a gravel road that veers from Upper Mud River. There is a tall pole with black wires dangling across the road from their small home. Pointing to the cables, Isaiah Vance said he couldn't get phone service anymore.
Verizon announced plans last year to buy Frontier for an estimated $20 billion. The deal, which must be approved by federal and state regulators, is expected to be completed in early 2026, according to an investor's press release.
In its federal merger application, Frontier stated that it had taken on too much debt after emerging from bankruptcy and that debt would make it difficult to finish the work of installing fiber to customers in 25 states.
In West Virginia, Frontier's Allison Ellis wrote in March 3 testimony, seeking approval for the merger from state regulators, that Verizon will honor the rural program commitments. The previous month, in February, Frontier filed a motion with the state public service commission to keep the number of customers using copper lines and the faster fiber-optic lines confidential.
Kelly Workman, West Virginia's broadband director, said during a November interview that her office has asked federal regulators for "greater visibility" into Frontier's rural program construction, particularly because those locations cannot win the Biden-era infrastructure money when it's available.
"The worst-case scenario would be for any of these locations to be left behind," Workman said.
Frontier's progress installing fiber-optic lines and its unreliable service have frustrated West Virginians for years. In a 2020 letter to the FCC, U.S. Sen. Shelley Capito (R-W.Va.) cited "the failure of Frontier to deliver on promises to federal partners" and its "mismanagement" of federal dollars, which forced the state to pay back $4.7 million because of improper use and missed deadlines.
Michael Holstine, a longtime member of the West Virginia Broadband Enhancement Council, said the company has "just used West Virginia as a money cow." Holstine has been fighting for the construction of fiber-optic lines in Pocahontas County for years. "I really just hope I get it before I die."
Across the state, people like Holstine and Adkins are eager for updated networks, according to interviews as well as letters released under a public records request.
Chrissy Murray, vice president of Frontier's external communications, acknowledged that the company was "building back our community efforts" in West Virginia after a bankruptcy filing and reorganization. She said there has been a "notable decline" in consumer complaints, though she did not provide specific numbers.
Murray said Frontier built fiber-optic cables to 20% of its designated rural funds locations as of the end of 2024. It has also invested in other infrastructure projects across the state, she said in a January email, adding that the company donated high-speed fiber internet to West Virginia University's rural Jackson's Mill campus.
According to data tracked by a federal agency, Frontier has connected 6,100 — or fewer than 10% — of the more than 79,000 locations it was awarded in the Rural Digital Opportunity Fund program.
The FCC oversees the rural fund. The agency did not respond to a request for comment. Frontier expects to receive $37 million annually from the agency through 2032, according to a federal filing.
In April, a new batch of letters from West Virginia residents filed as "support" for Frontier's merger with Verizon appeared in the state regulatory docket:
"My support for this case depends on whether Verizon plans to upgrade or replace the existing Frontier infrastructure," wrote one customer in Summers County, in the far southern corner of the state, adding, "West Virginians in my neck of the woods have been held hostage by Frontier for a generation now because no other providers exist."
A customer from Hardy County, in the state's northeastern corner, wrote: "This is [a] move by frontier to to [sic] escape its responsibility to continue services."
Adkins moved to Upper Mud River with her husband, Bobby, decades ago.
For years, Bobby and Ada Carol Adkins ran a "carry-out" on Upper Mud River Road. The old building is still at the rock quarry just down the hill and around the curve from where her trailer sits.
It was the type of store where locals kept a tab — which Bobby treated too much like a "charity," Adkins said. They sold cigarettes, beer, bread, bags of chips, and some food items like potatoes and rice. "Whatever the community would want," she said.
Then, Bobby Adkins' "health started deteriorating and money got tighter," Adkins said. He died at 62 years old.
Now, Adkins said, "I'm having kidney problems. I got arthritis, they're treating me for high blood pressure."
Her doctor has begun sending notes over the internet to refill her blood pressure medicine and, Adkins said, "I love that!"
But Adkins' internet was out again in early April, and she can't afford Starlink like her neighbors. Even as Adkins said she is "deep-rooted," her son's request is on her mind.
"I'm having health problems," Adkins said. "He makes a lot of sense."
This article was reprinted from khn.org, a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF - the independent source for health policy research, polling, and journalism.
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Lohit Khera
In this interview, industry expert Dr. Lohit Khera discusses the evolving role of microRNA in research, diagnostics, and precision medicine, highlighting the latest innovations in RNA extraction and analysis
Emily Lee and Boris Lazarov
Learn how experts are advancing benzodiazepine analysis and detection using insights from the lab.
Sir Prof. Cato T. Laurencin
In this interview, Sir Prof. Cato T. Laurencin, the 2025 Coulter Lecturer, discusses how he is addressing today's medical challenges using the technology of the future.
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May 14, 2025
SAN DIEGO — Disease-modifying antirheumatic drugs (DMARDs) and biologics were linked to as much as a 74.5% reduction in the risk for alopecia areata (AA) in patients with psoriasis, a new retrospective cohort study reported.
“With higher numbers and more data, this could definitely be clinically applicable in patients we know are at higher risk of AA,” said study Co-Author Bethany Rohr, MD, associate professor of dermatology, Case Western Reserve University School of Medicine, Cleveland, in an interview prior to the presentation of her findings at the annual meeting of the Society for Investigative Dermatology. “We could choose a medication for their psoriasis to give them some protective benefit,” she added.
Patients with psoriasis have an increased risk for AA. A 2022 systematic review and meta-analysis estimated that the pooled prevalence rate of AA in patients with psoriasis was 0.5% (95% CI, 0.3-0.7%). The pooled risk for AA in patients with psoriasis was estimated at 2.71 (95% CI, 2.29-3.21). Both AA and psoriasis are autoimmune disorders.
Some DMARDs and biologics are used to treat AA off-label, while others have not been evaluated as treatments for the disease, Rohr said. She noted that methotrexate can actually cause alopecia but not AA, and in fact, has been studied as a treatment for AA.
“We wanted to investigate if our drug choice for these patients who require systemic therapies could have some protective benefit,” Rohr said.
Via the TriNetX international electronic record database, she and her coauthors tracked 48,724 patients with psoriasis who were on DMARDs (average age, 52.6 years ± 16.3; 56.6% women; 70.4% White individuals; 21.9% with overweight/obesity) vs a propensity-matched cohort who were not taking systemic medications. The patients were followed for 5 years following the start of therapy.
The tracked DMARDs were methotrexate, cyclosporine, and apremilast. The primary outcome was AA within 5 years of medication initiation.
Researchers also tracked 66,837 patients with psoriasis who were on biologics (average age, 52.9 years ± 16.9; 54.8% women; 71.5% White individuals; 21.5% with overweight/obesity) vs a propensity-matched cohort who were not taking systemic medications.
The biologics were tumor necrosis factor inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol, and golimumab), interleukin (IL)-17 inhibitors (brodalumab, ixekizumab, secukinumab, and bimekizumab), and IL-12/23 and IL-23 inhibitors (ustekinumab, guselkumab, risankizumab, and tildrakizumab).
They found that 19 patients in the DMARD group developed AA vs 37 in the nonsystemic treatment group (risk ratio [RR], 0.514; 95% CI, 0.295-0.893; P = .019). In the biologics group, 13 developed AA vs 51 in the nonsystemic treatment group (RR, 0.255; 95% CI, 0.139-0.469; P < .001).
No statistically significant difference was seen between the DMARD and biologic groups (P = .322).
Other studies have reported similar links between psoriasis and AA.
Study lead author Nada Hentati, a medical student at Case Western Reserve, told Medscape Medical News that the researchers had to group many medications together because the sample size was small. “We lost some of the granularity regarding which medications might be independently protective,” she said.
In addition, she said, “the number of cases was pretty low. Part of that is because we constrained our data to make sure that all the cases we were seeing were within 5 years of starting the drugs.”
The reduction in risk “has the potential to be significant,” Rohr noted in the interview. “However, it's important to remember this is a pilot study,” she added, and the data has limitations.
“Ideally,” she said, “it would be nice to have a really large prospective study following individual drugs and patients with similar body surface area and severity of psoriasis to better understand the significance of our data.”
Asked to comment on the study findings, Deshan Sebaratnam, MBBS, MMed, associate professor of dermatology at the University of New South Wales, Sydney, Australia, told Medscape Medical News many DMARDs are used to treat AA, and “there have been small-volume case reports where patients with alopecia areata have improved on biologics.”
It's feasible that dampening the immune system may make patients less likely to develop AA, added Sebaratnam, who was not involved with the study. However, for psoriasis, he noted, “I don't think this is really going to change management. You wouldn't immunosuppress someone to decrease the likelihood of developing AA.”
No study funding was reported, and the authors have no disclosures. Sebaratnam disclosed relationships with AbbVie, Galderma, Bristol Squibb Meyers, Pfizer, Amgen, Novartis, Leo, Viatris, iNova, and Sun.
Send comments and news tips to news@medscape.net.
Cubic Sensor and Instrument Co., Ltd. officially released its 2024 Environmental, Social, and Governance (ESG) Report . The Report systematically presents Cubic's innovative practices and outstanding achievements in the areas of environmental protection, social responsibility, and corporate governance (ESG). It also highlights the Cubic's commitment as a tech-driven enterprise to promoting high-quality economic and social development and addressing global challenges.
With over 20 years of development, Cubic has become a leading enterprise in the domestic and international fields of intelligent gas sensors and high-end gas analysis instruments. The "Cubic" brand is increasingly recognized in global markets.
Dr. Youhui Xiong, Chairman of Cubic, emphasized that in the context of deep restructuring of global industrial chains, Cubic recognizes that ESG is not only a "passport" to international markets but also a strategic cornerstone for building long-term core competitiveness. Unlike evaluation systems based solely on financial indicators, ESG highlights the social responsibilities companies should undertake as corporate citizens during the business development, through the lenses of environment, society, and governance. Enterprises need to establish more comprehensive sustainability management frameworks and systems, enabling a bottom-up, self-driven, progressive improvement and continuous iteration cycle across business units, thus enhancing overall competitiveness.
Based on in-depth insights into industry trends and stakeholder expectations, Cubic has introduced the innovative ESG strategy known as the “I-GROW Growth Pyramid.” The strategy identifies five key material topics: innovation-driven, green development, responsible sourcing, organizational building-up, and winning clients. Through practical actions, the company demonstrates its strong commitment to ESG and brings fresh momentum into its sustainable development.
Cubic's commitment to sustainable development is not only an embodiment of its corporate social responsibility but also a cornerstone of its long-term competitiveness and robust growth. Guided by the philosophy of sustainability and in active response to “Dual Carbon” strategy, Cubic has been steadfast in advancing effective carbon reduction initiatives and leveraging technological innovation to drive environmental protection and social progress.
Relying on its diversified gas sensing technology platforms, Cubic closely aligns its technological innovation with policy directives, proactively addressing national environmental protection plans and carbon neutrality goals. The company has independently developed a series of innovative products for monitoring greenhouse gases, methane emissions, outdoor particulate matter, and fixed/mobile pollution sources—demonstrating the breakthrough application of environmental gas monitoring technologies in both environmental governance and industrial emission reduction.
The company's Environmental and Climate Action Management Rules comprehensively cover areas including climate change, energy management, circular economy, water resource management, air quality, and noise management. Making climate action and sustainable development strategic priorities, Cubic actively supports the global climate goals outlined in the Paris Agreement. By utilizing renewable energy and procuring green electricity, the company is committed to achieving low-carbon operations. Currently, two green photovoltaic projects have been implemented at Cubic R&D Center and Cubic Jiashan Factory, with an estimated annual electricity generation of 1.18 million kWh and a reduction of 804 tons of CO2 emissions. A 1,140 kW photovoltaic project at Cubic headquarters is also underway, which is expected to raise the green electricity self-sufficiency rate to 20%, providing solid support for the realization of the “Dual Carbon” goals.
As an enterprise advocate and practitioner of ESG principles, Cubic embeds social responsibility into its corporate DNA. The company takes a multi-dimensional approach across technological innovation, supply chain management, customer service, quality control, and public welfare to embody its commitment through concrete actions.
In recent years, Cubic has consistently strengthened its technological innovation capabilities and upgraded its R&D system, integrating circular economy concepts into product design. In 2024, R&D investment continued to increase, and the company had accumulated a total of 233 patents. Its Laser Raman technology was included in the General Technology Catalog for Smart Chemical Parks. Cubic has also supported continuous innovation and patent protection by bringing in postdoctoral research talent and improving intellectual property management, maintaining its technological leadership. In 2025, the company was successfully recognized as a National Enterprise Technology Center.
In terms of supply chain management, Cubic is committed to sustainable supply chain practices, aiming to integrate business development with social responsibility. The company has formulated the Cubic Supplier Sustainability Management Guidelines, which cover multiple critical aspects of the supply chain. ESG evaluations have been conducted for over 100 suppliers, and 43% of core suppliers have signed the Code of Conduct for Sustainable Development. These efforts are driving carbon reduction across the supply chain and facilitating a broader green transition.
Cubic firmly understands that ensuring product quality and customer satisfaction is fundamental to its sustainable development. With customer satisfaction as the core goal, the company focuses on value creation throughout the entire product lifecycle and leverages digital technologies to empower manufacturing, delivering high-quality products and services. Currently, Cubic serves as a supporting supplier for many Fortune Global 500 companies and industry leaders.
Guided by the principle of “people-oriented development, rooted in traditional Chinese culture,” Cubic has long been dedicated to advancing education and preserving traditional Chinese culture. The company fulfills its social responsibility through initiatives including supporting university education, establishing scholarships, promoting cultural heritage protection, and backing carbon reduction projects.
Cubic consistently adheres to the talent philosophy of “talent-driven, innovation-driven,” implementing a robust talent strategy to continuously improve its employee career development system.
In talent acquisition, Cubic adopts a dual approach of “global recruitment + university-enterprise collaboration,” bringing in 648 elite professionals with bachelor's degrees or higher every year and co-establishing talent pools with partner universities. Moreover, as a certified national postdoctoral research workstation, Cubic attracts a large number of highly skilled technical professionals, providing strong talent support for the company's technological innovation and sustainable development.
In talent development, Cubic provides equal opportunities for all employees, striving to build a comprehensive and in-depth training system, which includes structured programs such as onboarding initiatives, the “Leadership Development Program,” academic advancement support, and a competency-based employee development model—all aimed at fostering sustainable growth for its talent pool.
While focusing on employee growth and development, Cubic also places great emphasis on employee well-being. Through a series of thoughtful initiatives including employee canteens, dormitories, commuter shuttles, fitness equipment, birthday meals, daily health apples, and employee roundtable discussions, Cubic places care into concrete actions that enhance the daily work and life experience of its staff.
Cubic attaches great importance to corporate culture, regarding it as a key driver of high-quality development. A wide array of creative cultural and recreational activities including the Cubic Dragon Boat Race, annual health run, the “Winter Camp” for employees' children, the Cubic Lion Dance Team, classic cultural pottery, and flower arrangement workshops. The multiple activities integrate cultural heritage with team-building, showcasing the company's social responsibility and unique cultural charm. Notably, the Cubic Dragon Boat Race, held for three consecutive years, has become a signature element of the company's culture. In 2024, Cubic's dragon boat team won the championship in the Hubei Provincial Dragon Boat Competition.
By fostering a harmonious, equitable, and inclusive labor relationship with employees, the company has strengthened cohesion, productivity, and resilience across the workforce.
Amid the profound global changes and industrial transformation of the time, Cubic is currently leveraging ESG as a strategic pivot to build a virtuous cycle of “technological leadership – commercial success – social value.” Through continuous innovation and strong social responsibility, Cubic embodies the evolution of intelligent manufacturing toward the higher end of the global value chain, establishing “CUBIC” as a globally trusted benchmark for sustainable development.
Cubic Sensor and Instrument Co. Ltd
Posted in: Medical Research News
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Cubic Sensor and Instrument Co. Ltd. (2025, May 14). Driving sustainability through green technology: Cubic releases ESG 2024 report. News-Medical. Retrieved on May 14, 2025 from https://www.news-medical.net/news/20250514/Driving-sustainability-through-green-technology-Cubic-releases-ESG-2024-report.aspx.
MLA
Cubic Sensor and Instrument Co. Ltd. "Driving sustainability through green technology: Cubic releases ESG 2024 report". News-Medical. 14 May 2025.
May 14, 2025
From vector-borne illnesses to pavement burns, climate change poses wide-ranging threats to skin health, particularly in vulnerable populations, according to some of the authors of a clinical image series recently published in The New England Journal of Medicine's Images in Clinical Medicine section.
The cases were accompanied by a note that said that the featured images “spotlight some of the effects of the climate crisis on clinical health.”
One case was a 65-year-old man who presented with an itchy rash on his hip 1 week after removing an adult female Lone Star tick (Amblyomma americanum) from the area. The rash's bull's-eye appearance helped authors led by Eva R. Parker, MD, DTMH, assistant professor of dermatology at Vanderbilt University Medical Center, Nashville, Tennessee, diagnose southern tick-associated rash illness (STARI). There is no diagnostic test for STARI, since the causative organism remains unknown.
The Lone Star tick's range has spread from the southern United States (including Tennessee, where this case was diagnosed) to the northeastern United States, Parker and her co-author, Misha Rosenbach, MD, professor of dermatology at the University of Pennsylvania, Philadelphia, wrote. “This change in distribution is attributable at least in part to climate change, and further geographic spread of the vector and a longer active season are anticipated as temperatures increase,” they noted.
In a separate case, a 3-year-old boy who had recently immigrated from Venezuela to the United States presented with a 6-week history of painless bumps and ulcers on his leg, which developed after he had insect bites on his foot. Histopathology showed severe lymphohistiocytic infiltration, but no organisms were identified by routine stains. Polymerase chain reaction testing identified Leishmania guyanensis, a parasite transmitted by phlebotomine sandfly bites, and he was diagnosed with cutaneous leishmaniasis.
“Climate change is affecting the spread of leishmaniasis by altering the geographic distribution and size of sandfly populations. People experiencing poverty and migration are at highest risk for acquiring the infection,” wrote the authors of this case, led by Umber Dube, MD, PhD, of the University of California, San Diego, and Dawn Eichenfield, MD, PhD, of Rady Children's Hospital, San Diego.
The third case was a 56-year-old man with a history of alcohol use disorder, who was treated at a burn center for second-degree pavement burns. While intoxicated, he had walked barefoot on asphalt for 1 minute during a regional heat wave in the Pacific Northwest that created maximum air temperatures of 108°F, about 38°F higher than historical averages. “Extreme heat events increase the risk of contact burns from hot surfaces in the environment. Young children, older adults, unhoused persons, and persons with substance use disorder are at elevated risk for these types of burns,” wrote the author of this case, Jeremy J. Hess, MD, MPH, of the University of Washington, Seattle.
At press time, all three featured cases had resolved or were resolving with standard treatment.
In an interview, Rosenbach said that clinicians should be talking about climate-related issues because these issues are changing when, where, and which patients present with skin diseases and other manifestations.
Having climate change impacts highlighted in The New England Journal of Medicine helps to emphasize that such issues can affect every organ and medical subspecialty, said Rosenbach. “If people aren't staying up to date and informed, that can lead to missed or delayed diagnoses.”
“While many physicians are becoming more familiar with climate impacts on disease in general,” Parker told Medscape Dermatology, “there are still large gaps in our knowledge.” Many medical schools and residency programs fail to teach this curriculum, she explained, and practicing physicians have limited opportunities to learn it.
The American Academy of Dermatology (AAD) Annual Meeting included sessions that highlight the climate impact on skin disease. Additionally, a sustainability session at the upcoming AAD Innovation Academy meeting will address how dermatologists can limit the environmental impacts of care delivery. And for providers needing a basic understanding, the AAD basic dermatology curriculum includes free climate change modules. Dermatologists who wish to help raise awareness can join the AAD's Climate Change and Environmental Affairs Expert Resource Group (ERG), Parker added. She and Rosenbach are co-chairs of the ERG.
Many international dermatology meetings also spotlight the issue — usually more so than domestic meetings, Parker said.
Special journal issues devoted to climate change include a January 2021 edition of the International Journal of Women's Dermatology coedited by Rosenbach. Additionally, Parker and Rosenbach plan to coedit an early 2026 issue of Dermatologic Clinics.
Climate change alone causes no specific disease. “It's all existing diseases that are exacerbated by climate change,” said Parker. “Or the epidemiology has changed because of climate change. So a heightened awareness among clinicians to consider climate impacts on skin disease when evaluating patients and to collect environmental histories and act on that information, is critical. It means a pivot in our way of thinking.”
Along with helping physicians recognize the shifting patterns, she said, “it's an opportunity for us to educate our patients.” One of her recent patients could not believe she had a tick bite in April. “In Tennessee,” said Parker, “I sometimes pull ticks off in January and February now.” Accordingly, she said, people who do outdoor activities must protect themselves year-round.
The cases were published online in The New England Journal of Medicine on April 19 and 23.
Parker and Rosenbach reported no relevant financial relationships. Their comments reflected their own personal opinions, not the position of the AAD.
John Jesitus is a Denver-based freelance medical writer and editor.
Send comments and news tips to news@medscape.net.
Asynt is delighted to announce a unique and inspiring live demo at this year's highly anticipated CHEMUK exhibition, taking place on 21st–22nd May 2025 at the NEC, Birmingham. Visitors to Stand H102 on day two will be treated to a special “edible chemistry” demo, presented by Dr Josh Smalley, chemist, science communicator, and finalist on The Great British Bake Off.
Image Credit: Asynt
Dr Josh, based at the University of Leicester, is the founder of the Science Kitchen — an innovative initiative combining his expertise in chemistry with a passion for baking. Known for his ability to engage both young people and adults with the wonders of chemistry in everyday life, he brings a fresh perspective to the chemistry community through his lively and accessible approach.
In collaboration with Asynt, a leading provider of sustainable laboratory solutions, Dr Josh will bring chemistry to life with a live demo that explores the delicious chemistry behind some gorgeous chocolate creations. This interactive session will delve into the reactions, transformations, and principles at play in the kitchen — highlighting how chemistry plays a vital role far beyond the lab.
We are incredibly proud to be working in partnership with Josh, both supporting his work in the Science Kitchen and with Asynt at CHEMUK 2025,”
Martyn Fordham, Managing Director, Asynt
“His creativity and passion for both science and communication align perfectly with our own mission to make chemistry more engaging, sustainable, and accessible. We can't wait to share this exciting experience with visitors to our stand – some of the team aren't sure about sharing the chocolate creations, though!”
This lively and educational demo is a must-see for anyone interested in science, baking, or how chemistry shapes the world around us. Asynt warmly invites all attendees to Stand H102 to witness this unique fusion of culinary art and chemical science.
Admission to CHEMUK is free, and registration is now open for all industry professionals and local visitors. With over 400 exhibitors and a packed programme of talks, CHEMUK 2025 promises to be the UK's leading chemistry and chemical processing industry event.
Asynt
Posted in: Miscellaneous News
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MLA
Asynt. "GBBO finalist and chemist Dr Josh Smalley to headline live edible chemistry demo at CHEMUK 2025". News-Medical. 14 May 2025.
The skin microbiome plays an important role in health and disease. Researchers have now substantiated that certain skin bacteria can protect us from the sun's ultraviolet (UV) radiation specifically by metabolizing cis-urocanic acid using an enzyme called urocanase. This enables the skin's ability to fine-tune how it responds to UV radiation The findings of the study in the Journal of Investigative Dermatology, published by Elsevier, provide a striking case study that demonstrates the ability of the skin microbiome to remodel host immune functions.
The skin hosts a vast ecosystem composed of millions of microorganisms, including bacteria, fungi, and viruses. The composition of the cutaneous microbiome is highly unique, complex, and varies greatly depending on the anatomical location. Commensal microbes, also known as normal microbiota or indigenous microbiota that live in a beneficial or neutral relationship without causing harm, adapt their metabolism to the resources available in their microenvironment, feeding on our skin's nutrients and producing various molecules that affect their environment and interact with our skin cells.
Lead investigator VijayKumar Patra, PhD, Centre International de Recherche en Infectiologie; Lyon, France, and Research Unit for Photodermatology, Medical University of Graz, Austria, explains, "To date, many internal and external factors have been identified that influence the composition of the skin microbiome. These include various individual parameters such as race, gender, age, hormone levels, diet, and hygiene, but environmental factors and the effects of occupation, pollution, and climate also have a major influence. We have known for a long time that UV radiation modulates immune responses directed against environmental antigens on the surface of the skin and, more recently, that the skin microbiome also plays a role in regulating these responses. What intrigued us was the idea that certain microbes could be actively involved in or even interfere with UV effects. The overlap between microbial metabolism and host immunity became the focus of our investigation."
Researchers used a combination of microbiome sequencing, immunological assays, in vitro cultures, and gnotobiotic mouse models, in which all microorganisms present are defined, to study how skin bacteria respond to UVB radiation, the type of UV radiation that typically causes sunburn. They discovered that certain skin bacteria specifically metabolize cis-urocanic acid, a photoproduct of a major UV-absorbing chromophore of the stratum corneum, trans-urocanic acid, using an enzyme called urocanase. Compared to trans-urocanic acid, cis-urocanic acid is endowed with potent immunomodulatory properties. This microbial metabolism then limits the ability of cis-urocanic acid to inhibit immune responses, which means that skin bacteria fine-tune our skin's response to UV radiation.
The researchers point out the intriguing interplay between sunscreens, cis-urocanic acid, and the microbiome with each other, competing in and on the stratum corneum, as the most superficial layer of the skin.
Co-investigator Marc Vocanson, PhD, Centre International de Recherche en Infectiologie, Lyon, France, notes, "This is the first time we have demonstrated a direct metabolic link between UV radiation, a host-derived molecule, and bacterial behavior that affects immune function. As interest grows in both microbiome research and personalized medicine, understanding these microbe-host interactions could reshape the way we think about sun protection, immune diseases, skin cancer, or even treatments like phototherapy."
Co-investigator Peter Wolf, MD, Research Unit for Photodermatology, Medical University of Graz, Austria, concludes, "These findings open the door to microbiome-aware sun protection, where we not only protect the skin from UV radiation, but also consider how resident microbes can alter the immune landscape after exposure. In the future, topical treatments that modulate microbial metabolism could be used to minimize, maintain, or enhance UV-induced immunosuppression when clinically beneficial, such as with phototherapy."
Commenting on the findings, noted expert in the field Anna Di Nardo, MD, PhD, University of California San Diego, and San Gallicano Dermatological Institute IRCCS, Rome, says, "This pivotal study shows that microbial communities are not passive victims of environmental stress but dynamic regulators of immune responses, capable of metabolizing UV-induced skin products such as cis-urocanic acid. This newly uncovered role of microbial metabolism in modulating UV tolerance reshapes our understanding of the skin barrier — not just as a structural shield but as a metabolically active, microbially regulated interface. With increasing concerns about UV exposure, skin aging, and cancer, a deeper understanding of this axis offers promising avenues for therapy and prevention."
Elsevier
Patra, V., et al. (2025). Urocanase-positive skin resident bacteria metabolize cis-urocanic acid and in turn reduce the immunosuppressive properties of UV radiation. Journal of Investigative Dermatology. doi.org/10.1016/j.jid.2025.03.035.
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New research being presented at this year's European Congress on Obesity (ECO) in Malaga, Spain (11-14 May), reveals that 3- to 4- year olds in rural areas are more likely to be living with overweight and abdominal obesity (excess fat around waist), and spend more time on screens than their urban counterparts.
Our findings reveal distinct patterns of how physical activity, screen time, and sleep relate to overweight and abdominal obesity in urban and rural settings, indicating that one-size-fits-all strategies to tackle overweight and obesity in early childhood are unlikely to be effective."
Karoliina Uusitalo, lead author, doctoral researcher from the Folkhälsan Research Center and the University of Helsinki, Finland
Around 1 in 3 children in the WHO European Region is living with overweight or obesity [1], with an estimated 17 million boys and 11 million girls (aged 5-19 years) predicted to be living with obesity in Europe by 2035 [2]. Identifying those children most at risk and the environmental and geographic factors that contribute to this risk is critical to focusing prevention efforts.
Movement behaviours-insufficient physical activity, excessive sedentary behaviour (such as screen time) and poor sleep-are potential risk factors for overweight and obesity in children, but evidence in young children is inconsistent and primarily focused on body mass index (BMI), which may misrepresent true adiposity, as it fails to account for differences in body composition, such as fat distribution and muscle mass. Additionally, the effects of urbanisation on movement behaviours and adiposity in young children remain poorly understood.
To explore these issues further, researchers examined the urban-rural differences in movement behaviours (physical activity, sedentary time, screen time, and sleep) and adiposity indicators (BMI and waist-to-height ratio [WHtR]) in 1,080 3–4 year-old participants (46% girls) from the SUNRISE Finland study [3]-part of the international SUNRISE study, which aims to monitor the WHO Guidelines on physical activity, sedentary behaviour and sleep for children under 5 years globally [4]. Researchers also examined the associations between movement behaviours and adiposity indicators separately for urban and rural areas.
In 2022−2023, participants living in both urban (57%) and rural (43%) areas of Finland wore an ActiGraph accelerometer on their waist for one week to assess different intensities of physical activity and sedentary time, and parents reported children's sleep and screen time, as well as their consumption frequency of sugary drinks and unhealthy snacks.
Researchers measured children's height, weight and waist circumference to calculate BMI and weight categories (normal weight [including thinness] and overweight [including obesity]) according to sex and age using Finnish reference values, with a WHtR of 0.55 or higher indicating abdominal obesity.
The results were adjusted for potentially confounding factors like age, sex, data collection area, household education, sugary drinks and unhealthy snacks (and additionally for accelerometer wear time for physical activity and sedentary time) .
The analysis revealed clear rural-urban differences in patterns of adiposity, with 24% of 3-4 year olds in rural areas living with overweight or obesity compared to 16% of those in urban areas. Similarly, around 19% of rural preschoolers had abdominal obesity compared to 13% in urban environments.
Preschoolers living in rural areas also slept more (on average 11 h 19 min vs. 11 h 11 min) and had more screen time (1 h 26 min vs. 1 h 14 min) per 24 hours than their urban counterparts.
The researchers also found that higher moderate to vigorous intensity physical activity (e.g., running and energetic play) in urban environments and higher light physical activity (e.g., low-energy play) in rural areas were linked with a higher risk of overweight (based on BMI), but not with abdominal obesity (based on WHtR).
"This finding may reflect that waist-to-height ratio is a better indicator of adiposity, whereas BMI does not distinguish between fat and muscle mass, which tends to increase with higher physical activity," said Uusitalo.
Only in rural areas was more screen time associated with a higher risk of both overweight and abdominal obesity.
