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Mixed 46-54
Positive > 56
The New York Times and The Washington Post reportedly sought to “avoid endangering US troops.”
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Major American news outlets were informed of the Trump administration's plan to bombard Venezuela and abduct its president ahead of the operation early Saturday morning, but withheld their reporting on the operation to protect the military, Semafor reports.
Both The New York Times and The Washington Post knew about the raid before President Donald Trump approved it on Friday night at 10:46 pm, Semafor reported over the weekend.
However, according to two people familiar with the administration's communications with the outlets, they “held off publishing what they knew to avoid endangering U.S. troops.”
The report raises major questions about the media's role in the operation, which has been widely condemned as an illegal and authoritarian action by legal experts and foreign leaders; Semafor describes the withholding of coverage as potential “cooperation” with the military by news outlets.
Major news outlets in the U.S. have a history of coordinating with the Pentagon in order to protect military operations.
As Semafor notes, The New York Times reportedly withheld a story about the disastrous Bay of Pigs operation in 1961 before the Cuban invasion at the behest of the Kennedy administration.
There are numerous other such examples. In the mid-2000s, the Times withheld a major report on the National Security Agency's campaign of warrantless spying on American citizens, Stellar Wind, for a year at the Bush administration's request.
Most recently, The Atlantic withheld a potential report on a planned U.S. attack on Yemen that was the central focus of Signalgate. That attack, which the magazine's editor-in-chief Jeffrey Goldberg was notified about two hours in advance, killed 15 people, including six children, one of them a newborn baby.
Goldberg noted that he wasn't clear about the authenticity of the Signal chat. However, even in his article exposing the existence of the chat, he still withheld some of the most sensitive information that government officials discussed.
In reality, major outlets often protect government operations because those in charge at the outlets support them, a phenomenon those on the left have noted is observable in the practice of manufactured consent.
After the Trump administration's attack on Saturday, The Washington Post editorial board — which owner Jeff Bezos has revamped to be more conservative — published an editorial celebrating the abduction, calling the operation that killed at least 80 people, including civilians, an “unquestionable tactical success.”
Meanwhile, U.K. writer Owen Jones reported on Monday that BBC has directed its reporters to avoid using the word “kidnapped” when referring to the U.S.'s abduction of Maduro. Instead, according to the reported directive posted online by Jones, journalists are to use “seized” or “captured,” with attribution to the U.S. for the latter term — despite even Trump saying that kidnapping is “not a bad term” to use to describe the action.
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Sharon Zhang is a news writer at Truthout covering politics, climate and labor. Before coming to Truthout, Sharon had written stories for Pacific Standard, The New Republic, and more. She has a master's degree in environmental studies. She can be found on Twitter and Bluesky.
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The Centers for Medicare and Medicaid Services head pushed dubious MAHA strategies for dealing with the flu instead.
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Amid a significant spike in influenza cases across the United States, Mehmet Oz, the current administrator for the Centers for Medicare and Medicaid Services (CMS), is downplaying the importance of flu vaccinations, suggesting to the public, wrongly, that this year's shot is ineffective.
Oz made the comments in an appearance on Newsmax last week.
“Every year, there is a flu vaccine, it doesn't always work very well,” Oz claimed. “That's why it's been controversial of late. But like many illnesses, the best news out there is that you can take care of yourself so that when you do end up running into the flu, you can overwhelm it.”
Oz then pushed questionable “Make America Healthy Again” strategies for dealing with the flu, advising the public to get “sunlight,” include Vitamin D in their diets, or take zinc supplements to possibly shorten the duration of the flu. He also called on Americans to “eat the right food” and engage in physical activity.
While eating healthy and exercising are good advice in general, Oz's downplaying of vaccines has concerned many health experts. Notably, his recommendation of zinc — which has been shown in some studies to help boost the immune system — came without dosage recommendations, which could potentially lead to overdoses by viewers unaware of the proper dosage. Consuming too much zinc can lead to serious complications, including the same flu-like symptoms people may be trying to treat.
Oz has a history of providing faulty or dubious medical advice. His recommendation to take supplements echoes President Donald Trump's promotion of untested strategies during the coronavirus pandemic, such as ivermectin and hydroxychloroquine, two “remedies” that turned out to have no effect on treating the virus and led to overdoses, including thousands of deaths, throughout the world. Oz's comments are also similar to those made by Health and Human Services Secretary Robert F. Kennedy Jr. earlier this year, in which he touted Vitamin A and cod liver oil as possible treatments for measles, leading to overdoses from those remedies in children throughout the country.
Several medical experts, including Trump's first surgeon general Jerome Adams, spoke out against Oz's claims, reiterating that it's still important for Americans to get a flu vaccine this year, even with the new strain.
“Even in mismatched years, flu vaccines provide cross-protection because the strains are related,” Adams said on social media, adding that “mismatched vaccines can still reduce lab-confirmed flu risk by around 50-60 percent overall and are particularly good at preventing severe outcomes like hospitalization and death.”
A fact-check from Indian news site The Week notes that research from the Centers for Disease Control and Prevention (CDC), as well as multiple studies elsewhere, shows that “seasonal flu vaccines consistently reduce the risk of severe illness, hospitalization, intensive care admission, organ failure, and death, even in seasons when the vaccine is not a perfect match for circulating strains.”
Ashish Jha, the former dean of the Brown University School of Public Health, also touted the importance of getting vaccinated, even if the shot is not a complete match to the current flu strain.
“You still get about a third of lower chance of getting infected” from the mismatched vaccine, Jha conceded. “But where the benefit of the vaccine is clear is in preventing ER visits, hospitalizations, and obviously the thing we care most about, which is deaths.”
New CDC estimates about this year's flu season were released on Monday, showcasing numbers up to the final week of 2025. According to those figures, there have already been 120,000 hospitalizations this year, as well as 5,000 deaths from the flu this season. At this same time last year, those numbers were nearly half, with only 63,000 hospitalizations recorded and just 2,700 flu-related deaths at that point.
It's possible the hospitalization and death rates are higher this year due to fewer people getting vaccinated, as around 13 million fewer flu vaccine doses were administered this year compared to last.
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An oil tanker docked at El Palito port in Puerto Cabello, Venezuela, in December. U.S. President Donald Trump's plan to make money off Venezuelan oil faces moral, political and logistical problems, Chris Arsenault writes.Matias Delacroix/The Associated Press
Chris Arsenault is chair of the journalism program at Western University and a former reporter covering Venezuela.
When it comes to the country with the world's largest oil reserves, U.S. President Donald Trump didn't mince words on why U.S. commandos seized Venezuela's president. “They stole our oil,” Mr. Trump said.
Put aside for a moment clear violations of international law from U.S. actions and the fact “our” oil somehow ended up under Venezuela's soil.
A picture Mr. Trump posted on Truth Social of deposed Venezuelan President Nicolás Maduro handcuffed and blindfolded in a tracksuit aboard a U.S. navy ship conjures images of other oil-rich autocrats deposed by Washington and its proxies: Iraq's Saddam Hussein and Libya's Muammar Gaddafi. Neither of those interventions ended well.
A photo of Venezuelan President Nicolás Maduro handcuffed and blindfolded on a U.S. navy ship has echoes of past interventions by Washington into oil-rich countries.@realDonaldTrump/Reuters
Mr. Trump's plan to “have our very large United States oil companies” go and “spend billions of dollars” to “fix the badly broken infrastructure” and start making money, faces a host of problems: moral, political and logistical.
In short, don't expect a big influx of Venezuela's estimated 303 billion barrels of oil to end up on tankers heading north any time soon.
Mr. Maduro is a bumbling, brutal, inept autocrat. He blatantly stole the last election and his disastrous mismanagement forced nearly eight million Venezuelans to flee. Most Venezuelans are happy to see him gone. But like past U.S. interventions in major oil producers, power vacuums can create chaos.
War games simulations run previously by Washington on what could happen following Mr. Maduro's ouster indicate the chances for low-intensity civil conflict are substantial. Already, armed members of pro-Maduro civilian militias are out in force in the capital Caracas.
Leftist rebels from Colombia operate in jungle areas around Venezuela's borders. Attempts by Exxon or other U.S. oil majors – who had their assets nationalized by Maduro predecessor Hugo Chavez – to bring in technicians and repair infrastructure to expand production are likely to be met by resistance, just as U.S. forces and oil companies faced in Iraq.
What the U.S. attack on Venezuela could mean for oil and Canadian crude exports
Opinion: Donald Trump's plans for Venezuela, or rather the lack of them
Ahead of that invasion in 2003, the administration of former president George W. Bush changed the name of its planned Operation Iraqi Liberation (OIL) to Operation Iraqi Freedom, seemingly aware of the optics. Mr. Trump has no such scruples. He's almost refreshingly honest about U.S. foreign policy goals.
The plan, as it was for Iraq, is for Venezuela's oil wealth to finance the military and political costs of controlling the country, or as the U.S. Department of War put it to, “[reimburse the] people in our country who were forced out of Venezuela.”
America can deploy gunboat diplomacy around the globe, but Mr. Trump shouldn't hold his breath waiting for a cheque.
Venezuela's oil production dropped from over three million barrels per day in the early 2000s to less than one million in 2025, according to the consultancy Wood Mackenzie, owing to chronic mismanagement and U.S. sanctions.
Big increases in production, the kind of return on investment required for toppling a government and rebuilding an industry, will not be cheap or easy.
Change – but not regime change – comes to Venezuela
In a favorable scenario, a reasonable security environment and lots of capital, Wood Mackenzie estimates boosting production by one million barrels per day could happen within a couple of years.
Beyond refitting old wells or other repairs, expanding productive capacity is a longer-term and more expensive project. Venezuela's largest reserves sit in the Orinoco Belt, a region with heavy crude not so different from Canada's oil sands.
Boosting production to three-to-four million barrels per day means creating new infrastructure to access Orinoco crude which could take a decade and cost more than US$100-billion. The Trump administration, presumably, will be long gone by then.
As explosions rang out in Caracas, one subset of Canada's political class fretted about domestic oil exports to the U.S. being replaced by production from Venezuela.
“The consequences to Alberta and Canada's economy will be severe,” wrote Kevin M. Vickers, one-time New Brunswick Liberal Party leader and Canada's former ambassador to Ireland, who lamented the potential impact on shareholders and pension funds. In the midst of a blatant resource grab, his concerns are misplaced. Moreover, his worries aren't grounded in medium-term oil market realities.
Given Venezuela's current state, it is hard to imagine anyone wanting to invest tens of billions of dollars in long-term infrastructure today.
The real problem for the hemisphere, and Canada specifically, given recent U.S. annexation threats, is an unabashed return to powerful states taking natural wealth by force.
“Today it is Venezuela,” wrote Chilean President Gabriel Boric, “tomorrow it could be any other country.”
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UNITED NATIONS, January 5. /TASS/. The US operation may intensify instability in Venezuela, affect the broader Latin American region and set a dangerous precedent in the sphere of international relations, UN Secretary-General Antonio Guterres warned.
"I am deeply concerned about the possible intensification of instability in the country, the potential impact on the region, and the precedent it may set for how relations between and among states are conducted," Guterres said in a written statement read out by Under-Secretary-General Rosemary DiCarlo at a UN Security Council meeting on Venezuela.
US defense secretary also started proceedings that could strip Kelly from retired military rank and cut pension
Defense secretary Pete Hegseth said on Monday that he had issued a formal censure to Democratic senator Mark Kelly and initiated proceedings that could strip the Arizona lawmaker of his retired military rank and cut his pension, escalating a dispute that began when Kelly urged service members to resist unlawful orders.
Just days after a covert mission to capture Venezuelan dictator Nicolás Maduro and strike the capital city, Hegseth announced that Kelly faces retirement grade determination proceedings, a rare administrative action that could see the former astronaut and navy captain demoted in his retired rank. Hegseth accused Kelly of making “seditious statements” that undermined military discipline.
In November, Kelly and five other Democratic lawmakers, all military or intelligence veterans, released a 90-second video speaking directly to service members about the consideration of the national guard being deployed across the country, calling on troops to uphold the constitution and defy what they characterized as illegal commands
“Senator Mark Kelly — and five other members of Congress — released a reckless and seditious video that was clearly intended to undermine good order and military discipline,” Hegseth said in a statement posted on X, adding that Kelly “is still accountable to military justice” as a retired officer receiving military pay.
The Pentagon declined to comment further beyond the post on social media.
After learning of the censure, Kelly called Hegseth “the most unqualified secretary of defense in our country's history” and vowed to “fight this with everything I've got”.
“Pete Hegseth wants to send the message to every single retired servicemember that if they say something he or Donald Trump doesn't like, they will come after them the same way,” Kelly said in a statement. “It's outrageous and it is wrong. There is nothing more un-American than that.”
“If Pete Hegseth, the most unqualified secretary of defense in our country's history, thinks he can intimidate me with a censure or threats to demote me or prosecute me, he still doesn't get it.
Hegseth's statement claims Kelly's conduct between June and December 2025 violated articles 133 and 134 of the uniform code of military justice, which the senator remains subject to as a retired officer drawing pension payments. The defense secretary argues Kelly “characterized lawful military operations as illegal and counseled members of the Armed Forces to refuse lawful orders”.
But the accusation on its face has been contested for months. Military law already requires that troops refuse unlawful orders, which is what Kelly and other members of Congress were echoing. And federal judges have ruled Donald Trump's military deployments in Los Angeles and other cities violated the Posse Comitatus Act, suggesting the orders Kelly warned about may have actually been illegal.
In the video lawmakers released in November by Kelly and his colleagues – senator Elissa Slotkin and representatives Jason Crow, Chris Deluzio, Maggie Goodlander and Chrissy Houlahan, Slotkin acknowledged that military personnel were “under enormous stress and pressure right now” under the Trump administration's policies.
Days after the video's release, Trump accused the lawmakers of sedition “punishable by DEATH” in a social media post.
Kelly has 30 days to respond to the censure, which will be placed in his permanent military personnel file. The Pentagon chief has directed the navy secretary to complete the rank review within 45 days.
The move marks an extraordinary step by the defense department against a sitting US senator and threatened that more action could be coming.
“Captain Kelly's status as a sitting United States Senator does not exempt him from accountability, and further violations could result in further action,” Hegseth wrote.
Announcement comes after ongoing fraud of social services cases became focus of ire for Republicans and Trump
US politics live – latest updates
Tim Walz, the Democratic governor of Minnesota who ran for vice-president in 2024, announced on Monday that he is abandoning his quest for a third term in office.