According to co-author Dr. Elina Engberg from the Folkhälsan Research Center and the University of Helsinki in Finland, "The stronger association between screen time and adiposity indicators in rural areas may be partly explained by the higher screen time observed among rural children, whereas other factors appear to play a more significant role in adiposity in urban areas."
She continues: "The health consequences and persistence of young childhood obesity into adulthood highlight the need for efforts to improve society and family-oriented preventive strategies at the local level, which could narrow the gap in risk for young children in rural settings."
This is a cross-sectional study, and as such, no firm conclusions can be drawn about cause. And the researchers acknowledge that reverse causality-whereby more screen time might be a consequence of overweight and abdominal obesity rather than the other way round-might explain the associations found. The study also relied on parent assessment rather than objective measures of screen time and sleep patterns. Strengths of the study include a relatively large sample of young children, the use of measured height, weight, and waist circumference, as well as device-based assessment of physical activity and sedentary time.
European Association for the Study of Obesity
Posted in: Child Health News | Medical Research News
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Emily Lee and Boris Lazarov
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Sir Prof. Cato T. Laurencin
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Radiation sterilization technology destroys the DNA and cellular structures of bacteria and microorganisms using electromagnetic waves with far higher energy than ultraviolet radiation. This technique has become indispensable for sterilization in various fields, including medical devices (e.g., disposable syringes, catheters, artificial joints), pharmaceuticals (e.g., raw materials, tissue grafts), and food products (e.g., sprout inhibition in potatoes).
Traditionally, it has been believed that the effectiveness of radiation sterilization depends solely on the total irradiation dose. However, this assumption has now been challenged by a research team led by Professor Matsumoto and Associate Professor Iwata at Nagoya City University.
In their study, the team varied the X-ray dose rate significantly while keeping the total irradiation dose constant, using Escherichia coli as a model organism. The results revealed striking differences depending on the nutritional environment of the bacteria:
(a) In a nutrient-poor environment, long-term irradiation at a low dose rate (i.e., low-intensity X-rays) was more effective than short-term irradiation at a high dose rate.
(b) Conversely, in a nutrient-rich environment, short-term irradiation at a high dose rate achieved more than ten times the sterilization efficiency compared to long-term irradiation at a low dose rate.
These findings were further analyzed using stochastic differential equations-a cutting-edge mathematical tool-enabling a quantitative understanding of the mechanisms by which radiation damages bacterial and cellular structures.
This research not only provides a scientific foundation for optimizing sterilization and disinfection protocols using radiation, but also introduces a novel framework for designing irradiation strategies that can selectively eliminate rapidly proliferating lesion cells (e.g., cancer cells) while minimizing damage to healthy tissue. These insights hold great promise for the development of safer, more effective, and patient-friendly radiation therapies using X-rays and proton beams.
Nagoya City University
Matsumoto, T., et al. (2025). Time-dose reciprocity mechanism for the inactivation of Escherichia coli using X-ray irradiation. Scientific Reports. doi.org/10.1038/s41598-025-96461-1.
Posted in: Device / Technology News | Medical Science News
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Lohit Khera
In this interview, industry expert Dr. Lohit Khera discusses the evolving role of microRNA in research, diagnostics, and precision medicine, highlighting the latest innovations in RNA extraction and analysis
Emily Lee and Boris Lazarov
Learn how experts are advancing benzodiazepine analysis and detection using insights from the lab.
Sir Prof. Cato T. Laurencin
In this interview, Sir Prof. Cato T. Laurencin, the 2025 Coulter Lecturer, discusses how he is addressing today's medical challenges using the technology of the future.
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Announcing a new publication for Acta Materia Medica journal. The HIV-1 capsid protein (CA) plays a crucial role in viral replication by orchestrating nuclear entry through interactions with host nuclear pore complexes (NPCs).
Recent research has revealed that HIV-1 CA actively disrupts NPC architecture via phenylalanine-glycine (FG)-repeat nucleoporin interactions, thereby enabling nuclear translocation of viral components. This mechanistic insight has driven the development of lenacapavir, the first-in-class CA inhibitor approved for multidrug-resistant HIV-1.
Lenacapavir competitively blocks CA-NPC binding, stabilizes cytoplasmic capsids, disrupts viral maturation, and demonstrates pan-stage antiviral efficacy and long-acting pharmacokinetics. Clinical trials have indicated its 100% prophylactic efficacy and potential to decrease global HIV incidence. Advances in structural biology, molecular dynamics simulations, and nanotechnology are expected to further inform next-generation therapeutic strategies targeting CA-host interactions.
These findings not only redefine HIV-1 treatment paradigms but also have broader implications for combating CA-dependent viruses.
Compuscript Ltd
Wang, M., et al. (2025) Revolutionizing HIV treatment: unveiling the new frontiers of HIV capsid research. Acta Materia Medica. doi.org/10.15212/AMM-2025-0012.
Posted in: Medical Science News | Medical Research News | Disease/Infection News
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A four-year, $2.33 million grant from the National Eye Institute of the National Institutes of Health to Wayne State University is supporting research focused on improving and preserving vision and eye health in those with diabetes.
The research is led by Elizabeth Berger, Ph.D., associate professor of ophthalmology, visual and anatomical sciences in Wayne State University's School of Medicine. Her work seeks to study a newly identified mechanism of diabetes-induced damage while providing key preclinical evidence for the development of a novel therapeutic approach to improve eyesight and general corneal health in those with diabetes.
When most people think of diabetes and vision loss, they think of diabetic retinopathy. Complications in the front of the eye such as delayed healing and corneal nerve damage are often overlooked and under-reported. Patients with diabetic corneal complications often experience vision loss and poor healing, and there are very few treatment options right now. Our goal is to go beyond blood sugar control and address mechanisms of cellular damage in the eye."
Elizabeth Berger, Ph.D., associate professor of ophthalmology, visual and anatomical sciences, Wayne State University's School of Medicine
"This project will combine two naturally occurring peptides –thymosin beta 4 (Tβ4) and vasoactive intestinal peptide (VIP) – to target inflammation, delayed healing and nerve degeneration. Berger hypothesizes that this Tβ4/VIP combination treatment can prevent high glucose-induced damage to corneal structure and function.
"With diabetes predicted to reach epidemic levels in the next few years, we need treatments that prevent complications before it does irreparable damage to vision," Berger said. "This study will lay the preclinical groundwork for future clinical trials and help to better understand how diabetes affects the eye. If successful, this work could lead to new therapies to improve the quality of life for millions of people with diabetes."
"Dr. Berger's important research may one day change the outcomes of patients diagnosed with vision problems due to diabetes," said Ezemenari M. Obasi, Ph.D., vice president for research & innovation at Wayne State University. "This funding from the National Institutes of Health is a great example of why it is critical to develop innovative solutions to treat health challenges."
The grant number for this award from the National Eye Institute of the National Institutes of Health is EY035494.
Wayne State University
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This article is based on a poster originally authored by Carolina Gá ndara, Will Atkin, Hannah Steward, Madalaine Kay, George Buchanan, Lyle Armstrong, and Valeria Chichagova.
Due to the well-documented limitations of in vivo and existing in vitro retinal models, there is a pressing need for a reproducible 3D in vitro model of the human retina that can accurately predict in vivo outcomes.
The study's objective was to investigate the consistency of human iPSC-derived retinal organoids (ROs) produced at scale by quantifying the gene and protein expression levels of key retinal cell markers throughout differentiation across multiple batches.
Image Credit: Newcells Biotech
Figure 1. Photoreceptor (PR; Genes: RCVRN, RBP3, IMPG1, CRX; Protein: RCVRN), bipolar (BC; Genes: GRIK1, CADPS; Protein: PKCα), Müller glia (MG; Genes: RLBP1, CRYM; Protein: CRALBP), retinal ganglion cell (RGC; Genes: MATH5, BRN3; Protein: SNCG), horizontal and amacrine (HC/AC; Genes: PROX1, TFA2A; Protein: PROX1, AP2α), Cone PR (Genes: OPN1SW, OPN1MW, OPN1LW, ARR3, RXRG; Protein: OPN1MW/LW) and Rod PR (Gene: RHO, NRL; Protein: RHO) cell markers are expressed at different times throughout RO development which resembles in vivo development. (A) Gene expression and (B) protein expression of RGC markers peak between day 30-90, when PR progenitor cells start differentiating. Expression of cone and rod PRs initiate from day 120 and achieve highest expression and maturation levels after 210 days in culture. Image Credit: Newcells Biotech
Figure 2. (A) Distribution and localization of key retinal cells in RO at day 90 and 150 of differentiation. (B) Quantification of cell populations revealed that at day 150 of development, PRs, AC, RGC and HC represent on average 20%, 4.6%, 3% and 1.6% of the total number of cells This average was consistent across 4 biological replicates ( P>0.05 error bars = SD) for PR, AC and HC at d 150 and RGC at d 90 (mean 7%). (C) RGCs are more abundant in early developmental stages, whereas the appearance of PRs gradually increases throughout RO development and plateaus at day 210 with nearly 30% RCVRN+ cells. Image Credit: Newcells Biotech
This study analyzed the gene and protein expression profiles of key retinal cell markers during differentiation in four batches of human iPSC-derived ROs.
The findings indicate that photoreceptors (PRs), horizontal cells (HCs) and amacrine cells (ACs) exhibit consistent levels at later stages of development, while retinal ganglion cells (RGCs) display stable expression at early stages.
This data set provides essential information for pre-clinical studies involving ROs, with potential applications in drug discovery, disease modeling, and gene therapy.
Produced from material originally authored by Carolina Gándara, Will Atkin, Hannah Steward, Madalaine Kay, George Buchanan and Valeria Chichagova from Newcells Biotech and Lyle Armstrong from Newcastle University.
Newcells Biotech develops in vitro cell-based assays for drug and chemical discovery and development.
Using our expertise in induced pluripotent stem cells (iPSCs), cellular physiology, and organoid technology, we build models that incorporate the “best biology” for predicting in vivo behavior of new drugs.
Our experts have developed and launched assays to measure transporter function, safety, and efficacy in a range of cell and tissue types, including kidney, retina and lungs.
We have the capability to develop and implement protocols to measure cilia beat frequency and toxicity on small airway epithelial cells model, retinal toxicity and disease modelling on retinal organoids and retina epithelium, as well as drug transport in the kidney, DDI and nephrotoxicity across human and a range of preclinical species.
Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.
Last Updated: May 13, 2025
Please use one of the following formats to cite this article in your essay, paper or report:
APA
Newcells Biotech. (2025, May 13). Evaluating consistency in large-scale human iPSC retinal organoids. News-Medical. Retrieved on May 14, 2025 from https://www.news-medical.net/health/Evaluating-consistency-in-large-scale-human-iPSC-retinal-organoids.aspx.
MLA
Newcells Biotech. "Evaluating consistency in large-scale human iPSC retinal organoids". News-Medical. 14 May 2025.
This article is based on a poster originally authored by Fiona Leslie, Chloe Whiting, and Megan Webster.
TGF-β1-mediated activation of fibroblasts, their transition to α-SMA-expressing myofibroblasts, and the associated increase in the deposition and expression of extracellular matrix proteins represent key pathologic mechanisms of fibrosis.
Modeling this process in vitro enables the evaluation of potential anti-fibrotic therapeutics for their capacity to reduce or reverse fibroblast-to-myofibroblast transition (FMT).
The development and validation of robust assay systems require substantial time and effort.
Image Credit: Newcells Biotech
Newcells Biotech's team has worked diligently to overcome the many technical challenges to optimize their high-throughput, high-content imaging FMT assay. This article highlights several key difficulties and the corresponding resolutions.
Image Credit: Newcells Biotech
To guarantee consistent cell adherence to culture wells throughout the FMT assay process, including during mechanical washing, cell seeding densities and culture media were optimized to control cell proliferation.
After observing significant cell detachment as a result of mechanical washing, various plate coatings were compared to enhance fibroblast attachment and reduce assay variability. Further work was conducted to optimize immunocy-to-chemical detection of α-SMA and collagen 1.
Image Credit: Newcells Biotech
Ensuring a consistent and substantial assay window is vital for establishing a reproducible in vitro assay for compound screening.
Assay culture media was optimized to promote the activation of primary fibroblasts following stimulation with TGF-β1. As shown in Figure 2, Media 3 promoted the expression of both α-SMA and collagen 1 at the gene and protein levels.
Together with refined segmental analysis masks, one can accurately detect changes in the deposition and expression of α-SMA and collagen 1 in response to treatment with potential therapeutic compounds.
Image Credit: Newcells Biotech
To guarantee consistent data, independent of well position on the plate, α-SMA and collagen 1 were quantified after the stimulation of primary fibroblasts with increasing concentrations of TGF-β1 across both horizontal and vertical axes (arrows).
The effects of two different stimulation methods were also tested (dashes). Applied conditional formatting indicates increased expression of α-SMA and collagen 1, ranging from green to red, respectively.
Newcells' FMT assay utilizes high-content imaging to assess the effects of potential therapeutics on fibroblast activation, collagen expression, and deposition in a high-throughput format.
Produced from material originally authored by Fiona Leslie, Chloe Whiting, and Megan Webster from Newcells Biotech.
Newcells Biotech develops in vitro cell-based assays for drug and chemical discovery and development.
Using our expertise in induced pluripotent stem cells (iPSCs), cellular physiology, and organoid technology, we build models that incorporate the “best biology” for predicting in vivo behavior of new drugs.
Our experts have developed and launched assays to measure transporter function, safety, and efficacy in a range of cell and tissue types, including kidney, retina and lungs.
We have the capability to develop and implement protocols to measure cilia beat frequency and toxicity on small airway epithelial cells model, retinal toxicity and disease modelling on retinal organoids and retina epithelium, as well as drug transport in the kidney, DDI and nephrotoxicity across human and a range of preclinical species.
Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.
Last Updated: May 13, 2025
Please use one of the following formats to cite this article in your essay, paper or report:
APA
Newcells Biotech. (2025, May 13). Advancing in vitro assays to model fibroblast-to-myofibroblast transition in fibrosis. News-Medical. Retrieved on May 14, 2025 from https://www.news-medical.net/health/Advancing-in-vitro-assays-to-model-fibroblast-to-myofibroblast-transition-in-fibrosis.aspx.
MLA
Newcells Biotech. "Advancing in vitro assays to model fibroblast-to-myofibroblast transition in fibrosis". News-Medical. 14 May 2025.
Star-power and Supersubs – both proved crucial in the 2025 Lamar Hunt U.S. Open Cup Round of 32. We take a look at three U.S. Men's National Team players – each with multiple caps for their country – who powered their respective Major League Soccer (MLS) sides to glory and spots in the Round of 16.
Austin FC, since launching in the top flight in 2021, have yet to make a deep run in the Open Cup. The best the Texans managed was one win and a Round of 16 berth back in 2023. So when Los Verdes were down by two goals to Division II (USL Championship) side El Paso Locomotive in the 72nd minute at home in their 2025 opener, it smelled like more of the same disappointment in Cup play.
That all changed, however, in the space of six second-half minutes when Brandon Vazquez, the burly 26-year-old former FC Cincinnati striker, flexed his muscles and showed precisely why he's been called in on 11 occasions to play for the United States (tallying four goals in those appearances).
It may come as a surprise to some readers that Vazquez knows what it feels like to lift this country's oldest prize – having finished top-scorer for Atlanta United in their run to the 2019 Open Cup title.“Wild stuff will happen when you least expect it in the Open Cup,” he told ussoccer.com of the threat posed by lower-league teams in the topsy-turvy world of the U.S. Open Cup. “You have to adapt and you have to be focused and have the mentality to win. You have to push through.”
“When you least expect it, you'll get bit,” he added, knowing well the pitfalls that exist in domestic Cup play. “It happens when your head goes down and these games [against lower-level teams] are really dangerous. You need to be ready for what they bring you. You can't slip up.”
He was more than ready when, in the 73rd minute, the time came to go to work. Slipping in behind the Locomotive defence, Vazquez hit home a slick pass from Owen Wolff. In an ominous sign of things to come for El Paso, the striker skipped the elaborate celebration and marched back to the center circle.
It was just two minutes later when Vazquez, a master of hold-up play with his big frame, chested a long ball down for Myrto Uzuni to hammer home the equalizer. The writing was on the wall for the tiring Division II visitors and fellow Texans when, in the 79th minute, Vazquez put the finishing touches on the 3-2 win when he headed home his second of the night off another bit of pretty service from Wolff.
This time Vazquez took the time to celebrate his goal – and the huge comeback that saw Austin FC match their best-ever run in the Open Cup (a place in the Round of 16) and book another home date with our two-time Open Cup Champs Houston Dynamo on May 21 (LIVE on Paramount+).
Patrick ‘Big Pat' Agyemang didn't have the luxury of being on the field from the start like Vazquez did. He had to weave his game-changing magic after coming off the bench in the 78th minute for Charlotte FC. The big striker, who hails from Connecticut, entered the away-game against Division II (USL Championship) side North Carolina FC with the score tangled at 0-0.“I love the Open Cup. Teams from all the levels getting to play against each other – it's crazy,” Agyemang said earlier this year, while in his first camp with the U.S. Men's National Team. “You don't know what's gonna happen. The possibilities are all over the place. You got your favorites but at the end of the day you have to play the game and earn it.”
He did just that. The massive target man took control in an overtime session that produced five goals and an eventual 4-1 win for Charlotte FC.
With the score tied at 1-1 in the 103rd minute, Djibril Diani sent a looping cross into the area. It's the kind of ball that's the 24-year-old Agyemang's bread and butter. The striker rose highest and headed home off the inside of the post to earn a lead that Charlotte FC wouldn't relinquish – and which sent them through to a Round of 16 date with D.C. United on the road (LIVE on Paramount+).
“It's all about moments,” Agyemang has said about the historic Open Cup, and he couldn't be more right.
The game-winner was unsurprisingly named Man of the Match. He also had a hand in Nikola Petkovic's third goal for Charlotte FC and an assist on the insurance strike by Kerwin Vargas, in the dying seconds, that sealed the 1-4 win for the MLS men from North Carolina.
There was one more game of the Round of 32's 16-game schedule that went to OT. Curiously enough that matchup between our 2018 and 2023 Champs Houston Dynamo and Phoenix Rising (of the Division II USL Championship) also ended 1-4 after the extra-time session.
The highlight of those bonus 30 minutes in Arizona was a wonder goal for four-times capped Jack McGlynn (with one goal for the USMNT so far in his international career). The youngster, just 21 and with a big future ahead, arrived in Houston after coming through the youth system at Philadelphia Union and breaking into the club's first team. He carved open some space on the right side in the 99th minute, cut inside and unleashed a wicked curling volley with his left foot that was always destined for the top corner.
“He's a monster!” enthused Dynamo coach and three-time Open Cup winner Ben Olsen about young McGlynn's performance. “That's why we signed him.”
It was the go-ahead goal (1-2) and the Dynamo strolled on to an eventual 1-4 result (after regulation time ended 1-1). Aside from being a frontrunner candidate for Goal of the Round, McGlynn's wonder-strike helped the Dynamo seal a tricky contest on the road and book a place in the Round of 16 against Brandon Vazquez and his swashbuckling Austin FC (LIVE on Paramount+).You can WATCH all EIGHT Round of 16 GAMES on Paramount+ on May 20-21 with select GAMES on the CBS Sports Golazo Network and on air at CBS Sports Network.Angelo Maduro is a senior reporter at large forwww.ussoccer.com/us-open-cup.
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The United States men's national team announced friendly fixtures in September as Mauricio Pochettino continues preparation for the 2026 FIFA World Cup.
The USMNT will face South Korea and Japan, four days apart, in Harrison, NJ and Columbus, OH. South Korea and Japan are ranked 23rd and 15th respectively in the FIFA men's world rankings, as of writing. The Stars and Stripes will take the field and host supporters and their opponents at two Major League Soccer stadiums.
Here's everything you need to know about USMNT's September friendlies against two of the Asian Football Confederation's best.
Our September slate is set! Become an Insider for early access on tickets » https://t.co/i8njUnrI4X pic.twitter.com/AlQHXje6mT
USA and Japan have met just three times since their first match in 1993. Taylor Twellman fueled the Stars and Stripes to victory in a 2006 friendly, but the Samurai Blue got the better of USMNT last time they met before the 2022 World Cup.
The USMNT have more history against South Korea having played them seven times. USA holds a 2W-3L-2D record against South Korea. Chris Wondolowski featured the last time these two countries met in 2014 with USA winning 2-0 in California.
Match and Date
TV/Live Stream
vs. South Korea, Sept. 6 at 5 p.m. ET
TNT, Telemundo, Max, Universo, Peacock
vs. Japan, Sept. 9 at 7:30 p.m. ET
TNT, Max, Universo, Peacock
South Korea and Japan represent strong opponents for the USMNT bookending the start of summer and post-Concacaf Gold Cup. The USMNT play Turkey and Switzerland in June before taking on Trinidad and Tobago in their first Gold Cup match. Pochettino's team needs strong performances and a string of results under their belt as the disappointment from the Concacaf Nations League looms large.
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© 2025 ABG-SI LLC - SPORTS ILLUSTRATED IS A REGISTERED TRADEMARK OF ABG-SI LLC. - All Rights Reserved. The content on this site is for entertainment and educational purposes only. Betting and gambling content is intended for individuals 21+ and is based on individual commentators' opinions and not that of Sports Illustrated or its affiliates, licensees and related brands. All picks and predictions are suggestions only and not a guarantee of success or profit. If you or someone you know has a gambling problem, crisis counseling and referral services can be accessed by calling 1-800-GAMBLER.
The United States men's national team announced friendly fixtures in September as Mauricio Pochettino continues preparation for the 2026 FIFA World Cup.
The USMNT will face South Korea and Japan, four days apart, in Harrison, NJ and Columbus, OH. South Korea and Japan are ranked 23rd and 15th respectively in the FIFA men's world rankings, as of writing. The Stars and Stripes will take the field and host supporters and their opponents at two Major League Soccer stadiums.
Here's everything you need to know about USMNT's September friendlies against two of the Asian Football Confederation's best.
Our September slate is set! Become an Insider for early access on tickets » https://t.co/i8njUnrI4X pic.twitter.com/AlQHXje6mT
USA and Japan have met just three times since their first match in 1993. Taylor Twellman fueled the Stars and Stripes to victory in a 2006 friendly, but the Samurai Blue got the better of USMNT last time they met before the 2022 World Cup.
The USMNT have more history against South Korea having played them seven times. USA holds a 2W-3L-2D record against South Korea. Chris Wondolowski featured the last time these two countries met in 2014 with USA winning 2-0 in California.
Match and Date
TV/Live Stream
vs. South Korea, Sept. 6 at 5 p.m. ET
TNT, Telemundo, Max, Universo, Peacock
vs. Japan, Sept. 9 at 7:30 p.m. ET
TNT, Max, Universo, Peacock
South Korea and Japan represent strong opponents for the USMNT bookending the start of summer and post-Concacaf Gold Cup. The USMNT play Turkey and Switzerland in June before taking on Trinidad and Tobago in their first Gold Cup match. Pochettino's team needs strong performances and a string of results under their belt as the disappointment from the Concacaf Nations League looms large.
feed
Max Mallow is an editor for Sports Illustrated Soccer. Somehow, he has just enough time every matchday to tweet when an Arsenal player scores a goal.
Follow OddSlice
© 2025 ABG-SI LLC - SPORTS ILLUSTRATED IS A REGISTERED TRADEMARK OF ABG-SI LLC. - All Rights Reserved. The content on this site is for entertainment and educational purposes only. Betting and gambling content is intended for individuals 21+ and is based on individual commentators' opinions and not that of Sports Illustrated or its affiliates, licensees and related brands. All picks and predictions are suggestions only and not a guarantee of success or profit. If you or someone you know has a gambling problem, crisis counseling and referral services can be accessed by calling 1-800-GAMBLER.
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First launched in 2000 as the FIFA Club World Championship, the FIFA Club World Cup has long occupied a curious place in global football—not quite as prestigious as the UEFA Champions League or even some regional competitions like the Concacaf Champions Cup, yet still coveted enough for clubs to chase the title.
In a bid to elevate its stature, FIFA is giving the tournament a major overhaul in 2025.
Instead of the usual seven-team format, the 2025 edition will feature 32 clubs from across the globe in a four-week soccer spectacle hosted in the United States, running from June 15 to July 13. Giants like Real Madrid, Manchester City, Inter Miami, and River Plate will be among the elite teams competing for international glory.
As anticipation builds for the tournament's 21st edition, which comes with a new, hefty prize pool to boot, we take a look back at every previous FIFA Club World Cup winner, the most successful clubs in the competition's history, and some of its most iconic moments.
Just like in the Champions League, Real Madrid stands as the most successful club in FIFA Club World Cup history, having claimed the title five times—in 2014, 2016, 2017, 2018, and 2022.
Barcelona follows with three titles, while Bayern Munich and Brazilian side Corinthians have each won the tournament twice. Beyond those, eight other clubs have lifted the trophy once.
Team
FIFA Club World Cup Titles
Real Madrid
5
Barcelona
3
Bayern Munich
2
Corinthians
2
AC Milan, Chelsea, Inter Milan, Internacional, Liverpool, Manchester City, Manchester United, São Paulo
1
The inaugural Club World Cup was won by Corinthians, who defeated Vasco da Gama in a dramatic penalty shootout in 2000.
Following that first edition, the tournament was not held for another five years, largely due to financial difficulties. It was later reshaped, renamed, and relaunched in 2005, with São Paulo emerging as champions after beating Liverpool in the final.
The most recent champion is Manchester City, who claimed the title in 2023. Their Club World Cup triumph was part of an extraordinary five-trophy haul that season, which also included the Premier League, UEFA Champions League, FA Cup, and UEFA Super Cup.
The tournament was not held in 2024, as FIFA paused the competition in preparation for its expanded and revamped 2025 edition.
Below is a complete list of Club World Cup champions, year by year.
Year
FIFA Club World Cup Winner
2000
Corinthians
2001
-
2002
-
2003
-
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There have been many iconic moments in the history of the Club World Cup.
In 2005, São Paulo pulled off a stunning upset to defeat reigning UEFA Champions League winners Liverpool, with goalkeeper Rogério Ceni—who had also scored in the semifinals—delivering a performance for the ages. He denied the likes of Steven Gerrard, Peter Crouch, and Xabi Alonso with a series of outstanding saves.
A year later, in 2006, Internacional shocked Barcelona, then led by Frank Rijkaard, by claiming a 1-0 victory thanks to a goal from midfielder Adriano. The Brazilian underdogs triumphed despite facing a star-studded Barcelona lineup featuring Ronaldinho, Andrés Iniesta, and Xavi.
In 2011, the tournament featured a memorable meeting between Lionel Messi and a young Neymar, then starring for Santos, just years before they would become teammates at Barcelona. More recently, in 2023, the final was marked by a fiery confrontation between Kyle Walker and Felipe Melo, culminating in an on-pitch melee at the final whistle.
Perhaps the most iconic moment in Club World Cup history came in 2010, when Congolese side TP Mazembe made a historic run to the final.
Though they were ultimately outclassed by Inter Milan, Mazembe recorded unforgettable victories over Pachuca and Internacional along the way. Their journey was punctuated by the joyful celebrations of goalkeeper Robert Kidiaba, who became famous for scooting around the penalty area on his backside after each goal.
🇨🇩 Happy Birthday to former @TPMazembe & DR Congo's Robert Kidiaba! 🥳🔝 Goalkeeper with a unique celebration 🤩 pic.twitter.com/iWZICSpGsP
That celebration became almost as legendary as Mazembe's run itself—serving as a perfect metaphor for what the Club World Cup represented at the time: fun, inclusivity, and a pure soccer spectacle.
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Barnaby Lane is a highly experienced sports writer who has written for The Times, FourFourTwo Magazine, TalkSPORT, and Business Insider.
Over the years, he's had the pleasure of interviewing some of the biggest names in world sport, including Usain Bolt, Rafael Nadal, Christian Pulisic, and more.
© 2025 ABG-SI LLC - SPORTS ILLUSTRATED IS A REGISTERED TRADEMARK OF ABG-SI LLC. - All Rights Reserved. The content on this site is for entertainment and educational purposes only. Betting and gambling content is intended for individuals 21+ and is based on individual commentators' opinions and not that of Sports Illustrated or its affiliates, licensees and related brands. All picks and predictions are suggestions only and not a guarantee of success or profit. If you or someone you know has a gambling problem, crisis counseling and referral services can be accessed by calling 1-800-GAMBLER.
The 2025 FIFA Club World Cup is headed to Miami next month and fans are clamoring to see the action.
Set to be held at Hard Rock Stadium in Miami, Fla., the opening match for the venue is June 14 when Al Ahly FC takes on superstar Lionel Messi and Inter Miami CF.
The other teams set to play in Miami includes CA Boca Juniors, SL Benfica, Real Madrid C.F., Al Hilal, FC Bayern München, CA Boca Juniors, SE Palmeiras, Mamelodi Sundowns FC and Fluminense FC.
Soccer fans looking to witness a part of the action have plenty of options available as tickets are now available.
Here's how to buy 2025 FIFA Club World Cup tickets in Miami.
Our team of savvy editors independently handpicks all recommendations. If you make a purchase through our links, we may earn a commission. Prices were accurate at the time of publication but may change.
Chelsea are confident of beating Manchester United to the signing of £30m Liam Delap from Ipswich Town this summer.
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Enrique Sanz
The attempt to sign Trent Alexander-Arnold has taken a form that is very much liked in the offices of Valdebebas. The contacts between the white leadership and the English right-back's entourage have allowed positions to be brought closer more than notably, making his signing a practically 'closed' operation. In the absence of the security of the official announcement, many count on this player in future Real Madrid.
Especially because of the excellent disposition the British footballer has shown to join the merengue ranks as soon as possible. The Club World Cup has disrupted the roadmap devised for the summer of 2025, making the merengue bosses have to accelerate that signing... eliminating the possibility of doing it as a free agent.
Liverpool is willing to make that need of Real Madrid a reality, but it has imposed three well-known conditions in the European football elite. The white club will have to make a financial sacrifice amounting to 2.2 million euros, adding the remaining salary of Alexander-Arnold and a symbolic transfer to be able to sign the English defender. But Trent Alexander-Arnold himself will also be forced to make a double sacrifice.
Because the British footballer could refuse to play the Club World Cup with Real Madrid, staying at Liverpool until the end and receiving his June salary. That would not make the white sports management less interested in his incorporation, but it would put the new first-team coach, Xabi Alonso, in a bind. The lack of right-backs has been a constant this season, and Alexander-Arnold is the solution to that problem.