The move comes after ongoing fraud of social services cases caught the attention of US Republicans, including Donald Trump, who then used the cases as a pretext to go after Somali residents.
Walz said in a statement that he wasn't able to “give a political campaign my all”.
“Every minute I spend defending my own political interests would be a minute I can't spend defending the people of Minnesota against the criminals who prey on our generosity and the cynics who prey on our differences,” Walz said. “So I've decided to step out of the race and let others worry about the election while I focus on the work.”
According to reports in several media outlets, Walz spoke with Amy Klobuchar, a US senator, over the weekend about the possibility of her running for governor instead. She has served as a US senator for Minnesota since 2007 and regularly wins her statewide re-election bids handily.
Walz had announced in September that he would seek a third term as governor – an unprecedented move for the Minnesota governorship, which he has held since 2018. Before that, he served in Congress representing southern Minnesota for six terms after flipping a Republican seat.
A poll last summer conducted by the Minnesota Star Tribune and Hubbard School of Journalism and Mass Communication ahead of Walz announcing his bid for a third term found that about half of Minnesotans didn't think he should run again.
His campaign for vice-president on the ticket with Kamala Harris raised his profile significantly across the country. Along with legislative leaders, he used a government trifecta in 2023 to deliver a host of progressive reforms that caught the attention of the left.
This increased profile has also made him a target on the right. In recent weeks, Trump has gone after Minnesota and Walz, directing a surge of immigration enforcement agents to the state, where they have pulled over US citizens and apprehended hundreds, despite consistent pushback from local residents. Over the weekend, Trump shared a conspiracy theory about the killings of Melissa Hortman and her husband, Mark – close friends of Walz – attempting to tie Walz to the killings.
The fraud cases – which included organized theft of meals for children, services for kids with autism and housing programs – have served as a major liability for Walz during his re-election and more fodder for the right to attack him and the state. Last month, a rightwing YouTuber attempted to enter multiple daycare centers and alleged they weren't taking care of kids, which prompted the US government to freeze federal funding for childcare for the state.
In his announcement on Monday, Walz said the state had made progress in fighting the fraud and that people are right to be concerned about fraud in government, but there was now “an organized group of political actors seeking to take advantage of the crisis”.
“I won't mince words here,” Walz said. “Donald Trump and his allies – in Washington, in St Paul, and online – want to make our state a colder, meaner place. They want to poison our people against each other by attacking our neighbors. And, ultimately, they want to take away much of what makes Minnesota the best place in America to raise a family. They've already begun by taking our tax dollars that were meant to help families afford child care. And they have no intention of stopping there.”
He said that the “buck stops with me” with fighting and preventing fraud and that Republicans' “political gamesmanship” makes it harder to fight fraud.
“I cannot abide the actions of the political leadership in Washington – these opportunists who are willing to hurt our people to score a few cheap points,” he said. “They and their allies have no intention of helping us solve the problem – and every intention of profiting off of it.”
He said he believes if he gave his re-election bid his all, he would succeed in winning a third term. But he concluded he couldn't give it his all, and he would instead focus on the work of his office instead of a run for re-election. He said he made the decision with “zero sadness and zero regret” and was confident that a Democrat would continue to hold the governorship in November.
“Most of all, I want Minnesotans to know that I'm on the job, 24/7, focused on making sure we stay America's best place to live and raise kids. No one will take that away from us. Not the fraudsters. And not the president. Not on my watch.”
US vice-president was not at his Cincinnati home when attacker smashed windows trying to get into the house
JD Vance on Monday thanked law enforcement in Ohio for arresting someone he referred to as a “crazy person”, whom the US vice president said tried to break into his Cincinnati home with a hammer overnight.
The Secret Service said in a statement that one person was in custody after the incident, which took place in the early hours of Monday. Vance had returned to Washington DC the day before.
“I appreciate everyone's well wishes about the attack at our home. As far as I can tell, a crazy person tried to break in by hammering the windows. I'm grateful to the secret service and the Cincinnati police for responding quickly,” Vance wrote in a post to X.
He then assailed the media for covering the incident.
“One request to the media: we try to protect our kids as much as possible from the realities of this life of public service. In that light, I am skeptical of the news value of plastering images of our home with holes in the windows.”
Vance spent last week at the house overlooking the Ohio River, but left on Sunday afternoon, Cincinnati news channel WLWT reported. The channel published to its website a photograph purporting to show damage to at least four panes of glass in what looked to be a ground floor window.
The Secret Service said an adult male was arrested shortly after midnight “for causing property damage, including breaking windows on the exterior of a personal residence associated with the vice-president”.
“The US Secret Service is coordinating with the Cincinnati Police Department and the US Attorney's Office as charging decisions are reviewed,” a spokesperson, Anthony Guglielmi, said in a statement sent to the Guardian.
WLWT said Secret Service agents and Cincinnati police spent several hours at the house in the East Walnut Hills neighborhood after responding to reports of damage to windows.
Two unnamed law enforcement sources told the Associated Press that Secret Service agents heard a loud noise at the home around midnight and found a person who had broken a window with a hammer and was trying to get into the house. The man had also vandalized a Secret Service vehicle on his way up the home's driveway, one of the officials said.
While Vance enjoys round-the-clock personal protection by the Secret Service as vice-president, the level of security maintained at his private residence varies according to his travel plans.
Many politicians have taken steps to enhance security after the June 2025 killing of Minnesota state legislator Melissa Hortman and her husband at their Minneapolis home, and an attack on another Democratic lawmaker and his wife in the city on the same night.
In October 2024, a man was sentenced to 30 years in prison for attacking Paul Pelosi, husband of the Democratic former House speaker Nancy Pelosi, with a hammer at their California home.
Daily roundup of research and analysis from The Globe and Mail's market strategist Scott Barlow
RBC Capital Markets co-heads of research Graeme Pearson and mark Odendahl published the department's top 30 global stock ideas, a list of high-conviction equity stories from RBC analysts,
“The best-performing Top 30 stock selections in Q4/25 were Barrick (up 30 per cent), DuPont (up 23 per cent) and Loblaw (up 17 per cent). Over the past year, the Top 30 total return was 14.4 per cent vs. the benchmark at 20.1 per cent, and since inception of our quarterly list at year-end 2019, the Top 30 has delivered a total compound annual return of 14.0 per cent, above the benchmark at 12.8 per cent.
“Changes This Quarter Additions: Airbnb (ABNB-Q), Alcon (ALC SW), Amazon.com (AMZN-Q), Engie (ENGI FP), International Paper (IP-N), Royal Gold (RGLD-Q), Shopify (SHOP-N, SHOP-T), The Williams Companies (WMB US), Visa (V-N), Wisetech Global (WTC AU), Xcel Energy (XEL-Q)
“Deletions: Alimentation Couche-Tard (ATD-T), Barrick Mining (B-N, B-T), CSX (CSX-Q), EDP Renovaveis (EDPR PL), Ferrari (RACE IM), HubSpot (HUBS-N), NIKE (NKE-N), PayPal (PYPL-Q), Pembina Pipeline (PPL-T), Wells Fargo (WFC-N), Wix.com (WIX-Q)
“Maintains: Air Products and Chemicals (APD-N), Biogen (BIIB-Q), Boston Scientific (BSX-N), Brookfield Corp. (BN-N, BN-T), ConocoPhillips (COP-N), Constellation Software (CSU-T), DuPont de Nemours (DD-N), Loblaw (L-T), L'Oreal (OR FP), Microsoft (MSFT-Q), Moody's (MCO-N), Palo Alto Networks (PANW-Q), RB Global (RBA-N, RBA-T), Safran (SAF FP), Schneider Electric (SU FP), Snowflake (SNOW-N), U.S. Bancorp (USB-N), Ventas (VTR-N), Xylem (XYL-N)”
TD Cowen oil analyst Menno Hulshof provided an early assessment of Venezuela/U.S. geopolitics' effects on the crude market,
“We expect a limited impact from VZ's most acute geopolitical crisis since 1902-1903, but reiterate the potential for geopolitics to structurally alter global energy market dynamics in 2026. Any immediate-term disruptions to supply risk premia are likely mitigated by the ongoing glut, leaving markets focused on the risk that sanctioned barrels may instead enter into the system, and sentiment regarding the prospect of a medium-term recovery in exports. We also expect a muted war-effect owing to the limited nature of this operation”
Scotiabank analyst Paul Cheng and the energy research team also published a report on the longer term impact of the bizarre U.S. policy in Venezuela,
“We believe this development will have a mixed impact on the oil market. Near-term oil prices may initially rise modestly, reflecting uncertainties in the aftermath of this attack on Venezuela's oil production, while longer dated strip prices fall. The pace of the power transition and the overall security situation on the ground could also cause any near-term rally to fade. Longer term, the removal of Maduro could potentially mark the beginning of a new chapter for OPEC and the oil market, a complete opposite of the outlook in 1999 after Chavez was elected President of Venezuela in late 1998. As a result, we believe these developments will lead to lower longer term oil prices while widening U.S. and global light/heavy oil differentials”
From what I've read over the weekend, Venezuela's facilities are outdated and the quality of oil is broadly poor. Reading between the lines it seems like Venezuelan oil is marginally profitable at best in the current market, and obviously new supply would put downward pressure on the commodity price.
TD economist Andrew Hencic sees cracks under the surface of domestic growth,
“The economy has shown some mettle, likely growing 1.7 per cent in 2025 as data revisions revealed better-than-expected past performance and large swings in trade-flattered topline figures. However, there are real cracks under the surface (domestic demand contracted in two quarters this year) and focus is now firmly on how Ottawa's strategy of new infrastructure, defense spending, and greasing the wheels on major projects to diversify trade markets begins to be delivered … Thus far, Canada has managed to more than offset the $13.0-billion decline in exports to the U.S. with $16.3-billion in flows to the rest of the world. Moreover, roughly 87 per cent of Canadian exports to the U.S. in September (the last month for which we have data) were still duty-free … The protection conveyed by CUSMA doesn't extend to specific goods tariffed under Section 232 of the Trade Expansion Act. These levies have materially affected the competitiveness of Canadian manufactured goods south of the border. Motor and Other Vehicles (-$3.3 billion year-to-date), steel & iron (-$2.0 billion), and aluminum (-$1.4 billion) exports to the U.S. have contracted significantly. Moreover, flows abroad for most of those products have not been sufficient to offset the lost revenues”
“The Weekly Bottom Line” – TD Economics
Good morning, oil watchers!
Brent crude prices briefly collapsed below $60/bbl earlier this morning before popping back above $61/bbl.
Oil market not quite sure what to make of Venezuela news—volatile and uncertain immediate impact, months-to-years effect likely bearish.[image or embed]
https://bsky.app/profile/roryjohnston.bsky.social/post/3mbofiud5ks2l
“Nanoparticle therapy reprograms tumor immune cells to attack cancer from within” – Phys.org
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Hello, this is Kateryna Hodunova reporting from Kyiv on day 1,412 of Russia's full-scale invasion of Ukraine.
Today's top story so far:
An oil extraction plant in Dnipro was damaged in a Russian drone strike on Jan. 5, spilling about 300 tons of sunflower oil onto city streets, Mayor Borys Filatov said.
The spill forced the closure of the city's embankment to traffic for two to three days, Filatov said.
The facility reportedly belongs to Bunge, a U.S. agribusiness company based in St. Louis, Missouri, according to Filatov.
The mayor did not specify what the enterprise produced, but said it was a "civilian site."
"(Vladimir) Putin is targeting American business — striking U.S. investments in Ukraine and humiliating American interests," Andy Hunder, president of the American Chamber of Commerce in Ukraine, told the Kyiv Independent following the attack.
"This must stop. Washington must act to defend American business."
Bunge told the Kyiv Independent that the damage to part of its facility in Dnipro is still being assessed and that the company is working with local authorities to mitigate the impact.
"We can confirm that there were no injuries at the facility, and our immediate focus is on the safety of the people at the site and restoring operations," the spokesperson told the Kyiv Independent, adding that the company currently has no additional details on the consequences of the attack.
The damaged facility is reportedly an oil plant related to Oleina, one of Ukraine's largest brands of bottled sunflower oil. The plant specializes in processing, refining, and bottling sunflower oil, according to the Ukrainian media outlet Liga.net.
The attack also damaged a car and a power line, Dnipropetrovsk Oblast Governor Vladyslav Haivanenko said.
Local authorities reported no civilian casualties at the time of publication.
Dominic Culverwell contributed to this report.
Last updated 6:40 p.m. Kyiv time.
Ukrainian troops have been repelling repeated Russian assaults near the village of Hryshyne over the past two days, while the situation in the town of Myrnohrad remains difficult in Donetsk Oblast, Ukraine's 7th Rapid Response Corps said on Jan. 5.
The Russian army "has increased pressure" in the Pokrovsk area, which includes the cities of Pokrovsk, Dobropillia, Myrnohrad, Novohrodivka, and Selydove, since the beginning of 2026, the statement read.
Russian forces are attempting to bypass the area primarily at night to minimize their losses, advancing via the settlements of Hryshyne and Rodynske, according to the 7th Rapid Response Corps.
Hryshyne lies northwest of Pokrovsk, while Rodynske is to the north. Both settlements are less than 5 kilometers (3 miles) from the embattled city.
Ukrainian forces killed over 30 Russian soldiers and destroyed up to 10 pieces of equipment in the area over the past two days, the corps said.
Ukrainian forces are also observing small Russian groups of six to eight soldiers attempting to operate north of Pokrovsk.
The situation in Myrnohrad, a satellite town of Pokrovsk, remains difficult, according to the statement.
The 7th Rapid Response Corps, in conjunction with the 14th Operational Brigade of Ukraine's National Guard, is concentrating on securing the northern part of the city, containing Russian forces in central areas, and preventing them from bringing in equipment from the south.
Russian troops are attempting to gain a foothold on Myrnohrad's eastern outskirts, but Ukrainian forces "remain in control of the situation," the corps said.
Last updated 3:45 p.m. Kyiv time.
Russia launched five missile strikes on Kharkiv on Jan. 5, injuring a 58-year-old man and causing "very significant damage" to the city's energy infrastructure, local authorities said.
The injured man, an employee of a company near the strike site, was hospitalized, according to Governor Oleh Syniehubov and the Kharkiv Oblast Prosecutor's Office.
The first strike occurred at 12:45 p.m. local time, followed by four more at intervals of several minutes.
The first two strikes hit an industrial area in the Slobidskyi district, Kharkiv Mayor Ihor Terekhov said on Telegram. The mayor did not specify where the remaining strikes landed.
"The enemy deliberately launched five missile strikes on Kharkiv's energy infrastructure. The damage is very significant," Terekhov said.
The mayor added that while it is possible to strengthen the protection of facilities, "no concrete structures can withstand five ballistic missiles."
Last updated 3:04 p.m. Kyiv time.
Russia attacked a facility where local residents were receiving humanitarian aid with three drones, killing a 64-year-old man, and injuring a 79-year-old woman and a 71-year-old man in the Dariivka community in Kherson Oblast, Governor Oleksandr Prokudin said on Jan. 5.
Those injured suffered blast injuries and shrapnel wounds. The victims were taken to the hospital in moderate condition, Prokudin said.
Last updated 2:34 p.m. Kyiv time.
Ukraine's 7th Rapid Response Corps said on Jan. 5 that it had thwarted Russia's latest attempt to launch an attack on the Kupiansk sector in northeastern Kharkiv Oblast by using the Soyuz ("union" in English) gas pipeline.
Russia attempted to use the pipeline for "a covert exit and further accumulation of forces" in the Kupiansk area, in an operation that involved around 50 people, according to the 7th Corps. It claimed it "eliminated" at least 40 of them.
Russia's recent pipeline operation had occurred north of Novoplatonivka, a village just five kilometers above the town of Borova, trying to move upward along the Oskil River in the direction of Kupiansk, the 7th Corps said.
While its latest pipeline operation failed to achieve its objectives, Russia continues to deploy its troops in small groups to infiltrate between positions, according to the 7th Corps.
The report comes as Russia tries to push across the front by launching heavy offensive operations on multiple axes, including in the Kupiansk sector, to recapture the city it lost to a 2022 Ukrainian counteroffensive.
Last updated 2:13 p.m. Kyiv time.
Russian troops are trying to expand the combat zone near the state border area in Sumy and Kharkiv oblasts, Border Guard Service spokesperson Andrii Demchenko said on Jan. 5 on national television.
The most active fighting is in the Khotyn and Yunakivka communities in Sumy Oblast, as well as the Vovchansk sector of the front line and near the settlements of Dvorichanske and Sotnytskyi Kozachok in Kharkiv Oblast, Demchenko said.
Russian forces are also attempting to widen the combat zone near the Krasnopillia community and the border village of Hrabovske, Sumy Oblast, where fighting has continued for several weeks, Demchenko said.
In these areas, Russian forces are using small assault groups without heavy equipment, he said, adding: "But the enemy cannot achieve results or advance deeper into our country's territory. And at the same time, it is suffering heavy losses."
Last updated 1:36 p.m. Kyiv time.
President Volodymyr Zelensky announced on Jan. 5 that Vasyl Maliuk will step down as head of Ukraine's Security Service (SBU) but remain in the agency to focus on asymmetric operations against Russia.
Zelensky has also appointed Yevhenii Khmara, head of the Special Operations Center "A," as the acting head of the SBU.
"(Maliuk) knows how to do this best and will continue within the SBU system," Zelensky said. "Together, we discussed candidates for the new head of the SBU."
In a statement, Maliuk said he would stay in the service to carry out what he described as world‑class asymmetric operations aimed at inflicting "maximum damage" on Moscow.
Despite leading several of Ukraine's most consequential operations against Russia, Maliuk's tenure has been marked by controversy, particularly over his involvement in actions targeting anti-corruption bodies.
His departure follows days of speculation that Zelensky was preparing to dismiss him.
The move is one of several key dismissals and appointments Zelensky has announced in 2026, in a government reshuffle driven in part by Ukraine's recent corruption scandal.
Most of the officials who were dismissed from their posts were soon reappointed to positions of similar rank.
At least four people have been killed and 15 others injured in Russian attacks against Ukraine over the past day, local authorities said on Jan. 5.Russia launched nine Iskander-M ballistic missiles and S-300 anti-aircraft missiles, as well as 165 drones at Ukraine overnight, the Air Force said. Ukrainian air defenses intercepted 137 drones.
At least 26 drones made it through, striking 10 locations. The fall of debris was recorded at nine locations.
Russian forces attacked Ukrainian energy infrastructure overnight on Jan. 5, causing power outages in Donetsk, Kharkiv, and Chernihiv oblasts in the morning. The strike also left the city of Slavutych in Kyiv Oblast completely without electricity, Ukraine's state grid operator Ukrenergo said. In Kyiv, Russian forces targeted a private hospital in the Obolonskyi district, killing a patient and injuring four others, Mayor Vitalii Klitschko said. Two victims are in serious condition, Klitschko added.The Russian attack sparked a fire, forcing the transfer of 16 of the private hospital's 26 patients to public facilities. Firefighters extinguished the blaze by morning.In Kyiv Oblast, a Russian attack also killed a man in the village of Kozhukhivka, the local military administration said.
In Kherson Oblast, Russian forces targeted 33 settlements, injuring three people over the past day, the local military administration said in its daily report at around 8 a.m. local time. On the morning of Jan. 5, a Russian drone injured a 64-year-old man in the Beryslav district at 7:20 a.m. Russian forces shelled a hospital in Kherson at 11 a.m., injuring a 36-year-old woman and a 57-year-old medical worker.
In Donetsk Oblast, one person was killed and two others were injured in Russian strikes against the city of Kramatorsk, Governor Vadym Filashkin said. In Zaporizhzhia Oblast, a Russian drone attacked the regional center of Zaporizhzhia, killing a driver, according to the local military administration. Russian forces also targeted the Polohy district, injuring a 69-year-old woman. In Sumy Oblast, a 54-year-old man suffered injuries in the Putyvl community due to a Russian drone strike, the local military administration said. In Kharkiv Oblast, Russian forces attacked the village of Kupiansk-Vuzlovyi, injuring a 67-year-old woman, Governor Oleh Syniehubov said.
Russia has lost around 1,212,520 troops in Ukraine since the beginning of its full-scale invasion on Feb. 24, 2022, the General Staff of Ukraine's Armed Forces reported on Jan. 5.
The number includes 990 casualties that Russian forces suffered over the past day.
According to the report, Russia has also lost 11,507 tanks, 23,857 armored fighting vehicles, 72,945 vehicles and fuel tanks, 35,785 artillery systems, 1,592 multiple launch rocket systems, 1,268 air defense systems, 434 airplanes, 347 helicopters, 100,564 drones, 28 ships and boats, and two submarines.
News Editor
Kateryna Hodunova is a News Editor at the Kyiv Independent. She previously worked as a sports journalist in several Ukrainian outlets and was the deputy chief editor at Suspilne Sport. Kateryna covered the 2022 Olympics in Beijing and was included in the Special Mentions list at the AIPS Sport Media Awards. She holds a bachelor's degree in political journalism from Taras Shevchenko University and a master's degree in political science from the National University of Kyiv-Mohyla Academy.
Prime Minister Mark Carney and U.S. President Donald Trump wait for the FIFA World Cup draw to begin at the Kennedy Center, in Washington, on Dec. 5, 2025.Adrian Wyld/The Canadian Press
It should have been clear in November, 2024, when Donald Trump won re-election that Canada needed to act with urgency to end the drift of (especially) the last decade, during which the federal government dangerously neglected the basics of safeguarding national sovereignty.
The alarm bells were seemingly heeded last spring, when Mr. Trump launched his trade war and started greedily eyeing Canada as the 51st state. Against the odds, the Liberals won re-election under Mark Carney on the promise of an elbows-up response to Mr. Trump's provocations.
But that promised response has not materialized, despite other worrying developments. In November, the U.S. administration published a National Security Strategy that would dramatically curtail the sovereignty of any Western Hemisphere country, Canada included.
Then came the U.S. military strike on Venezuela on Saturday. Any thought that Canada could simply wait out Mr. Trump's term in the White House ended this weekend.
There has been no shortage of rhetoric from Prime Minister Mark Carney about the need to expand Canada's military capacity and to end economic stagnation. What has been lacking for more than a year is action commensurate to the national emergency in which Canada finds itself.
Carney hails ouster of Maduro in Venezuela but calls for respect for international law
The conundrum that Canada faces is that there is no immediate fix to today's emergency. It will take years to build a new pipeline, and years to fully rebuild Canada's military. Which is why there is not a moment more to lose.
The Liberals have talked about doubling non-U.S. exports over the coming decade. But what will happen this year? This month? The Liberals have talked about increasing Canada's military spending to five per cent of GDP by 2035. What steps will be taken in 2026? The Liberals have signed a memorandum with Alberta that sets the stage for an oil pipeline to the Pacific. It's a solid first step, but when will the next one come?
The right answer, the only answer, must be immediately, for the three herculean tasks of diversifying Canada's exports, revitalizing the domestic economy and rebuilding this country's military capacity.
The single biggest step that Ottawa can take in diversifying exports is to ensure a new bitumen pipeline to the West Coast is constructed. The economic logic was unassailable before the U.S. seized Venezuela's Nicolás Maduro. Now, the United States is vowing to ramp up Venezuelan crude production, which would swell supplies of heavy oil for U.S. refiners – driving down prices for Alberta producers. The immediate response must be to green-light additional capacity for the Ottawa-owned Trans Mountain pipeline. The company has said it intends to boost capacity over the next five years. That timeline needs to be accelerated to start this year.
What the U.S. attack on Venezuela could mean for oil and Canadian crude exports
More important, Ottawa must work with Alberta to secure a private proponent in the coming months for a new oil pipeline, underpinned by a commitment that all regulatory approvals will be granted in under two years.
There will need to be consultation and accommodation with Indigenous communities to fulfill Ottawa's constitutional duty. But the Liberal government must make it clear in those talks (and to any obstructionist premier) that the only question to be discussed is how a pipeline will be built.
The same kind of leadership is needed for the forging of a national economy. The promise of internal free trade has devolved, yet again, into inter-provincial squabbling. The federal government needs to step in to ensure that internal trade barriers are dismantled speedily and permanently.
Opinion: A Venezuelan oil reset is an economic risk Canada cannot ignore
Ottawa already has the only tool it needs, in the form of its very deep pockets. Federal funds should be made contingent on provinces and territories tearing down trade barriers.
On national defence, the Carney government has taken some initial measures to boost military capacity. But the announcements last year of an increase in defence spending and procurement reform are, at most, an overdue first step.
Recruitment needs to quicken, now. Procurement delays need to end, now. Any minister who attempts to detour spending into regional pork-barrelling should be booted from cabinet. Any staff officer who gets in the way of ending the bureaucratic snarls of procurement must be cashiered.
In June, former U.S. ambassador Kelly Craft told a Toronto business audience that if Canada doesn't like being called a 51st state, it should stop acting like one. Those may be hard words for Canadians to hear, but they underscore the seriousness of the moment, and the urgency of action.
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US President Donald Trump has threatened Colombia with military action similar to last week's raid on Venezuela.
Speaking to reporters aboard Air Force One on Sunday, Trump said Colombia is “run by a sick man,” referring to President Gustavo Petro, whom he labeled a “drug leader.” The US president suggested that Petro, whom he sanctioned last year, could be removed from power too.
“Colombia is very sick… run by a sick man who likes making cocaine and selling it to the United States. And he's not going to be doing it very long, let me tell you,” Trump stated. Asked directly whether the US would launch a military operation against the country, he replied: “It sounds good to me.”
Petro responded sharply in a series of posts on X, urging Trump to “stop slandering” and calling on Latin American nations to unite or risk being “treated as servants and slaves.”
The exchange follows growing outrage over Washington's unprecedented military operation to seize Nicolas Maduro in Venezuela, which the Trump administration says was needed to bring the Venezuelan president to trial on drug trafficking charges. Caracas rejects this explanation as a pretext for regime change. Media reports say at least 80 people, both military and civilian, were killed in the raid. Maduro, who has denied all allegations, was abducted and forcibly flown to the US along with his wife.
The raid has drawn condemnation from the Global South, while China slammed the abduction as a violation of international law. Brazil, Chile, Colombia, Mexico, Uruguay, and Spain have issued a joint statement warning that America's action has set “an extremely dangerous precedent” for regional security.
Trump justified the raid by invoking the 19th-century Monroe Doctrine, which designates Latin America as Washington's sphere of influence, while asserting that the US is now “in charge” of Venezuela. He told reporters that Saturday's military intervention was not about regime change or resources but securing “peace on Earth,” particularly in the Western Hemisphere. He went on to warn that the US could strike again if Caracas “doesn't behave.”
Besides Colombia and Venezuela, Trump has also ramped up rhetoric against other countries in the region, claiming Cuba “is ready to fall” due to the loss of Venezuelan oil revenue and threatening Mexico with possible military intervention, saying the country “has to get their act together because [drugs] are pouring through Mexico and we're going to have to do something.”
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President Volodymyr Zelensky announced on Jan. 5 that Vasyl Maliuk will step down as head of Ukraine's Security Service (SBU) but remain in the agency to focus on asymmetric operations against Russia.
"(Maliuk) knows how to do this best and will continue within the SBU system," Zelensky said. "Together, we discussed candidates for the new head of the SBU."
In a statement, Maliuk said he would stay in the service to carry out what he described as world‑class asymmetric operations aimed at inflicting "maximum damage" on Moscow.
Despite leading several of Ukraine's most consequential operations against Russia, Maliuk's tenure has been marked by controversy, particularly over his involvement in actions targeting anti-corruption bodies.
His departure follows days of speculation that Zelensky was preparing to dismiss him.
The move is one of several key dismissals and appointments Zelensky has announced in 2026, in a government reshuffle driven in part by Ukraine's recent corruption scandal.
Most of the officials who were dismissed from their posts were soon reappointed to positions of similar rank.
According to Ukrainian Pravda, Maliuk's resignation followed direct pressure from Zelensky.
The president's team reportedly views Maliuk as one of the key figures associated with a coordinated move against Ukraine's anti-corruption institutions and effectively trying to contain the fallout and deflect responsibility for the attack.
The controversy traces back to July, when parliament passed legislation that effectively stripped independence from the National Anti-Corruption Bureau (NABU) and the Specialized Anti-Corruption Prosecutor's Office (SAPO).
Under Maliuk's leadership, the SBU — widely seen as loyal to the President's Office — arrested several NABU employees, accusing them of having ties to Russia.
The service framed the crackdown as a counterintelligence effort aimed at neutralizing Moscow's alleged influence within the bureau.
Anti-corruption activists and civil society groups rejected that explanation, arguing the arrests targeted detectives investigating figures close to Zelensky.
The detectives were later released.
The political backlash stands in contrast to Maliuk's operational record during the war.
Maliuk was appointed SBU head by parliament on Feb. 7, 2023, after serving as acting chief since July 2022. Zelensky dismissed his predecessor, Ivan Bakanov, citing endemic treason within the agency following Russia's full-scale invasion.