In this situation, Trent Alexander-Arnold faces the double sacrifice of salary and his vacations. Playing the Club World Cup with Real Madrid not only implies not receiving the last month of his contract with Liverpool. It also means going directly into action, with barely two weeks of preparation and 'rest' typical of mid-season, to achieve victory in the Club World Cup.
From the offices of Valdebebas, they have closely followed the mood of the English right-back and his receptivity to that idea is more than positive news. Trent Alexander-Arnold seems willing to make that double sacrifice a reality to play as soon as possible with the Real Madrid jersey... while the white club hopes it is not too much to demand from the player.
Because Trent Alexander-Arnold could well 'regret' signing for Real Madrid, given what he has to lose if he wants to play the Club World Cup, and change his mind. Such a decision would be catastrophic for the short-term future of the first team, because it has relied on one of the most critical positions on a footballer who would arrive as a free agent.
For now, Real Madrid is prepared to receive Trent Alexander-Arnold between June 1 and 10. That period corresponds to the transfer window opened by FIFA to allow clubs playing in the World Cup to strengthen their squads as they see fit. Real Madrid would take advantage of that period by incorporating Alexander-Arnold himself, securing one of the most important signings of recent years.
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Human rights groups are warning of a "surge" of deaths of migrant construction workers in Saudi Arabia, as it prepares to host the World Cup in 2034.
Labourers are already dying from preventable workplace accidents in the country, according to Human Rights Watch and FairSquare which have both published reports today.
Many such deaths are wrongly classified as having occurred due to natural causes and the families of workers are not compensated, the reports say.
Both groups have called on the Saudi Authorities to ensure basic safety protections for the country's huge migrant work-force.
"The 2034 Saudi World Cup will be the largest and most expensive ever, but it could also have the highest cost in human lives, as millions of migrant workers build infrastructure, including 11 new stadiums, a rail and transit network, and 185,000 hotel rooms," Minky Worden, director of Global Initiatives at Human Rights Watch, said.
The warnings come a day after the President of FIFA, Gianni Infantino, visited the country along with Donald Trump - attending a US-Saudi investment forum.
FIFA – football's global governing body - says it has a "steadfast commitment to the protection and promotion of human rights in the context of its operations."
But Human Rights Watch has accused FIFA of failing to learn lessons from migrant worker deaths in the lead-up to the World Cup in Qatar in 2022.
Data on migrant deaths is hard to come by in a country where human rights groups have very limited access and labour unions are banned.
But Human Rights Watch interviewed the families of 31 workers from Bangladesh, India and Nepal who fell from heights, were crushed or decapitated by heavy machinery or were electrocuted.
Heat is another major concern, as Saudi Arabia ramps up construction work in preparation for hosting the 2034 tournament.
In March, a Pakistani foreman, Muhammad Arshad, was reported to have fallen from a construction site at a stadium being built in the eastern city of Al Khobar – the first death related to the World Cup.
Last year, the Saudi government said that there had been "tangible achievements" in occupational health and safety, with rates of deaths and injuries decreasing.
FIFA also praised "significant steps" taken by Saudi Arabia to reform its labour laws since 2018.
But the global construction worker's union, BWI, said there had been an "alarming rise" in accidents that could have been prevented.
"These are the result of systematic negligence, corruption and inadequate oversight and accountability," said BWI General Secretary, Ambet Yuson.
And Saudi medical authorities rarely conduct autopsies to establish the exact cause of migrant workers' deaths, according to FairSquare.
"Hundreds of thousands of young men, many of whom have young families, are being pitched into a labour system that poses a serious risk to their lives, a medical system that doesn't have the capacity to determine the cause of their deaths, and a political system that doesn't appear to either protect them or find out how they died, let alone compensate the families shattered by Saudi Arabia's negligence," FairSquare co-director James Lynch said.
He described FIFA's human rights policies as a "sham."
"While FIFA praises Saudi Arabia to the rafters and highly-paid western law firms generate vast profits for curating Saudi's reputation, children in places like Nepal grow up without their fathers and never even learn how they died, he said."
FIFA told Human Rights Watch that it plans to establish a workers' welfare system dedicated to mandatory standards and enforcement mechanisms for World Cup-related construction and service delivery in Saudi Arabia.
In a letter it said: "We are convinced that the measures implemented to ensure construction companies respect the rights of their workers on FIFA World Cup sites can set a new standard for worker protection in the country and contribute to the wider labour reform process, helping to enhance protections for workers on World Cup sites and beyond."
But Human Rights Watch said no further details were provided on how the welfare system would work.
"Saudi authorities, FIFA, and other employers should ensure that all migrant worker deaths, regardless of perceived cause, time, and place are properly investigated and that families of deceased workers are treated with dignity and receive fair and timely compensation," the group said.
The BBC has approached the Saudi authorities for comment.
Copyright 2025 BBC. All rights reserved. The BBC is not responsible for the content of external sites. Read about our approach to external linking.
Francesco Farioli's side have seen a nine-point lead cut to just one ahead of Wednesday's must-win meeting with Groningen
It's often argued that winning is the only thing that matters in football, with the implication being that nobody remembers the runners-up. It's simply not true, of course.
Sometimes, the story of a season is not the team that claimed the title, but the one that threw it away. Ask anyone about the 1995-96 Premier League campaign and Kevin Keegan's Newcastle will be the side that immediately comes to mind, while the abiding memory of the 2001-02 Serie A title race is Ronaldo in tears at the Stadio Olimpico as Inter gifted the Scudetto to Juventus.
And who could forget Real Madrid's Galacticos going from first to fourth in La Liga by losing six of their final seven games in 2003-04 - or Steven Gerrard's infamous slip at Anfield a decade later? Botafogo, meanwhile, would never have gotten over their historic Brasileiro collapse in 2023 had they not won both the league and the Copa Libertadores last year. As for Bayer Leverkusen, they became so synonymous with falling at the final hurdle that they were known as 'Neverkusen' until Xabi Alonso came along.
There's a very real possibility, then, that Ajax's 2024-25 season will forever be remembered for all the wrong reasons, with Francesco Farioli's men in danger of adding their name to the list of football's biggest bottle-jobs..
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Two leading human rights groups have accused FIFA of being “utterly negligent” in its responsibility to the millions of migrant workers who will build the stadiums and infrastructure Saudi Arabia needs for the 2034 World Cup.
The scathing criticism of world football's governing body is detailed in two new reports on migrant-worker deaths in the Gulf state published on Tuesday by FairSquare and Human Rights Watch (HRW). And they come a day after FIFA boss Gianni Infantino accompanied U.S. President Donald Trump on visit to Saudi Arabia's capital Riyadh, where they met the Gulf state's de facto ruler Crown Prince Mohammed Bin Salman.
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The research, which is based on investigations into the recent deaths of 48 migrant workers from Bangladesh, India and Nepal, paints a picture of a host nation that still pays lip service to safety on building sites, has no interest in properly investigating accidents and is painfully slow to compensate bereaved families.
But the two studies also criticise FIFA for failing to learn the lessons from the 2022 World Cup in Qatar, where government officials eventually admitted that hundreds of migrant workers had died while working on projects linked to the tournament.
“The gruesome workplace accidents killing migrant workers in Saudi Arabia should be a huge red flag for businesses, football fans and sports associations seeking to partner with FIFA on the 2034 Men's World Cup and other Saudi ‘giga-projects',” said HRW's deputy Middle East director Michael Page.
The HRW study includes accounts of workers dying in awful accidents but also dropping dead due to heat exhaustion. The families of these men are usually left with no information about what really happened and often face long delays in repatriating the bodies of their loved ones or in receiving any financial compensation.
In March of this year, British newspaper The Guardian reported that Pakistani migrant worker Muhammad Arshad had become the first known death at a stadium construction site when he fell from the upper level of the Aramco Stadium in Al Khobar.
FairSquare's report focuses on the lack of data collected by the Saudi authorities on their migrant worker population, the failure to certify deaths properly and the absence of any attempt to learn from accidents when they happen or to hold anyone to account.
“Millions of workers are going to be pitched into this system,” said FairSquare's founding co-director Nick McGeehan.
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“There was a 40 per cent increase in the migrant-worker population in the five years leading up to Saudi Arabia being awarded the World Cup in 2024 — it's up to 13.2million. It's a system where the people in charge have very little regard for their welfare or the welfare of their families.
“The inevitable result is there will be a surge in deaths in construction and most of those of deaths will be unexplained. It will be hard to determine how many will die but it's indubitably the case that many thousands will, and that's utterly unacceptable.
“It's particularly galling when you consider that many of the deaths will be a direct result of the FIFA 2034 World Cup. FIFA's response to the risks was amateurish, and that's being kind. It was utterly negligent. They gave Saudi Arabia's bid the highest score of any they had received with scant regard to any of the very obvious risks.
“We published a report last year that found that FIFA was entirely unfit to govern something as important as world football. At the time that felt like quite a bold claim but it now it just feels like a statement of the obvious.”
As part of its bid for the world's biggest sports event, Saudi Arabia has committed to building 11 new stadiums, eight of which it is yet to start, 134 training facilities, 185,000 new hotel rooms, fan zones, conference centres and a railway between Riyadh and Jeddah. And that is before you factor in the completion of the world's biggest construction site at Neom, the futuristic city in the desert that is the centrepiece of Mohammed Bin Salman's strategic plan for the country.
Saudi Arabia's bid team did not respond to a request for comment from The Athletic but FIFA shared with us the letter it sent to HRW from its general secretary Mattias Grafstrom.
The letter, which was sent last month, lists the steps FIFA has taken in recent years to integrate human-rights commitment into its statutes and points out that Saudi Arabia has “been investing heavily in the development of its society and economy”, efforts that have been helped and encouraged by western companies and governments.
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Grafstrom, who is preparing for FIFA's 2025 Congress in Paraguay this week, continues by noting the various steps the Saudi government has taken to reform its labour laws since 2018, such as abolishing parts of the kafala system which ties workers to their employers, and introducing standardised workers' contracts.
The Saudi government, he notes, has also committed to working with the United Nations' International Labour Organization (ILO) “on the further expansion and effective implementation of these reforms”.
“It is against this background that the FIFA Congress composed of all its 211 member associations has awarded the FIFA World Cup 2034 to Saudi Arabia,” he wrote.
“In that respect, and in line with its human rights commitments, FIFA seeks to play its part in ensuring strong protections for workers employed by third parties in the construction of FIFA World Cup sites.”
FairSquare and HRW, however, are far from convinced and have called on FIFA to demand that the Saudis make four seemingly straightforward commitments:
In a briefing with journalists to explain their reports, FairSquare and HRW were joined by Ambet Yuson, general secretary of Builders' and Wood Workers International (BWI), a global federation of construction workers' trade unions from 111 countries.
Earlier this year, the BWI filed a forced labour complaint against Saudi Arabia at the ILO on behalf of 21,000 migrant workers who are still owed unpaid wages by two bankrupt Saudi construction firms.
Yuson hopes to get a response to that complaint before the end of this year but said the Saudi authorities are not letting him or the BWI into the kingdom to conduct any inspection visits, despite requests to do so from overseas contractors. Qatar, on the other hand, did allow him and his colleagues to make visits.
(GIUSEPPE CACACE/AFP via Getty Images)
Based in North West England, Matt Slater is a senior football news reporter for The Athletic UK. Before that, he spent 16 years with the BBC and then three years as chief sports reporter for the UK/Ireland's main news agency, PA. Follow Matt on Twitter @mjshrimper
Two reports published today catalogue ‘gruesome yet avoidable accidents' on construction sites despite the Gulf kingdom's claims that work-related deaths have fallen
Thousands of migrant workers are likely to die in Saudi Arabia as a result of a building boom fuelled by the 2034 Men's World Cup and other major construction projects, human rights groups have warned.
The Gulf kingdom has seen a surge in demand for cheap migrant labour, with a significant increase in foreign workers since 2021, as it starts preparations for hosting the World Cup and drives forward projects including the futurist megacity Neom.
In two reports released today, human rights groups said workers face severe risks to life and have criticised the lack of transparency surrounding the deaths of migrant workers.
“Hundreds of thousands of young men … are being pitched into a labour system that poses a serious risk to their lives,” said James Lynch, a co-director of FairSquare, which has written a report on the risks faced by workers.
“While Fifa praises Saudi Arabia to the rafters,” he said, “children in places like Nepal grow up without their fathers and never even learn how they died.”
In a separate report on migrant worker deaths in Saudi Arabia, Human Rights Watch (HRW) accused Fifa of “knowingly risking yet another tournament that will unnecessarily come at a grave human cost”.
Earlier this year the Guardian revealed a worker from Pakistan fell to his death while constructing a stadium for the World Cup in the eastern city of Al Khobar.
The HRW report documented a catalogue of deaths caused by “gruesome yet avoidable workplace-related accidents” in Saudi Arabia, including by decapitation, electrocution and falls from height, leaving the families of victims devastated and impoverished.
Under Saudi law, when a worker dies in the course of their job their family members should receive compensation from a government insurance scheme or directly from the employer. However, HRW called the process “long and burdensome” and recorded numerous cases where families received little or no compensation.
The Saudi authorities have claimed that the rates of work-related injuries and deaths have fallen significantly.
But rights groups such as FairSquare have raised concerns about, “serious shortcomings in the manner in which the authorities in Saudi Arabia investigate and certify migrant worker deaths”. Many deaths may be misclassified as “natural” when it is likely they are linked directly or indirectly to the working and living conditions faced by workers.
The term “natural” provides no meaningful explanation for the underlying cause of death, said FairSquare, whose report stated: “It appears that the Saudi authorities are using it as a shorthand for any deaths that did not result from workplace accidents, road traffic accidents or other violent deaths.”
That view is supported by a 2019 study by a Saudi pathologist, who examined all death certificates from a hospital in Riyadh between 1997 and 2016 and found that in every case the cause of death was “either incorrect or absent” and that in 75% of cases there was no cause of death provided at all.
In response to the Guardian's request for comment, Fifa shared a letter it had sent to HRW in which it stated: “Fifa seeks to play its part in ensuring strong protections for workers employed by third parties in the construction of Fifa World Cup sites. This work involves a close collaboration with its Saudi counterparts and engagements with relevant international labour organisations … we are convinced that measures implemented … can set a new standard for worker protection.”
The Ministry of Human Resources and Social Development in Saudi Arabia was approached for comment.
New Delhi [India], May 14 (ANI): Italy's Jannik Sinner, the number one-ranked tennis star, who had an off day in the ongoing Italian Open on Wednesday, went to the Vatican City and met Pope Leo XIV.
Sinner, his parents Johann and Siglinde, his manager Alex Vittur and a delegation from the Italian Tennis Federation, including president Angelo Binaghi, were among those present during the meeting with Pope Leo XIV.
During his audience, the 23-year-old presented Pope Leo XIV, who was elected just six days ago, with one of his racquets. In a video posted by Internazionali BNL d'Italia on Instagram, Pope Leo XIV asked Sinner about his Tuesday night victory against Argentina's Francisco Cerundolo, to which the Italian replied, "Yes, we managed."
After Sinner presented his racket, Pope Leo XIV shared a laugh with Sinner. "Could I play at Wimbledon?" he asked.
Last Thursday, the Vatican conclave chose a new Pope, Robert Prevost, the first American Pope, Vatican News said. The Cardinals gathered in the Vatican's Sistine Chapel and elected 69-year-old Cardinal Robert Francis Prevost as the 267th Pope, who took the name Pope Leo XIV. He is the first American to lead the Catholic Church.
Cardinal Protodeacon Dominique Mamberti, the senior cardinal deacon appeared on the St. Peter's balcony that overlooks the St Peter's square and announced, "Habemus Papam!" - "We have a pope."
Meanwhile, Sinner will be keen on continuing his scorching form in the Italian Open when he squares off against Casper Ruud in the quarter-final clash on Thursday. He secured a spot in the last eight with a 7-6(2), 6-3 victory over Cerundolo.
"He's a very tough competitor, it's a great challenge for me. Especially now trying to get used to so many difficult situations on the court. I just tried to stay there mentally, trying to play every point. But I'm very happy because I felt like I raised my level. Game wise, I felt a little bit better. It was very heavy conditions, and it was a long day. The crowd helped me, so I'm happy to go through," Sinner said after the win, as quoted from ATP. (ANI)
(The story has come from a syndicated feed and has not been edited by the Tribune Staff.)
The Tribune, now published from Chandigarh, started publication on February 2, 1881, in Lahore (now in Pakistan). It was started by Sardar Dyal Singh Majithia, a public-spirited philanthropist, and is run by a trust comprising five eminent persons as trustees.The Tribune, the largest selling English daily in North India, publishes news and views without any bias or prejudice of any kind. Restraint and moderation, rather than agitational language and partisanship, are the hallmarks of the newspaper. It is an independent newspaper in the real sense of the term.The Tribune has two sister publications, Punjabi Tribune (in Punjabi) and Dainik Tribune (in Hindi).
Remembering Sardar Dyal Singh Majithia
The Spaniard will return to No. 2 on the rankings next Monday after reaching the semifinals in the Italian capital.ByJohn BerkokPublished May 14, 2025 copy_link
Published May 14, 2025
A day after becoming the first man born in the 2000s to reach the quarterfinals of every single Masters 1000 event, Carlos Alcaraz kept his run going in Rome, reaching the semifinals in the Italian capital with a 6-4, 6-4 quarterfinal victory against Jack Draper.And that win had major implications—literally.The Spaniard is now guaranteed to rise from No. 3 to No. 2 when the new rankings come out next Monday, after Rome, switching spots with Alexander Zverev, who will dip from No. 2 to No. 3.Those are the rankings that determine the seedings for Roland Garros, so Alcaraz will be the No. 2 seed in Paris, meaning he can't play guaranteed No. 1 seed Jannik Sinner until the final.Zverev can't be passed for No. 3, so he'll be the No. 3 seed.The No. 4 seed at the second major of the year will be either Taylor Fritz or Casper Ruud—if Ruud goes on to win the title in Rome he'll snap it up, otherwise Fritz will round out the Top 4.
And that win had major implications—literally.The Spaniard is now guaranteed to rise from No. 3 to No. 2 when the new rankings come out next Monday, after Rome, switching spots with Alexander Zverev, who will dip from No. 2 to No. 3.Those are the rankings that determine the seedings for Roland Garros, so Alcaraz will be the No. 2 seed in Paris, meaning he can't play guaranteed No. 1 seed Jannik Sinner until the final.Zverev can't be passed for No. 3, so he'll be the No. 3 seed.The No. 4 seed at the second major of the year will be either Taylor Fritz or Casper Ruud—if Ruud goes on to win the title in Rome he'll snap it up, otherwise Fritz will round out the Top 4.
The Spaniard is now guaranteed to rise from No. 3 to No. 2 when the new rankings come out next Monday, after Rome, switching spots with Alexander Zverev, who will dip from No. 2 to No. 3.Those are the rankings that determine the seedings for Roland Garros, so Alcaraz will be the No. 2 seed in Paris, meaning he can't play guaranteed No. 1 seed Jannik Sinner until the final.Zverev can't be passed for No. 3, so he'll be the No. 3 seed.The No. 4 seed at the second major of the year will be either Taylor Fritz or Casper Ruud—if Ruud goes on to win the title in Rome he'll snap it up, otherwise Fritz will round out the Top 4.
Those are the rankings that determine the seedings for Roland Garros, so Alcaraz will be the No. 2 seed in Paris, meaning he can't play guaranteed No. 1 seed Jannik Sinner until the final.Zverev can't be passed for No. 3, so he'll be the No. 3 seed.The No. 4 seed at the second major of the year will be either Taylor Fritz or Casper Ruud—if Ruud goes on to win the title in Rome he'll snap it up, otherwise Fritz will round out the Top 4.
Zverev can't be passed for No. 3, so he'll be the No. 3 seed.The No. 4 seed at the second major of the year will be either Taylor Fritz or Casper Ruud—if Ruud goes on to win the title in Rome he'll snap it up, otherwise Fritz will round out the Top 4.
The No. 4 seed at the second major of the year will be either Taylor Fritz or Casper Ruud—if Ruud goes on to win the title in Rome he'll snap it up, otherwise Fritz will round out the Top 4.
Alcaraz was down 4-2 in the first set but bounced back to beat Draper in straight sets.© 2025 Getty Images
© 2025 Getty Images
Draper had beaten Alcaraz in their last meeting, earlier this year in the semifinals of Indian Wells, and early on it looked like another upset might be brewing in Rome as he broke serve for a 4-2 lead.Alcaraz broke right back—at love, too—and ended up winning the next five games in a row to go up a set and a break at 6-4, 1-0. Draper snapped that streak, breaking back for 1-all, and the two went into a holding pattern until 4-all, where Alcaraz pounced one last time, breaking at love for 5-4 and then serving it out."I think the most important thing I did today was not thinking about the result," Alcaraz said in his on-court interview. "Not thinking if I was up, if I was down, just trying to do the things that make me happy on the court—just try to play aggressive, hitting good shots, drop shots, coming to the net. That's what I like to do on the court."I think that made the difference today."Had Draper won the match, the rankings scenario would have been a bit different—he would have secured a rise to No. 4 on the ATP rankings, guaranteeing him the No. 4 seed at Roland Garros, and Zverev could have kept No. 2 by winning the title in Rome.
Alcaraz broke right back—at love, too—and ended up winning the next five games in a row to go up a set and a break at 6-4, 1-0. Draper snapped that streak, breaking back for 1-all, and the two went into a holding pattern until 4-all, where Alcaraz pounced one last time, breaking at love for 5-4 and then serving it out."I think the most important thing I did today was not thinking about the result," Alcaraz said in his on-court interview. "Not thinking if I was up, if I was down, just trying to do the things that make me happy on the court—just try to play aggressive, hitting good shots, drop shots, coming to the net. That's what I like to do on the court."I think that made the difference today."Had Draper won the match, the rankings scenario would have been a bit different—he would have secured a rise to No. 4 on the ATP rankings, guaranteeing him the No. 4 seed at Roland Garros, and Zverev could have kept No. 2 by winning the title in Rome.
"I think the most important thing I did today was not thinking about the result," Alcaraz said in his on-court interview. "Not thinking if I was up, if I was down, just trying to do the things that make me happy on the court—just try to play aggressive, hitting good shots, drop shots, coming to the net. That's what I like to do on the court."I think that made the difference today."Had Draper won the match, the rankings scenario would have been a bit different—he would have secured a rise to No. 4 on the ATP rankings, guaranteeing him the No. 4 seed at Roland Garros, and Zverev could have kept No. 2 by winning the title in Rome.
"I think that made the difference today."Had Draper won the match, the rankings scenario would have been a bit different—he would have secured a rise to No. 4 on the ATP rankings, guaranteeing him the No. 4 seed at Roland Garros, and Zverev could have kept No. 2 by winning the title in Rome.
Had Draper won the match, the rankings scenario would have been a bit different—he would have secured a rise to No. 4 on the ATP rankings, guaranteeing him the No. 4 seed at Roland Garros, and Zverev could have kept No. 2 by winning the title in Rome.
100 mph ROCKET forehand 🚀@jackdraper0 is finding his form in the second set 💪#IBI25 pic.twitter.com/4sO4O33lhu
Up next for Alcaraz in Rome will be either Zverev or Lorenzo Musetti, who played their quarterfinal match on Wednesday night.Alcaraz actually has a losing overall record against Zverev, 5-6, but he does lead 3-1 on clay. The two haven't played in Rome.He's 4-1 against Musetti, losing their first tour-level meeting in the Hamburg final in 2022 but winning all four meetings since, including a 3-6, 6-1, 6-0 victory in the Monte Carlo final just a few weeks ago.
Alcaraz actually has a losing overall record against Zverev, 5-6, but he does lead 3-1 on clay. The two haven't played in Rome.He's 4-1 against Musetti, losing their first tour-level meeting in the Hamburg final in 2022 but winning all four meetings since, including a 3-6, 6-1, 6-0 victory in the Monte Carlo final just a few weeks ago.
He's 4-1 against Musetti, losing their first tour-level meeting in the Hamburg final in 2022 but winning all four meetings since, including a 3-6, 6-1, 6-0 victory in the Monte Carlo final just a few weeks ago.
COCO Gauff told the tennis fans they were welcome to boo her during a 'controversial' on-court interview.
Gauff, 21, just won her quarterfinal clash with Mirra Andreeva at the Italian Open in Rome.
And the US star was interviewed on court in front of the crowd after reaching the semifinals.
The 2023 US Open champion was grilled about her food preferences.
Gauff was asked why she prefers Cacio e pepe pasta over carbonara.
The 21-year-old gave an awkward laugh before admitting she could be about to cause controversy.
"I just think Cacio e pepe is better," she laughed.
"I don't know if that is controversial here - I just like that better.
"But carbonara is still good, I just think Cacio e pepe is great.
"If I had to choose between one I would choose Cacio e pepe."
Turning to the crowd, Gauff added, "I don't know if you guys agree.
"If you don't, you can boo me - it's OK."
The crowd's response was muted with no audible boos heard for Gauff's bold claim.
Gauff is currently No. 3 in the world and in a rich vein of form.
She is one of the favorites for the French Open at Roland Garros in Paris later this month.
But this week in Italy she has a semifinal to look forward to.
No. 4 seed Gauff swept past No. 7 seed Andreeva 6-4, 7-6 in the last eight.
She's also beaten Emma Raducanu, Magda Linette and Victoria Mboko on the way.
Gauff's only slam title to date was in New York two years ago.
She won the US Open title in front of her home crowd at Arthur Ashe Stadium.
The tennis star was selected as a US Olympic team flag bearer for the Paris 2024 Games.
Gauff carried the flag at the opening ceremony alongside LeBron James.
Her French Open campaign ended in tears when she was beaten by Iga Swiatek and she made her feelings clear at an umpire's call.
And Gauff suffered the same fate at the Olympics when she lost to Donna Vekic in the third round.
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COCO Gauff told the tennis fans they were welcome to boo her during a 'controversial' on-court interview.
Gauff, 21, just won her quarterfinal clash with Mirra Andreeva at the Italian Open in Rome.
And the US star was interviewed on court in front of the crowd after reaching the semifinals.
The 2023 US Open champion was grilled about her food preferences.
Gauff was asked why she prefers Cacio e pepe pasta over carbonara.
The 21-year-old gave an awkward laugh before admitting she could be about to cause controversy.
"I just think Cacio e pepe is better," she laughed.
"I don't know if that is controversial here - I just like that better.
"But carbonara is still good, I just think Cacio e pepe is great.
"If I had to choose between one I would choose Cacio e pepe."
Turning to the crowd, Gauff added, "I don't know if you guys agree.
"If you don't, you can boo me - it's OK."
The crowd's response was muted with no audible boos heard for Gauff's bold claim.
Gauff is currently No. 3 in the world and in a rich vein of form.
She is one of the favorites for the French Open at Roland Garros in Paris later this month.
But this week in Italy she has a semifinal to look forward to.
No. 4 seed Gauff swept past No. 7 seed Andreeva 6-4, 7-6 in the last eight.
She's also beaten Emma Raducanu, Magda Linette and Victoria Mboko on the way.
Gauff's only slam title to date was in New York two years ago.
She won the US Open title in front of her home crowd at Arthur Ashe Stadium.
The tennis star was selected as a US Olympic team flag bearer for the Paris 2024 Games.
Gauff carried the flag at the opening ceremony alongside LeBron James.
Her French Open campaign ended in tears when she was beaten by Iga Swiatek and she made her feelings clear at an umpire's call.
And Gauff suffered the same fate at the Olympics when she lost to Donna Vekic in the third round.
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By LUKE POWER
Published: 11:18 EDT, 14 May 2025 | Updated: 11:18 EDT, 14 May 2025
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Emma Raducanu has reportedly anointed Mark Petchey as her coach for the grass court season after an impressive partnership so far.
The 22-year-old is set to go into Wimbledon with the man who has helped her to eight wins in 11 matches in two months.
It comes as a blow to Andy Murray's hopes of an immediate return to coaching with Raducanu after his split with Novak Djokovic on Tuesday.
Murray named Raducanu as his dream women's player to work with in 2022 but kicked off his coaching career with a six-month stint helping Djokovic.
But Raducanu, who also worked with Petchey in the summer of 2020, would like to extend her progress with her current aide as per The Telegraph. Coincidentally, Petchy used to coach Murray.
Petchey is her eighth trainer in four years but has helped the youngster relax on an ad-hoc basis, putting emphasis on fun warm-ups such as spikeball or football.
Emma Raducanu has reportedly agreed for Mark Petchey to continue coaching her
Petchey has overseen a run of eight wins in 11 matches in the two months he has been with her
It comes as a blow to Andy Murray, who on Tuesday split from Novak Djokovic
Raducanu made it to the quarter-finals of the Miami Open in March and has been playing some of her best tennis of recent years under Petchey.
Petchey, 54, is employed by the Tennis Channel but they do not have the rights to Wimbledon, meaning he should be free to work with Raducanu on her favourite surface this summer.
But his TV commitments could prevent a more serious, permanent position being taken up with Raducanu.
As for Murray, he finds himself looking for a new gig just six weeks before Wimbledon, where Raducanu ended his SW19 career by pulling out of the doubles arrangement last summer.
He Murray stunned the tennis world in November by announcing he would be coaching his old rival, but results tailed off after a positive start.
‘Thanks to Novak for the unbelievable opportunity to work together,' said Murray. ‘And thanks to his team for all their hard work over the past six months. I wish Novak all the best for the rest of the season.'
Djokovic said: ‘Thank you, coach Andy, for all the hard work, fun & support over last six months on & off the court, really enjoyed deepening our friendship together.'
After a 10-day pre-season training camp in Marbella last winter, Murray's first tournament in the coaching box was the Australian Open.
Murray, who Petchy used to coach, named Raducanu as one of his dream players to work with
The retired star worked with Novak Djokovic for six months but they have split amicably
Raducanu, who prefers the grass surface, has the potential for a deep run at Wimbledon
Djokovic played some of his best tennis of the last 12 months in reaching the semi-finals, when a muscular tear forced him to retire against Alexander Zverev.
But since Melbourne, Djokovic has lost his first match in four of his five events, the exception being a run to the final in Miami, where he was beaten in straight sets by Jakub Mensik.
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Published by Associated Newspapers Ltd
Part of the Daily Mail, The Mail on Sunday & Metro Media Group
Top half quarterfinal matches of the ATP Italian Open men's singles draw will be played on Thursday in Rome. Jannik Sinner's comeback is the main story of the week and the Italian is yet to drop a set in three matches, despite getting pushed by Francisco Cerundolo. Now it's time for him to face Casper Ruud, who's on a 9-match winning streak after claiming the title in Madrid. Who do you think will make the final four?