During Maliuk's tenure, the SBU carried out several high-profile operations deep inside Russia and in occupied territories.
On June 1, the agency executed Operation Spiderweb, deploying drones concealed in trucks across Russia to strike air bases thousands of kilometers from Ukraine's border.
On Dec. 15, the SBU reported that its Sea Baby naval drones struck a Russian Varshavyanka-class submarine in the port of Novorossiysk, marking the first publicly acknowledged underwater drone attack of its kind.
Under Maliuk, the service was also involved in multiple attacks on the Russian illegally constructed Crimean Bridge, a critical logistical artery for Russian forces.
Ukrainian Pravda reported that Maliuk initially resisted Zelensky's decision to remove him, warning that several large-scale operations comparable to Spiderweb were in their final stages and that halting them would be reckless.
As pressure mounted over Maliuk's future, senior Ukrainian military commanders publicly warned against his dismissal, cautioning that removing him during active combat could weaken one of Ukraine's most effective security institutions.
Commander of the Unmanned Systems Forces Robert "Madyar" Brovdi and Joint Forces Commander Mykhailo Drapatyi urged restraint, pointing to SBU's performance.
"No matter which of the proposed security structures Maliuk could potentially be effective in the near future, replacing the head of the Security Service at this moment would be a risk."
Their public intervention was unusual and highlighted the seriousness with which they view the decision, given their general avoidance of political commentary.
Maliuk's resignation now moves to the political arena. Parliament, where Zelensky's party holds a majority of seats, must vote on his dismissal.
Ukrainian media report that Yevhenii Khmara, head of the SBU's Alpha special operations unit, is a leading candidate to replace him.
Khmara is a seasoned special forces officer who has served in Alpha since 2011 and was appointed its commander in 2023.
The unit is consistently among the most effective in Ukraine's defense forces, credited with destroying significant Russian equipment and personnel, often with drone support.
Shortly after announcing Maliuk's resignation, Zelensky signed a decree appointing Khmara as acting head of Ukraine's Security Service.
Maliuk's resignation follows closely after Zelensky appointed military intelligence chief Kyrylo Budanov to head the President's Office, making Maliuk the second senior security figure to leave his post in a short span.
Reporter
Tim Zadorozhnyy is the reporter for the Kyiv Independent, specializing in foreign policy, U.S.-Ukraine relations, and political developments across Europe and Russia. Based in Warsaw, he is pursuing studies in International Relations and the European Studies program at Lazarski University, offered in partnership with Coventry University. Tim began his career at a local television channel in Odesa in 2022. After relocating to Warsaw, he spent a year and a half with the Belarusian independent media outlet NEXTA, initially as a news anchor and later as managing editor. Tim is fluent in English, Ukrainian, and Russian.
Maduro's extradition marks the climax of US secretary of state's ambition to restore democracy to Central America
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In 2017, Marco Rubio was placed under police protection when Venezuela's security chief was accused of plotting to assassinate him.
The former Florida senator had long been a thorn in the side of Nicolas Maduro's regime, taking to the Senate floor in 2014 to scold the Obama administration for its “shameful” failure to sanction the strongman leader.
A decade later, the US secretary of state finally got his revenge when the US military captured Mr Maduro in a daring pre-dawn raid.
Dubbed the “viceroy of Venezuela” by the US media, Mr Rubio, who has taken on an ever-growing list of titles in the Trump administration – serving as national security adviser, acting national security adviser and US archivist – may just have added another one to his ledger.
For the US, the extradition of Mr Maduro marks the culmination of an extraordinary pressure campaign that began in September, when the Pentagon started to build up military forces in the region and blow up boats accused of “narco-trafficking”.
For Mr Rubio, a politician who frequently describes himself as the son of Cuban exiles, building his political identity on his family story, it marks the climax of a lifelong ambition to restore democracy to Central America.
“This is part of his DNA, it's something he has worked on his whole life,” a former aide told The Telegraph.
“His parents passed away without ever seeing freedom. He fundamentally believes in freedom and democracy because that was taken away from his family.”
The secretary of state is said to have played a vital role in steering the Trump administration towards ousting Venezuela's leader.
Now, with no long-term successor to govern the country of 29 million people, the president has tasked Mr Rubio with helping to “run” Venezuela, fix its oil infrastructure and usher in a stable government, to add to his long list of responsibilities.
“The transition process will not be easy, but there is no one more capable in the US government than secretary Marco Rubio for this moment,” said one former adviser.
Known as the “virtual secretary of state for Latin America” during Donald Trump's first term, Mr Rubio's proficiency in Spanish and close ties to Latin American leaders and the Venezuelan opposition make him a natural pointman for the president, a senior official told The Washington Post.
Described by sources as a “Latin America whisperer”, Mr Rubio allegedly had a direct line to the president during his first term when it came to the socialist governments of Cuba, Venezuela and Nicaragua, former officials told Politico.
He organised a meeting between Mr Trump and the wife of a jailed Venezuelan opposition leader in 2017, and received weekly briefings about the administration's crackdown on Latin American governments, the outlet reported.
His sharp criticism had long been a source of frustration for Mr Maduro, who had branded him the “craziest of the crazies” and whose head of security forces, Diosdado Cabello Rondon, was said to be behind a plot to assassinate the outspoken senator, according to a US intelligence memo.
“It sent shockwaves throughout the senator's orbit,” one former aide recalled, adding that Mr Rubio was unperturbed by the threats.
Although it was never proven, the threat prompted federal officials to provide Mr Rubio and his family with round-the-clock protection.
Central to the success of Saturday's high-stakes operation, insiders say, is the close relationship between Mr Trump and his secretary of state, who has grown into one of the most powerful advisers of his second term.
“I think the president really respects him,” a former Rubio adviser said.
The pair see each other nearly every day, have offices next to each other in the White House and have a warm public relationship, which has resulted in the president bestowing titles on his adviser like a medieval king.
Speaking to reporters after Mr Maduro's arrest, Mr Trump was vague about who would run the Latin American country, saying “the people that are standing right behind me” will do so for a “period of time”, as he gestured to his secretary of state and Pete Hegseth, the defence secretary.
The president also hailed Mr Rubio's initial talks with Mr Maduro's vice president, Delcey Rodríguez, who was formally made interim leader on Sunday, saying “she's essentially willing to do what we think is necessary to make Venezuela great again”.
Deftly dealing with Ms Rodríguez's response that Venezuela “will never return to being the colony of another empire”, Mr Rubio clarified on Sunday that the US would not govern Venezuela day-to-day other than enforcing an existing “oil quarantine” on the country.
The military operation – the fastest toppling of a regime in the modern era – also represents a political victory for him within an administration that includes staunch opponents of regime change, notably JD Vance.
“I see [the military operation] really as the merging of minds between secretary Rubio and president Trump,” said Carrie Filipetti, a former Venezuela and Cuba adviser at the state department.
Pushing back on suggestions that Mr Trump is averse to foreign intervention, Ms Filipetti said the president has “always had a penchant for these displays of American might”, pointing to his strikes on Iran and plans to send naval assets to the coast of Venezuela in his first term, which she said were stymied by bureaucratic hurdles.
“It very much has Trump's mentality to it of reinforcing American strength and power,” she said. “But I think the specificity and the precision screams Marco Rubio.”
During the president's first term, Mr Rubio was instrumental in pushing for sanctions against Venezuela, Cuba and Nicaragua, the so-called “troika of tyranny”.
With the fall of Venezuela's regime, former aides have suggested the secretary of state and the president may view ridding the Western hemisphere of communist dictatorships as “part of their legacy”.
On Sunday evening, Mr Trump set pulses racing in Colombia too, calling the country's Left-wing president, Gustavo Petro, a “sick man” who “likes making cocaine and selling it to the United States”.
Asked if the US would pursue military action against the country, he said: “It sounds good to me.”
Dismissing comparisons to the US invasion of Iraq, which led to nearly nine years of conflict and the death of around 5,000 servicemen, a former Rubio adviser pointed out that the Venezuelan people had voted against Mr Maduro's government for a decade and argued that they were “excited for what's ahead”.
Meanwhile, they said: “Cuban Americans see the fall of the regime in Venezuela as having a domino effect that will directly impact Cuba.”
Mr Maduro and his wife, Cilia Flores, 69, are expected to appear in court on Monday, facing charges of narco-terrorism.
As the fallen leader contemplates a future locked up in a US prison, Mr Rubio may well be setting his eyes on his next prize – this one much closer to home.
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WASHINGTON, January 5. /TASS/. US President Donald Trump said that he does not believe Ukraine launched an attack on Russian President Vladimir Putin's official residence.
"We don't believe that happened," he told reporters aboard his presidential plane on the way to Washington from West Palm Beach, Florida, where he spent the Christmas and New Year holidays at his Mar-a-Lago estate. Trump was responding to questions about Kiev's shelling of the Russian president's official residence in the Novgorod Region. "There is something that happened fairly nearby [to the Russian president's official residence]," Trump said in this context. "But [it] had nothing to do [with the attack on the Russian leader's official residence]," the US leader said, without providing any details.
When asked why he had previously condemned Kiev, Trump said: "Nobody knew at that moment. I mean, that was the first I heard about it. He (Putin - TASS) said that his house was attacked." "We do not believe that (Ukraine's attack on Putin's official residence - TASS) happened. As you know now that we have been able to check," the US leader said. "We just hope that Russia and Ukraine get it [the conflict] settled," Trump added.
In the early morning hours of December 29, Kiev launched an attack on Putin's state residence in the Novgorod Region using 91 drones, Russian Foreign Minister Sergey Lavrov reported earlier. All drones were destroyed. According to the top diplomat, there was no information about casualties or damage from the UAV debris.
In turn, Kremlin aide Yury Ushakov said that, during a telephone conversation, Putin pointed Trump's attention to Kiev's attack, which occurred "almost immediately" after the US-Ukraine talks in Mar-a-Lago. The Russian leader warned that Kiev's attack would not go unanswered. The head of state also informed his US counterpart that Russia would review its position in the negotiations to settle the conflict in Ukraine.
U.S. President Donald Trump said on Jan. 4 that he does not believe Ukraine attacked a residence used by Russian President Vladimir Putin, casting doubt on Moscow's claims following a recent phone call with Putin.
"We don't believe that happened now that we've been able to check," Trump told the reporters while aboard Air Force One.
"There is something that happened fairly nearby but had nothing to do with this. .... nobody knew at that moment. I mean, that was the first I heard about it. He said that his house was attacked," Trump added.
The allegation emerged as Ukraine and the United States were coordinating an updated peace framework, a timing Ukrainian officials described as deliberate.
On Dec. 29, Russia publicly accused Ukraine of launching 91 drones toward a residence used by Putin — a claim Putin personally conveyed to Trump during the phone call. Trump initially reacted to the allegation, saying he was "very angry," before later expressing skepticism after reviewing additional information.
On Dec. 31, Trump shared a New York Post editorial titled "Putin 'attack' bluster shows Russia is the one standing in the way of peace," which questioned the credibility of Moscow's account.
The U.S. Central Intelligence Agency (CIA) has assessed that Ukraine did not target a residence used by Russian President Vladimir Putin, confirming Kyiv's immediate denial and undercutting Moscow's claims, U.S. officials told CNN on Jan. 1.
Answering a question about his New Year's resolution of "peace on Earth", Trump reiterated his goal of ending the Russia-Ukraine war. "We just hope that Russia and Ukraine get it settled," he said.
"25,000 to 30,000 soldiers are being killed every single month. And they're not from America. They're from Russia and they're from Ukraine," Trump added. "And if I could get it stopped, I'd like to get it stopped. And I think we will."
Head of North America desk
Olena Goncharova is the Head of North America desk at The Kyiv Independent, where she has previously worked as a development manager and Canadian correspondent. She first joined the Kyiv Post, Ukraine's oldest English-language newspaper, as a staff writer in January 2012 and became the newspaper's Canadian correspondent in June 2018. She is based in Edmonton, Alberta. Olena has a master's degree in publishing and editing from the Institute of Journalism in Taras Shevchenko National University in Kyiv. Olena was a 2016 Alfred Friendly Press Partners fellow who worked for the Pittsburgh Post-Gazette for six months. The program is administered by the University of Missouri School of Journalism in Columbia.
The Jan. 6 leaders' meeting will focus on long-term security arrangements for Ukraine.
"(Indian Prime Minister Narendra) Modi is a good guy. He knew I was not happy, and it was important to make me happy," U.S. President Donald Trump said.
Despite leading several of Ukraine's most consequential operations against Russia, Maliuk's tenure has been marked by controversy, particularly over his involvement in actions targeting anti-corruption bodies.
Russian troops are attempting to close in on Kupiansk from the north and east, aiming to solidify their presence on the western side of the Oskil River.
The move comes as Zelensky lays the groundwork for either a peace deal and Ukraine's post-war reconstruction, or the continuation of the war, with recent appointments aimed at preparing the country for both.
Russian forces launched 165 strike drones overnight, of which roughly 100 were Shahed-type drones, according to Zelensky. Two of the four wounded victims are in serious condition.
Russia had publicly accused Ukraine of launching 91 drones toward a residence used by Putin — a claim Putin personally conveyed to Trump during the phone call.
Speaking to reporters aboard Air Force One on Jan. 4, Trump said: "We need Greenland from the standpoint of national security."
The Energia factory in Lipetsk Oblast produces components for Russian missiles and drones, including batteries for the Iskander ballistic missile system and cruise missiles.
Kyiv is ready for "both options," Zelensky said: the diplomatic track, or ongoing active defense against Russia. "Ukraine will never surrender," he said.
The death toll has risen as rescue workers uncover the remains of more victims buried beneath the rubble of a destroyed apartment building.
Deineko has been appointed as an adviser to Interior Minister Ihor Klymenko. A permanent replacement to lead the State Border Guard Service will be named shortly, Zelensky said.
PYONGYANG, January 5. /TASS/. Recent events on the international stage require North Korea to strengthen its nuclear deterrent forces, leader Kim Jong Un said while observing the Korean People's Army's fire strike group drills on the launch of hypersonic missiles on January 4.
The Korean Central News Agency quoted the supreme commander-in-chief as saying that strengthening nuclear deterrence forces is required due to "the latest geopolitical crisis and complex international events." Kim Jong Un added that the purpose of the drills was to assess the combat readiness of the hypersonic weapons system and the effectiveness and mobility of North Korea's deterrence forces.
He called testing and improving the characteristics of the main components of the nuclear deterrent forces and practicing the use of such forces an "important strategic task." The leader emphasized that North Korea must "constantly bolster its military capabilities, particularly its offensive weapons systems," as this is necessary for effective self-defense.
"It is also necessary to constantly demonstrate to opponents the constant combat readiness and lethality of strategic offensive weapons," Kim Jong Un stressed. In his opinion, this is one of the most effective ways to deter war.
Hypersonic missiles launched from Pyongyang's Ryongsong district in a northeastern direction struck targets 1,000 kilometers away in the Sea of Japan, which North Korea calls the East Sea.
Live Updates
• Minnesota Gov. Tim Walz this morning issued a statement saying he was dropping his bid for a third term as a welfare-fraud scandal in his state intensified. In a later news conference, he largely read from that statement and didn't take questions.
• The former Democratic nominee for vice president is awash in fallout from a recent viral video that propelled yearslong fraud allegations to the forefront of a national conversation.
• Walz: The state has fought scams, but even small amounts of fraud are intolerable and “the buck does stop with me.”
• Walz is set to testify before a Republican-led US House Oversight Committee next month.
The Trump administration is deploying around 2,000 federal agents to Minneapolis as part of an immigration crackdown and on the heels of a welfare fraud scandal in Minnesota, according to two law enforcement officials.
Senior Trump officials have fixated on Minnesota and its Somali community after accusations of alleged fraud by members of the community. Last month, President Donald Trump called the community “garbage” and sent federal immigration authorities to the state.
The latest mobilization marks an escalation in the immigration enforcement push. Immigration and Customs Enforcement agents, as well as US Border Patrol agents are deploying to Minnesota, including US Customs and Border Protection Commander Gregory Bovino, whose controversial tactics have come under increased scrutiny in multiple cities.
In response to questions about the deployment, DHS Assistant Secretary Tricia McLaughlin told CNN, “While for the safety of our officers we do not get into law enforcement footprint, DHS has surged law enforcement and has already made more than 1,000 arrests of murderers, rapists, pedophiles, and gang members.”
Andy Beshear, the governor of Kentucky and chair of the Democratic Governors Association, praised Minnesota Gov. Tim Walz as “a true leader” after Walz announced he will not seek reelection.
“Governor Tim Walz has been a true leader who has delivered results that will make life better for Minnesota workers and families for years to come,” Beshear said in a release. “He's been a national leader in fighting for the middle class, ensuring free school meals, investing in public schools, and expanding access to affordable health care. As DGA Chair he helped grow our historic momentum and lay the foundation for big wins over the last two years. Above all, as a veteran, educator, coach, and member of Congress, he's also a great example of a public servant always working hard for the people of his state.”
As Democrats and Republicans alike consider throwing their names in the hat for Minnesota governor, Beshear added that the association “remains very confident Minnesotans will elect another strong Democratic governor this November.”
Responding to news that Minnesota Gov. Tim Walz would not seek a third term reelection in this year's governor's race, the Republican Governors Association said Walz' “failed leadership is emblematic of Minnesota Democrats' agenda.”
“After presiding over one of the biggest fraud scandals in history it's no wonder that Tim Walz is being forced to drop his re-election bid,” RGA Communications Director Courtney Alexander said in a statement.
“This scandal isn't just reflective of Minnesota Democrats: it is the banner of the Democrat Party nationally,” she continued.
Walz has not been accused of any wrongdoing, but Republicans have sought to blame him and Democrats for alleged – and in some cases proven – fraud on the part of Minnesota child care providers who accepted federal funding.
The Council on American-Islamic Relations is calling on law enforcement and public officials to “take concrete actions to protect Somali-American day care centers and businesses” in the wake of a viral video alleging fraud in Somali-run child care centers in Minnesota.
Somali-American day care centers and businesses have been targeted with threats and harassment after the video and ensuing scandal, according to CAIR. Minnesota is home to the country's largest Somali population, many of whom came to the US as refugees after the start of a brutal civil war in their home country.
“Baseless and inflammatory allegations targeting an entire community are putting innocent people in danger,” CAIR's national director, Nihad Awad, and the executive director of CAIR's Minnesota chapter, Jaylani Hussein, said in a joint statement. “Somali-American parents are afraid to send their children to school, workers fear showing up to their jobs, and small businesses are suffering, all because of reckless rhetoric dehumanizing a community that has long been an integral part of Minnesota and this nation.”
The video, in which 23-year-old conservative YouTuber Nick Shirley attempted to enter what he said were Somali-owned day care centers, has inspired copycats seeking to do the same, CAIR said.
“We are deeply concerned for the safety and welfare of children attending day care centers who are now facing heightened risks due to unauthorized individuals attempting to access facilities, as well as the very real danger that predators, including those seeking to exploit chaos and fear, may take advantage of this moment,” the CAIR statement reads.
Minnesota Attorney General Keith Ellison lauded Gov. Tim Walz as a “remarkable leader” in a post on X after the governor announced he would drop his bid for a third term.
“Minnesota has benefitted immensely from the compassion he brought to his decades of public service,” Ellison wrote.
He praised the governor's accomplishments, including fighting hunger in Minnesota schools and passing paid family leave.
“Tim's legacy is one of putting people first and delivering for Minnesotans in every corner of our state, and that's a legacy to be damn proud of,” he went on. “Tim led Minnesota through some of the greatest challenges faced by any governor in living memory.”
Both Walz and Ellison have been called to testify before the Republican-led House Oversight Committee in February.
The decision of Minnesota Gov. Tim Walz to drop out of his race for reelection is unlikely to take the heat off from allegations that he allowed fraudsters to take root and steal potentially billions of dollars from the state.
The Republican-led House Oversight Committee in Washington says it will continue to call for Walz to appear at a hearing next month investigating the fraud allegations, which have mostly revolved around the Somali community in the Twin Cities.
“Though Tim Walz is not running for governor again, he cannot run from accountability,” Chairman James Comer said in a statement Monday.
The same committee also has called for Minnesota state representatives to appear Wednesday to testify about “fraud and misuse of federal funds.”
The Trump administration announced last week it would freeze federal child care funding for Minnesota unless it received more information by Friday to verify the money is going to legitimate recipients.
Walz continues to face calls from some Republicans to resign, and state House Speaker Lisa Demuth — a GOP gubernatorial candidate — said a party change is needed.
“If Democrats think they can sweep Minnesota's fraud scandal away by swapping out Tim Walz, they are wrong,” she posted Monday on X.
Walz took no questions after reading his statement Monday but promised to say more later.
“Tomorrow, I'll be back with you … and at that time I'll take all your questions,” Walz said.
All eyes now are on US Sen. Amy Klobuchar.
Klobuchar, who has served Minnesota in the Senate for two decades, is “seriously considering” running for governor, a person close to her tells CNN, after Gov. Tim Walz announced Monday his intention to abandon his bid for reelection.
Klobuchar “has been getting a lot of outreach, encouraging her to run,” the person said, speaking on condition of anonymity to discuss closely held conversations.
While Klobuchar has offered no timeframe for making her decision, whatever conclusion she reaches will have a domino-like effect on the midterm election map. Minnesota already has a wide-open Senate race, to fill the seat of retiring Sen. Tina Smith, as well as competitive House contests.
Klobuchar met with Walz on Sunday, two people familiar with the meeting told CNN, and she is expected to return to the Senate when it reconvenes Monday evening.
Calling Minnesota Gov. Tim Walz a “dedicated public servant who's spent his career putting others before himself,” the governor of neighboring Wisconsin, Tony Evers, praised Walz after the Minnesota Democrat announced he would not seek a third term reelection in 2026.
“Tim has always been a good friend and a good neighbor to us across the river, and I'm incredibly grateful we've had the opportunity to serve as governors of our states together,” Evers said in a statement.
“I look forward to working with Tim in the days and months ahead as we continue getting good things done for the people of our states,” Evers continued.
Walz announced he was dropping out of the 2026 governor's race in the wake of renewed scrutiny and new investigations into claims of fraud in the use of federal child care funding in multiple Minnesota organizations.
Even as he announced his decision to drop out of the gubernatorial race for a third term, Minnesota Gov. Tim Walz defended himself from allegations that he has done too little to address fraud in government funding.
“A single taxpayer dollar wasted on fraud should be intolerable,” Walz said during a news conference Monday. “And while there's a role to play for everyone — from the legislature to prosecutors to insurance companies to local and county government — the buck does stop with me.”
Walz — who took no questions despite an earlier statement from his office saying that he would — argued his administration was already making changes in response to investigations.
“We've gone to the legislature time and time again to get more tools to combat fraud. We've fired people who weren't doing their jobs. We've seen people go to jail for stealing from our state,” Walz said. “We've cut off whole streams of funding, in partnership with the federal government, where we saw widespread criminal activity. We've put new locks on the doors of our remaining programs, and we've hired a new head of program integrity to make sure those locks can't be broken.”
Republicans have disputed the idea that Walz has demanded accountability.
“No one's lost their job,” state House Speaker Lisa Demuth said last week. “No one has been publicly disciplined in any way.”
The Republican chairman of the House Oversight Committee said Monday he expects Minnesota Gov. Tim Walz to still appear for a public hearing next month, even though he is no longer running for reelection.
“Massive fraud of taxpayer dollars occurred on Tim Walz's watch. He's either complicit in this theft or grossly incompetent in preventing it. Though Tim Walz is not running for governor again, he cannot run from accountability,” Chairman James Comer, the Kentucky Republican, said in a statement.
Comer previously announced his panel expects to hear testimony from Walz and Minnesota Attorney General Keith Ellison in a hearing on Minnesota fraud allegations on February 10.
The committee has separately called Minnesota state representatives to appear before the panel on Wednesday about “fraud and misuse of federal funds” in the state.
Minnesota Gov. Tim Walz took no questions at a news conference held hours after announcing he was dropping his reelection bid for a third term.
The governor briefly read the news release put out hours earlier and condemned Republicans, “conspiracy theorist right wing YouTubers,” and President Donald Trump, before promising another news conference tomorrow and said he would take questions at that time.
Speaking at a news conference Monday, Gov. Tim Walz seemed to be largely reading from the statement his office released earlier in the day announcing he would not seek reelection.
He said he was confident he would have won a third term if he stayed in the race, but he had come “to the conclusion that I can't give a political campaign my all.”
The governor's attitude was defiant as he called out what he characterized as politicization of the state's fraud scandals by Republicans.
“We've got conspiracy theorist right-wing YouTubers breaking into day care centers and demanding access to our children,” he said. “We've got the President of the United States demonizing our Somali neighbors and wrongly confiscating child care funding that Minnesotans rely on. It is disgusting. And it is dangerous.”
Minnesota Gov. Tim Walz's news conference is now starting.
The governor announced he would drop out of his bid for a third term Monday morning, following a scandal from a viral video alleging fraud involving federal child care funding in the state.
Opponents of Minnesota Gov. Tim Walz took to social media to pile on after news broke this morning that he would be dropping his bid for a third term.
Nick Shirley, the conservative YouTuber behind the viral video alleging fraud at Minnesota child care facilities, appears to have taken credit for the announcement.
“I ended Tim Walz,” Shirley posted on X soon after the news.
When Walz announced he wouldn't run again, he cited a need to focus on “defending the people of Minnesota against the criminals who prey on our generosity and the cynics who prey on our differences.”
Republicans have sought to blame Walz and Democrats for what they say is a massive abuse of taxpayer dollars. Walz has not been accused of any wrongdoing.
State Rep. Lisa Demuth, speaker of the Minnesota House and Republican candidate for Minnesota governor, said she would defeat any Democrat the party chooses to run against her.
“If Democrats think they can sweep Minnesota's fraud scandal away by swapping out Tim Walz, they are wrong,” she posted on X.
Another Republican member of the Minnesota House, gubernatorial candidate Kristin Robbins, accused Walz of dropping out to avoid the fraud investigations.
“He knows he will lose in November, and would rather give up than take responsibility,” she said.
States will be allowed to verify child care center attendance records and require services up front before releasing federal funds to child care providers, the US Department of Health and Human Services announced this morning, touting a pending change to rules established during the Biden administration.
“The change will roll back provisions in the 2024 Child Care and Development Fund rule that weakened oversight and increased the risk of waste, fraud and abuse in federally funded state child care — including programs now under investigation in Minnesota,” a news release from HHS said.
The 2024 rules required states to base payments on enrollment as opposed to attendance, and gave preference in funding to contracted providers — a practice the pending changes also would end, HHS said.
The proposed changes are subject to a 30-day public comment period, according to HHS.
State officials must supply the federal government with a trove of information about the recipients of child care funding by January 9, an HHS spokesperson told CNN.
The deadline comes after HHS froze all funding for child care in the state, throwing families and providers both into limbo. Typically, the state receives about $185 million annually in federal child care funding, supporting care for 19,000 children.
The federal government has asked the state to provide information about the total amount of funding received by five specific centers as well as documentation about “attendance, inspections, assessments,” according to a bulletin sent to child care providers by the Minnesota Department of Children, Youth, and Families and shared with CNN.
Additionally, the state has to provide administrative data – like names and social security numbers – for all recipients of child care funding.
The government may withhold funds “and impose other penalties if satisfactory responses are not provided,” according to the bulletin.
A video posted by conservative content creator Nick Shirley last month featured disputed claims of fraud against specific day care centers but the larger issue of fraudulent use of government funds in Minnesota's Somali community has been investigated for years, and allegations the Walz administration did not do enough to stop it helped lead to the end of his reelection campaign.
The first blockbuster fraud investigation was revealed in 2022, when the Justice Department announced indictments against people associated with Feeding Our Future, a nonprofit group which allegedly pocketed money that was supposed to be going to feed needy children during the Covid-19 pandemic.
Charges have been brought against more 78 people associated with the organization, according to the US Attorney's Office for the District of Minnesota, with more than $300 million lost. The vast majority of those indicted are of Somali ancestry, although the group's founder – who prosecutors have called the “mastermind” of the deception – is not.
In addition to Feeding Our Future, federal indictments have been brought against at least 20 other people accused in fraud cases related to housing and autism services, Assistant US Attorney Melinda Williams told CNN last week.
President Donald Trump has called Minnesota a “hub of fraudulent money laundering activity” in Minnesota, announcing plans in November to terminate Temporary Protected Status for Somali residents in the state. In December, ICE launched operations in the Minneapolis-St. Paul area to specifically target undocumented Somali immigrants.
Minnesota Gov. Tim Walz is dropping his bid for a third term as the welfare-fraud scandal in his state has intensified, he announced this morning.