Head-to-head: Paul 2-1
Hubert Hurkacz has been struggling with different injuries for a while now, one of them keeping him out of Miami, Monte Carlo, and Munich. The Pole returned with a very weak performance in Madrid, but he's back on his feet now after spending a week doing some heavy training. The win over Jakub Mensik was kind of vintage Hurkacz with not much action on return and two tie-breaks won. His last match against Tommy Paul came in the quarterfinals last year and was a 3-set loss. It feels like the American should be able to prevail in most longer exchanges off the ground with how athletic he is and Hurkacz usually doesn't respond well to having to attack with his forehand.
Prediction: Paul in 3
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Head-to-head: Sinner 3-0
Opponents like Mariano Navone and especially Francisco Cerundolo didn't need to be easy for Jannik Sinner after spending three months off the court. But pushing through them is going to be massive for the Italian, who's hoping to get himself ready for the French Open with this one tournament. The way things stand at the moment, Sinner looks very likely to reach the final in Rome. Especially as the next matchups coming up might be more pleasant for him. Even when they played in 2020/21, he wasn't dropping sets against Casper Ruud. And while they're yet to play on clay, the Norwegian might be running low on steam by this point after winning Madrid.
Prediction: Sinner in 2
Main Photo Credit: Mike Frey-USA TODAY Sports
Wimbledon finalist Jasmine Paolini and Peyton Stearns reached the WTA Rome semifinal after dramatic quarterfinal matches. Paolini will undoubtedly have a raucous home crowd behind
ATP Masters 1000 Rome quarterfinals Draper – Alcaraz: 14.05.2025 15:00 CEST H2H: 2-3 Jack Draper has won four of his last five matches. Last week
Two of the four ATP Italian Open quarterfinal matches will be held on Wednesday in Rome. Carlos Alcaraz and Jack Draper have been the best
The Italian Open, one of tennis's most prestigious clay-court tournaments, has taken a firm stance against disruptive behaviour that aims to influence gambling outcomes. On
By Santiago Tovar
Updated on May 14, 2025 10:47AM EDT
World No. 1 Jannik Sinner paid a visit to Vatican City on Wednesday, where he met with Pope Leo XIV during a break in the Italian Open. The Pope, a self-proclaimed tennis fan, seemed delighted to welcome Sinner, especially with Wimbledon on the horizon, and even shared a lighthearted moment that drew laughter from the Italian star.
A lifelong supporter of the sport, Pope Leo XIV mentioned he had played tennis as a child. In addition to hosting Sinner, the Vatican also displayed the Davis Cup trophy during the visit. The Italian ace, currently leading the ATP rankings, spent time with the Pope and presented him with a tennis racket as a gift.
Sinner spoke about how meaningful it is to have someone as influential as the Pope show interest in tennis. After receiving the racket, Leo XIV turned to Sinner with a smile and asked, “Could I play at Wimbledon with this?”
The question brought laughter from those in attendance. While Wimbledon remains a major goal for Sinner, his immediate focus is on Roland Garros, just weeks away.
Pope Leo XIV receives professional tennis player Jannik Sinner in the Vatican and asks for some sporting tips.
The audience took place in the rooms attached to the Vatican's Paul VI Hall, and the Pope also met with Mr. Sinner's family and the President of the Italian Tennis
After Pope Leo XIV revealed his lifelong passion for tennis and joked about which player he'd prefer to avoid in a charity match, Sinner reacted with a thoughtful message about the Pope's influence on the sport from the Vatican.
see also
Sinner surpasses Del Potro's milestone after latest win in Rome, sets sights on Andy Murray next
“Obviously, I heard that he played as a kid. I think it's a good thing for us tennis players to have a pope who likes this sport that we're playing,” Sinner told the media ahead of the Italian Open, marking his return to international competition.
Sinner has enjoyed a strong return to the ATP Tour. With a place secured in the Italian Open quarterfinals, the home favorite is preparing for a key clash against Madrid Open champion Casper Ruud.
The matchup presents a major opportunity for Sinner, who has never lost to Ruud. He holds a 3–0 head-to-head record, including a straight-sets win (7–5, 6–1) in the 2021 Vienna Open quarterfinals.
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Santiago Tovar is a bilingual sports journalist who joined Bolavip US in 2024. With over seven years of experience, he has covered a diverse range of sports, including soccer, NFL, NBA, tennis, and Formula 1. Santiago has provided real-time coverage of major events such as the 2021 Women's Copa America, Copa Libertadores, Copa Sudamericana, and the Davis Cup qualifiers. Before joining Bolavip US, he worked at Kienyke.com and Redmas.com.co, where he developed strategies to highlight key sports moments across websites and social media platforms.
Bolavip, like Futbol Sites, is a company owned by Better Collective. All rights reserved.
"It's an honor," the world No. 1 said in Italian, as he and his parents arrived in a reception room of the Vatican's auditorium.ByAssociated PressPublished May 14, 2025 copy_link
Published May 14, 2025
© Vatican Media
VATICAN CITY (AP) — Pope Leo XIV has made peace with Jannik Sinner.The top-ranked tennis player visited the new pope on Wednesday, gave him a tennis racket and offered to play, during an off day for Sinner at the Italian Open.Leo, the first American pope, is an avid tennis player and fan and had said earlier this week that he would be up for a charity match when it was suggested by a journalist.But at the time, Leo joked "we can't invite Sinner," an apparent reference to the English meaning of Sinner's last name.By Wednesday, all seemed forgotten.
The top-ranked tennis player visited the new pope on Wednesday, gave him a tennis racket and offered to play, during an off day for Sinner at the Italian Open.Leo, the first American pope, is an avid tennis player and fan and had said earlier this week that he would be up for a charity match when it was suggested by a journalist.But at the time, Leo joked "we can't invite Sinner," an apparent reference to the English meaning of Sinner's last name.By Wednesday, all seemed forgotten.
Leo, the first American pope, is an avid tennis player and fan and had said earlier this week that he would be up for a charity match when it was suggested by a journalist.But at the time, Leo joked "we can't invite Sinner," an apparent reference to the English meaning of Sinner's last name.By Wednesday, all seemed forgotten.
But at the time, Leo joked "we can't invite Sinner," an apparent reference to the English meaning of Sinner's last name.By Wednesday, all seemed forgotten.
By Wednesday, all seemed forgotten.
"It's an honor," Sinner said in Italian as he and his parents arrived in a reception room of the Vatican's auditorium. Holding one of his rackets and giving Leo another and a ball, Sinner suggested a quick volley. But the pope looked at the antiques around and said, "Better not."Leo, a 69-year-old from Chicago, then appeared to joke about his white cassock and its appropriateness for Wimbledon, noting the All England Club's all-white clothing rule.He asked how the Italian Open was going. "Now I'm in the game," Sinner said. "At the beginning of the tournament, it was a bit difficult."The top-ranked player has a quarterfinal match on Thursday in his first tournament back after a three-month ban for doping that was judged to be an accidental contamination.Sinner will next face either freshly-crowned Madrid champion Casper Ruud or Jaume Munar. Sinner is attempting to become the first Italian man to win the Rome title since Adriano Panatta in 1976.
Leo, a 69-year-old from Chicago, then appeared to joke about his white cassock and its appropriateness for Wimbledon, noting the All England Club's all-white clothing rule.He asked how the Italian Open was going. "Now I'm in the game," Sinner said. "At the beginning of the tournament, it was a bit difficult."The top-ranked player has a quarterfinal match on Thursday in his first tournament back after a three-month ban for doping that was judged to be an accidental contamination.Sinner will next face either freshly-crowned Madrid champion Casper Ruud or Jaume Munar. Sinner is attempting to become the first Italian man to win the Rome title since Adriano Panatta in 1976.
He asked how the Italian Open was going. "Now I'm in the game," Sinner said. "At the beginning of the tournament, it was a bit difficult."The top-ranked player has a quarterfinal match on Thursday in his first tournament back after a three-month ban for doping that was judged to be an accidental contamination.Sinner will next face either freshly-crowned Madrid champion Casper Ruud or Jaume Munar. Sinner is attempting to become the first Italian man to win the Rome title since Adriano Panatta in 1976.
The top-ranked player has a quarterfinal match on Thursday in his first tournament back after a three-month ban for doping that was judged to be an accidental contamination.Sinner will next face either freshly-crowned Madrid champion Casper Ruud or Jaume Munar. Sinner is attempting to become the first Italian man to win the Rome title since Adriano Panatta in 1976.
Sinner will next face either freshly-crowned Madrid champion Casper Ruud or Jaume Munar. Sinner is attempting to become the first Italian man to win the Rome title since Adriano Panatta in 1976.
During the audience, Angelo Binaghi, the head of the Italian Tennis and Padel Federation, gave Leo an honorary federation card."We all felt the passion that Leo XIV has for our sport and this filled us with pride," Binaghi said in a statement. "We hope to embrace the Holy Father again soon, maybe on a tennis court."The pope and Sinner posed for photos in front of the Davis Cup trophy that Sinner helped Italy win for the second consecutive time last year. Also on display in the room was the Billie Jean King Cup trophy won by Italy in 2024, the biggest women's team event in tennis.Earlier in the week, after Leo's first quip about not wanting to invite him, Sinner said it was "a good thing for us tennis players" that the new pope likes to play the sport.In addition to tennis, Leo is an avid Chicago White Sox baseball fan.His predecessor, Pope Francis, was a lifelong fan of Buenos Aires soccer club San Lorenzo.
"We all felt the passion that Leo XIV has for our sport and this filled us with pride," Binaghi said in a statement. "We hope to embrace the Holy Father again soon, maybe on a tennis court."The pope and Sinner posed for photos in front of the Davis Cup trophy that Sinner helped Italy win for the second consecutive time last year. Also on display in the room was the Billie Jean King Cup trophy won by Italy in 2024, the biggest women's team event in tennis.Earlier in the week, after Leo's first quip about not wanting to invite him, Sinner said it was "a good thing for us tennis players" that the new pope likes to play the sport.In addition to tennis, Leo is an avid Chicago White Sox baseball fan.His predecessor, Pope Francis, was a lifelong fan of Buenos Aires soccer club San Lorenzo.
The pope and Sinner posed for photos in front of the Davis Cup trophy that Sinner helped Italy win for the second consecutive time last year. Also on display in the room was the Billie Jean King Cup trophy won by Italy in 2024, the biggest women's team event in tennis.Earlier in the week, after Leo's first quip about not wanting to invite him, Sinner said it was "a good thing for us tennis players" that the new pope likes to play the sport.In addition to tennis, Leo is an avid Chicago White Sox baseball fan.His predecessor, Pope Francis, was a lifelong fan of Buenos Aires soccer club San Lorenzo.
Earlier in the week, after Leo's first quip about not wanting to invite him, Sinner said it was "a good thing for us tennis players" that the new pope likes to play the sport.In addition to tennis, Leo is an avid Chicago White Sox baseball fan.His predecessor, Pope Francis, was a lifelong fan of Buenos Aires soccer club San Lorenzo.
In addition to tennis, Leo is an avid Chicago White Sox baseball fan.His predecessor, Pope Francis, was a lifelong fan of Buenos Aires soccer club San Lorenzo.
His predecessor, Pope Francis, was a lifelong fan of Buenos Aires soccer club San Lorenzo.
Peyton Stearns made history at the Internazionali BNL d'Italia by edging past No. 16 seed Elina Svitolina in a thrilling quarterfinal match. Stearns rallied to win in a third-set tiebreak, becoming the first player in the Open Era to win three straight WTA main-draw matches in third-set breakers.
Peyton Stearns made history at the Internazionali BNL d'Italia with her latest nail-biting victory.
In a late-night thriller that ended just before 1 a.m. local time, Stearns became the first player in the Open Era to win three consecutive WTA main-draw matches in third-set tiebreaks.
After letting a 6-2, 4-2 lead slip through her fingers, the unseeded Stearns rallied from a double-break down in the third set to outlast No. 16 seed Elina Svitolina of Ukraine 6-2, 4-6, 7-6(4) in Tuesday's nightcap quarterfinal.
In their first meeting, Stearns needed 2 hours and 38 minutes to prevail in the back-and-forth affair, besting Svitolina, who won the Rome title twice consecutively in 2017 and 2018.
Stearns will now have to face not just Paolini, but the weight of a partisan crowd when she meets Italy's top player in Thursday's semifinals. The No. 6 seed Paolini advanced to her first Rome semifinal with a three-set win over No. 13 seed Diana Shnaider earlier on Tuesday.
The rise continues: Currently ranked World No. 42, Stearns is into the first WTA 1000 semifinal of her career, which guarantees her a new career-high ranking in Monday's updated PIF WTA Rankings. It will potentially also garner her a first-ever Grand Slam seeding at Roland Garros.
It has been a tremendous Rome journey for 2022 NCAA champion Stearns (U. of Texas), who is making her tournament debut this year, but has been playing like an Internazionali BNL d'Italia veteran. Coming into the event, Stearns had not reached a quarterfinal this season, but it all clicked into place for her at the Foro Italico.
In her last two rounds, Stearns toppled Grand Slam champions Madison Keys and Naomi Osaka in third-set tiebreaks, setting up her history-making streak. Her upset of World No.6 Keys was her career-best win by opponent ranking.
Now Stearns has ousted one of this season's top clay-court performers in Svitolina. The Ukrainian had won 12 of her 13 WTA matches on clay this year (including a title at Rouen and a semifinal at Madrid) but she could not close out Stearns in Rome.
Stearns had already shown that she can play much of her best WTA tennis on this surface. Both of her WTA singles finals have come at WTA 250 events on clay -- she reached her first final at 2023 Bogota, then won her first title at 2024 Rabat.
Now, she is the first player to make the semifinals at her Rome main-draw debut since Daria Saville in 2015, and the first American woman to do so since Venus Williams in 1998.
Topsy-turvy contest: Stearns is the tournament leader in forehand winners, and she used that shot spectacularly to reel off eight straight games and lead 6-2, 2-0 on Tuesday. Stearns was a point away from leading 6-2, 5-2 before Svitolina pulled back on serve in the second set.
At that juncture, Svitolina ramped up her aggression to match the American's, and she saved four break points in a crucial hold for 4-4. Suddenly, Svitolina wrested the momentum away from Stearns, and it was her turn to dominate. From 6-2, 4-2 down, Svitolina won the next seven games to lead by a double-break at 3-0 in the third set.
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But Stearns doubled down on her power plays, going for even more bold winners, and it paid off as she pulled back on serve. Svitolina reclaimed her advantage at 4-3, but Stearns struck right back, cranking a backhand winner for 4-4.
Svitolina hit two consecutive aces to move into the tiebreak, where she again led 3-1. But Stearns fought back to have the final say, thumping another forehand winner to grab the first match point at 6-4. The American forced a rally forehand from Svitolina long to seal another marathon victory.
Peyton Stearns made history at the Internazionali BNL d'Italia by edging past No. 16 seed Elina Svitolina in a thrilling quarterfinal match. Stearns rallied to win in a third-set tiebreak, becoming the first player in the Open Era to win three straight WTA main-draw matches in third-set breakers.
Emma Raducanu will reportedly be coached by Mark Petchey at Wimbledon, with their partnership expected to span the entirety of the grass-court swing. They previously worked together in 2020 before rekindling their alliance during this year's Miami Open. Since then, Raducanu has won eight of her 11 matches and recently entered the world's top 50 for the first time in three years.
She will continue to work alongside Petchey until at the conclusion of the grass-court season, according to The Telegraph. It means they will be together at Wimbledon and the other grass events, which will include a women's tournament at Queen's Club for the first time since 1973. Their next outing will be in Strasbourg later this month as Raducanu prepares for the upcoming French Open.
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Petchey has been juggling his media commitments with his coaching role since teaming up with Raducanu. He also works as a tennis commentator but has reportedly cleared his schedule for the grass-court swing, a big sacrifice that will benefit the young Brit.
The 54-year-old has been working on building Raducanu's confidence by focusing on repetitive drills rather than fine-tuning her technique. Warm-up exercises like football and spikeball have also helped the former US Open champion to stay relaxed.
It comes just days after Raducanu insisted that she was in a positive frame of mind leading up to the French Open. Speaking after her one-sided defeat to Coco Gauff in Rome, she made it clear that she was not looking to 'hide in a hole somewhere'.
"I would love to just keep improving, keep playing," Raducanu told Sky Sports. "I think that's a positive for me. I don't want to go and hide in a hole somewhere. I want to get back out there, so that's good.
"We'll see how it goes in the next week before the French [Open], if I get into Strasbourg. But, for now, I've played a good 12 days on the trot, so I'm looking forward a day off or so and then getting back to it."
Don't miss... Jack Draper addresses angry Italian Open incident as Brit 'bamboozled' [REACTION] Emma Raducanu accepts wildcard as French Open plans take new twist [NEWS] Aryna Sabalenka shows true colours after Italian Open rival refuses handshake [LATEST]
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Raducanu added that her impressive run at the Italian Open has delivered a fresh wave of confidence, with the 22-year-old having fun on the court once again.
"It makes it more enjoyable, it makes it more sustainable," she explained. "It doesn't make the losses feel as bad, because I just know that every day I'm trying to be the best version of myself. I'm trying to win the day and I've kind of gone back to that.
"I didn't win on the match court today but I'm going to find a way to win the day still today. It was a tough day in the office. I just have to take a lot of positives.
"I am getting out more, I am enjoying myself and taking it in wherever I go, because it is tough on the road, so I think just trying to find small pockets of the day, small glimmers, to make it more enjoyable."
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Exclusive: Former British No 1 Mark Petchey will be working alongside 2021 US Open champion for entire grass-court season
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Sir Andy Murray is highly unlikely to develop a Wimbledon tie-up with Emma Raducanu this summer after ending his coaching relationship with Novak Djokovic.
A British dream team was the first thought on many tennis-lovers' minds but the explanation has nothing to do with any lingering ill-feeling from the dispute over Murray's planned mixed-doubles appearance with Raducanu at Wimbledon last year, which she cancelled at the last minute.
Rather, it is because Raducanu's coaching vacancy has already been filled – at least for the grass-court season.
Telegraph Sport understands that former British No 1 Mark Petchey – the old ally who has combined broadcasting work with assisting Raducanu during her last three tournaments – has made himself available for the entirety of the grass-court swing, without any competing commitments to distract him.
This will be welcome news for Raducanu's supporters. She clearly has the potential to go deep at Wimbledon and the other grass events, which this year will include a women's tournament at Queen's for the first time since 1973.
In three previous appearances at Wimbledon, she has reached the last 16 twice. Like most British players, she understands how to move on the surface, whereas many overseas players find the footing too slippery.
Raducanu has entered Strasbourg next week as a final build-up event before the French Open. The decision confirms that she is dealing far better with the physical challenges of the WTA Tour than in any previous season.
The appointment of an experienced fitness trainer – Yutaka Nakamura – in December, has delivered a swift impact, even if hindsight suggests that this basic step should have been taken several years ago.
And the return of Petchey, who previously helped Raducanu refine her game in the summer of 2020, has also worked out well to date.
Since he began helping her on an initially ad hoc basis in Miami two months ago, she has won eight matches from 11: a solid return which would, if continued, carry her well inside the seeded positions at the majors.
Petchey has helped Raducanu relax by using light-hearted warm-up exercises such as spikeball or football. He has also taken some of her focus off technique and concentrated on repetitive drills to build confidence in her shots.
Warm-up complete for Emma Raducanu ⚽️🔥She faces Veronika Kudermetova as she hunts for a place in the final 16 ⚔️ pic.twitter.com/fM6EDoJa9H
The results were evident in Rome last week, where Raducanu played some eye-catching tennis to reach the fourth round before eventually running into an in-form Coco Gauff.
The fact that Petchey had worked with her before she rose to international fame is clearly an important aspect of their relationship. As Raducanu said in Rome last week: “The last few years, it's been very difficult for me to trust new people, especially those who have not necessarily known me from the years before the US Open. I just find myself gravitating towards those people now who I've known, and I'd say my circle is smaller than ever.”
While Petchey will be present during the French Open, he will be working for TNT Sports, now part of the Discovery group, alongside an eye-catching commentary team that also includes John McEnroe, Andre Agassi, Chris Evert and Jim Courier.
It is anticipated that Petchey should be able to find gaps in his schedule to assist Raducanu, although TV commitments could also clash with his coaching work at times.
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Tennis legend Novak Djokovic split on Tuesday with coach Andy Murray just two weeks ahead of the start of the French Open in Paris.
Issued on: 14/05/2025 - 12:02
Djokovic and Murray – rivals on the senior ATP circuit for nearly two decades before Murray's retirement last August – joined forces in January just before the Australian Open.
The 37-year-old Serb, a 10-time winner in Melbourne, surged to the semi-finals but withdrew from his match with Alexander Zverev due to a hamstring injury.
After the event, Djokovic said that Murray had agreed to continue the partnership through the European clay court swing that culminates at the French Open at the end of May.
Djokovic, who has won a record 24 titles at the Grand Slam events in Melbourne, Paris, London and New York, hailed Murray's efforts on social media.
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"Thank you, coach Andy, for all the hard work, fun & support over last six months on & off the court. I really enjoyed deepening our friendship together."
Djokovic won 25 of his 36 matches against Murray between 2006 and 2022. His move to recruit Murray initially raised eyebrows. But his run to the last four at the Australian Open and the final at the Miami Masters in March silenced the doubters.
However, Djokovic lost his opening match on the clay at the Monte Carlo Masters in April and he was also defeated in the opening round at the Madrid Masters later that month.
“Thanks to Novak for the unbelievable opportunity to work together," said Murray in a statement. "And thanks to his team for all their hard work over the past six months. I wish Novak all the best for the rest of the season.”
On Tuesday, Djokovic, who has dropped to six in the world rankings, confirmed he would play at the Geneva Open which begins on 17 May.
The Geneva line-up includes the world number four Taylor Fritz and the seventh ranked Casper Ruud who beat Jack Draper to take the Madrid Masters.
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Tennis legend Novak Djokovic split on Tuesday with coach Andy Murray just two weeks ahead of the start of the French Open in Paris.
Djokovic and Murray – rivals on the senior ATP circuit for nearly two decades before Murray's retirement last August – joined forces in January just before the Australian Open.
The 37-year-old Serb, a 10-time winner in Melbourne, surged to the semi-finals but withdrew from his match with Alexander Zverev due to a hamstring injury.
After the event, Djokovic said that Murray had agreed to continue the partnership through the European clay court swing that culminates at the French Open at the end of May.
Djokovic, who has won a record 24 titles at the Grand Slam events in Melbourne, Paris, London and New York, hailed Murray's efforts on social media.
"Thank you, coach Andy, for all the hard work, fun & support over last six months on & off the court. I really enjoyed deepening our friendship together."
Djokovic won 25 of his 36 matches against Murray between 2006 and 2022. His move to recruit Murray initially raised eyebrows. But his run to the last four at the Australian Open and the final at the Miami Masters in March silenced the doubters.
Read more on RFI EnglishRead also:Popyrin ousts defending champion Djokovic at US OpenMonte Carlo win gives Tsitsipas rankings boost and lift for tilt at French OpenWawrinka outwits fellow veteran Murray to move into second round at French Open
Diane Parry, Tiantsoa Rakotomanga Rajaonah, Iva Jovic and Lois Boisson have all been awarded Roland Garros main-draw wild cards this year.
Six Frenchwomen, including former No. 48 Diane Parry and Rouen quarterfinalist Tiantsoa Rakotomanga Rajaonah, have received wild cards for Roland Garros, which begins on May 25.
A post shared by FFT (@fftennis)
The full list of main-draw wild cards is as follows:
Nine qualifying wild cards have all been awarded to Frenchwomen:
Diane Parry, Tiantsoa Rakotomanga Rajaonah, Iva Jovic and Lois Boisson have all been awarded Roland Garros main-draw wild cards this year.
LONDON — Novak Djokovic is splitting with coach Andy Murray just two weeks ahead of the French Open, following a dismal start to the clay-court season.
Murray's representatives announced Tuesday that the two former No. 1-ranked players will “no longer be working together.”
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“I don't know if I'll mess up the whole video!” the 18-year-old joked on Tennis Channel's VIP Tennis Lounge with Garbiñe Muguruza.ByTennis ChannelPublished May 14, 2025 copy_link
Published May 14, 2025
© Matt Fitzgerald
Mirra Andreeva's talent in tennis is undeniable: This year, the teen phenom hit new heights by winning back-to-back WTA 1000 titles in Indian Wells and Dubai, and she's in contention in singles and doubles this week at the Internazionali BNL d'Italia. But when it comes to other talents, the 18-year-old is admittedly still a work in progress.Andreeva sat down with former world No. 1 Garbiñe Muguruza on Tennis Channel's VIP Tennis Lounge to talk about the ups and downs of tour life, and a bit of the glitz and glamour that comes with it.Read More: Mirra Andreeva escapes in two sets, cools down with Carlos Alcaraz in RomeWhen it comes to bouncing back after a tough loss, Andreeva has her method all figured out: “I don't talk to anyone,” she revealed. But when host Muguruza asked if she would ever feature in a music video for her favorite artist, Andreeva quickly cast herself as an extra.“I'd like to go with Taylor Swift,” she said. “I like her music, and I think that it's pretty energetic so I would just be having fun in the background.“I love to dance, but I'm bad at it... I don't know if I'll mess up the whole video!”
Andreeva sat down with former world No. 1 Garbiñe Muguruza on Tennis Channel's VIP Tennis Lounge to talk about the ups and downs of tour life, and a bit of the glitz and glamour that comes with it.Read More: Mirra Andreeva escapes in two sets, cools down with Carlos Alcaraz in RomeWhen it comes to bouncing back after a tough loss, Andreeva has her method all figured out: “I don't talk to anyone,” she revealed. But when host Muguruza asked if she would ever feature in a music video for her favorite artist, Andreeva quickly cast herself as an extra.“I'd like to go with Taylor Swift,” she said. “I like her music, and I think that it's pretty energetic so I would just be having fun in the background.“I love to dance, but I'm bad at it... I don't know if I'll mess up the whole video!”
Read More: Mirra Andreeva escapes in two sets, cools down with Carlos Alcaraz in RomeWhen it comes to bouncing back after a tough loss, Andreeva has her method all figured out: “I don't talk to anyone,” she revealed. But when host Muguruza asked if she would ever feature in a music video for her favorite artist, Andreeva quickly cast herself as an extra.“I'd like to go with Taylor Swift,” she said. “I like her music, and I think that it's pretty energetic so I would just be having fun in the background.“I love to dance, but I'm bad at it... I don't know if I'll mess up the whole video!”
When it comes to bouncing back after a tough loss, Andreeva has her method all figured out: “I don't talk to anyone,” she revealed. But when host Muguruza asked if she would ever feature in a music video for her favorite artist, Andreeva quickly cast herself as an extra.“I'd like to go with Taylor Swift,” she said. “I like her music, and I think that it's pretty energetic so I would just be having fun in the background.“I love to dance, but I'm bad at it... I don't know if I'll mess up the whole video!”
“I'd like to go with Taylor Swift,” she said. “I like her music, and I think that it's pretty energetic so I would just be having fun in the background.“I love to dance, but I'm bad at it... I don't know if I'll mess up the whole video!”
“I love to dance, but I'm bad at it... I don't know if I'll mess up the whole video!”
Read More: How Mirra Andreeva coach Conchita Martinez keeps teen star groundedMuguruza and Andreeva also bonded over having a coach in common in Conchita Martinez—the 1994 Wimbledon champion who worked with two-time Grand Slam winner Muguruza during later stages of her career, and joined Andreeva's team last year.Andreeva said it would “make her day” if the three of them could get together, as she extended an open invitation to Muguruza:“I think I would have a lot of fun if we would all go to dinner, me, Conchita and you,” she said. “That would make my day.”Check out VIP Tennis Lounge with Garbiñe Muguruza for unique conversations and fun vibes featuring Nick Kyrgios, Carlos Alcaraz, Aryna Sabalenka and more.>>PHOTOS: Garbiñe Muguruza hosts Tennis Channel's VIP Tennis Lounge
Muguruza and Andreeva also bonded over having a coach in common in Conchita Martinez—the 1994 Wimbledon champion who worked with two-time Grand Slam winner Muguruza during later stages of her career, and joined Andreeva's team last year.Andreeva said it would “make her day” if the three of them could get together, as she extended an open invitation to Muguruza:“I think I would have a lot of fun if we would all go to dinner, me, Conchita and you,” she said. “That would make my day.”Check out VIP Tennis Lounge with Garbiñe Muguruza for unique conversations and fun vibes featuring Nick Kyrgios, Carlos Alcaraz, Aryna Sabalenka and more.>>PHOTOS: Garbiñe Muguruza hosts Tennis Channel's VIP Tennis Lounge
Andreeva said it would “make her day” if the three of them could get together, as she extended an open invitation to Muguruza:“I think I would have a lot of fun if we would all go to dinner, me, Conchita and you,” she said. “That would make my day.”Check out VIP Tennis Lounge with Garbiñe Muguruza for unique conversations and fun vibes featuring Nick Kyrgios, Carlos Alcaraz, Aryna Sabalenka and more.>>PHOTOS: Garbiñe Muguruza hosts Tennis Channel's VIP Tennis Lounge
“I think I would have a lot of fun if we would all go to dinner, me, Conchita and you,” she said. “That would make my day.”Check out VIP Tennis Lounge with Garbiñe Muguruza for unique conversations and fun vibes featuring Nick Kyrgios, Carlos Alcaraz, Aryna Sabalenka and more.>>PHOTOS: Garbiñe Muguruza hosts Tennis Channel's VIP Tennis Lounge
Check out VIP Tennis Lounge with Garbiñe Muguruza for unique conversations and fun vibes featuring Nick Kyrgios, Carlos Alcaraz, Aryna Sabalenka and more.>>PHOTOS: Garbiñe Muguruza hosts Tennis Channel's VIP Tennis Lounge
>>PHOTOS: Garbiñe Muguruza hosts Tennis Channel's VIP Tennis Lounge
A post shared by ☺︎︎ Mirra Andreeva ☺︎︎ (@_mirraandreeva_)
By Gianni Taina
May 13, 2025 09:22PM EDT
With Roland Garros just around the corner, it's customary for top-ranked players to skip ATP tournaments scheduled between the Italian Open and the French Open to focus on preparation. However, this year, several elite players have opted to participate in the Hamburg Open and the Geneva Open—a decision that left Courier baffled.
The Hamburg Open, recently upgraded to an ATP 500 event, and the Geneva Open, an ATP 250 tournament, are scheduled from May 17-24, ending just two days before Roland Garros.
Among those competing in Hamburg are Jannik Sinner (World No. 8), Lorenzo Musetti (No. 9), and Holger Rune (No. 10). The field also includes Tommy Paul (No. 12), Frances Tiafoe (No. 16), Andrey Rublev (No. 17), Francisco Cerundolo (No. 18), and Stefanos Tsitsipas (No. 19).