“I can't give a political campaign my all,” Walz said in a release. “Every minute I spend defending my own political interests would be a minute I can't spend defending the people of Minnesota against the criminals who prey on our generosity and the cynics who prey on our differences.”
Walz has not been accused of any wrongdoing, but Republicans have sought to blame him and Democrats for the massive abuse of taxpayer dollars.
In his statement announcing his decision, Walz took aim at President Donald Trump, accusing him of seeking to politicize the scandal by attacking the Somali population in Minnesota.
“I won't mince words here. Donald Trump and his allies — in Washington, in St. Paul, and online — want to make our state a colder, meaner place,” he said. “They want to poison our people against each other by attacking our neighbors.”
Walz is scheduled to hold a news conference today at 11 a.m. CT (noon ET) in St. Paul.
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DHS public affairs assistant secretary Tricia McLaughlin discusses the capture of Nicolas Maduro and the Trump administration's continuing crackdown on illegal immigration on ‘The Big Weekend Show.'
Venezuelan authorities have been ordered to find and arrest anyone involved in supporting the military operation that led to the arrest of Nicolás Maduro.
A state of emergency decree issued Saturday, but published Monday, orders police to "immediately begin the national search and capture of everyone involved in the promotion or support for the armed attack by the United States," according to the text of the decree, Reuters reported.
It was not clear what charges could be levied against those taken into custody.
Maduro made his first court appearance Monday in New York, days after he and his wife were arrested by U.S. forces over the weekend.
FETTERMAN DEFENDS TRUMP'S VENEZUELA MILITARY OPERATION AGAINST CRITICISM FROM FELLOW DEMOCRATS
Government supporters hold dolls from the TV program, Super Bigote, based on President Nicolás Maduro and first lady Cilia Flores, during a protest demanding their release from U.S. custody in Caracas, Venezuela on Sunday. The government has ordered police to search for and arrest anyone involved in supporting the U.S. military operation that happened over the weekend. (AP Photo/Ariana Cubillos)
Both have been charged by the Justice Department with narco-terrorism and other offenses.
"I am innocent. I am not guilty of anything that is written here," Maduro said in court as the charges against him were read.
DEMOCRATS LABEL TRUMP'S VENEZUELA OPERATION AN 'IMPEACHABLE OFFENSE'
A side-by-side photo of President Donald Trump and Venezuelan Vice President Delcy Rodriguez. (Joe Raedle/Kirill Kudryavtsev/AFP/Getty Images)
In Maduro's absence, Delcy Rodríguez, his former number two, has been sworn in as the interim president of Venezuela. Rodriguez, 56, has long been a confidant and backer of Maduro.
She was the country's vice president from 2018 through Sunday.
Despite denouncing the U.S. military operation, Rodriguez said in a Sunday social media post that the country aspires towards balanced and respectful international relations between Caracas and Washington.
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"We invite the US government to collaborate with us on an agenda of cooperation oriented towards shared development within the framework of international law to strengthen lasting community coexistence," she wrote.
Louis Casiano is a reporter for Fox News Digital. Story tips can be sent to louis.casiano@fox.com.
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Live Updates
• Maduro in court: A defiant Nicolás Maduro and his wife Cilia Flores entered not guilty pleas in their first court appearance in New York after being captured in a US military operation. The ousted leader, who faces drugs and weapons charges, told the judge he's “still the president of Venezuela.” The couple is not seeking bail for now. Sigue nuestra cobertura en español.
• Venezuela's uncertain future: President Donald Trump said the US, which has not recognized Maduro as the country's legitimate leader, is “in charge,” as acting president Delcy Rodríguez called for “cooperation” with the US. Trump previously said he's counting on American companies to rebuild Venezuela's battered oil industry. Meanwhile, Venezuelans are hunkering down amid apprehension of what may come next.
• Trump's threats: Trump implied he could take military action in Colombia, told Mexico to get its “act together” on drugs, and said the US “needs Greenland.”
Before even getting to the evidence of the charges against Nicolás Maduro, his lawyers are likely to argue that he is not legally in custody in the first place, CNN's chief law enforcement and intelligence analyst John Miller said.
The first thing Maduro's legal team will do will be to “attack the arrest and the legitimacy of his custody,” Miller said. In court today, Maduro's lawyer, Barry Pollack, told the judge that there are issues with the legalities of his client's military abduction.
Maduro himself also said in court that he was captured at his home and insisted that he is the president of Venezuela — another point his legal team will likely argue early on in the process, Miller said.
Pollack told the judge that Maduro is the head of a sovereign state and is entitled to the privilege and immunity of that office. However, that is disputed, with the United States not recognizing Maduro or his regime as the legitimate government after several disputed elections.
Nicolás Maduro's first court appearance in New York today has had a “show aspect” to it, CNN Senior Justice Correspondent Evan Perez said on air.
“They paraded him in front of cameras,” Perez said while outside the court on Monday. “This is very unusual in federal court here in the federal system.”
“Usually, you don't have mugshots of people released because of the danger that (it) poses for their ability to present their defense, innocent until proven guilty,” he added.
Perez noted that as the president of another country, Maduro is used to calling the shots himself.
“He's used to running things himself, he's used to being able to issue orders and decide how things (are) going,” Perez said.
Within minutes of his first federal court appearance, Venezuelan president Nicolás Maduro stood before a judge and said, “I was captured at my home in Caracas, Venezuela.”
The statement previews what is likely to be one of the main defenses: that his dead of night arrest in a foreign country by US law enforcement – a “military abduction,” in his attorney's words – violated the law.
It's not the first time that a defendant has made this argument. Over three decades ago, Panama's Manuel Noriega accused the US of violating both international law and due process protections by invading Panama and arresting him abroad.
But that argument was unsuccessful, as the courts refused to consider the legality of the Panama invasion itself and only focused on the allegations in Noriega's indictment. Whether courts will reconsider that precedent in Maduro's case remains to be seen.
It is unusual to for a criminal defendant to say anything to a judge during an initial appearance, as defense attorneys typically warn their clients that anything they say could be used in their prosecution.
Judge Alvin Hellerstein made a similar warning to Maduro on Monday as the Venezuelan president spoke.
“There will be a time and a place to go into all of this,” the judge said.
Jorge Rodríguez, the brother of Venezuela's acting President Delcy Rodríguez, has been re-appointed President of the National Assembly.
Lawmakers reelected him to lead parliament on Monday with overwhelming support.
This puts the Rodriguez siblings in control of Venezuela's executive and legislative branches.
Ousted Venezuelan leader Nicolás Maduro is speaking using a translator during his first court appearance in New York today — something that could make it more difficult for the judge to limit the scope of Maduro's answers.
CNN senior legal analyst Elie Honig said the former Venezuelan leader “seems to be answering a little bit more than the judge is asking for.”
For example, when entering a plea, Maduro said, “I am innocent, I am not guilty.” He also added that he was “a decent man.” When he was asked by the judge to confirm his name, Maduro said he was the president of Venezuela and said he was captured at his home.
When answers and responses are going through a translator, “it's harder for a judge to control the proceedings, because if someone's speaking in English, the judge can just cut them off if he's saying too much,” Honig said.
In this case, the judge has to wait for everything to be translated. “So we'll see to what extent Maduro is disciplined and stays within the parameters of the court,” Honig added.
Crowds of people have been gathering near the New York courthouse where ousted Venezuelan President Nicolás Maduro is currently appearing.
Two groups divided into opposite pens were on scene to demonstrate, some cheering on his capture and others protesting against it.
People waving Venezuelan flags were seen shouting chants including: “Who are we? Venezuela! What do we want? Libertad!”
One person was seen waving a large flagpole with a Venezuelan flag, as well as a flag that said “Trump for king.” Another person held a sign reading, “Free our political prisoners in Venezuela.”
Others were seen holding banners reading, “Free President Maduro.” They were also waving Venezuelan flags.
Ousted Venezuelan President Nicolás Maduro is making his first court appearance in New York after his capture following a US operation on Saturday. He is facing drug and weapons charges.
Here's what we can expect from today's hearing, according to CNN's senior legal analyst Elie Honig.
Energy and oil stocks jumped higher Monday as investors assessed the prospect of US companies gaining access to Venezuela's oil reserves and the country's drilling potential.
Oil stocks' gains reflect expectations that US companies might benefit as President Donald Trump says the US will revamp Venezuela's oil industry.
While oil stocks surged, oil prices rose by roughly 1.3%. Venezuela's beleaguered oil infrastructure and the challenges associated with ramping up production make the recent developments less consequential for global oil markets.
“Venezuela's global economic importance has diminished significantly over the past 50 years,” Neil Shearing, group chief economist at Capital Economics, said in a note.
“In theory, Venezuela could again become a major producer,” Shearing said. “But theory and reality diverge sharply … Venezuela's oil infrastructure has also been heavily degraded by decades of underinvestment and much of Venezuela's oil is extremely heavy, making it relatively costly to extract and process.”
The capture of Venezuela's President Nicolas Maduro was a “law enforcement operation,” the United States envoy to the United Nations said Monday, stressing that the US is “not occupying a country.”
Mike Waltz described US military action in Venezuela on Saturday as a “surgical law enforcement operation facilitated by the US military against two indicted fugitives of American justice: narco-terrorist Nicolas Maduro and (his wife) Cilia Flores.”
He told a UN Security Council meeting that Maduro is “responsible for attacks on the people of the United States, for destabilizing the western hemisphere and illegitimately repressing the people of Venezuela.”
“There is no war against Venezuela or its people. We are not occupying a country,” Waltz said.
The envoy said that US President Donald Trump – who said Saturday that the US will “run” Venezuela until a “safe, proper and judicious transition” can be ensured – had “(given) diplomacy a chance,” which he claimed Maduro failed to take.
“The United States wants a better future for Venezuela. We believe a better future for the people of Venezuela and for the people of the region and the world is stabilizing the region and making the neighborhood that we live in a much better and safer place,” Waltz said.
Russia's envoy to the United Nations on Monday called for the United States to release Venezuela's President Nicolas Maduro, and warned that Washington's actions could usher in a new era of colonialism and imperialism.
“The assault against the leader of Venezuela… has become a harbinger of a turn back to the era of lawlessness and US domination by force,” Vasily Nebenzya said at a meeting of the UN Security Council.
Russia condemned the “US act of armed aggression against Venezuela” and called for Washington “to immediately release the legitimately elected president of an independent state and his spouse,” Cilia Flores.
“Washington is generating fresh momentum for neocolonialism and for imperialism, which were repeatedly and decisively condemned and repudiated by the peoples of this region and by the global south as a whole… The bell now tolls across the region, ringing for every country of the Western Hemisphere,” Nebenzya said.
Given the US actions, the envoy said “those who, in other circumstances, froth at the mouth and demand that others respect the UN Charter, today seem particularly hypocritical and unseemly,” in apparent reference to Western criticism of Russia for its all-out invasion of Ukraine in 2022.
The National Assembly of Venezuela began a new legislative term on Monday, in which lawmakers reiterated that Executive Vice President Delcy Rodríguez had assumed the role of acting president.
They also demanded the release of Venezuelan President Nicolás Maduro and his wife, Cilia Flores, who were captured on Saturday in a US military operation in Caracas. Rodríguez became acting president on Sunday following an order from the Supreme Court.
“The president of the Bolivarian Republic of Venezuela, Nicolás Maduro Moros, has been kidnapped by the government of the United States, in a barbaric, treacherous, and cowardly attack,” said pro-government deputy Fernando Soto Rojas, debate director for the parliamentary session.
“The president of the United States, Mr. Trump, intends to be prosecutor, judge, and policeman of the world. From Bolivarian Venezuela, we say to him: “you will not succeed. And we are now going to develop full solidarity so that our legitimate president, Nicolás Maduro, returns victorious,”” he insisted.
The session is held days after Maduro's capture, which has been condemned by the government of Venezuela and some other Latin American countries, including Cuba, Colombia, Chile, Mexico, and Uruguay.
Deposed Venezuelan leader Nicolás Maduro will be represented Monday by Barry Pollack, a deeply experienced US trial attorney who represented Julian Assange and brokered the deal for his plea deal and release last summer.
Mark Donnelly, a white collar lawyer from Houston and a former Justice Department prosecutor, notified the court he will represent Maduro's wife, Cilia Flores. Donnelly's firm biography says he speaks Spanish.
Pollack doesn't come from the typical world of lawyers who represent defendants in drug trafficking cases. Instead, he specializes in more unusual white collar and national security matters, especially ones with an intense political cross-section.
He briefly represented Pras Michel, the former Fugees star convicted in a sprawling campaign finance case.
This post has been corrected to reflect that Pollack represented Assange in the past.
Abandoning the United Nations (UN) Charter and its prohibition of the kind of action undertaken by US President Donald Trump against Venezuela “would carry consequences of the gravest kind,” according to economist Jeffrey Sachs.
Speaking at a meeting of the UN Security Council on Monday, Sachs called on member states to consider the wider implications of their reaction to Washington's decision to carry out military strikes on Venezuela and detain deposed leader Nicolás Maduro and his wife Cilia Flores.
“The issue before the council today is not the character of the government of Venezuela,” Sachs said.
“The issue is whether any member state, by force, coercion or economic strangulation, has the right to determine Venezuela's political future or to exercise control over its affairs,” he said, adding that such actions contravene the UN charter.
“The council must decide whether that prohibition is to be upheld or abandoned,” Sachs said. “Abandoning it would carry consequences of the gravest kind.”
“Peace and the survival of humanity depend on whether the United Nations Charter remains a living instrument of international law or is allowed to wither into irrelevance,” he said.
“That is the choice before this Council today.”
The Justice Department unsealed a superseding indictment on Saturday against ousted Venezuelan President Nicolás Maduro, along with his wife Cilia Flores, his son Nicolás Maduro Guerra and other Venezuelan officials.
In the indictment, federal prosecutors in New York allege that “for over 25 years, leaders of Venezuela have abused their positions of public trust and corrupted once-legitimate institutions to import tons of cocaine into the United States.”
Maduro was “at the forefront of that corruption,” the indictment says, and used “his illegally obtained authority and the institutions he corroded to transport thousands of tons of cocaine to the United States.”
According to the indictment, Maduro, in various government roles, provided Venezuelan diplomatic passports to drug traffickers, gave diplomatic cover to planes used to launder drug money from Mexico to Venezuela, and his co-conspirators, “partnered with some of the most violent and prolific drug traffickers and narco-terrorists in the world” for their own profit.
Flores is accused, among other things, of accepting “hundreds of thousands of dollars in bribes to broker a meeting between a large-scale drug trafficker and the director of Venezuela's National Anti-Drug Office” in 2007.