In Geneva, Taylor Fritz (No. 4), Novak Djokovic (No. 6), and Casper Ruud (No. 7) headline the draw, alongside Grigor Dimitrov (No. 15) and Tomas Machac (No. 20). This high-profile participation in pre-major events is atypical and left Courier “shocked”.
🚨𝙒𝙄𝙇𝘿 𝘾𝘼𝙍𝘿
𝐍𝐎𝐕𝐀𝐊 𝐃𝐉𝐎𝐊𝐎𝐕𝐈𝐂 🇷🇸
Will play at the Gonet Geneva Open 2025 🤩🔥
📷 @mutuamadridopen
#gonetgenevaopen #atpgva #atp #novakdjokovic #djokovic #tennistv #atptour #geneva #geneve #suisse #switzerland #genevaevent #tennis #welovetennis #tennislove
While Courier acknowledged the rationale behind players like Sinner and Djokovic participating, he questioned the motivations of others. “There is a lot of insurance at play for someone like Sinner. For Djokovic, he needs the matches as he hasn't played much, and he's likely looking to get two or three matches in and then withdraw to focus on Paris,” Courier explained on the Tennis Channel.
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However, he suggested financial incentives may have influenced many of these decisions. “But I'm really shocked, honestly, to see some of these names on here,” he said. “Look, let's set the table. These tournaments can pay appearance fees. So some of these players will have accepted a big guarantee, I'm talking hundreds and thousands of dollars just to show up to play and they don't have to win a match to get that money, so there is some commercial aspect to this”.
Courier highlighted the Hamburg tournament's upgrade to an ATP 500 as a key factor in attracting top players. He noted that this year's ATP 500 events feature a new bonus pool worth $3 million, shared among players who compete in at least four such tournaments.
“The serious players who think they're going to win Roland Garros or challenge for Roland Garros, they don't play these tournaments, and one thing that is different this year, and this is the only time that I've seen this, there's an ATP 500 tournament here, Hamburg, that's been put into this section,” Courier noted. “That doesn't happen before Wimbledon, doesn't happen before Australia, doesn't happen before the US Open”.
“There is a new bonus pool for ATP 500 this year. Six players who play at least four of these ATP 500 tournaments will share $3m in extra money so there are substantial financial incentives to play for players that are in that conversation,” he added. “So there is a lot that goes into this. [But] there's no amount of appearance money or bonus pool money that can replicate the kind of money you make if you win Roland Garros”.
Gianni Taina is a bilingual journalist, fluent in English and Spanish, with a specialization in soccer, the NBA, and tennis. He began his professional career in 2020 with Mundo Deportivo US, where he first established himself as a writer. Throughout his career, Gianni has covered major sports events such as the FIFA World Cup in Qatar, the NBA Finals, and Grand Slam tournaments like the French Open. His ability to report on real-time events and perform well under pressure has made him a valuable member of a top-tier team of journalists. In 2024, he joined Bolavip US, where he now covers a wide range of sports, including European soccer, MLS, and the NBA.
Bolavip, like Futbol Sites, is a company owned by Better Collective. All rights reserved.
The 2025 French Open is now just a few weeks away as the stars of the ATP Tour ramp up their preparations for the second Grand Slam of the year.
Rome is the current stop on the journey to Paris for the French Open, which begins later this month.
Seven of the world's top ten players advanced to the last 16 of this year's Italian Open, which is for many the final tournament before Roland Garros.
However, in a change from tradition, that won't be the case for everyone, as several top ATP stars have signed up for tournaments the week before the French Open.
24-time Grand Slam champion Novak Djokovic will play in Geneva, and so will some of his biggest rivals.
When asked about the players' schedules, former world number one Jim Courier revealed that he was ‘shocked'.
Speaking on the Tennis Channel, Courier shared his thoughts on the decision of top players to play tournaments in Geneva and Hamburg ahead of the French Open.
“With someone like [Jannik] Sinner, there is a lot of insurance at play,” he said.
“For [Novak] Djokovic, he needs the matches because he has not played, and he is going to try and do what he did last year, which is get two or three matches and maybe try and pull the cord with a little bit of match toughness.
“But I am really shocked honestly, to see some of the names on here.”
13 top 20 players will be in action next week, six of whom are currently ranked inside the top ten.
Courier explained why some players will have chosen to play in Geneva and Hamburg in 2025.
“Let's set the table, these tournaments can pay appearance fees so some of these players will have accepted a big guarantee, I am talking hundreds of thousands of dollars just to show up and play and they don't have to win a match to get that money, so there is some commercial aspect to this,” he said.
“But the serious players who think they are going to win Roland Garros or challenge for Roland Garros, they do not play these tournaments.
“One thing that is different this year, and this is the only time I have seen this, is that there is an ATP 500 tournament in Hamburg, which has been put into this section.
“That does not happen before Wimbledon or Australia. It does not happen before the US Open. There are [ATP] 250 tournaments around which you just don't see the top players playing.”
The American then outlined the details of the new ATP 500 ‘bonus pool', which may have impacted players' decisions.
“There is a new bonus pool for ATP 500 this year. Six players who play at least four of these ATP 500 tournaments will share $3 million in extra money, so there are substantial financial benefits for players to play who are in that conversation,” said Courier.
“So there is a lot that goes into this. But one thing which I know is that there is no amount of appearance money or bonus money that can replicate the kind of money you make if you win Roland Garros.
“So be careful what you wish for. If you are going for the easy grab, you might miss out on the life-changing generational wealth that sits at the end of these tournaments.
2003 US Open champion, Andy Roddick, agreed with Courier for the most part and shared whether he would've scheduled a warm-up tournament before the French Open during his playing days.
“Sinner, this is an insurance entry, in my opinion. I don't know if Jim [Courier] thinks he has already done enough getting two matches, even three matches guaranteed going into Roland Garros. We will see,” said Roddick.
“Taylor [Fritz] wants to play the week before. Novak, taking a wildcard, he had to have some matches.
“What will be interesting, is is a guy like Casper Ruud looking for more matches? Is a guy like Lorenzo Musetti looking for more matches the week before?
“When I was playing, if I had gotten in the semis of Madrid and quarters of Rome, I was good to go. I wanted to get to Roland Garros and get prepared.”
Courier is worried that players who travel to Geneva and Hamburg could be risking their chance at French Open glory, but what happened last year?
Geneva and Lyon were the two pre-French Open destinations in 2024, where seven top 20 players made the trip.
None of the seven went on to win the title in Paris, although that's not to say some didn't enjoy strong tournaments.
2024 Geneva Open champion, Ruud, qualified for the French Open semi-finals, but came up short against Alexander Zverev in four sets.
Only time will tell if the likes of Ruud, Sinner, and Djokovic will be able to perform at both their warm-up tournaments and the French Open in 2025.
The Geneva Open and Hamburg Open are scheduled to begin on May 19, before the French Open gets underway on Sunday, May 25.
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Formula 1 and Global Partner AWS have announced the launch of a brand-new interactive digital experience that allows fans to design, create, customise, and share their own F1 circuit – then enter a sweepstake to win a trip to a Grand Prix.
Using AI-powered analysis from Amazon Nova, 'Real-Time Race Track' lets fans design an original race circuit of any shape and length using their computer's mouse or by tracing their finger on any touchscreen device.
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When complete, every turn and straight of the circuit is then analysed by Amazon Nova, producing key on-track metrics including top speed and projected lap time, as well as two viable race strategies to further evaluate the optimal pit timing, tyre recommendations and tactical adjustments for various weather scenarios.
The detailed level of data across the experience offers fans a real insight into the world of F1 team strategists, and creates an authentic strategic dimension to each custom circuit design.
Fans can also share an AI-generated retro racing poster, created with Amazon Nova Canvas, that features their unique racing circuit
After creating and submitting a circuit, fans can enter a sweepstake to win a trip to the 2026 British Grand Prix, providing the opportunity to see first-hand a variety of team strategies across the race weekend.
The draw for the sweepstake will close on 16 July 2025, with the winner being selected at random.
This latest experience builds upon the strategic partnership between Formula 1 and AWS that began in 2018, with the collaboration consistently delivering innovations that elevate the on-track competition and the off-track experience for fans.
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With more than a million data points per second coming off the cars, the cornerstone of the partnership between F1 and AWS is the ability to extract valuable insights from all this data.
The 'Real-Time Race Track' experience puts the power of the sport's comprehensive data and AWS' advanced analytics and artificial intelligence directly in the hands of fans.
Fans can enter a sweepstake to win a trip to the 2026 British Grand Prix at Silverstone
Jonny Haworth, Director of Commercial Partnerships, Formula 1 said: "Our ongoing partnership with AWS continues to evolve and transform how fans interact with Formula 1. The 'Real-Time Race Track' experience exemplifies how we're using cloud technology and AI to bring fans closer to the sport than ever before.
"As we celebrate our 75th anniversary, we're giving fans an inside look at the complexities and innovation of race strategy, using the same technology that helps to power our sport.”
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Kristin Shaff, Global Director of Strategic Partnerships, AWS added: “When we first began working with Formula 1, they presented us with a unique challenge – how to use telemetry data to further engage fans during live races. That vision has since materialized into 23 data-driven F1 Insights that appear during the broadcast to help fans better understand how teams devise strategies.
“With today's launch of the 'Real-Time Race Track experience', we're taking this approach to a new level of interactivity. Now anyone can design their own circuit and instantly see how weather conditions, track configurations, pit timing, and tyre selection influence performance.”
For more information on the 'Real-Time Race Track' experience, click here.
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Nikki McCann Ramirez
Homeland Security Secretary Kristi Noem testified before the House of Representatives on Wednesday. The leader of the Trump administration's deportation push had a lot to answer for.
In a hearing before the House Homeland Security Committee, Democrats grilled Noem about the arrest of Newark, New Jersey, Mayor Ras Baraka; the deportation of citizen children along with their immigrant parents; and the Trump administration's continued noncompliance with court orders mandating due process for migrants.
In one contentious moment, Noem defended the deportation of Kilmar Abrego Garcia, a Maryland man with a protection order preventing his removal to El Salvador — and whom the Trump administration admitted was deported in error. Multiple federal courts, including the Supreme Court, have since ruled that Abrego Garcia's rights were violated. Instead of complying with court rulings ordering relief for Garcia, the administration has spent weeks accusing him of being a terrorist, child trafficking member of MS-13, while providing no evidence to support the claim.
Last month, President Donald Trump insisted during an interview with ABC News that an edited image of Abrego Garcia's knuckle tattoos — over which the letters “MS-13” had been sloppily superimposed — was a real photo of his hand, and clear proof of his supposed gang affiliation. In a complete break with reality during Wednesday's hearing, Noem repeatedly refused to acknowledge that the photo had been edited, instead doubling down on unsubstantiated claims that Abrego Garcia was a human trafficker and refusing to directly answer questions from Rep. Eric Swalwell (D-Calif.).
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Swalwell — who had an enlarged copy of an image of Trump holding up a printout of the edited photo — repeatedly asked Noem to look at the photo and tell him if it had been doctored, while the secretary petulantly refused to look directly at the image. The exchange became so tense that at one point Swalwell had staff bring the large poster board down to the witness' table so Noem could get a better look.
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I don't “have any knowledge of that photo you're pointing to,” Noem claimed at one point.
“It's so telling that you won't look at the photo,” Swalwell said.
Swalwell wasn't the only Democrat to press Noem about Abrego Garcia. Rep. Dan Goldman (D-N.Y.) asked her if she would “give Abrego Garcia the due process that the Supreme Court has required you to give him,” given the court's ruling that the government needed to “facilitate” his return to the United States.
Abrego Garcia, “is an El Salvador resident” who has “been treated appropriately,” Noem said.
“How can you say that if the Supreme Court has ruled 9-0 that he hasn't,” Goldman exclaimed. “Why does your opinion […] have more authority than the Supreme court?”
On the arrest of Baraka — the Newark, New Jersey, mayor the Trump administration arrested and accused of trespassing during a congressional visit to an ICE facility last week — Noem claimed the Democratic lawmakers' visit to the detention center “was not oversight,” but “a political stunt that put the safety of our law-enforcement officers, our agents, our staff, and our detainees at risk.”
Noem claimed that three members of Congress — Reps. Robert Menendez, LaMonica McIver, and Bonnie Watson Coleman, all of New Jersey — attempted to “storm” the facility, and accused them of “slamming their bodies into our law-enforcement officers, shoving them, screaming profanities in their faces, striking them with their fists and otherwise assaulting law enforcement.”
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On Tuesday night, Noem accused the lawmakers of “committing felonies” during a Fox News interview and called for Republicans in Congress to remove the representatives from their committee assignments. A video filmed at the gates of the facility shows a chaotic scene as ICE agents pushed and jostled lawmakers and protesters as they moved to arrest Baraka.
The secretary was also questioned about the deportation of a four-year-old citizen child who was sent to Honduras alongside their mother. Noem claimed that the mother had been given the option to take her child with her, an assertion attorneys for the family dispute. Swalwell questioned what Noem was doing to help the child, who was receiving treatment for stage 4 cancer, return to the U.S.
“For this child, medical care was confirmed in their home country, so that it was continued” Noem replied, referring to Honduras.
“That child's home country is the United States,” Swalwell countered, asking Noem if she felt she had the “right to deport a U.S. citizen.”
Rep. Seth Magaziner (D-R.I.) added that Noem had just “stated under oath that the mother consented to having her U.S.-citizen children removed. But I have spoken with the attorney for that U.S.-citizen child with stage 4 cancer, [and she has] made numerous statements to the press in which she stated unequivocally that at no time did the mother consent to her U.S.-citizen children being removed.”
When Magaziner asked what evidence Noem had that the mother had agreed to the children's removal, the secretary said she would get that information to lawmakers. “Please do,” Magaziner replied. “I understand it's hard to keep them all straight because you've deported multiple U.S.-citizen children.”
“You have been sloppy,” the Democratic lawmaker added. “Your department has been sloppy. And instead of focusing on real criminals, you have allowed innocent children to be deported, while you fly around the country playing dress-up for the cameras. Instead of enforcing the laws, you have repeatedly broken them. You need to change course immediately before more innocent people are hurt on your watch.”
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Noem has staged several photo ops in which she dons tactical gear and poses with ICE officers as they move to deport people. She has been mocked for accidentally pointing a gun toward an officer's head, as well as for wearing a Rolex worth tens of thousands of dollars during a heavily-staged camera op in front of prisoners in El Salvador. Magaziner wasn't the only Democrat to call out Noem's dress-up act.
“I'm glad you found time among your many photo ops and costume changes to testify about why President Trump is seeking more taxpayer dollars, and what you plan to do with that money if you get it,” Rep. Bennie Thompson (D-Miss.) said early in the hearing. Swalwell also dunked on her publicity push around the administration's deportation efforts. “I'm a former prosecutor,” he said. “I have put people away for life sentences who are gang members. I don't need to wear costumes to show how tough I am. What makes me different from you is when I put those individuals away, I did it with the weight of the law behind me.”
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By Andreas Wiseman
Executive Editor, International & Strategy
EXCLUSIVE: BAFTA-winner Aimee Lou Wood (Sex Education), coming off a lauded turn in HBO's The White Lotus S3, is set to star opposite Oscar winner Angelina Jolie in the Marc Forster feature adaptation of Anxious People, the Black Bear and Hope Studios project we told you about coming into the Cannes market.
A buzzy project just got buzzier. The synopsis reads: “The day before Christmas Eve, investment banker Zara (Jolie) begrudgingly finds herself mingling with a group of strangers at an open house. When a reluctant bank robber, Grace (Wood), inadvertently takes the group hostage, chaos and oversharing ensues, secrets are revealed and literally nothing goes according to plan. A film about a crime that never took place, a would-be bank robber who disappears into thin air, and eight extremely anxious strangers who find they have more in common than they ever imagined.”
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Based on A Man Called Ove, author Fredrik Backman's novel, the film is being sold for international at Cannes by Black Bear and WME Independent for domestic. The story has been adapted for the screen by Oscar-nominated screenwriter David Magee, known for movies including A Man Called Otto, Life of Pi, and Finding Neverland.
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The movie will reunite some of the key players behind the 2022 feature adaptation of A Man Called Otto ($110M global box office), also based on Backman's novel. Hope Studios' Fredrik Wikström Nicastro (A Man Called Otto) and Renée Wolfe (A Man Called Otto) of 2DUX2 will produce, with A Man Called Otto and World War Z director Forster, Magee and Neda Backman executive-producing.
Wood's feature work includes starring with Bill Nighy in Oscar nominated Living, and opposite Benedict Cumberbatch in The Electrical Life of Louis Wain.
Hope Studios, which has offices in Stockholm and London, develops, finances, produces, and sells international films and TV for the global market. The firm has an overall deal with Black Bear, which partners with the company on international sales and distribution. 2DUX2, owned by Marc Forster and Renée Wolfe, will produce with Hope Studios.
Hope Studios' current slate also includes The Night House, an adaptation of master storyteller Jo Nesbø's chilling novel of the same name starring Aaron Paul, which is set to shoot this summer in Álava, Spain. The studio is also setting up a feature adaptation of Robin Sharma's The Monk Who Sold His Ferrari.
Black Bear's Cannes slate also includes David O. Rusell's Shutout, starring Robert De Niro and Jenna Ortega.
Wood is represented by CAA, Independent Talent Group and Slone, Offer.
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By
Ryan Bort
Robert F. Kennedy Jr., the man Donald Trump and Republicans in Congress put in charge of the nation's health systems, doesn't think he's qualified to dispense medical advice.
Kennedy, a longtime vaccine conspiracy theorist, was asked about the measles vaccine during a House Appropriations Committee hearing on Wednesday. The United States is currently facing its most significant measles outbreak in decades, one that Kennedy has tried to downplay while simultaneously touting the vaccine and several dubious alternative medicine remedies.
“If you had a child would you vaccinate that child for measles?” Rep. Marc Pocan (D-Wisc.) asked Kennedy.
Kennedy hesitated before saying “probably,” then adding that his opinion is “irrelevant” and stressing that he doesn't want it to seem like he is advising people on how to protect their children against measles — despite the vaccine's proven effectiveness, as well as the fact that he is literally the nation's chief health official.
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“I don't think people should be taking medical advice from me,” Kennedy said.
“That's kind of your jurisdiction, because the CDC does give advice,” Pocan replied.
Pocan also asked Kennedy if he would give his children the polio vaccine, which has almost completely eradicated the disease worldwide. Kennedy wouldn't say. “Again, I don't want to be giving advice,” he said.
The hearing comes as Kennedy guts the health systems under his control — from the Centers for Disease Control, to the Food and Drug Administration, to the National Institute of Health.
“I do not believe the American people want less health research, more infectious disease outbreaks, and cuts to Medicaid,” Rep. Rosa DeLauro (D-Conn.), the ranking Democrat on the Appropriations Committee, wrote in an op-ed for Rolling Stone last month. “The administration has fired or pushed out thousands of experts and experienced staff who help keep Americans safe from infectious diseases, including Measles, HIV, and tuberculosis.”
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DeLauro was ready to grill Kennedy during the hearing on Wednesday.
“Are you planning to break the law by impounding congressional-appropriated funds?” she asked, noting how Kennedy is cutting $18 billion from the NIH and wants to cut more. Kennedy replied by saying that if Congress appropriates the money, he will spend it, to which DeLauro emphasized that the money has indeed been appropriated.
“The White House proposal is to do very large cuts to the NIH,” Kennedy said, before somehow continuing to insist that if the money is appropriated he will spend it. “You have the power of the purse here,” Kennedy said.
“I'm not sure the administration has internalized that,” DeLauro said, noting Office of Management and Budget Director Russell Vought's contention that the president can impound congressionally appropriated money. Kennedy kept repeating that he will spend money if it's appropriated, though, and DeLauro ultimately said the committee would hold him to it.
Kennedy was again grilled about cuts to the NIH during a Senate hearing later on Wednesday.
“How many staff have been cut from the NIH's clinical center?” asked Sen. Patty Murray (D-Wash.) after telling the story of one of her constituents who needs cancer treatment. Kennedy said he didn't know and he'd provide that information later, which Murray said was “not acceptable.” Murray then asked if Kennedy genuinely believes that cutting the NIH by half isn't going to lead to more stories about Americans who cannot receive the care they need.
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“I think the cuts that are now proposed by NIH are going to hurt,” Kennedy acknowledged.
Kennedy may be confused about congressionally appropriated funding for the nation's health management and research and how cuts are hitting the NIH, but he's certainly correct in that it's probably not a good idea for Americans to take medical advice from him: He recently posted pictures of himself swimming with his grandchildren in a creek where the National Park Service barred swimming due to sewage runoff and fecal contamination.
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Married in 2022, divorced in 2025?
By
Tony Maglio
For two years, we were fed a steady stream of why Warner Bros. Discovery dropped the “HBO” from HBO Max. The short version: it was too limiting, Max is the streaming home to more than just prestige TV, etc, etc. Well, now HBO Max is back — albeit in an improved app — and the rebranding (debranding?) of the rebrand is likely the latest sign of a potential division of WBD assets.
On May 8, after Warner Bros. Discovery reported its March-quarter earnings, CNBC's David Faber had a report of his own: WBD is “moving towards…a split.”
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“It's become relatively clear to me from the many conversations that I've had that we could get some sort of an announcement in the not-too-distant future that they are planning to try to split the company,” Faber said.
Warner Bros. Discovery did not respond to The Hollywood Reporter's request for comment on the Faber report.
The only split that makes sense for Warner Bros. Discovery, which was just formed in April 2022 as the combination of WarnerMedia (under AT&T) and Discovery, Inc., would be to pair the WB studios with Max and spin the Discovery linear cable channels off into a new company. Faber's reporting concurs, but we can also just source our intuition and logic on this one. A WBD split-and-spin would not come without hurdles: like the fact that (HBO) Max also houses most of the same programming that populates Discovery+. How do you rectify that problem? You reattach Max to the HBO brand and remove the Discovery stuff later.
We're not quite there yet, but it sure feels imminent.
Thirty minutes into Wednesday's Warner Bros. Discovery upfront, HBO chief Casey Bloys declared HBO Max is back. The absurdity of it all was met with laughter, light applause and exactly one whistle. It felt like the advertisers in the Madison Square Garden theater were laughing at Max, and not with it. (Later in the show, the announcement of new Shark Week programming Dancing with Sharks, hosted by ousted Dancing with the Stars host Tom Bergeron, got a similar “are-you-kidding-me?” kind of laughter.) Bloys did follow with a solid joke: “I know you're all shocked, but the good news is I have a drawer full of stationary from the last time around.”
Good one.
Bloys has to be happy with the development. Though he oversees both the HBO and Max brands, a re-elevation of HBO is a further endorsement of Bloys.
The onstage self-deprecation continued when HBO Max Chief Marketing Officer Shauna Spenley displayed the three Spider-men pointing meme on the big screen behind her, replacing the Marvel Spideys with DC Supermen and overlaying the logos of Max, HBO Max and the old SVOD service HBO Go, which (first) beget the (first) HBO Max. The press release got in on the joke with a meme of its own: Ross (David Schwimmer) from Friends, in bed between the Max and HBO logos, shouting, “We were on a break!”
HBO Max first launched in 2020; it was a buggy user experience, so the Max platform was built from scratch for a 2023 launch. This summer that new platform stays but the name reverts.
Warner Bros. Discovery President and CEO David Zaslav came into this whole WBD endeavor as the Discovery, Inc. chief, but he's spent the past few years aligning himself with the Warner Bros. side. Zaslav literally ordered Jack Warner's desk out of storage; he now rules the iconic Warners lot from behind it.
Zaslav is one split away from fully turning his former position atop a withering bundle of cable channels into the man exclusively in charge of HBO and Warner Bros., two giant brands in Hollywood history — and its present. The looming question: What to do with that $35 billion in remaining debt as created by the literal creation of Warner Bros. Discovery? We don't have that answer, yet, but it'd sure be nice to bury billions with a Discovery SpinCo.
Speaking of a SpinCo., Zaslav is watching the very blueprint unfold in front of him as NBCUniversal spins out its own cable channels into a company now called Versant. Basically, NBCU (owned by Comcast), is keeping its studios, its streamer Peacock, the NBC broadcast channel and Bravo. The rest goes on the junk pile to SpinCo. Versant.
The former NBCUniversal president, Jeff Shell, is keeping a close eye on the happs as well: Shell will be president of Skydance Paramount (our guess at a name, but names are getting real dumb) when that merger goes through — it's expected to happen by this summer. Paramount Global has a bunch of bad linear cable channels as well, a result of the re-merging of Viacom and CBS in 2019, which became Paramount Global in 2022. Shell and David Ellison could CBS, Paramount Pictures and maybe Paramount+, and spin the rest of their troubles away.
And hey, maybe Versant will buy all of their leftovers.
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By Matt Grobar
Senior Film Reporter
EXCLUSIVE: Maya Hawke is the newest addition to the cast of The Hunger Games: Sunrise on the Reaping, Lionsgate‘s adaptation of the bestselling book by Suzanne Collins. The Stranger Things breakout will take on the role of Wiress, former Hunger Games champion-turned-District 12 mentor.
Hawke joins an ensemble led by Joseph Zada and Whitney Peak, who respectively play Haymitch Abernathy and Lenore Dove Baird. Others set include Mckenna Grace as Maysilee Donner, Jesse Plemons as Plutarch Heavensbee, and Kelvin Harrison Jr. as Beetee.
The latest installment in Collins' bestselling dystopian YA franchise was published on March 18. The story revisits the world of Panem 24 years before the events of The Hunger Games, starting on the morning of the reaping of the 50th Hunger Games, also known as the Second Quarter Quell. Our protagonist, 16-year-old Haymitch, is a clever and resourceful boy from District 12 who's unexpectedly chosen for this edition of the games, which will feature a deadly twist: twice the number of tributes, with 48 children sent into the arena to battle for their lives.
Francis Lawrence has returned to direct from a script by Billy Ray. Color Force's Nina Jacobson and Brad Simpson are producing, with Cameron MacConomy exec producing. Meredith Wieck and Scott O'Brien are overseeing the project for the studio, for whom Robert Melnik negotiated the deals. Slated for release on November 20, 2026, the new film comes on the heels of five Hunger Games entries that have grossed more than $3.3 billion worldwide.
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Best known for her role as Robin on Netflix's Stranger Things, which is expected to return this year for its final season, Hawke recently voiced Anxiety in the global hit Inside Out 2, also taking on roles in prestige projects including Bradley Cooper's Maestro, father Ethan Hawke's Flannery O'Connor biopic Wildcat, and Wes Anderson's Asteroid City. Upcoming, she'll be seen portraying Lucia Joyce, Irish dancer and daughter of writer James Joyce, in a biopic from Aisling Walsh. She's represented by CAA, Untitled Entertainment, and Hansen, Jacobson, Teller.
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Taylor Sheridan is coming back to the big screen and has written the script for “F.A.S.T.,” an original crime story that is set up at Warner Bros. Pictures, the studio announced during its Upfronts on Wednesday.
Brandon Sklenar of Sheridan's “1923” will star in the film, and “1923” series director and cinematographer Ben Richardson will make his feature directorial debut on the film. Warner Bros. has even already set a release date for “F.A.S.T.,” April 23, 2027 in theaters.
“F.A.S.T.” follows a former special forces commando who is tapped by the DEA to lead a black ops strike team against CIA-protected drug dealers.
Sheridan has an overall deal with Paramount, but Warner Bros. commissioned the script prior to that deal beginning, and Paramount ultimately granted Sheridan's request to make the film, albeit within Paramount's exclusive window. As a result, Sheridan is currently in negotiations along with Jenny Wood of Bosque Ranch Productions to produce “F.A.S.T.”
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David Heyman and Jeffrey Clifford of Heyday Films are also producing. The film will be overseen by Warner Bros. Pictures President of Production Jesse Ehrman and EVP of Production Kevin McCormick.
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Warner Bros. Motion Picture Group's Michael De Luca and Pam Abdy said, “The breadth of Taylor Sheridan's body of work is simply astounding and unparalleled in sheer excellence and consistent quality and we could not be more honored to be making this film with him. With the hugely talented director Ben Richardson behind the camera and the exceptional producing talents of Heyday Films and Bosque Ranch, we are thrilled to have such an incredible creative team bringing F.A.S.T. to the big screen.”
In film, Sklenar just starred in “Drop” and recently in “It Ends With Us” and will soon be seen in “The Housemaid.”
Taylor Sheridan is represented by CAA, LBI Entertainment, ID-PR, and Meyer & Downs. Ben Richardson is represented by CAA. Brandon Sklenar is represented by WME, Neon Kite, Relevant, Goodman, Genow, Schenkman, Smelkinson & Christopher.
THR first reported the news.
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It's a bird, it's a plane, it's the dawn of a new day for the Superman IP. James Gunn is giving his take on the iconic character with his DC feature “Superman,” starring David Corenswet as the title character.
Gunn, who is the co-CEO of DC Studios with Peter Safran, wrote the feature which is decidedly not an origin story about Clark Kent embracing his alienhood to save the world. There will be plenty of world saving, but he is already well known to his colleague and love interest Lois Lane (Rachel Brosnahan) and nemesis Lex Luthor (Nicholas Hoult).
“We just start in the middle of the action,” Gunn previously told TheWrap. “Superman already exists. Lois and Clark already know each other. Lex hates Superman's guts from the beginning, although they don't know each other personally. So we start right in the middle of the action.”
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“Superman” is among the latest DC installments, which also includes the return of the “Peacemaker” series for Max.
Warner Bros. Pictures will release “Superman” in theaters on July 11. Check out the trailer below.
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Sheridan, who has been building a massive television empire for Paramount since the late 2010s, is back in the movie business thanks for a unique deal being finalized now.
By
Borys Kit
Senior Film Writer
It may have taken the slow route of almost a decade, but Taylor Sheridan's action thriller F.A.S.T. is finally on the, um, fast track.
In a deal involving high-level talks between Warner Bros. Discovery and Paramount, Sheridan has navigated a feature package that includes Brendon Sklenar, the star of the multi-hyphenate's hit 1923, and that series' main director and renowned cinematographer Ben Richardson, to land at Warners.
And how fast is F.A.S.T. moving? Warners has set an April 23, 2027 theatrical release date.
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Sklenar, who also starred in last year's It Ends with Us and the recent suspense movie Drop, will headline the action thriller with Richardson, who worked on The Fault in Our Stars and Beasts of the Southern Wild as DP, making his feature directorial debut. David Heyman and Jeffrey Clifford of Heyday Films will produce the project with Sheridan and Jenny Wood of Bosque Ranch Productions in negotiations to join them.