While allegedly trafficking cocaine between 2004 and 2015, Maduro and Flores jointly “ordered kidnappings, beatings, and murders against those who owed them drug money or otherwise undermined their drug trafficking operation, including ordering the murder of a local drug boss in Caracas, Venezuela,” the indictment alleges.
Maduro is indicted on four counts: narco-terrorism conspiracy, cocaine importation conspiracy, possession of machine guns and destructive devices and conspiracy to possess machine guns and destructive devices.
Flores is facing counts of cocaine importation conspiracy, possession of machine guns and destructive devices and conspiracy to possess machine guns and destructive devices.
UN Secretary-General Antonio Guterres said that he is “deeply concerned that rules of international law have not been respected” during US military action in Venezuela.
In a statement read out at a meeting of the UN Security Council on Monday, Guterres stressed that international law “provides the foundation for the maintenance of international peace and security.”
He also highlighted concerns around the knock-on effects of the detainment of deposed Venezuelan leader Nicolás Maduro and his wife Cilia Flores.
“I am deeply concerned about the possible intensification of instability in the country, the potential impact on the region and the precedent it may set for how relations between and among states are conducted,” Guterres said.
“Venezuela has experienced decades of internal instability and social and economic turmoil,” he said.
“Democracy has been undermined. Millions of its people have fled the country. The situation is critical, but it is still possible to prevent a wider and more destructive conflagration,” Guterres added.
“In situations as confused, as complex, as the one we now face, it is important to stick to principles,” he said.
“International law contains tools to address issues such as illicit traffic in narcotics, disputes about resources and human rights concerns,” added Guterres.
“This is the route we need to take.”
In the early hours of Saturday morning, US President Donald Trump announced that Venezuela's President Nicolás Maduro and his wife Cilia Flores had been “captured and flown out of the country.”
Here's what we know about what's happened to him since then:
CNN's Simone Pathe, Kevin Liptak, Kit Maher, Emma Tucker, Bonney Kapp, Omar Jimenez and Alejandra Jaramillo contributed to this reporting.
The morning after US forces bombed Caracas, dragged President Nicolás Maduro out of bed, carted him over the Caribbean and installed him in a Brooklyn jail, many Venezuelans hurried to the grocery store.
“Why did I have to go out?” said Judith Ledezma. “I have a pet that needs exercise and I was really stressed out staying indoors.”
Her orange dog sat beside her on a park bench in Caracas, along with numerous shopping bags. Ledezma, who lives near one of the airbases hit by US airstrikes, told CNN the noise from the attack woke her up.
“I thought it was an earthquake,” Ledezma said. “I got scared and came running out with my daughter and the dog.”
“We have no idea what our fate will be now with this new situation,” Ledezma continued. “I am completely in the dark. I have no idea what is going to happen to the country, to us.”
The government in Caracas wants Venezuelans out and about, though the streets are quiet, apart from a few militia members mustering with their motorcycles. Defense Minister Vladímir Padrino Lopez told people Sunday to “resume their economic activities, work, and all other types of activities, including educational activities, in the coming days.”
Olga Jimenez told CNN she finally left her house on Sunday after staying in all of Saturday. Maduro or no Maduro, Jimenez said, she doesn't expect much to change in Venezuela – except maybe the lines at the shops. Maria Azocar, meanwhile, told CNN that “having lived through so much, nothing really worries me anymore.”
Read more about what Venezuelans are saying in Caracas. And follow our live coverage in Spanish of the situation in the country here.
Delcy Rodríguez, who was Venezuela's vice president under Nicolás Maduro, has now become the country's acting president.
Rodríguez – who was also minister for both finance and oil – stepped into the role on Saturday afternoon after an order from Venezuela's Supreme Court.
The 56-year-old is from Caracas and studied law at the Central University of Venezuela. She has spent more than two decades as one of the leading figures of Chavismo, the political movement founded by the Venezuela's late President Hugo Chávez and led by Maduro since Chávez's death in 2013.
After the capture of Maduro and Flores, Rodríguez accused the US of “kidnapping” her country's leader and said that violations of international law were committed, accusing US forces of having “savagely attacked” Venezuela's territorial integrity.
Following remarks from US President Donald Trump that Rodriguez would face a worse fate than Maduro if she doesn't “do the right thing,” the acting Venezuelan leader softened her reaction, extending an invitation to the United States government to collaborate on an “agenda of cooperation.”
“President Donald Trump: our peoples and our region deserve peace and dialogue, not war. This has always been President Nicolás Maduro's message, and it is a message of all Venezuela right now,” Rodríguez said in comments made directly to the US president.
“Venezuela has the right to peace, to development, to sovereignty and to a future,” she added.
Read more about Delcy Rodríguez and her role in the Venezuelan government.
CNN's Helen Regan contributed to this reporting.
As we reported earlier, ousted Venezuelan President Nicolás Maduro and his wife Cilia Flores were transported from the Metropolitan Detention Center to a New York courthouse this morning,
They were heavily flanked by armed Drug Enforcement Administration Agents.
If you missed it, take a look at photos from their transfer:
Colombian President Gustavo Petro has warned that would “take up arms” if the US decides to attack him or his country following a series of threats from President Donald Trump.
In a post on X, Petro underlined his efforts to combat drug trafficking, which Trump has criticized, and went on to claim that US military strikes against traffickers in Colombia would risk killing children and driving recruitment for separatist groups that have been in conflict with the state for decades.
“And if they arrest a president that has the support and respect of a large part of the country, they will unleash a popular uprising,” he added.
Petro, a former member of the M19 guerilla group, also said that he would himself fight to defend Colombia.
“I swore not to touch a weapon again … but for the homeland I will take up arms again,” he said.
Trump had harsh words for Petro on Sunday, describing him as “a sick man who likes making cocaine and selling it to the United States, and he's not going to be doing it very long.”
When pressed by a reporter if those comments meant there could be an “operation” in Colombia in the future, Trump responded, “sounds good to me.”
Speaking to The New York Times on Monday, Colombia's defense minister Pedro Sánchez refused to address Trump's threats, instead emphasizing that the two countries have “a very close relationship.”
Sánchez said he remains in communication with US officials, and that possible military strikes on Colombia have not been discussed during recent conversations, the Times reported.
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Nicolás Maduro and his wife are set to make his first appearance Monday in a U.S. courtroom on the narco-terrorism charges the Trump administration used to justify capturing him and bringing him to New York.
U.S. President Donald Trump spoke to reporters on Air Force One on Sunday. Trump said he wanted Venezuela's vice president, Delcy Rodríguez, to provide “total access” to the country. He also commented on the 32 Cuban security officers killed in Venezuela.
Protesters gathered outside a courthouse Monday to denounce the U.S. government's moves in Venezuela. Chants like “No boots on the ground, no bombs in the air! U.S. out of everywhere!” were heard.
An armored vehicle carrying Venezuelan President Nicolas Maduro and his wife Cilia Flores arrives at Manhattan Federal Court, Monday, Jan. 5, 2026, in New York. (AP Photo/Stefan Jeremiah)
Venezuela's President Nicolas Maduro places his hand over his heart while talking to high-ranking officers during a military ceremony on his inauguration day for a third term, in Caracas, Venezuela, Jan. 10, 2025. (AP Photo/Ariana Cubillos, File)
Reward posters are passed out at a gathering celebrating the deposing of Venezuelan President Nicolás Maduro, Sunday, Jan. 4, 2026, in Katy, Texas. (Elizabeth Conley/Houston Chronicle via AP)
People protest outside Manhattan Federal Court before the arraignment of Venezuelan President Nicolas Maduro, Monday, Jan. 5, 2026, in New York. (AP Photo/Stefan Jeremiah)
An armored vehicle carrying Venezuelan President Nicolas Maduro and his wife Cilia Flores arrives at Manhattan Federal Court, Monday, Jan. 5, 2026, in New York. (AP Photo/Stefan Jeremiah)
NEW YORK (AP) — A defiant Nicolás Maduro declared himself the “president of my country” as he protested his capture and pleaded not guilty on Monday to the federal drug trafficking charges that the Trump administration used to justify removing him from power.
“I was captured,” Maduro said in Spanish as translated by a courtroom reporter before being cut off by the judge. Asked later for his plea to the charges, he stated: "“I'm innocent. I am not guilty. I am a decent man, the president of my country.”
The courtroom appearance, Maduro's first since he and his wife were seized from their home in a stunning middle-of-the-night military operation, kick-starts the U.S. government's most consequential prosecution in decades of a foreign head of state. The criminal case in Manhattan is unfolding against the diplomatic backdrop of an audacious U.S.-engineered regime change that President Donald Trump has said will enable his administration to “run” the South American country.
Maduro, wearing a blue jail uniform, was led into court along with his co-defendant wife just before noon for the brief, but required, legal proceeding. Both put on headsets to hear the English-language proceeding as it is translated into Spanish.
The couple were transported to the Manhattan courthouse under armed guard early Monday from the Brooklyn jail where they've been detained since arriving in the U.S. on Saturday.
Stay up to date with the news and the best of AP by following our WhatsApp channel.
The trip was swift. A motorcade carrying Maduro left jail around 7:15 a.m. and made its way to a nearby athletic field, where Maduro slowly made his way to a waiting helicopter. The chopper flew across New York harbor and landed at a Manhattan heliport, where Maduro, limping, was loaded into an armored vehicle.
AP correspondent Julie Walker reports Maduro's case will revive a legal debate over immunity for foreign leaders tested in Noriega trial.
A few minutes later, the law enforcement caravan was inside a garage at the courthouse complex, just around the corner from the one where Trump was convicted in 2024 of falsifying business records. Across the street from the courthouse, the police separated a small but growing group of protesters from about a dozen pro-intervention demonstrators, including one man who pulled a Venezuelan flag away from those protesting the U.S. action.
As a criminal defendant in the U.S. legal system, Maduro will have the same rights as any other person accused of a crime — including the right to a trial by a jury of regular New Yorkers. But he'll also be nearly — but not quite — unique.
Maduro's lawyers are expected to contest the legality of his arrest, arguing that he is immune from prosecution as a sovereign head of state.
Panamanian strongman Manuel Noriega unsuccessfully tried the same defense after the U.S. captured him in a similar military invasion in 1990. But the U.S. doesn't recognize Maduro as Venezuela's legitimate head of state — particularly after a much-disputed 2024 reelection.
Venezuela's new interim president, Delcy Rodríguez, has demanded that the U.S. return Maduro, who long denied any involvement in drug trafficking — although late Sunday she also struck a more conciliatory tone in a social media post, inviting collaboration with Trump and “respectful relations” with the U.S.
Before his capture, Maduro and his allies claimed U.S. hostility was motivated by lust for Venezuela's rich oil and mineral resources.
The U.S. seized Maduro and his wife in a military operation early Saturday, capturing them in their home on a military base. Trump said the U.S. would “run” Venezuela temporarily, but Secretary of State Marco Rubio said Sunday that it would not govern the country day-to-day other than enforcing an existing " oil quarantine.”
Trump suggested Sunday that he wants to extend American power further in the Western Hemisphere.
Speaking aboard Air Force One, he called Colombia's president, Gustavo Petro, “a sick man who likes making cocaine and selling it to the United States. And he's not going to be doing it very long.”
He called on Venezuela's Rodriguez to provide “total access” to her country, or else face consequences.
Trump has suggested that removing Maduro would enable more oil to flow out of Venezuela, but oil prices rose a bit more than 1% in Monday morning trading to roughly $58 a barrel. There are uncertainties about how fast oil production can be ramped up in Venezuela after years of neglect and needed investments, as well as questions about governance and oversight of the sector.
A 25-page indictment made public Saturday accuses Maduro and others of working with drug cartels to facilitate the shipment of thousands of tons of cocaine into the U.S. They could face life in prison if convicted.
He and his wife, Cilia Flores, have been under U.S. sanctions for years, making it illegal for any American to take money from them without first securing a license from the Treasury Department.
While the indictment against Maduro says Venezuelan officials worked directly with the Tren de Aragua gang, a U.S. intelligence assessment published in April, drawing on input from the intelligence community's 18 agencies, found no coordination between Tren de Aragua and the Venezuelan government.
Maduro, his wife and his son — who remains free — are charged along with Venezuela's interior and justice minister, a former interior and justice minister and Hector Rusthenford Guerrero Flores, an alleged Tren de Aragua leader who has been criminally charged in another case and remains at large.
Among other things, the indictment accuses Maduro and his wife of ordering kidnappings, beatings and murders of those who owed them drug money or undermined their drug trafficking operation. That included a local drug boss' killing in Caracas, the indictment said.
Maduro's wife is also accused of accepting hundreds of thousands of dollars in bribes in 2007 to arrange a meeting between “a large-scale drug trafficker” and the director of Venezuela's National Anti-Drug Office, resulting in additional monthly bribes, with some of the money going to Maduro's wife, according to the indictment.
___
Tucker reported from Washington. Associated Press writers John Hanna in Topeka, Kan., Josh Boak in Washington, Darlene Superville aboard Air Force One and Joshua Goodman in Miami contributed to this report.
Copyright 2026 The Associated Press. All Rights Reserved.
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NASA's 15th administrator Jared Isaacman discusses President Donald Trump's executive order aimed at advancing America's space policy on ‘The Will Cain Show.'
FIRST ON FOX: Recently confirmed NASA Administrator Jared Isaacman is moving to demolish several testing facilities in Alabama as the space agency looks to modernize its infrastructure under Isaacman's new leadership.
The agency will demolish the Dynamic Test Stand and the Propulsion and Structural Test Facility, known as the T-Tower at the Marshall Space Flight Center in Huntsville, Alabama. The removal is set to begin Saturday, Jan. 10.
"NASA is embarking on an exciting infrastructure modernization effort to prepare for the future of exploration," Isaacman told Fox News Digital in a statement. "The first phase will make way for new facilities by retiring outdated ones, enabling investments in the capabilities needed to deliver on our world-changing mission of science and discovery."
Sources at NASA tell Fox News Digital the demolition of the facilities is the first step in an initiative to remove 25 outdated structures at the Alabama flight center.
INSIDE NASA'S FAST-TRACK PLANS FOR LUNAR NUCLEAR POWER AND NEW SPACE STATIONS TO OUTPACE GLOBAL RIVALS
Recently confirmed NASA Administrator Jared Isaacman is moving quickly to modernize the agency, ordering the demolition of historic testing facilities at Marshall Space Flight Center as part of a broader infrastructure overhaul backed by new federal funding. (Patrick T. FALLON / AFP / Getty Images)
Funding for updated facilities at the Marshall Space Flight Center comes from the One Big Beautiful Bill Act, which was signed into law by President Donald Trump last July. Isaacman and the agency are looking to utilize the funding to bolster NASA's infrastructure broadly, beyond the Alabama location.