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“The breadth of Taylor Sheridan's body of work is simply astounding and unparalleled in sheer excellence and consistent quality and we could not be more honored to be making this film with him,” Warner Bros. Motion Picture Group's Michael De Luca and Pam Abdy said in a statement. “With the hugely talent director Ben Richardson behind the camera and the exceptional producing talents of Heyday Films and Bosque Ranch, we are thrilled to have such an incredible creative team bringing F.A.S.T. to the big screen.”
The coming together of the F.A.S.T. deal in one way encapsulates the shifting vagaries of the theatrical and streaming movie business. And it also exposes the tricky nature of navigating inter-studio relations.
F.A.S.T. concerns a former special forces commando, down on his luck after he returns Stateside, who is tapped by the DEA to lead a black op strike team against CIA-protected drug dealers in his town.
Sheridan wrote the script in the mid-2010s, when he was an established feature scribe with movies such as Sicario and Hell or High Water Under his belt. Warners, then owned by Time Warner, picked it up in 2018, with Sheridan initially signaling he wanted to direct and Chris Pratt circling to star. Gavin O'Connor later came on board as director in 2019, but by then, the studio was owned by AT&T, which didn't see a financial upside of releasing a movie with the budget in the $60 million to $70 million range theatrically. It was also, however, thought as too expensive to make as a streaming movie for its then-launching streaming service HBO Max. This was against a backdrop of a pandemic that was savaging the moviegoing experience and a streaming war that had gripped studios with the hallucinatory idea that streaming was the only future coming. Warners thus put F.A.S.T. into turnaround (only to have Amazon briefly flirt with it).
Now, a project that was once a Warners theatrical feature with a Marvel star that almost morphed into streaming feature, was reacquired by Warners, now part of Warner Bros. Discovery and back in the theatrical game.
But studios and movie releasing aren't the only things that have changed. Sheridan's lot in Hollywood has changed plenty as well. He created modern western Yellowstone for the Paramount Network in 2018, and it quickly became the most watched series on cable — a title it hasn't relinquished. Soon, Yellowstone spinoffs such as 1883 and 1923 sprouted on Paramount+, becoming a major draw for the service. Sheridan grew to one of the biggest showrunners in Hollywood, scorching his brand on Paramount+ with shows Tulsa King, Lioness, and Landman, among others.
“Taylor at this stage is Paramount+,” says one insider.
The showrunner also has a strict exclusive deal with Paramount, which initially made moving forward on F.A.S.T. with Sheridan a non-starter — Until WBD head David Zaslav made it a priority. Sources say that dealmaking is still being finalized to give Sheridan a carve out from his Paramount pact to render screenwriting and producorial duties.
That wrinkle is making the setting of a budget for F.A.S.T. a tricky proposition, as Warners wants to settle Sheridan's producorial involvement first, according to sources. It will likely be considerably less than the $65 million or so from over a decade ago, when it was initially judged to be too high for a theatrical release.
F.A.S.T. will be overseen by Warner Bros. Pictures president of production Jesse Ehrman and exec vp of production Kevin McCormick.
Sheridan is repped by CAA, LBI Entertainment, and Meyer & Downs. Sklenar is repped by WME, Neon Kite, and Goodman Genow while Richardson is repped by CAA.
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By Damon Wise
Film Editor, Awards
One is the loneliest number in Mascha Schilinsky's superb second feature, a fractured reflection on childhood and family that eschews linear narrative for immersive atmosphere, telling the story of four young girls from different eras whose lives play out, in the words of Harry Nilsson, by making rhymes of yesterday. Cinema is too small a word for what this sprawling yet intimate epic achieves in its ethereal, unnerving brilliance; forget Cannes, forget the Competition, forget the whole year, even — Sound of Falling is an all-timer.
The one constant in a kaleidoscopic timeline that plays out across a hundred years is a farmhouse in northern Germany, established in the opening scenes — perhaps in the '30s or '40s — as home to Erika (Lea Drinda), who amuses herself by binding her left leg and walking on her Uncle Fritz's crutches. Fritz, an amputee, is largely bedbound and suffers night terrors, a casualty of the First World War, but not in the way you might think. So far, everything is fairly traditional, like any other well-appointed period drama. Things suddenly take a bizarre turn, however, when Erika seems to break character, looking into the camera — and smiling.
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From here we flash back to a time when little Alma (Hanna Heckt) lived there with her sisters. Nothing is explained, but from their dress it appears to be the early 20th century, perhaps sometime during or even before the First World War. Alma's mother is throwing a party for All Soul's Day and has put out a special black dress for her youngest daughter to wear. The mantelpiece is full of photographs of deceased relatives, but one in particular stands out: the body of a little girl, propped up on a sofa with a doll. It's a macabre tableau, made even stranger by a creepy double exposure that transforms the woman behind her (is it Alma's mother?) into a faceless kind of ectoplasm.
The little girl looks like Alma, and her sisters tell her that it is her. But how can that be? It's the first of many mysteries, the most likely explanation being that, given the high infant mortality rate of the time and the haunting image of a little boy in a coffin that recurs, Alma's mother has lost more than one child along the way. But while Alma is pondering this, the film shifts its attentions to the present day, where Lenka (Laeni Geiseler) and her little sister Nelly (Zoë Baier) live with their parents. The farmhouse is now something of a fixer-upper, and we can tell from the horribly dated décor that the place hasn't had much love since the Cold War. This is our cue for another timeslip; the next period is some undefined postwar period where we meet Angelika (Lena Urzendowsky), Erika's niece.
From here, Schilinsky engages in a weird but effective kind of hypnosis, showing the life cycle of a family home through the eyes of the young girls who lived there. Phrases and situations repeat in different periods, and, in the boldest strategy of all, the girls' voice-overs — as if speaking to us from beyond the grave — don't always tally with what we see. Memory, like time, is an abstract concept here, and Fabian Gamper's restless camera has a ghost-like presence, always observing and yet never quite telling, shooting sometimes in such little light that it's hard to see what's happening in the gloom.
Given the subject matter, death is everywhere — a fair enough reflection of the morbid interior lives of young girls still drawn, like moths, to books like The Bell Jar and films like The Notebook — but what's real and what's imagined is left for the viewer to decide (Angelika, especially, devises a devastating end for herself in a cornfield). An obvious comparison is Sofia Coppola's debut film The Virgin Suicides, and one can also make a case for Peter Weir's enigmatic Picnic at Hanging Rock, which is much closer in spirit. But Schilinsky's film is absolutely its own beast, that rare film that has no music except for one startlingly wonderful song (“Stranger” by Anna Von Hausswolff), resting instead on a mix of ambient clicks and hums that give the film a low-fi analog quality that fits just perfectly with its Proustian themes of les temps perdus.
One viewing might not be enough, two will certainly make things a bit clearer, but Sound of Falling — like its moody title — is not a puzzle waiting to be solved. Instead, it's an exhilarating experience, frustrating at times, but in the best, most challenging way. If Terence Davis and David Lynch made a movie together, it would look and sound like this. Quite frankly, there's no higher praise than that.
Title: Sound of FallingFestival: Cannes (Competition)Director: Mascha SchilinskyScreenwriters: Mascha Schilinsky, Louise PeterCast: Hanna Heckt, Lea Drinda, Lena Urzendowsky, Laeni Geiseler, Zoë Baier, Luise Heyer, Susanne WuestSales agent: MK2Running time: 2 hr 29 min
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Unfolding like 100 years of home video footage that were shot by the family ghosts, Mascha Schilinski's rich and mesmeric “Sound of Falling” glimpses four generation of young women as they live, die, and suffuse their memories into the walls of a rural farmhouse in the north German region of Altmark.
In the 1940s, after some of the local boys are maimed by their parents in order to avoid fighting Hitler's war, teenage Erika (Lea Drinda) hobbles through the halls with one of her tied legs up in string, eager to know what losing a limb might feel like. Unbeknownst to her, cherubic little Alma (Hanna Heckt) expressed a similar curiosity some 30 years earlier when she played dead on the parlor room couch, posing in the same position that her late grandmother's corpse had been placed for a post-mortem daugerreotype.
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And yet, coming of age in the German Democratic Republic of the 1980s, Angelika (Lena Urzendowsky) might think she's inventing her girlish impulse towards self-negation when she fantasizes about lying down in front of her father's tank-sized land imprinter as it mulches her body into the earth, just as Lenka (Laeni Geiseler) — living in our present — wonders if she's the first person to be looked at in a way that burns under her skin. We rarely see these characters overlap in a literal sense, and their specific relationships to one another remain hard to define (it would take a professional arborist to untangle the roots of this movie's family tree, at least on first watch), but “Sound of Falling” is deeply attuned to the echoes between them.
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Somehow both hyper-subjective and hauntingly disembodied all at once, Schilinski's recursive second feature floats through the decades like an errant thought hoping to find someone who might recognize it as one of their own. The film lopes forwards and backwards in time without notice or warning, Fabian Gamper's camera often peering through keyholes and floorboards in order to reconcile the tunnel vision of being alive with a quietly Teutonic awe at the vastness of having lived. Some eye-level shots are clearly tethered to the perspective of a certain character, while others seem to stem from the POV of an invisible spirit crouching next to them, as if assigning physical dimension to the third-person of our remembered pasts.
Intimate and infinite in equal measure, the movie's freeform structure and emotional tonality might evoke everything from “The Hours” and “The Virgin Suicides” to Robert Zemeckis' “Home,” and Charli XCX's “Girl, so confusing” (why not), but its style found me returning to Edward Yang's magnificent “Yi Yi” as the most immediate point of reference. Specifically, the character of eight-year-old Yang-Yang, who photographs the backs of people's heads in order to show them the parts of themselves they can't see on their own.
“You always see things from the outside, but never yourself,” one of Schilinski's characters muses in a snippet of the diaristic voiceover that holds this film together. She rues the fact that blushing externalizes the exact emotion that someone is trying to hide, just as Angelika — who's cannonballing into her sexuality, and rumored to be sleeping with her uncle — resents that she can will her legs to move, but not her heart to stop beating.
Do our brains flip the world rightside up, or do they force us to see it upside down? “Sound of Falling” isn't disinterested in personal drama, but that drama is reliably sublimated into the perspective through which it's experienced. So tenderly in touch with the shared but unspoken traumas that are visited upon her cast of young women, Schilinski mines tremendous sorrow from the secret poetics of girlhood; she weaponizes cinema's ability to access the deepest interiors of human feeling, and swirls her characters together in a way that tortures them for their subjectivity.
The more intimately we come to understand the hurt and heartache that Alma, Erika, Angelika, and Lenka all experience in their own ways, the more it kills us that they aren't able to commiserate with each other (the film's temporal porousness is heightened by its glancing attention to various social and political borders, some of which are more easily crossed than others). Nothing is new in this world, but pain turns us all into pioneers.
If only the film's characters had the chance to compare notes, perhaps they might not share the same affinity for self-erasure. But they do feel one another (intangibly, the way that an amputee might scratch at a phantom limb), and the 150-minute “Sound of Falling” is held aloft by its compelling attention to sense memory. As one of the girls puts it: “It's funny how something can hurt that's no longer there,” and that hurt accrues an ethereal power of its own as Schilinski doubles back to flesh it out.
Her film is piloted by sense memory, its story (a lot) less concerned with conflict or incident than it is with the buzz of a housefly, the bite of a fish, or the beat of that one pop song that Lenka and her only friend listen to all summer long. Brittle silences give way to an ominous hum, and occasionally to the fuzz of a record needle in search of the groove it needs to know its purpose. It's the perfect soundtrack for a reverie that spins in smaller and smaller circles until its attention grows focused enough to observe a single mote of sublime transcendence — and to defy the gravity that's been accumulated from almost 100 years of solitude.
“It's too bad you never know when you're at your happiest,” one of the girls laments, and it's true that none of these characters may ever be able to contextualize their emotions with the perspective necessary to survive them. But Schilinski's arrestingly prismatic film — so hazy and dense with detail that it feels almost impossible to fully absorb the first time through — keeps sloshing its way through the years until those blind spots begin to seem revelatory in their own right. These girls can only see so much of themselves on their own, but “Sound of Falling” so vividly renders the blank space between them that it comes to feel like a lucid window into the stuff of our world that only the movies could ever hope to show us.
“Sound of Falling” premiered at the 2025 Cannes Film Festival. It is currently seeking U.S. distribution.
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By
Andy Greene
The 2025 incarnation of Willie Nelson and Bob Dylan‘s Outlaw Music Festival Tour launched Tuesday evening at the Talking Stick Resort Amphitheatre in Phoenix, Arizona. And much like last summer, Dylan sent shockwaves through his fan community by shredding his standard Rough and Rowdy Ways setlist, and breaking out surprise covers and originals he hadn't touched in ages.
The set began in standard 2025 fashion with “I'll Be Your Baby Tonight” and “It Ain't Me, Babe,” and then veered off course with “Forgetful Heart,” a Tempest tune he hadn't touched since 2015. What followed was initially described as “unknown blues song” until fans frantically googled the lyrics and realized it was “Axe and the Wind” by relatively obscure blues singer George “Wild Child” Butler. There's no record of Dylan playing the tune at any point in history.
Dylan returned to his song catalog for the first “To Ramona” since 2017, and he followed it up with the Forties R&B classic “(Get Your Kicks on) Route 66,” which has been covered over the years by everyone from Nat King Cole to Bing Crosby and the Rolling Stones. It's the first time Dylan has ever performed it live, and he was likely inspired by the close proximity of the original Route 66 to Phoenix.
Another surprise cover came just two songs later when he broke out Charlie Rich's 1958 Sun Records classic “I'll Make It All Up To You.” This was yet another live debut for Dylan, and the first time he's ever performed a Charlie Rich song.
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Dylan has completely ignored the vast majority of his hits in concert over the past few years, which made the reintroduction of “Mr. Tambourine Man” into the set after a 15-year absence even more stunning. This was a stripped-down version that emphasized the lyrics, and it was spellbinding.
The final shock of the night came at the very end when the band kicked into “A Right Night in Soho” by the Pogues. It's the only time Dylan has ever played a Pogues song, and it was a beautiful tribute to the late Shane MacGowan.
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The Outlaw Music Festival continues Friday night at the North Island Credit Union Amphitheatre in Chula Vista, California. It's impossible to know if Dylan will stick to this set or continue to play around with it. The opening date of the 2024 Outlaw Music Festival featured a completely unique set that included Little Walter's “My Babe” and Sanford Clark's “The Fool.” They were both one-offs, and he settled into a predictable (albeit eccentric) set later that week.
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What we do know is that Dylan will be on the road with Willie Nelson and the rest of the Outlaw gang until September 19. And on any given night, it's possible that he'll play basically anything.
Bob Dylan's May 13 setlist at the Outlaw Music Tour Festival in Phoenix, AZ
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Trent Reznor and Atticus Ross have announced Future Ruins, a new music and arts festival that celebrates film and television composers. The inaugural lineup includes Reznor and Ross, as well as John Carpenter, Mark Mothersbaugh, Claudio Simonetti's Goblin, Questlove performing the score works of Curtis Mayfield, and more. Future Ruins will take place November 8 at the Equestrian Center in Los Angeles. See the festival poster below.
“It's about giving people who are, literally, the best in the world at taking audiences on an emotional ride via music the opportunity to tell new stories in an interesting live setting,” said Reznor in a statement. “There's no headliner. There's no hierarchy. This is a stacked lineup of visionaries doing something you might not see again.”
Future Ruins will take place across three stages at the Equestrian Center, and prides itself on encouraging its artists to “take big swings and reimagine their work for a live audience.” Rounding out the lineup are Cristóbal Tapia de Veer, Ben Salisbury & Geoff Barrow, Danny Elfman, Hildur Guðnadóttir, Isobel Waller-Bridge, Kyle Dixon & Michael Stein, Robert Aiki Aubrey Lowe, Tamar-Kali, Terence Blanchard, Volker Bertelmann, and a performance of Howard Shore's score for Crash by David Cronenberg.
Reznor and Ross seem always to be in the studio working on film scores these days, and that also extends to racking up nominations at awards shows for their compositions, too. Earlier this year, the Nine Inch Nails musicians won Best Original Score at the 2025 Golden Globe Awards for Challengers—much to the delight of Elton John, who presented them with the award and let out a hearty “Yay!” upon opening the envelope.
Read about Carpenter's Halloween, Reznor and Ross' The Social Network, and more in “The 50 Best Movie Scores of All Time” and revisit “John Carpenter on the Music That Made Him a Horror Icon.”
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Trent Reznor and Atticus Ross have announced Future Ruins, a new music and arts festival that celebrates film and television composers. The inaugural lineup includes Reznor and Ross, as well as John Carpenter, Mark Mothersbaugh, Claudio Simonetti's Goblin, Questlove performing the score works of Curtis Mayfield, and more. Future Ruins will take place November 8 at the Equestrian Center in Los Angeles. See the festival poster below.
“It's about giving people who are, literally, the best in the world at taking audiences on an emotional ride via music the opportunity to tell new stories in an interesting live setting,” said Reznor in a statement. “There's no headliner. There's no hierarchy. This is a stacked lineup of visionaries doing something you might not see again.”
Future Ruins will take place across three stages at the Equestrian Center, and prides itself on encouraging its artists to “take big swings and reimagine their work for a live audience.” Rounding out the lineup are Cristóbal Tapia de Veer, Ben Salisbury & Geoff Barrow, Danny Elfman, Hildur Guðnadóttir, Isobel Waller-Bridge, Kyle Dixon & Michael Stein, Robert Aiki Aubrey Lowe, Tamar-Kali, Terence Blanchard, Volker Bertelmann, and a performance of Howard Shore's score for Crash by David Cronenberg.
Reznor and Ross seem always to be in the studio working on film scores these days, and that also extends to racking up nominations at awards shows for their compositions, too. Earlier this year, the Nine Inch Nails musicians won Best Original Score at the 2025 Golden Globe Awards for Challengers—much to the delight of Elton John, who presented them with the award and let out a hearty “Yay!” upon opening the envelope.
Read about Carpenter's Halloween, Reznor and Ross' The Social Network, and more in “The 50 Best Movie Scores of All Time” and revisit “John Carpenter on the Music That Made Him a Horror Icon.”
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Events
© 2025 Condé Nast. All rights reserved. Pitchfork may earn a portion of sales from products that are purchased through our site as part of our Affiliate Partnerships with retailers. The material on this site may not be reproduced, distributed, transmitted, cached or otherwise used, except with the prior written permission of Condé Nast. Ad Choices
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The star hasn't released music since 2022's "Lift Me Up" for Black Panther: Wakanda Forever.
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Hannah Dailey
Rihanna fans who are desperate for new music don't need to feel blue any longer — the superstar finally has a new song coming out soon, recorded for the Smurfs movie soundtrack.
As revealed Wednesday (May 14) with the release of the film's new trailer, Ri will drop a track called “Friend of Mine” on Friday (May 16). The teaser also features snippets of the song, which finds the Fenty mogul singing over a dreamy Afrobeats-inspired dance track, “You're looking like a friend of mine.”
Starring Ri as the voice of Smurfette opposite John Goodman, James Corden, Nick Offerman, Sandra Oh and more, the Smurfs movie is set to hit theaters July 18. In addition to the “Umbrella” singer's new song, its soundtrack will also feature Tyla as well as a song called “Higher Love” by DJ Khaled, Cardi B and DESI TRILL, which dropped in February.
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The new teaser opens with a shot of Rihanna — aptly wearing a blue jacket and blue beads in her hair — dancing in the studio as she records some of Smurfette's lines. It then shows a preview of the film's storyline, with the residents of Smurf Village traveling to the real world to save Papa Smurf (Goodman) after he's kidnapped by evil wizard Gargamel (J. P. Karliak).
In addition to starring and singing in the film, Ri also served as an executive producer on the latest addition to the Smurfs franchise. While announcing the project back in 2023 at that year's CinemaCon alongside Paramount and Nickelodeon, the musician — who was pregnant with second son Riot Rose at the time — said, “I get to show up in my PJs in my third trimester … I hope this gives me cool points with my kids one day.”
“Friend of Mine” will mark Ri's first release since 2022's “Lift Me Up” from the Black Panther: Wakanda Forever soundtrack. She hasn't dropped an album since 2016's Anti, which spent two weeks at No. 1 on the Billboard 200.
The new trailer comes a week after Ri attended the Met Gala with partner A$AP Rocky, who was one of the event's co-chairs this year. On the red carpet, she showed off her baby bump, revealing that she's expecting her third child with the rapper.
And though fans have been waiting for a new Rihanna album for nine years at this point, the musician says that her latest pregnancy isn't going to stop her from working on Anti‘s follow-up. “Noooooo!” she told Entertainment Tonight when asked whether that would be the case on the Met red carpet May 5. “Maybe a couple videos! I can still sing!”
Watch the new Smurfs trailer and listen for snippets of Ri's new song “Friend of Mine” below.
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By
Andy Greene
Few would have been surprised if Cyndi Lauper had entered the Rock & Roll Hall of Fame during her first year of eligibility back in 2008. After all, she's one of the most successful artists of the Eighties, and songs like “Time After Time,” “True Colors,” and “Girls Just Want to Have Fun” have enjoyed stunning staying power. The video for “Girls Just Want to Have Fun” has racked up 1.5 billion plays on YouTube; the song itself 1.4 billion plays on Spotify. (And that's not even getting into the juggernaut of Kinky Boots.)
Yet for some reason, it took Lauper 17 years and three ballots to finally earn her rightful place in the Hall of Fame. We connected with her on Zoom to chat about the honor, in between her Girls Just Wanna Have Fun Farewell Tour dates and her preparations for the upcoming musical Working Girl.
Are you surprised by your induction? Is it something you hoped would happen?I didn't know what to think. But you know me, I was thinking about what I'm doing at the moment. And if accolades come, they come. That said, I still think rock & roll can save the world, and so you never stop moving forward and trying to help out, since I am in the field of humanities anyway.
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I do appreciate the fact that all the women actually voted for me, and they were a lot, and that's humbling. You just hope you can live up to their expectations.
How did you find out?My manager told me. Then I thought about all of the women who were inducted before me, and all the shoulders that I stand on, but all the women coming up who stand on my shoulders. It's wonderful to be part of that legacy.
They didn't bring in Cher until last year. Tina Turner didn't get in without Ike until right before she died. That just baffles me.Well, in the beginning, who was doing the voting?
Very good point. It was primarily men.As more women become involved, of course they're going to…I just think for me, you knock on a door and it depends on what you want. If you keep knocking, eventually that door opens. I think if you persist, you prevail.
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It's a pretty diverse class this year with you, Chubby Checker, Bad Company, the White Stripes, Salt-N-Pepa, Outkast, Soundgarden. Are you fans of any of them?Yeah. I got to sing with one of the guys from OutKast at one of the Home for the Holidays shows in Los Angeles. It was awesome. And with Bad Company, my first gig as a lead singer, not a background singer, was singing one of their songs.
I always wanted to be a background singer, like Merry Clayton. I just loved Merry Clayton growing up. I started to feel like background singers had more freedom than lead singers because you could get to really sing high. It was cool in the background.
And then because I wasn't good at dancing in platforms, and I used to fall a lot…that helped me learn how to talk to the audience, because if you fall, you gotta say something. I got the job to be the lead singer because the manager said, “Look, you see that girl in the back who can't dance, but sings really good? Just make her the lead singer.” That's what happened. I sang a Free song and a Bad Company song.
It's a real full circle moment for you.Yeah. It was at the Boardy Barn in front of 5,000 nickel beer-drinking folks in the Hamptons. I remember being terrified. But as soon as I started swinging that tambourine to the rhythm and singing, that was it. I stepped off the platform, and I was the lead singer.
I'm excited about Salt-N-Pepa because they also did Home for the Holidays. I got to sing Spinderella's rap in “What a Man.” I was so excited to do that because when Salt-N-Pepa first came out, I was still on the hamster wheel. I didn't have a lot of time to listen and get into it. But they were so much fun. They were kind of like the me of hip-hop.
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I hate when people complain about hip-hop being in the Rock and Roll Hall of Fame.Yeah. It's bullshit. It is rock & roll. When rock & roll first came out, people like Chuck Berry and Little Richard changed everything. It was a new thing. When hip-hop started, it was also a new thing. That was again rock & roll. It was changing the world. It was changing the sound of music. And whether they were taking our hooks and putting it into their rhythm and changing what they were doing, it inspired me even in the Nineties when I did Hat Full of Stars, to take the rhythm and put it into the hooks.
I think rock & roll changes the world. And so if a rhythm comes along and changes the world, it's rock & roll, baby.
I couldn't agree more. Now, there tends to be a big jam session at the end of the night. Can you imagine singing alongside a big group of your fellow inductees?As long as I get to sing with Salt-N-Pepa, I'll be okay. And Paul Rodgers actually.
Chubby Checker should have been in a long time ago. But, once again, he's a person of color. And we stand on the shoulders of the African-American community that gave us a rhythm, mixed in with a Native American rhythm, and is truly how the rhythm of rock & roll started in the first place.
If you watch a Big Mama Thornton television performance of “Hound Dog,” which spent weeks on the top of the charts before Elvis covered it, and you hear the drums, that's rock & roll, baby. Don't tell me it ain't. And there's Big Mama in a bucket hat. She was a bad motherfucker.
Are you thinking yet about who might induct you?First of all, I'm not allowed to tell you. Second of all, actually, no. The person would have to have a free schedule, and want to do it. I guess I should make a list. I just got back from Japan. I've been busy doing my farewell tour.
I was at the MSG show. It was amazing.Oh my God. I invited everybody. And I knew if I suck, it was going to be on me because I had everybody come. I had to tell myself, “Okay, okay. Just stop. You don't have a Superman cape. Be you who are, put your best foot forward, and go.” That's what you have to do.
I always say, “Well, what does Mick Jagger say to himself?” I don't know. I never asked him. But in my mind, I did want to have a Superman or Superwoman cape. Wonder Woman, right? I didn't have the belt. It wouldn't work. I just had to be me.
It was wonderful when Sam Smith came out and the two of you played together.Wasn't that something! Didn't he look so great. I know he loves “Time After Time” because he was doing it during Covid. And then I did a thing with him after that because he was so sweet, so cute. And he was like, “Let's do this.”
Artists usually perform three songs when they get in. Any idea which ones you might sing?I know one song. I want to have a super girl band backing me for “Girls Just Want to Have Fun.” And I don't mean just singing girls, but a band of motherfuckin' players who could kick ass. That will be so awesome. And then it's really “Girls Just Want to Have Fun,” at least how I hear it.
The timing is pretty great since you wrap up your farewell tour just a couple of months earlier.On top of that, Working Girl opens up the next night in La Jolla. It doesn't really stop.
How is that going?I'm almost done. I have three songs, and three re-writes. They're mostly easy to move around. One will be challenging. But if it works, it'll be great. I have to get it done by June. But hey, it'll be okay.
After this year, might you still do one-off gigs, festivals, residencies? Are you still open to doing shows?I would do a show that I don't have to move around all the time, packing and unpacking, trying to make a plane. Doing that again would kill me. But doing a little show where I could bring the art and music together, something that's a step forward, that's an exciting prospect for me.
After Working Girl, there's another project I want to get done. You only have a certain amount of time in your life. I want to be able to do it, and do a really good job. And I want to be proud of my singing. And it's live. Everything is live. I think it's important if it's live, that it's live. In live, you never know exactly what's going to happen. You have to be in time to the visuals, but you don't have to sing it the same way every night. Sometimes I consciously change it just to find a new thing, a tiny bit, not to freak everyone out, but to make it live.
What do you think it'll feel like to stand at the podium on Hall of Fame night and realize that you're entering the same club as the Beatles and the Stones and Joni Mitchell?If you remember, they didn't have Joni Mitchell in there right away either. And the same with Joan Baez, who actually did change things in the world. She introduced me to Bob Dylan. I never would have ever, ever heard him without hearing her first. I was very young.
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I even went to the first woman's demonstration. I burnt my training bra. It wasn't just for me, but for my mother and grandmother. I wanted to break the lineage of oppression.
I realized that music can change the world. And rock & roll has always been saving the world. Look at what happened with Live Aid. I think the first thing I would want to remind all of the community is not just thank you, but please remember that our music can and has changed the world. It has contributed to the world to make it better. You can't forget that we are a community of people who can make a difference, and should always remember to make a difference.
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By Anthony D'Alessandro
Editorial Director/Box Office Editor
The Warner Bros wave at the box office continues this weekend with New Line's Final Destination: Bloodlines, the first sequel in 14 years in the 25-year-old horror franchise. It is eyeing a series -ecord start between $35 million-$40 million at 3,400 locations.
The global outlook for Bloodlines is $70M, with 74 territories going with the U.S.-Canada debut.
The R-rated Zach Lipovsky- and Adam B. Stein-directed feature is very strong with women under 25 both in unaided awareness and first choice, followed by guys under 25. The best Final Destination opening to date belongs to 2009's The Final Destination, which posted a $27.4M three-day total. Through five movies, the Final Destination titles have minted north of $666M worldwide.
The first installment in the series was written by Jeffrey Reddick, intended to be an X-Files episode, but he flipped it into a spec script. The setup entails a group of people who escape death after one of them has a premonition that a tragic catastrophe is about to occur. However, each of them dies by bizarre circumstances. The sixth film centers on a college student with violent nightmares, who returns home to find the one person who can break the cycle and save her family from the horrific fate that inevitably awaits them. Rotten Tomatoes reviews are at 93% certified fresh. Previews start around 3:30 p.m.
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Meanwhile, horror doesn't die entirely with Bloodlines flowing at 3,400 sites, as Warner Bros' own Sinners is expected to ease another 30% with a fifth weekend of $15.4M. The final outlook for the Michael B. Jordan-starring, Ryan Coogler-directed vampire movie is around $270M stateside.
Disney's third weekend of MCU's Thunderbolts* looks to dip another 40% in weekend 3 with around $19M.
Meanwhile, The Weeknd aka Abel Tesfaye has a multiplatform experiment going on with his lead star title from Trey Edward Shults, Hurry Up Tomorrow, set to hit theaters Friday timed to his new sold-out tour “After Hours Til Dawn” kicking off in Glendale, AZ. The movie, which also stars Jenna Ortega, was independently financed by Live Nation to the tune of $15M, and is named after Weeknd's January album of the same name. The tour is expected to be the highest-grossing in North America this year with $400M.
The movie, however, is only expected to open to mid- to high-single digits. Wednesday fan screenings this week, we hear, generated $1M. Previews start Thursday at 6 p.m. It's a distribution deal for Lionsgate, so if the movie makes $2M or $20M, the studio ala Megalopolis walks away with a paycheck. That said, Lionsgate jumped at the opportunity to team with The Weeknd and support his vision. The four-time Grammy winner dazzled exhibitors with a mini-concert at CinemaCon to jazz them up for the film, which follows a version of himself, an insomniac musician, who encounters a mysterious stranger. No reviews yet on RT. Not a good outlook: Unaided awareness and first choice are in the very, very low single digits, under that of Ortega's A24 genre comedy Death of a Unicorn, which didn't exactly gallop into theaters with a $5.7M opening and final U.S.-Canada take under $13M.
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With so many talented artists, it can be difficult for The Voice coaches to decide who to pick and eliminate. This is why John Legend, Adam Levine, Kelsea Ballerini, and Michael Bublé were so excited about the Super Save option. For Ballerini, this meant bringing back Derby singer Jaelen Johnston. He had been eliminated in favor of Iris Herrera and Alanna Lynise. While she stands by her decision, she understands why fans were disappointed that Johnston wasn't one of her first picks.
“As much as I represent country, I want to represent good music and I want to represent artists that are storytellers, and I believe Alanna and Iris to be two of the best on the show that do that,” Ballerini told Parade, defending her decision to choose them initially. “My goal as a coach was never to only support country artists, it was just to support great artists.”
“Sometimes there's an artist that just has such a slam dunk of a performance on that stage that it's undeniable, even if that's not what you thought going into it, and then sometimes you really buy into the growth that you've seen of the artist and you believe that they can continue to show up well,” she explained about her selection. But she also recognizes that Johnston is a great artist and country singer. Now that he's been brought back, he could be victorious.
“If Jaelen were to win, I would not be surprised at all,” Ballerini admitted. “Then everybody would be like, ‘Kelsea, we told you so.' And I'd be like, ‘Yeah, yeah, yeah, I'm a newbie here.'”
Legend and Levine admit they struggled as much as Ballerini when creating the Top 8. After seeing the Super Saves perform, they realized they may have made a mistake with their initial choices.
“Honestly, I was agonizing over the fact that I could only pick two, and I was like, ‘Obviously, I have three people that should be going to the Lives,' and I knew that,” Legend said. “It was so painful not picking Olivia because she was amazing, Bryson was amazing, RENZO was amazing, and it was an agonizing decision.”
Levine agreed. “Everybody was so good and everyone had done so well that there was just no version of this that was going to make everybody happy, including myself, I don't think, unless I could take everybody with me. So that was really where I was at,” he revealed.
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Bruce Springsteen has released “Repo Man,” the latest in a series of rarities from lost albums unvaulted for a new box set. This one comes from Somewhere North of Nashville, the country album Springsteen recorded in 1995 “on the side” of his concurrent work on The Ghost of Tom Joad, as he put it in a press release. Below, listen to the song and read Springsteen's summary of the album's origins.
What happened was I wrote all these country songs at the same time I wrote “The Ghost of Tom Joad.” Those sessions completely overlap each other. I'm singing “Repo Man” in the afternoon and “The Line” at night. So the country record got made right along with The Ghost of Tom Joad. “Streets of Philadelphia” got me connected to my socially conscious or topical songwriting. So that's where “The Ghost of Tom Joad” came from. But at the same time I had this country streak that was also running through those sessions and I ended up making a country record on the side.
Tracks II: The Lost Albums is out June 27. Before today, Springsteen had shared the title track from Faithless, the score to a movie that never got made; “Blind Spot” from the sample-based record Streets of Philadelphia Sessions; and “Rain in the River” from his compilation Perfect World. The box set collects a further 70 unreleased songs.
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After weeks of internal deliberations, backroom tug-of-wars, and public policy disputes, Republicans have their first drafts of the committee bills that will encompass President Donald Trump's much coveted “big, beautiful” reconciliation package. While the working masses will be thrown a couple bones, the legislative package is at its core a smorgasbord of MAGA wishcasting focused on protecting billionaire interests, solidifying tax breaks for the wealthy, and cutting social safety net programs.
The chief priority of congressional Republicans is to make permanent an extension of Trump's first-term tax cuts. The version of the tax bill currently being considered by Republicans on the House Ways and Means Committee preserves much of the 2017 legislation while folding in some of Trump's 2024 campaign promises, including no taxes on tips, no taxes on overtime, and even less taxes for the wealthy.
However, just like the 2017 cuts, this new tax bill would add trillions to the deficit — and it would once again disproportionately benefit the rich. The poorest Americans, meanwhile, could see a tax increase. In order to pay for the legislation, Republican lawmakers won't look toward the people who are hoarding the vast majority of the wealth in this nation, but will instead take a hacksaw to social services and safety-net programs that help the nation's poorest families survive, as well as raise taxes on universities, charities, and nonprofits.
According to the bipartisan Joint Committee on Taxation, the GOP's proposed tax provisions would increase the national debt by $5.3 trillion. It's a phenomenal cost that Republicans intend to offset, to some degree, by forcing 10 million Americans off Medicaid, pushing millions off food stamps, and increasing health care costs for many.
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There will likely be several weeks of debate and negotiations to finalize what will surely be Trump's signature second-term legislation.
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Here are 10 of the worst policy changes in the president's “big, beautiful” super bill.
For one brief moment, it seemed that the president was entertaining the possibility of raising taxes on the highest incomes in the nation. It took less than a week for him to discard the idea.
The planned extension of Trump's 2017 cuts would make permanent the income boons the president gave to Americans during his first term, which heavily favored the highest income brackets in the country — giving the rich big tax cuts while doing little to nothing for the nation's lowest earners. This time around, the tax bill is expected to raise the average tax rate, by roughly one percent, on Americans earning less than $15,000 next year, according to the Joint Committee on Taxation. Millionaires would see a three percent tax cut.
Meanwhile, the legislation would also boost the wealthiest Americans' families when they die, raising the estate tax exemption up to $15 million.
In order to fund these tax cuts for the rich, Republicans are moving to punish the nation's poor by slashing Medicaid, the government health insurance program for low-income Americans and the disabled.
Despite warnings from health care providers that a loss of Medicaid revenue could lead to widespread hospital closures, and data showing that there's not a single electoral district in the country with upwards of 15-percent support for Medicaid cuts, Republicans are planning to amputate $880 billion from the budget of the Energy and Commerce Committee. That amount could only come from the committee's Medicaid budget.
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House Republicans have proposed several ways to slash Medicaid spending. One change would limit so-called provider taxes, which states use to provide supplemental payments to hospitals, doctors, and other providers. As Rolling Stone reported this week, providers warn this change could force many rural hospitals to “close their doors.” Republicans have also proposed imposing mandatory work requirements on able-bodied Medicaid beneficiaries, a change that would add more bureaucracy to an already maddeningly complex program and likely cost many recipients their coverage. According to the Congressional Budget Office, more than 10 million Americans are expected to lose Medicaid and Children's Health Insurance Program coverage as a result of Republicans' reconciliation bill.
In an opinion piece written for The New York Times, Sen. Josh Hawley (R-Mo.) bashed “corporatist Republicans” who favor “corporate giveaways, preferences for capital and deep cuts to social insurance.”
“This wing of the party wants Republicans to build our big, beautiful bill around slashing health insurance for the working poor. But that argument is both morally wrong and politically suicidal,” Hawley wrote. Will his party actually listen to him over the demands of the president? The jury is still out.
Changes proposed by Republicans on the House Ways and Means Committee could levy heavy tax penalties on Americans who purchase individual health insurance plans through marketplaces created under the Affordable Care Act (ACA).
Low-income individuals who purchase their insurance using an advance premium tax credit could wind up owing the government thousands of dollars if their income ultimately exceeds the estimates they are required to provide to the IRS.
According to a memo published by Third Way, Republicans' under-the-radar tweaks to the ACA could increase health insurance premiums by hundreds of dollars, and force tens of thousands of people out of the marketplace. The changes could also reduce the number of people purchasing coverage through the ACA marketplace by shortening the enrollment period.
The House Agriculture Committee's reconciliation bill would authorize around $300 billion in cuts to the Supplemental Nutrition Assistance Program (SNAP) over the next ten years. SNAP — commonly referred to as “food stamps” — is the national program that provides financial support for the nutritional needs of low-income individuals and families. The program serviced around 42.1 million participants per month in fiscal year 2023, and about 40 percent of recipients of SNAP benefits were children under the age of 18.
The proposed cuts would shift some cost burdens of the program onto individual states, add new work requirements for recipients, and cut recipients' ability to use SNAP funds on other amenities like internet access. Millions could lose access to food stamps, according to research from the Center on Budget and Policy Priorities.
Tax season just ended, and if you're thinking of ways to avoid the minefield of extra payments and upgraded services offered by tax preparation services like H&R Block and Turbotax, you may soon be working with more limited options, thanks to Republicans.
House Republicans' reconciliation bill includes the elimination of Direct File, a free service provided by the Internal Revenue Service that currently allows eligible individuals in over 25 participating states to file their taxes directly to the IRS at no charge. The program was created under President Joe Biden, and faced heavy political and financial opposition from for-profit tax preparation companies.
The House Judiciary Committee's first stab at reconciliation legislation includes $80 billion for domestic immigration enforcement. According to an analysis by Immigration Impact, the figure “includes $45 billion dollars for U.S. Immigration and Customs Enforcement (ICE) detention and $14.4 billion for ICE transportation and removal operations.”
On top of that, the bill would seek to raise additional funds for the Department of Homeland Security's immigration operations by increasing fees — and leveling new ones — on common legal immigration processes. These include a $1,000 fee to apply for asylum; $1,000 for humanitarian parole; $500 for temporary protected status; $550 fees for work permits (billed every six months); $900 to appeal a rejection; and $5,000 for missing a court hearing.
This would be in addition to any legal fees and other costs typically associated with immigration to another country, and is primarily intended as a deterrent against the immigration of low-income individuals into the United States.
The Trump administration has already made a habit of accusing individuals of terrorism, with little evidence, as a way to justify actions that clearly violate the laws, legal principles, and basic rights that are supposed to govern the nation (see: the unlawful imprisonment of hundreds of migrants in Salvadoran gulags). While the government has already targeted migrants and pro-Palestine protesters with broad powers and specious claims, charities and nonprofits could be next.
The Ways and Means reconciliation text revives a proposal that would give the Trump administration the power to unilaterally terminate the tax-exempt status of disfavored nonprofits, on the grounds that those nonprofits are “terrorist-supporting organizations” that have provided “material support or resources” to terrorist groups. The measure would likely aid Trump's crackdown on pro-Palestine protesters — though officials could potentially try to use it to target climate groups.
In 2022, Joe Biden signed the Inflation Reduction Act (IRA) into law. The legislation was maligned by Republicans who framed it as a sneaky way for Democrats to pass a coveted “Green New Deal.” Three years later, the law has pumped over $843 billion worth of subsidy-fueled clean energy investments into struggling communities (many in red districts and states) — which is why some Republicans are begging their party to leave the IRA alone. But the GOP serves a higher power, and his name is Trump.
According to a report from Heatmap, the House Ways and Means Committee is prepared to phase out the electric vehicle tax credit; get rid of technology-neutral production and investment tax credits that supported the development of renewable energy plants; eliminate tax credit sales by companies that were already reaching sustainability targets; and repeal tax credits for residential use of sustainable energy sources like solar power.
Trump has vowed to keep the United States the global capital of artificial intelligence development and sales. With any new technology come challenges stemming from the mundane to the truly bizarre, and as states attempt to legislate and regulate the emergence of AI, Republicans are handing a major gift to tech companies.
The House Energy & Commerce Committee has included a 10-year provision that would prevent any “state or subdivision” from enforcing “any law or regulation regulating artificial intelligence models, artificial intelligence systems, or automated decision systems during the 10-year period beginning on the date of the enactment of this Act.”
The proviso would preempt multiple state and local laws on the books already to regulate AI. Given how vague and expansive the provision is as currently written, it could conceivably bar any regulation of social media firms, which rely heavily on AI, or health insurance companies, which have been using AI to deny patients' claims. Broadly-speaking, the provision would provide a massive shield to Silicon Valley giants like Meta, Google, and OpenAI, which have been courting the AI-friendly Trump administration.
One of the ways the AI preemption provision could potentially impact consumers is keeping rent prices high. According to a report from The Lever, the 10-year block on state and local AI regulations would kill efforts by local governments to crack down on real estate brokers and rental companies using AI software to jack up rent prices across their large inventories of properties.
RealPage, a company that produces software for other real estate companies, has been sued several times in the last few years over accusations that their software can create algorithmic price-fixing monopolies by helping landlords coordinate rent hikes. Several cities have banned the use of RealPage and other algorithmic pricing software, and in response the company has heavily invested in its D.C. lobbying apparatus. The investment seems to be paying off.
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The Ways and Means' reconciliation text includes a provision that would eliminate a $200 excise tax on the transfer of firearm silencers. Rep. David Kustoff (R-Tenn.) said in a statement on X: “I proposed [the] policy that would eliminate the tax on suppressors. This would be more than $1.5 billion in tax savings for gun owners over the next 10 years.”
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Larisha Paul
When Aimee Lou Wood referred to Sarah Sherman‘s parody of her in a recent White Lotus-themed sketch on Saturday Night Live as “mean and unfunny,” it highlighted just how much the show missed the mark. Reflecting on the incident in a recent interview with Vanity Fair, Sherman acknowledged the contrast between her intention and the overall execution of the bit, which largely mocked Wood's appearance.
“I was excited to play her because she's so iconic, her character is so iconic,” Sherman said. “And I fucking obviously never meant to hurt anyone's feelings. Never in a million years did I get into comedy to make anyone upset. I feel terrible that anyone would feel bad.”
Last month, Wood shared that Sherman sent her flowers in apology and said she received an additional apology from Saturday Night Live. Wood also noted that while she understands the nature of the sketch comedy series as one that is rooted in popular culture, she saw the treatment of her character in particular as cheap comedy. “I don't mind caricature – I understand that's what SNL is. But the rest of the skit was punching up and I/Chelsea was the only one punched down on,” she said at the time. “Not Sarah Squirm's fault and not hating on her. Hating on the concept.”
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Sherman has been on Saturday Night Live for four seasons, but the responsibility attached to her work is ever-changing. “The show is in constant dialogue with culture as it's happening, and it happens really fast,” she said. “You have to be vigilant, you know what I mean? There are a lot of things out of your control. You're playing a lot of different parts, you're doing a lot of different roles that you're not in control.”
She added: “Being in conversation with everything popular culture, there's such a danger there. Sometimes you just don't realize how it comes across, but you're put in a position to be engaging with it all the time, because you are a part of a show that's constantly interacting with culture and popular politics and popular whatever. As I get thrown more and more into the show, it's just this other thing that I have to learn about.”
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Two of the biggest young actors in Hollywood are facing off for a gritty crime drama that is now being set up at A24. A24 has set “Enemies,” a new film that will star Austin Butler and Jeremy Allen White and will be produced by Ari Aster.
This is the second feature for Henry Dunham, the director of the 2018 thriller “The Standoff at Sparrow Creek.” He wrote and will direct the feature about a relentless detective and an infamous contract killer who collide in a deadly game of cat and mouse.
Aster and Lars Knudsen are producing for their Square Peg banner alongside A24. Alejandro De Leon will also produce. Josh Bachove will executive produce.
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“Enemies” will also return White to the home of “The Bear” and “Shameless,” as it's set to kick off production in Chicago later this summer.
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After the return of Season 4 of “The Bear” later this summer, White will next be seen in “Deliver Me From Nowhere,” the Bruce Springsteen biopic for 20th Century Studios. He was also set to star in a film from Jeremiah Zagar called “The Painted Bride” that just landed on the Cannes market. The film is a reunion between him and A24 after he starred in “The Iron Claw” for the distributor. Allen White is represented by WME, Entertainment 360 and Hansen, Jacobson, Teller, Hoberman, Newman, Warren, Richman, Rush, Kaller, Gellman, Meigs & Fox.
Butler, who last was seen in “Dune Part 2” and “The Bikeriders,” will appear in another A24 movie actually playing this week at Cannes, Ari Aster's “Eddington,” and he'll next be seen in Darren Aronofsky's neo-noir crime film “Caught Stealing.” Butler is represented by WME, Brillstein Entertainment Partners, The Lede Company and Sloane, Offer, Weber & Dern.
Dunham is the writer of “Bushido,” a film that will be directed by Hiro Murai. Dunham is represented by Anonymous Content and attorney Stephen Clark of Lichter, Grossman, Nichols, Feldman, Rogal, Shikora & Clark.
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By Anthony D'Alessandro
Editorial Director/Box Office Editor
A24 had made official that which has already been out there in the ether: 2x The Bear Emmy winner Jeremy Allen White and Oscar nominated Austin Butler are leading Henry Dunham's new crime saga Enemies.
Dunham is directing and writing. Cameras roll this summer in Chicago on the reported $25M production. In Enemies, a relentless detective and an infamous contract killer collide in a deadly game of cat and mouse.
Ari Aster and Lars Knudsen of Square Peg are producing alongside A24. Alejandro De Leon will also produce. Josh Bachove will executive produce.
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Dunham previously directed the 2018 crime thriller The Standoff at Sparrow Creek which follows a former cop-turned-militia man who investigates a shooting at a police funeral
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A24 and Aster have the filmmaker's latest movie, a western set during Covid, world premiering in competition at Cannes, Eddington. Pic stars Pedro Pascal and Joaquin Phoenix. It's the first time that Aster has hit the Croisette with a feature here.
A24 also has the Spike Lee directed movie, Highest 2 Lowest, which is a redo of Akira Kurosawa's 1963 crime thriller High and Low. Pic reteams Lee reunites for the fifth time with Denzel Washington. Set in NYC, pic follows a music mogul gets entangled in a ransom plot. The Apple Original Film co-production also stars A$AP Rocky and Ice Spice, Jeffrey Wright and Ilfenesh Hadera.
Dunham is represented by Anonymous Content and attorney Stephen Clark of Lichter, Grossman, Nichols, Feldman, Rogal, Shikora & Clark.
Butler is represented by WME, Brillstein Entertainment Partners and Sloane, Offer, Weber & Dern.
Allen White is represented by WME, Entertainment 360 and Hansen, Jacobson, Teller, Hoberman, Newman, Warren, Richman, Rush, Kaller, Gellman, Meigs & Fox.
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The singer/actress said she had to pay a visit to a Beverly Hills plastic surgeon to get stitches.
By
Gil Kaufman
Jennifer Lopez is known for giving her all. But it looks like she might have given too much during rehearsals for her upcoming gig hosting the 2025 American Music Awards. On Tuesday (May 13), the singer/actress posted a series of pictures on her Instagram Story chronicling a nasty workplace injury she suffered during walk-throughs for the show.
In the first one, a smiling Lopez, 55, is holding an ice pack to the right side of her face with the caption reading, “So this happened…” The next image reveals the extent of the damage, with Lopez sitting in her car with a small cut clearly visible on the bridge of her puffy nose and the explanation, “During @amas rehearsals.”
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The third slide featured a patched-up JLo standing next to Beverly Hills plastic surgeon Dr. Jason B. Diamond, with her nose looking no worse for the wear. “Thank you for stitching me up Dr. Diamond,” she wrote. “A week later and a whole lotta ice, I'm good as new.” At press time Lopez had not revealed how she she suffered the injury.
Lopez will host the 2025 AMAs from the Fountainbleau Las Vegas on Memorial Day (May 26). In her second go-round hosting the event — she first hosted in 2015 — Lopez will also perform on this year's show; she is just the fourth music artist to solo-host the AMAs twice, following Lionel Richie (1984-85), Diana Ross (1986-87) and Pitbull (2013-14).
Tickets are available now on Ticketmaster, with fan voting open via VoteAMAs.com and the @AMAs Instagram profile in all award categories. Voting closes on Thursday (May 15), at 11:59 p.m. PT, with the exception of collaboration of the year and social song of the year, which will remain open through the first 30 minutes of the AMAs broadcast.
The 51st AMAs will air live coast-to-coast at 8 p.m. ET/5 p.m. PT on CBS and stream on Paramount+ in the U.S.
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"Lose Control" was named the No. 1 song on Billboard's Year-End Hot 100 Songs chart for 2024.
By
Jessica Lynch
The Voice Season 27 is officially down to five finalists, but not before one of its most emotionally charged moments yet, a last-chance performance from Team Bublé's Adam David, who took on Teddy Swims' chart-topping hit “Lose Control” during Monday night's (May 13) Instant Save round.
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Originally released in June 2023, “Lose Control” marked Swims' breakthrough moment, becoming his first entry on the Billboard Hot 100. The single debuted at No. 99 and made a historic 32-week climb to No. 1 in March 2024, the longest consecutive rise to the top in the chart's history. It went on to spend a record-breaking 60 non-consecutive weeks in the Hot 100's top 10 and was named the No. 1 song on Billboard's Year-End Hot 100 Songs chart for 2024.
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Covering such a chart-dominating hit wasn't a small feat, but David delivered. His rendition showcased vulnerability and vocal control and secured him the final spot in next week's finale.
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The Voice Season 27 finale lineup is officially set, with the Top 5 finalists including RENZO (Team Legend), Lucia Flores-Wiseman (Team Adam), Jadyn Cree (Team Bublé), Jaelen Johnston (Team Kelsea), and Adam David (Team Bublé), who clinched the final spot via Instant Save.
The remaining contestants were eliminated following the live vote and Instant Save round: Conor James (Team Adam), Alanna Lynise (Team Kelsea), Kolby Kordell (Team Adam), Kaiya Hamilton (Team Bublé), Olivia Kuper Harris (Team Legend), Iris Herrera (Team Kelsea), and Bryson Battle (Team Legend).
It was an emotional night for all four coaches as they said goodbye to team members, including John Legend, who lost standout vocalist Bryson Battle in the Instant Save round.
“I find it difficult to even talk about this because I did not think you would be in this position today,” Legend told him. “You have given us performances that said you should be in the finale of this show. You gave us one yesterday, you gave us one just now on this stage, and you continue to be the epitome of what this show is all about.”
The Voice Season 27 live finale airs Monday, May 20 on NBC.
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JENNIE gets her Billboard birth chart read by Drew Afualo and she finds out what her sun, moon and rising are at Billboard Women in Music 2025.
Drew Afualo:
Team, here we are backstage at Billboard Women in Music, with the iconic, the legendary, the stunning, gorgeous, JENNIE period. How excited are you to be here at Billboard? Women in Music?
JENNIE:
So excited. This is my first time being here, yeah, and as soon as I heard I was honored with an award here, I obviously, you can see in my eyes. I'm all over the place. I'm just super happy. And today feels like a present.
Right? It is. It's a gift to have you here. Miss JENNIE is popular. Everyone's been like, oh my god, when's JENNIE coming? Me too, but I'm playing it cool. You can't tell I'm being real chill.
Professional.
Oh, thank you.
I need to know how to do this.
It's okay. You have all the singing and dancing talent. I have the yapping talent.
Totally.
So yeah, we compliment each other that way.
Love that.
Okay, so on to some fun questions, how much do you know about astrology? Are you familiar at all like your your sign?
I know I'm a Capricorn myself.
Okay, love that.
That's probably about it, but…
Okay, tea, so you don't know your moon or your rising?
No.
Okay, no worries. Capricorn, we can deal with that. We can, we can do that. Love that. But I do have your big three in Billboard Hot 100 terms. They're very fun. Would you like to hear them?
Yes.
Keep watching for more!
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The stripped-back performance saw Queens of the Stone Age surrounded by skulls and bones in the Catacombs of Paris.
By
Tyler Jenke
Queens of the Stone Age have announced the release of their unique live performance in the Catacombs of Paris as a concert film and album.
Recorded in July 2024 and set to be released on June 6 via Matador Records/Remote Control Records, the unique performance saw the rock outfit head beneath the surface of Paris to perform within the sprawling 200-mile ossuary. According to a description of the location, its foundation is built out of “several million bodies buried in the 1700s,” with many of the walls composed of skulls and bones.
Frontman Josh Homme had dreamed of organizing such a performance since visiting almost two decades earlier, though was denied permission by the city of Paris, who had never previously allowed a band to play within. However, the respect the band held for the location ultimately resulted in their performance officially being sanctioned.
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“The Catacombs of Paris are a fertile ground for the imagination,” said Hélène Furminieux of Les Catacombes de Paris. “It is important to us that artists take hold of this universe and offer a sensitive interpretation of it. Going underground and confronting reflections on death can be a deeply intense experience.
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“Josh seems to have felt in his body and soul the full potential of this place. The recordings resonate perfectly with the mystery, history, and a certain introspection, notably perceptible in the subtle use of the silence within the Catacombs.”
The unique nature of the location results in Homme and his bandmates – Troy Van Leeuwen, Michael Shuman, Dean Fertita and Jon Theodore – being backed by three-piece string section as they perform a stripped-back set planned and played with deference to the Catacombs.
Recorded live with no overdubs or edits, the performance is paired with the acoustic ambience of dripping water, echoes and natural resonance as atmospheric lighting spotlights the band.
“We're so stripped down because that place is so stripped down, which makes the music so stripped down, which makes the words so stripped down,” Homme explains. “It would be ridiculous to try to rock there. All those decisions were made by that space. That space dictates everything, it's in charge. You do what you're told when you're in there.”
Queens of the Stone Age: Alive in the Catacombs will be available to rent or purchase via the band's website, with an audio-only release to be announced in the coming weeks.
Notably, this isn't Queens of the Stone Age's first subterranean gig, with the group previously performing 2,300 feet underground at German salt mine, Erlebnisbergwerk Sondershausen, in November 2007. Originally planned for wider release, the semi-acoustic performance is yet to see the light of day, with the band's split with Interscope Records assumed by fans to be the reason for its indefinite delay.
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Tony Gilroy reveals why Serkis' prison breakout leader from season one didn't return during season two.
By
James Hibberd
Writer-at-Large
In the wake of the series finale of Disney+'s Andor, creator Tony Gilroy is explaining why a couple of characters did not show up in season two.
During an in-depth Hollywood Reporter interview about the final three episodes, Gilroy was asked about why Andy Serkis‘ fan favorite character Kino Loy — who helped lead the Narkina 5 Imperial prison rebellion — and why Cassian Andor's (Diego Luna) missing sister Kerri never showed up.
“Andy dropped the mic, man,” Gilroy explained. “What am I going to do that's going to be better than what we did? All it does is minimize that moment. I knew a lot of people were talking about whether we had a way of [bringing him back]. But I didn't want to have that sort of coincidental environment.”
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The moment that Gilroy is referring to is Loy saying to Cassian “I can't swim” right after busting out of the floating island prison before being swarmed by other escaping prisoners and going into the water, his fate ultimately unknown.
As for Cassian's sister, the show's first season opened with Cassian trying to find his sister on Morlana One, a quest that led to him killing two Imperial Security Bureau officers and setting in motion the events of the show. She's also seen during a series of flashbacks throughout the first season.
“[Kino Loy] is like the sister — people wanted to know if we're going to resolve the sister,” Gilroy continued. “And the sister, in the beginning, is so much more interesting to me as a deficit. She's much more valuable to me for Cassian as an absence. As he says in the end, ‘Maybe I should stop saving people.' His need to return and save people and to be a savior and the compulsion to do that comes from this hole in his life, and I didn't really didn't want to fill that in.”
In Gilroy's full interview, he also talks about Dedra's ironic destiny, Bix's surprise pregnancy, and another character whose fate was left uncertain — Mon Mothma's daughter. Read the whole interview.
Andor is now streaming all episodes on Disney+. Read THR's season coverage.
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The Amazon MGM Studios feature is directed by David O. Russell.
By
Abid Rahman
International Editor, Digital
Boom! Tough actin' is guaranteed in Amazon MGM Studios‘ Madden, the John Madden sports biopic starring Nicolas Cage and Christian Bale, which revealed a first look on Tuesday.
In Madden, Cage plays the NFL legend who served as head coach of the Oakland Raiders as well as had a long and successful stint as a commentator and later a pop culture icon through the Madden NFL video game series. Bale portrays Al Davis, the owner of the Raiders during Madden's time with the team.
The film tracks Madden's journey from humble beginnings to coaching the Raiders to the Super Bowl in 1976 and later finding further success on television, video games and becoming a reliable pitch man for a wealth of advertisers. The Hollywood Reporter previously reported that the film will serve as more of an origin story of Madden NFL, one of the biggest video game franchises of all time.
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Madden is written and directed by Oscar-nominated filmmaker David O. Russell (The Fighter, American Hustle and Silver Linings Playbook). Cambron Clark wrote an earlier version of the script.
As well as Cage and Bale, the cast includes John Mulaney (playing Electronic Arts founder Trip Hawkins), Kathryn Hahn (as Virginia Madden) and Sienna Miller (as Carol Davis).
Madden is produced in association with Skydance Sports. Todd Black, Jason Blumenthal, Steve Tisch, Jonathan Shukat, David O. Russell, Matthew Budman and Colin Wilson serve as producers with David Bloomfield, Michael Strahan and Constance Schwartz-Morini on board as executive producers.
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The singer/actress filed a police report against the 27-year-old streamer & rapper, saying "things got physical" starting in January.
By
Heran Mamo
Halle Bailey has been granted a restraining order against DDG, her ex-boyfriend and the father of her 1-year-old son, Billboard can confirm.
TMZ was first to report Tuesday (May 13) that the 25-year-old singer/actress had filed a police report against the 27-year-old streamer and rapper and requested court-ordered protection, claiming he had attacked her multiple times.
In court documents obtained by Billboard, Bailey alleged “things got physical” starting in January, when DDG (real name Darryl Dwayne Granberry Jr.) came over to pick up their then-13-month-old son Halo and she initiated a conversation about scheduling his visits.
Bailey claims that as she was buckling Halo into his car seat in the back of Granberry's car, he yelled, “Get out of my car, bi—.” At that point, she alleges, Halo started crying, making her nervous to leave the baby with him in his agitated state. When she stayed in the car, she alleges that Granberry pulled her hair, slammed her face on the steering wheel and chipped her tooth. After they arrived at Granberry's family's house, Bailey says she told his family what happened and left the baby with them.
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Bailey attached photos of her alleged injuries, including her chipped tooth, to the restraining order request.
In the docs, Bailey went on to detail two more alleged incidents of abuse: one in March, which she says she filed a police report over, and one this past weekend, when she says Granberry accused her of vacationing with Brent Faiyaz in a series of texts while she was on a Mother's Day trip with their son and her mother.
Granberry announced the couple had split in October 2024, ending their two-year relationship.
“This decision was not easy, but we believe it's the best path forward for both of us. I cherish the time we've spent together and the love we've shared,” he wrote on his Instagram Story at the time. The following month, Bailey shared in a since-deleted X post that she felt “extremely upset” when Granberry brought Halo with him during an “unapproved” appearance on Kai Cenat's live stream. She later backpedaled, writing, “maybe i did overreact…. i know that halo is always safe with his dad. i just don't like finding out with the rest of the world what my baby is doing.”
Shortly after those tweets, Granberry came to Bailey's defense in a YouTube video in which he implored negative commenters to leave her alone, citing her transparency over her struggles with postpartum depression. “When situations like this happen, I try to handle it with as much grace as possible because Halo needs her. I need her,” he said at the time. “We need each other to try to create a childhood that's safe, fun and memorable for him.” But in March, Granberry aired his grievances over their custody issues in a song titled “Don't Take My Son.”
In the restraining order request, Bailey also requested permission to take Halo with her while she travels to Italy to film a movie, where she will have family and a traveling nanny to help care for him. She also asked the judge for a cease-and-desist order to prevent Granberry from “posting and/or streaming on any and all platforms about Halo and/or me. He is a YouTube and Twitch Blogger and creates a fan frenzy by making false claims about me. This has caused me to feel afraid and victimized. His fans then threaten me. I am often scared for my life and Halo's safety.”
A hearing has been set for June 4 over whether a more permanent restraining order should be put in place.
Representatives for Bailey and Granberry did not immediately respond to Billboard‘s requests for comment.
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By
Cheyenne Roundtree
Follow all our Sean Combs trial coverage
Casandra “Cassie” Ventura spoke publicly for the first time about the alleged sexual, physical, and emotional abuse she endured during her decade-long relationship with Sean “Diddy” Combs, going into painstaking detail about the drug-fueled “freak-offs” that have become synonymous with the accusations against Combs.
The 38-year-old R&B singer, model, and actress took the stand on today in the first week of Combs' sex trafficking and racketeering conspiracy trial. The hip-hop mogul has pleaded not guilty to the five charges against him.
Today marked the first time the former celebrity couple have seen each other in person since their 2018 breakup. Supported in court by her husband, Alex Fine, her brother, and other loved ones, a composed Ventura testified for the majority of the day about the alleged ritualistic and “choreographed” sexual encounters that she “hated” but felt had no choice but to comply.
Ventura told jurors that after her first freak-off at age 22 — a time that she described herself as “naive” and “enamored” with her label boss Combs — the dayslong, “humiliating” sexual encounters with Combs and male escorts occurred almost weekly. Ventura testified the male escorts were paid thousands of dollars in cash, and their payment was contingent on the completion of their performance during the sexual encounter.
She alleged that Combs controlled nearly every aspect of her daily life and that she was fearful of making him angry, which could result in physical violence. When it came to testifying about participating in freak-offs, Ventura — who is more than eight months pregnant with her third child — briefly became overwhelmed with emotion and cried when trying to explain why she continued to engage in freak-offs and the overall toll they took on her.
Ventura is expected to testify Wednesday about her decade-long “abusive” relationship with Combs. Prosecutors indicated they would be asking further questions about the InterContinental Hotel attack from March 2016 that was caught on surveillance video, as well as introducing photo evidence related to videotaped freak-offs. Following direct examination, Combs' all-star defense team plans to question Ventura well into Thursday.
Here are seven of the biggest takeaways from Ventura's testimony.
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Ventura walked jurors through every step of the highly ritualistic “freak-offs” that she claimed Combs orchestrated and controlled. Although the locations varied, Ventura testified, the setup was usually similar: The hotel suites and personal bedrooms were stocked with bottles of baby oil, lubricant, and strong-smelling mood candles. In later years, Ventura said the lighting was switched to LED-colored lights used in recording studios.
The sexual encounters with male escorts followed a pattern, Ventura said, with the pair rubbing baby oil on each other until they were “glistening.” Touching and massaging came next, according to Ventura, followed by oral sex and then intercourse. “It was his fantasy,” Ventura said. “He was controlling the whole situation. He was directing it. He was doing the lighting. He was telling us where to be, what to say, how to act in the room.”
Sometimes, Ventura said, she'd try to “speed up” the events because she just wanted to be alone with Combs. “I, more often than not, would just want to be able to get to the other room where we could just spend time with each other alone,” she said.
Ventura said she signed to Combs' record label as a “naive” 19-year-old, and by the time they entered into a relationship, she was “enamored” with him. Ventura claimed that Combs asserted dominance both over her career and personal life.
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Combs allegedly directed Ventura on her hairstyle and the color she should paint her nails, even suggesting certain body piercings. “Sean controlled a lot of my life, whether it was career, the way I dressed, like, everything,” Ventura testified. “I just didn't feel like I had much say in it at that time being a really super young, naive, total people-pleaser.”
Regarding her living situation, Combs paid for nearly all of Ventura's apartments in New York City and Los Angeles — all convenient distances from his residence.
Despite signing a 10-album deal with Combs' label Bad Boy, Ventura only released one studio album. Ventura said she was constantly recording new music, but it wasn't getting released. Lots of the songs she recorded “just didn't see the light of day,” she testified.
Venture said that Combs wanted to know where she was at all times, and if he couldn't get a hold of her by phone immediately, Combs would incessantly call until she responded. Other times, Combs allegedly sent his team of security guards to physically track down Ventura. She claimed he'd often take away her car and phone, and kick her out of her apartment as a form of punishment.
Ventura claimed Combs began physically abusing her by the time she was 22 years old. “He would mash me in my head, knock me over, drag me, kick me, um, stomp me if I was down,” she testified.
She said the abuse happened “too frequently,” resulting in “knots in my forehead, busted lips, swollen lips, black eyes, the whites of my eyes would be red, um, bruises all over my body.”
Ventura said that the physical beatings could stem from a shift in Combs' mood. “I make the wrong face, and the next thing I knew, I was getting hit in the face,” she testified. Ventura said she was seriously concerned about potentially setting Combs off and would go to great lengths to avoid making him angry.
During her multiple hours of testimony, Ventura broke down when she tried to explain her rationale for continuing to participate in freak-offs with Combs. “I just didn't want anything bad to happen,” Ventura said, clarifying that “anything bad” could be Combs “being violent” with her as well as him finding another woman willing to do freak-offs with him. “When you really care about somebody, and you're in love with them, you don't want to disappoint them,” she added.
But continuing to participate in the freak-offs, Ventura testified, took a detrimental toll on her mental health. “I just felt, like, it was all I was good for to him,” she said shakily. “I just felt pretty horrible about myself. I felt disgusting. I was humiliated. I didn't have those words to put together at the time, like, how horrible I really felt.”
Ventura alleged that the male escorts were typically paid a few thousand dollars at the end of freak-offs. She said that some men had trouble maintaining an erection. “It was actually pretty frequent with people that we didn't know well,” Ventura said. “They would express … every time Sean would talk, it would throw them off, or if he moved a candle, just was distracting.”
Those who were unable to perform in the way Combs expected, Ventura claimed, “definitely didn't get paid the normal amount” for the encounters.
Ventura claimed Combs directed her to hire the male escorts for freak-offs and give them a spiel about the situation when they arrived at the hotel suite or one of their homes.
She said she was responsible for ensuring the person was “safe.” Ventura clarified that it meant that Combs “wanted me to clarify if the person was a cop,” she said. “At first, I didn't understand, and I learned later why.”
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Ventura testified that Combs made her and the male escorts perform sexual acts that she found “humiliating,” including having freak-offs while she was menstruating and men urinating on her.
“It was disgusting,” Ventura said. “It was too much. It was overwhelming. I choked. There couldn't have been anything on my face that was reading that I wanted to be doing that. I just laid on the floor in a position that I couldn't easily get out of.”
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Is the Beast of Bray Road calling Illinois home now? This Northern Illinois resident's bizarre encounter is raising questions, and eyebrows.
I have a weird fascination with bizarre cryptid stories, but I would 100 percent lose it if I ever saw one in real life.
For those that don't know, a cryptid is an animal or being that people claim exists, but science has never proven is real.
READ MORE: Illinois Mothman Sightings Featured on 'Unsolved Mysteries'
Here's a video featuring some of Illinois's most famous cyptids...
While Illinois may claim creepy cryptids like the Chicago Mothman and Big Muddy Monster, one of Wisconsin's most famous cryptids, (besides The Hodag), is the Beast of Bray Road...but is the Beast venturing into Illinois now?
The Phantoms and Monsters: Pulse of the Paranormal website recently posted a comment they received about a run-in someone had with an "upright human-like canine monster towering 3-4 feet taller than my 54-inch (give or take 2-3 inches) tall horse fence" in northern Illinois. (YIKES!!)
Here's the description of what they saw:
I saw the animalistic glowing eyes when I flashed my headlamp in its direction, and a "human-like" figure, as It followed me to the north separated by an electric fence, my firearm drawn, aimed, and unlocked. I didn't have a need to hurt it, so I just gave it space and privacy, as I retreated undoubtedly, fearful, intimidated, confused, and full of wonder, as I still questioned WTF on Earth it was that I was looking at.
Was this the Beast of Bray Road roaming south of the Wisconsin border, or was it something else? We may never know the truth.
Gallery Credit: Nicole Caldwell & Matt Albasi
The Newsmagazine of Long Beach Island and Southern Ocean County
SPIRITUAL GROUNDS:The vendors set up inside the chapel of the former Episcopal Church, now museum. (Photos by Jack Reynolds)
In the opening act of its 50th year of operation, the Long Beach Island Historical Association hosted its fourth Psychic and Wellness Fair at the LBI Museum in Beach Haven on Saturday, May 10.
Tarot is a popular tool for personal readings.
In the chapel of the former Holy Innocents' Episcopal Church, visitors waited their turns to be sequestered for palm, tarot, reiki or numerology readings and browsed the wares of the fair's vendors, who'd pitched their jewel- and crystal-laden tables along the pews. The stir of the fair spilled across Engleside and Centre Street, with private reading sessions occurring in the museum, Show Place Ice Cream Parlour and the Fisherman's Cottage. The Wellness section, which was incorporated for the first time at the 2024 fair, took place four blocks south at the Holy Innocents'.
“About four or five years ago, one of the members of the museum and I were talking about something different as a fundraiser,” said Ellen Kehr, chair of the Psychic and Wellness Fair and a trustee of the LBIHA. “We thought that the museum, and the ambience, lends itself to being spiritual, so we thought, ‘Let's do something like that.'”
Erin Stamm finds stillness and feels the transfer of energy.
Kehr said the fair has been a consistent success for the museum.
“I think people are intrigued by the unknown,” she said. “The more you talk about it, it encourages others to be more interested in it. They want to know more about it.”
Among the vendors was Emily Perchalluk, proprietor of StayFresh Creations, who hawked her framed and flower-pressed tarot cards, stones and digital art pieces. Louisa and Astrid Befumo offered digital chakra readings using AuraVid, a program that displays and colorizes electromagnetic energy. The colors denote chakras, aspects of life or personality traits. Blue, for instance, generally represents honesty and creative expression.
Kasandra Chasmar, who runs Waretown's Charmed In Company with her daughter, Victoria, read for visitors in the warmly lit Victorian Parlor. A mainlander, Chasmar has been a reader for over 60 years and was first taught to read playing cards by her mother. She sensed profound energy in the parlor's artifacts and aged furniture through psychometry, or feeling energy through touch.
“I think the veil has become very thin, and people are experiencing more,” Chasmar said. “You can feel it in different places down here, stronger than in other places, definitely the Island. Tuckerton is another place you can feel the energy is very strong. The water definitely has a lot to do with it. I think you feel it a lot stronger. Maybe it's the movement of the water, the air.”
Brittany Histing performs healing touch as Surfing Waves of Light.
Belief in the supernatural and communication with spirits through mediums often serves as a source of comfort and hope. Kehr partook in a session with Toms River-based medium Leslie Lagani, who helped develop the first fair.
“It's comforting if you have a parent or someone who has passed, who comes back – through her – and says, ‘I'm fine,'” Kehr said. “It's such a comfort. It's not just the end when you pass away.”
Betty Lou Cote, an attendee, echoed Kehr's sentiment. A firm believer in the paranormal, the Pennsylvania native and current Manahawkin resident believes the spirits of loved ones offer a guiding hand to their living relatives.
“I'm a believer because I've had experiences – several of them,” she said. “I had a death that was very close to me, and I was reading all of these grief books. And they're all mediums. telling you that they're still with you. So, I like that, it gives me immense comfort.”
South Jersey seems to hold a patent inclination toward supernatural and spiritual subjects. Stories of hauntings are plentiful on LBI, and over half a dozen psychics have stores across Southern Ocean County. Pinpointing a sole cause for the area's marked receptiveness to the supernatural is difficult, though it likely derives from regional folklore and culture. Stories of the Jersey Devil first took root in Leeds Point in the Pine Barrens, while LBI and the towns along local shores are suffused with the famously superstitious and tall-tale traditions of fishermen and sailors who composed so much of their early populations.
“Leeds Point is where Stockton is, close by. So, the legend of the Jersey Devil, it kind of hits close to home, and it gets people interested in it,” said Erin Stamm, who recently began interning for the LBIHA.
Ron Marr, former president of the LBIHA, offered another interpretation.
“If you look at the statistics of the whole Island, we're all older,” Marr said. “Preceding generations tend to be more religious than the current generations. We all grew up going to church or synagogue. We're older, so we're closer to the wall. When you've lost somebody or you're close to your own end of life, it makes you think about things differently.”
Nonetheless, Marr recognizes the human need for an empathic presence in times of grief or strife and how helpful such a voice can be.
“Sometimes having somebody to understand your problems and commiserate with you is all you need,” he said.
— Trevor Regan
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FASCINATION WITH THE SUPERNATURAL
Lee points to the fact that public fascination with supernatural phenomena has surged in recent years, largely due to media. “Interest in the supernatural is incredibly high in our culture. And it's not just in films, in articles, or at conferences. In fact, you don't have to persuade most Americans that supernatural phenomena are authentic. They're already convinced.” He cites findings from 2023 Pew Research Center and Gallup studies:
• Eight in ten Americans believe in something spiritual beyond the physical world.
• Nearly 50% report having sensed something from the spiritual realm.
• 69% believe in God, angels, and heaven, while 58% believe in hell and the devil.
• 38% claim to have experienced at least one supernatural event.
Lee states his motivation for writing the book: “As an evangelist, seeing that non-believers are fascinated in the supernatural, too, I want to provide a bridge to the gospel.”
DEATH-BED VISIONS
One aspect of the supernatural world that Lee found most intriguing is death-bed visions. These encounters differ from near-death experiences (NDE) in that the person sees something in the heavenly realm before irreversibly dying. In an NDE, a person is found clinically dead for a time, but comes back to life, reporting what he saw in an out-of-body experience. For this topic, Lee interviewed Dr. Steve Miller of Kennesaw State University, who wrote his doctoral dissertation on death-bed visions, based on eight hundred relevant sources. One of Miller's studies showed that 88% of patients in a New York hospice facility had such visions. “They were so realistic that patients reported them as the most awake, alert, and present they had ever felt,” Miller says.
An example of one such death-bed vision is quoted by Miller about a woman named Doris in 1920's London. Dying after giving birth, Doris looked toward one corner of her room with a radiant smile and talked about the lovely brightness and wonderful beings she saw, as well as God Himself. Then she said, “He has Vida with him!” Lee asked Miller who Vida was. “That was her sister,” he replied. “She had died three weeks earlier, a fact that everyone had kept from Doris because they didn't want to upset her.”
ANGELS
“I've been a Christian since 1981,” Lee says, “and I've never heard a sermon on angels, though the Bible clearly teaches their existence.” While studying what Scripture teaches about angels, he acknowledges that there are many false notions which have arisen from a variety of sources. “For instance, the idea that people become angels when they die seems to persist, despite having no biblical support. (I blame Looney Tunes.)” Lee points out that angels are mentioned in half the books of the Bible, roughly 300 times, but are not the focus. “The primary focus of Scripture is on God and our relationship with him. This means that a lot of details about angels aren't spelled out with specificity. They aren't supposed to be. Why? Because they are a sidelight to the central plot of the Bible and unnecessary information for us to have at this point.”
Talking with Professor Douglas Potter of Southern Evangelical Seminary, Lee asked Potter to describe what Scripture clearly tells us about these celestial beings. Potter was able to cite a long list. “First of all, angels are not eternal like God is. There's a finite number of them, but that number is incredibly large. Because they are immaterial in nature, they have no gender and don't engage in marriage or reproduction. And they are persons because they have the characteristics of personhood – intellect, will, and emotions.” They are not omniscient. “Only God is omniscient. Angels are greater in both knowledge and power than humans. Angels rank lower than God, but higher than humans.” Potter went on to affirm the idea of guardian angels, based on Matthew 18:10, where Jesus says, “For I tell you that their angels in heaven always see the face of my Father in heaven,” and in Acts 12:15, where Peter, having escaped prison, shows up at the gathering of disciples, who don't believe it's him, saying, “It must be his angel.”
MYSTICAL DREAMS AND VISIONS
Lee shines a light on the countless Muslims who have experienced supernatural visions or dreams – many of them corroborated by outside events – which led them out of Islam to a saving faith in Christ. “In fact, more Muslims have become Christians in the last couple of decades than the previous fourteen hundred years since Muhammed, and it's estimated that a quarter to a third of them experienced a dream or vision of Jesus before their salvation experience. If those statistics are accurate, this phenomenon of Jesus supernaturally appearing to people is one of the most significant spiritual awakenings in the world today.”
Lee interviewed Middle East missionary and expert, Tom Doyle, who told him much more about Jesus dreams to Muslims, along with a number of examples. One story revolves around Kamal, an underground church planter in Egypt. Strongly impressed to go the busy, Friday market in Cairo one day, Kamal didn't have time, but heeded what he believed was God's leading. Once there, a Muslim woman named Noor spotted him across the market and began yelling, “You're the one! You're the one!” She pushed her way through the crowd to Kamal, and exclaimed, “You were in my dream last night!” She knew because he was wearing the same clothes, glasses, and smile. Knowing what the woman meant, Kamal asked her if he was with Jesus in the dream. Noor said He was, and explained how Jesus told her He loves her, gave everything for her, and died for her. She said she felt greater peace than she'd ever known. The encounter led to a three-hour discussion about faith, and Noor left wanting to know more about Jesus and counting the cost of leaving Islam.
USING DISCERNMENT
Realizing there are many misunderstandings, a thirst for sensationalism, and just plain error regarding the supernatural realm, Lee consulted with expert Ron Rhodes, who debunks much of what is believed to be spiritual, but is in fact, demonic. This includes ghosts, psychics, and the paranormal, which Lee describes as a twisted version of the supernatural. Rhodes offers a number of ways to exercise discernment in the supernatural arena:
• Immerse ourselves daily in the Scripture to know truth versus error.
• Pray for discernment, asking God to keep you from false and misleading ideas.
• Seek counsel when needed.
• Always consider the source of the report for reliability, beliefs, biases, and motives.
Lee adds, “The Bible warns about the dangers of pursuing answers about life from sources that aren't grounded in God's truth.” He reminds us to assess spiritual experiences though a biblical lens to ensure they align with God's nature and Christian doctrines.
For more information on Lee Strobel click the LINK!
CREDITS
NY Times Bestsellling author, Seeing the Supernatural (Zondervan, 2025) / Former teaching pastor at Willow Creek Community Church, Saddleback Church, and The Woodlands Church / Former TV host, Faith Under Fire / taught First Amendment Law at Roosevelt University in Chicago / Professor of Christian Thought at Houston Baptist University / former investigative journalist, The Chicago Tribune / married to Leslie more than 50 years, two grown children, four beloved grandchildren
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Julie produced and assigned a variety of features for The 700 Club since 1996, meeting a host of interesting people across America. Now she produces guest materials, reading a whole lot of inspiring books. A native of Joliet, IL, Julie is grateful for her church, friends, nieces, nephews, dogs, and enjoys tennis, ballroom dancing, and travel.More
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The Independent
May 14, 2025
Business
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KAMPALA, UGANDA | THE INDEPENDENT | UAP Old Mutual Insurance has officially launched its new online motor and travel insurance portals, marking a significant step forward in its digital transformation strategy, it said on May 14.
These platforms are designed to streamline the insurance purchase process and offer customers a seamless, self-service experience accessible from anywhere, at any time.
The portals empower customers to easily onboard, explore product benefits, get quotes, and manage their policies online. With an intuitive interface and chatbot support for real-time assistance, the platforms represent UAP Old Mutual's commitment to delivering efficient, customer-centric digital solutions.
Antony Mutyabule, the business transformation manager at UAP Old Mutual, emphasized the strategic importance of this milestone: “These portals are designed with the customer at the centre. As Uganda's internet user base surpasses 13 million, we are meeting customers where they are-online,” he said, “This is a critical move to boost convenience, and operational efficiency.”
“We aim to digitize the entire customer journey, from onboarding to claims. We are committed to continuous improvement and innovation with purpose,” he added.
“Our goal is to transform how insurance is accessed and experienced in Uganda,” said James Maguru, General Manager at UAP Old Mutual. “With the launch of these portals, we are making insurance more accessible, convenient, and aligned with customer expectations. Whether it is digitizing access, easing the payment process, or supporting customers on the road, we are here to serve better,” he said.
Together with the portals, UAP Old Mutual also launched the Mpola Mpola campaign, a flexible payment model allowing customers to pay their annual motor insurance premiums in manageable monthly instalments.
This customer-first approach ensures that quality insurance remains affordable and within reach for all, reinforcing UAP Old Mutual's role as a trusted financial partner.
Additionally, motor policyholders will benefit from roadside assistance services such as tyre changes, jump-starts, fuel refills, and towing. This additional service is presented to ensure that customers are not stranded when a motor issue arises.
Representing the Insurance Regulatory Authority of Uganda, Katete Kevin, the licensing and compliance manager, commended the initiative, stating, “The launch of these portals is a significant step towards enhancing insurance penetration and promoting financial inclusion. As a regulator, we actively support innovations that make insurance more accessible, customer- centric, and responsive to the needs of today's digital-savvy consumers. At the Authority, we prioritize innovation that is accurate, convenient, and designed with the customer in mind, ensuring these elements are embedded in every solution we endorse.”
The launch underscores UAP Old Mutual's broader goal to lead digital innovation in the insurance industry, creating smarter, more inclusive solutions for today's evolving market.
UAP Old Mutual Insurance, as an integrated financial services provider, is committed to empowering individuals and businesses with comprehensive solutions that foster a culture of financial security, executives said.
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May 14, 2025
May 14, 2025
May 14, 2025
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Is the Turing test still relevant in today's AI landscape? The advent of large language models has challenged its importance.
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"Can machines think?" That's the core question legendary mathematician and computer scientist Alan Turing posed in October, 1950. Turing wanted to assess whether machines could imitate or exhibit human-level intelligent behavior, and so he came up with a test called the "imitation game." This later became known as the Turing test, which is commonly used to assess how well a machine can mimic human behavior.
The genesis of Turing's test came from the inherent difficulty in establishing objective criteria that distinguishes original thought from the imitation of it. The challenge is that evidence of original thought could be denied with the argument that a machine was simply programmed to seem intelligent. Essentially, the crux of proving if machines can think is defining what thinking is.
Related: 8 of the weirdest robots in the world right now
Turing wanted to challenge the idea that the mechanical nature of computers means they cannot, in principle, think. The mathematician was positing that, if a computer appears indistinguishable from a human, then why should it not be considered a thinking entity?
Turing proposed a three-party game. He first outlined a test in which a man and woman go into separate rooms and party guests use typewritten answers to try and determine which person is which, while the man and woman try to convince them that they are the opposite sex.
From there, Turing proposed a test whereby a remote interrogator is tasked with asking questions to a computer and human subject, both unseen, for five minutes in order to determine which is sentient. A computer's success at "thinking" could then be measured by how likely it is to be misidentified as a human.
A later iteration of the imitation game, proposed by Turing in 1952 in a BBC broadcast, would see a computer try and convince a jury of people that it was human.
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The Turing test was created as more of a philosophical thought experiment than a practical means of defining machine intelligence. However, it grew to be seen as an ultimate target for machine learning and artificial intelligence (AI) systems to pass in order to demonstrate artificial general intelligence.
Turing predicted that by the early 2000s, a programmed computer would be able to “play the imitation game so well that an average interrogator will not have more than 70 per cent chance of making the right identification after five minutes of questioning.”
But, that did not come to pass. However, the rise of ChatGPT and other artificial intelligence systems and large language models (LLM) has reignited the conversation around the Turing test.
In June 2024, researchers claimed that the LLM GPT-4 was judged to be human 54% of the time in the Turing test within five minutes of questioning. That resoundingly beats Turing's prediction of 30%, despite being two decades on from the mathematician's predicted date. But this research from the University of San Diego only involved two players in the test rather than Turing's original three-player game, so GPT-4 didn't pass the Turing test in the specific conditions he defined.
Nevertheless, this research still shows how such AIs can at least imitate humans with some success.
While passing the Turing test might be the big goal to prove thinking in AI systems, the test has its limitations and opponents.
Turing himself detailed and addressed nine objections to his test and theory in proving machines could think; these range from the theological concept of thought and the idea that machines can't feel emotions, or have a sense of humor, to logical mathematical limitation that will simply prevent a machine from answering a question or getting it correct.
But perhaps the most relevant objection comes from mathematician Ada Lovelace, who when commenting on computing pioneer Charles Babbage's Analytical Engine, suggested that a machine cannot "originate anything" and can only do whatever we order it to perform. Turing's retort in his paper was to ask whether humans can indeed ever do anything really new in a deterministic world bound by the laws of nature and the boundaries of the universe. Turing also noted that computers may be constrained but could still potentially do unexpected things — in the same way that humans can despite being constrained by our genetic makeup and biology.
Beyond this is the fact that the Turing test does not, per se, indicate consciousness or intelligence; rather it works to critique what is understood as thought and what could constitute thinking machines. The test is also reliant on the judgement of the interrogator, a comparison to humans and the judgment of behaviors only.
Then there's the argument that the Turing test is designed around how a subject acts, meaning a machine can merely simulate human consciousness or thought rather than actively having its own equivalent. This can lead to the Turing trap — in which AI systems are excessively focused on imitating humans rather than being designed to have functions that allow humans to do more or boost their cognition beyond the possibilities of the human mind.
While the Turing test might be held as a benchmark for AI systems to surpass, Eleanor Watson, an expert in AI ethics and member of the Institute of Electrical and Electronics Engineers (IEEE),told Live Science that "The Turing Test is becoming increasingly obsolete as a meaningful benchmark for artificial intelligence (AI) capability."
Watson explained that LLMs are evolving from simply mimicking humans to being agentic systems that are able to autonomously pursue goals via programming "scaffolding" — similar to how human brains build new functions as information flows through layers of neurons.
"These systems can engage in complex reasoning, generate content creation and assist in scientific discovery. However, the real challenge isn't whether AI can fool humans in conversation, but whether it can develop genuine common sense, reasoning and goal alignment that matches human values and intentions," Watson said. "Without this deeper alignment, passing the Turing Test becomes merely a sophisticated form of mimicry rather than true intelligence."
Essentially, the Turing test may be assessing the wrong things for modern AI systems.
—Meet 'Chameleon' — an AI model that can protect you from facial recognition thanks to a sophisticated digital mask
—Large language models not fit for real-world use, scientists warn — even slight changes cause their world models to collapse
—'Put glue on your pizza' embodies everything wrong with AI search — is SearchGPT ready to change that?
As such, scientists "need to develop new frameworks for evaluating AI that goes beyond simple human imitation in order to assess capabilities, limitations, potential risks, and most importantly, alignment with human values and goals," Watson said.
Unlike the Turing test, these frameworks will need to account for the strengths of AI systems and their fundamental differences from human intelligence, with the goal of ensuring AIs "enhance, rather than diminish, human agency and wellbeing," Watson added.
"The true measure of AI will not be how well it can act human,” Watson concludes, “but how well it can complement and augment humanity, lifting us to greater heights."
Roland Moore-Colyer is a freelance writer for Live Science and managing editor at consumer tech publication TechRadar, running the Mobile Computing vertical. At TechRadar, one of the U.K. and U.S.' largest consumer technology websites, he focuses on smartphones and tablets. But beyond that, he taps into more than a decade of writing experience to bring people stories that cover electric vehicles (EVs), the evolution and practical use of artificial intelligence (AI), mixed reality products and use cases, and the evolution of computing both on a macro level and from a consumer angle.
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UAP Old Mutual Insurance has launched online motor and travel insurance portals, marking a significant step forward in the company's digital transformation strategy.
These platforms are designed to streamline the insurance purchase process and offer customers a seamless, self-service experience accessible from anywhere, at any time.
The two portals empower customers to easily onboard, explore product benefits, get quotes, and manage their policies online.
With an intuitive interface and chatbot support for real-time assistance, the platforms represent UAP Old Mutual's commitment to delivering efficient, customer-centric digital solutions.
Antony Mutyabule, the Business Transformation Manager at UAP Old Mutual, emphasised the strategic importance of this milestone.
He explained that these portals are designed with the customer at the centre and as Uganda's internet user base surpasses 13 million, UAP Old Mutual is meeting customers where they are-online.
“This is a critical move to boost convenience, and operational efficiency. We aim to digitise the entire customer journey, from onboarding to claims. We are committed to continuous improvement and innovation with purpose,” he said.
According to James Maguru, the General Manager at UAP Old Mutual, the company's goal is to transform how insurance is accessed and experienced in Uganda.
He shared that with the launch of these portals, they are making insurance more accessible, convenient, and aligned with customer expectations.
“Whether it is digitising access, easing the payment process, or supporting customers on the road, we are here to serve better,” he emphasized.
Together with the portals, UAP Old Mutual also launched the Mpola Mpola campaign, a flexible payment model allowing customers to pay their annual motor insurance premiums in manageable monthly instalments.
This ‘customer-first' approach ensures that quality insurance remains affordable and within reach for all, reinforcing UAP Old Mutual's role as a trusted financial partner.
Additionally, motor policyholders will benefit from roadside assistance services such as tyre changes, jump-starts, fuel refills, and towing. This additional service is presented to ensure that customers are not stranded when a motor issue arises.
Katete Kevin, the Licensing and Compliance Manager at the Insurance Regulatory Authority of Uganda commended the initiative, saying the launch of these portals is a significant step towards enhancing insurance penetration and promoting financial inclusion.
“As a regulator, we actively support innovations that make insurance more accessible, customer-centric, and responsive to the needs of today's digital-savvy consumers. At the Authority, we prioritize innovation that is accurate, convenient, and designed with the customer in mind, ensuring these elements are embedded in every solution we endorse.”
The launch underscores UAP Old Mutual's broader goal to lead digital innovation in the insurance industry, creating smarter, more inclusive solutions for today's evolving market.
UAP Old Mutual Insurance, as an integrated financial services provider, is committed to empowering individuals and businesses with comprehensive solutions that foster a culture of financial security.
The PML Daily, published via www.pmldaily.com is a publication of Post Media Ltd, a professional Digital/New Media company in Uganda.
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