The Propulsion and Structural Test Facility ("T-Tower") was originally constructed by the U.S. Army Ballistic Missile Agency in 1957 before being given to NASA to test boosters featured on Space Shuttle solid rocket boosters and Saturn launch vehicles.
The SpaceX Falcon 9 rocket and Dragon spacecraft launch from the Launch Complex 39A at NASA's Kennedy Space Center on March 14, 2025 in Cape Canaveral, Florida. (Brandon Bell/Getty Images)
The Dynamic Test Stand was built in 1964 and is used for conducting mechanical and vibrational testing. The facility tested the Saturn V rockets as well as the Space Shuttles.
TRANSPORTATION SECRETARY DUFFY TO ANNOUNCE NUCLEAR REACTOR DEVELOPMENT PLAN FOR THE MOON
Jared Isaacman, President Donald Trump's nominee to be National Aeronautics and Space Administration (NASA) administrator, was confirmed by the Senate on December 17, 2025. (Kevin Dietsch/Getty Images)
Isaacman was confirmed by the Senate in a 67–30 vote on Dec. 17, 2025, after the Trump administration pulled his nomination earlier in the year. Department of Transportation Secretary Sean Duffy served as acting administrator before Isaacman was renominated.
The decision to demolish the nearly 70-year-old facilities comes in the new administrator's first month of running America's top space exploration agency.
Isaacman, a 42-year-old billionaire entrepreneur and space fanatic, founded and served as CEO of Shift4 Payments and his passion for space led him to command the first all-civilian orbital space mission in 2021, and complete the first-ever commercial spacewalk in 2024.
President Donald Trump issued an executive order to promote space exploration the day after Isaacman's confirmation. (Reuters)
The NASA administrator faces tall orders from the White House after Trump signed an executive order the day after Isaacman's confirmation stating the U.S. will be the first to land on Mars and will continue moon exploration.
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"We will lead humanity back to the moon, and the United States will be the first nation to land an astronaut on Mars," Trump stated.
The executive order also calls for Americans' return to the moon by 2028, the deployment of nuclear reactors on the moon and in orbit by 2030, and promoting private sector investment by upgrading launch infrastructure and developing a commercial pathway to replace the International Space Station by 2030.
Preston Mizell is a writer with Fox News. Story tips can be sent to Preston.Mizell@fox.com and on X @MizellPreston
Preston Mizell is a writer with Fox News Digital covering breaking news.
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Secretary of War Pete Hegseth issued a letter of censure and moved to demote retired captain and sitting Sen. Mark Kelly (D-AZ) over a video he and other lawmakers made warning service members not to carry out illegal orders.
Hegseth announced the decision on Monday, saying that the department “has initiated retirement grade determination proceedings under 10 U.S.C. § 1370(f), with reduction in his retired grade resulting in a corresponding reduction in retired pay.” He also issued a letter of censure, which he said will be in Kelly's permanent military personnel file.
There was a possibility the review could result in Hegseth recalling Kelly to active duty to court-martial him, though he made no mention of it in his Monday announcement.
Kelly and five other Democrats, who had either served in the military or intelligence community, participated in the video, which was released in November 2025. In the video, they specifically reminded service members of their legal obligation not to follow illegal orders, though Hegseth and President Donald Trump have accused them of trying to sow doubts to have service members question their orders.
Kelly responded to the letter, vowing to “fight” the demotion.
“My rank and retirement are things that I earned through my service and sacrifice for this country. I got shot at. I missed holidays and birthdays. I commanded a space shuttle mission while my wife Gabby recovered from a gunshot wound to the head– all while proudly wearing the American flag on my shoulder,” Kelly said. “Generations of servicemembers have made these same patriotic sacrifices for this country, earning the respect, appreciation, and rank they deserve. Pete Hegseth wants to send the message to every single retired servicemember that if they say something he or Donald Trump doesn't like, they will come after them the same way. It's outrageous and it is wrong. There is nothing more un-American than that.”
“If Pete Hegseth, the most unqualified Secretary of Defense in our country's history, thinks he can intimidate me with a censure or threats to demote me or prosecute me, he still doesn't get it. I will fight this with everything I've got — not for myself, but to send a message back that Pete Hegseth and Donald Trump don't get to decide what Americans in this country get to say about their government,” he concluded.
Rep. Jason Crow (D-CO), Rep. Maggie Goodlander (D-NH), Rep. Chris Deluzio (D-PA), and Rep. Chrissy Houlahan (D-PA) were in the video as well.
Hegseth said Kelly — the only one of the group still under the Uniform Code of Military Justice — violated Articles 133 and 144. Article 133 is about “conduct unbecoming an officer,” and Article 144 is more of a broad catch-all of more than 50 unique criminal offenses.
Kelly now has 30 days to submit a response.
“Almost anything can fall into the nebulous of conduct unbecoming of an officer as long as it's considered something that's bringing dishonor or discredit to the military,” Sean Timmons, the managing partner at Tully Rinckey PLLC with a focus on military law, previously told the Washington Examiner.
PENTAGON ANNOUNCES ‘THOROUGH REVIEW' INTO MARK KELLY OVER ‘ILLEGAL ORDERS' VIDEO
Hegseth did not specifically mention Article 94 of the UCMJ, which is the statute regarding “sedition,” defined as having the “with intent to cause the overthrow or destruction of lawful civil authority, creates, in concert with any other person, revolt, violence, or other disturbance against that authority is guilty of sedition.”
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Democratic strategist Melissa DeRosa and Sen. Bernie Sanders' senior advisor Faiz Shakir debate the Democratic Socialists of America's influence and future within the Democratic Party.
The Democratic Socialists of America, the nation's largest socialist group with ties to left-wing leaders such as New York City Mayor Zohran Mamdani, published a lengthy rebuke of the U.S. capture of Venezuelan dictator Nicolás Maduro, demanding he and his wife be returned to power as they face criminal charges on U.S. soil.
"The Trump Administration has started an illegal war against Venezuela," the DSA published in a rebuke Saturday. "This is a nakedly imperialist war to install a US puppet government that will give Venezuela's oil resources over to US corporations and to force US hegemony over Latin America — the new ‘Trump Corollary' to the Monroe Doctrine. This war is illegal both under international law and the laws governing the declaration of war within the United States."
President Donald Trump confirmed a successful strike on Venezuela Saturday morning in a military operation that did not kill any U.S. military personnel, did not damage U.S. military equipment, and yielded the arrests of Maduro and his wife, Cilia Flores, on sweeping narcotics charges.
The dictatorial president of Venezuela, who was first elected in 2013, is accused of working with cartels and narco gangs in South America and Mexico to distribute millions of pounds of cocaine to the U.S. Trump had vowed to curb the flow of illicit drugs into the U.S. while on the campaign trail. When he took office for his second term nearly a year ago, he imposed tariffs on nations such as China over deadly fentanyl or boat strikes in the Carribean targeting suspected drug traffickers from Venezuela.
CAPTURED VENEZUELAN DICTATOR MADURO FACES NEW YORK FEDERAL JUDGE AFTER DRAMATIC PALACE RAID
Nicolas Maduro was captured by the U.S. military Jan. 3, 2026. (Jesus Vargas/Getty Images)
The DSA hit back in its statement, saying, "Trump's war has nothing to do with drug trafficking."
"There is no substantiated evidence that high-level members of the Venezuelan government are 'narco-terrorists,'" the DSA wrote. "Yet, the Trump administration is using this claim as the pretext for this illegal war. This is another regime-change war to steal another country's oil, just like the failed war against Iraq, and to crush any resistance to US imperialism. Trump's war will only impoverish the people of Latin America."
Trump called the strike a massive success over the weekend, celebrating to the media that Maduro and his wife were swiftly captured while commending the military for its execution of the operation.
"The United States military is the strongest and most fearsome military on the planet. By far. With capabilities and skills our enemies can scarcely begin to imagine. We have the best equipment anywhere in the world," he said Saturday during a press conference on the strike.
The DSA is supported by a handful of left-wing politicians and lawmakers. Most recently, longtime DSA member Mamdani rose through the ranks of New York politics and was elected mayor of the Big Apple in the November election. Lawmakers such as New York Democratic Rep. Alexandria Ocasio-Cortez and Michigan Rep. Rashida Tlaib are also prominent members of the left-wing group and have received its endorsement in previous elections.
Protesters rally outside the White House, Saturday, Jan. 3, 2026, after the U.S. captured Venezuelan President Nicolás Maduro and his wife in a military operation. (Julia Demaree Nikhinson/AP Photo)
TRUMP'S MADURO TAKEDOWN RESETS THE GLOBAL CHESSBOARD AND REASSERTS AMERICAN POWER
The DSA listed seven demands following the capture of the dictator, including that Maduro and his wife be returned to Venezuela, "an end to the failed 'war on drugs,'" an "immediate end to the war," including the removal of all military presence in the "Caribbean and an end to any operations with intervention purposes driven by SOUTHCOM."
Maduro and his wife are being held at the federal Metropolitan Detention Center in Brooklyn. Maduro is expected to be arraigned on Monday afternoon.
"Democratic Socialists of America calls on the people of the United States to protest and resist this illegal war and to stand in solidarity with the sovereign people of Venezuela," the DSA added.
Zohran Mamdani was elected mayor of New York City in November 2025. (Yuki Iwamura/AP)
Left-wing political leaders such as Mamdani have railed against the U.S. operation in Venezuela, with the newly minted mayor telling the public that he spoke directly with Trump following the strike.
TRUMP SAYS CUBA IS ‘READY TO FALL' AFTER CAPTURE OF VENEZUELA'S MADURO
"I called the president and spoke with him directly to register my opposition to this act and to make clear that it was an opposition based on being opposed to a pursuit of regime change, to the violation of federal international law and a desire to see that be consistent each and every day," Mamdani said Saturday. "I registered my opposition, I made it clear and we left it at that."
Fox News Digital reached out to the mayor's office Monday morning inquiring if Mamdani supports the DSA's rebuke of the operation and list of seven demands, but did not immediately receive a reply.
President Donald Trump speaks at his Mar-a-Lago club, Saturday, Jan. 3, 2026, in Palm Beach, Florida, as Secretary of State Marco Rubio and War Secretary Pete Hegseth listen. (Alex Brandon/The Associated Press )
More moderate Democrats have also taken issue with the strike as unjustified and for failing to notify Congress ahead of the attack, while Republicans have for the most part backed the operation.
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"Nicolas Maduro wasn't just an illegitimate dictator; he also ran a vast drug-trafficking operation. That's why he was indicted in U.S. court nearly six years ago for drug trafficking and narco-terrorism," Sen. Tom Cotton, R-Ark., posted on X. "I just spoke to @SecRubio, who confirmed that Maduro is in U.S. custody and will face justice for his crimes against our citizens. I commend President Trump and our brave troops and law-enforcement officers for this incredible operation."
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Sen. Rick Scott, R-Fla., joins 'Fox & Friends Weekend' to weigh in on the arrest of Nicolás Maduro, the transition of power and the ripple effects for Cuba.
The top lawmaker on the House Intelligence Committee believes that the weekend capture of Venezuelan President Nicolás Maduro may have a domino effect in Cuba.
Chairman Rick Crawford, R-Ark., called it "the beginning of the end" for the regime there.
"Cuba and Venezuela have had a symbiotic relationship for a long, long time. Cuba needs Venezuelan oil. They no longer have the resources that will be provided by Venezuela," Crawford said on Fox News' "The Big Weekend Show."
MADURO AND 'LADY MACBETH' CILIA FLORES MARRIAGE SPELLS 'WORST CASE' CUSTODY SCENARIO
Rep. Rick Crawford, R-Ark., speaks as House Republicans hold a news conference in the Capitol in Washington, May 6, 2025. (Bill Clark/CQ-Roll Call, Inc via Getty Images)
According to Crawford, Venezuela also benefited from the partnership by receiving medical assistance from Cuba and military protections used by Maduro.
President Miguel Díaz-Canel leads Cuba's government — a one-party Communist state that has long been at odds with the United States. The U.S. has an economic embargo on the country, restricting exports to and from Cuba as well as travel restrictions that limit tourism.
Those measures have been in place for 63 years.
"In February 1962, President John F. Kennedy proclaimed an embargo on trade between the United States and Cuba and directed the Departments of Commerce and the Treasury to implement the embargo, which remains in place today," the Department of State explains on its website.
TRUMP VOWS US 'IN CHARGE' OF VENEZUELA AS HE REVEALS IF HE'S SPOKEN TO DELCY RODRÍGUEZ
Cubans hold a Venezuelan national flag with a Cuban one during a gathering in support of Venezuelan leader Nicolás Maduro in Havana on Jan. 3, 2026, after U.S. forces captured him. (Adalberto Roque/AFP via Getty Images)
Despite those longstanding tensions, Crawford noted that an impulse for change may also come from a cultural closeness between Cuba and the United States on top of the crumbling of its Venezuelan partnerships.
"You may very well see a popular uprising there. There's a lot of connective tissue. We have really, for lack of a better term, we have a familial bond with Cuba," Crawford said. "We have so many families in South Florida that are directly connected to family members in Cuba that remittances are a big part of their economy. They rely on the United States, whether they want to admit it or not.
"We can play an outsize role there in influencing those folks and helping them to organically rise up and help overcome that oppressive regime," Crawford added.
Crawford did not immediately respond to a request for comment on whether the U.S. should also take military action in Havana.
Crawford said the political cascade caused by the capture of Maduro and the American presence in Venezuela would not be limited to Cuba.
TRUMP'S MADURO TAKEDOWN RESETS THE GLOBAL CHESSBOARD AND REASSERTS AMERICAN POWER
Rep. Rick Crawford, R-Ark., questions witnesses during a House Permanent Select Committee on Intelligence hearing in Washington, March 26, 2025. (Nathan Posner/Anadolu via Getty Images)
"This also plays into what I call the communist triad of the Western hemisphere, that is Cuba, Venezuela, and Nicaragua. This probably doesn't bode well for Nicaragua if we're being honest about it. I mean, I'm sure they're watching anxiously, wondering when the next boot is gonna fall and where they'll be in relation to that," Crawford said.
He also sent a message to America's larger adversaries who have built relationships with those countries in Latin and South America.
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"Iran, Russia, China, you're playing in the wrong sandbox," Crawford said.
Leo Briceno is a politics reporter for the congressional team at Fox News Digital. He was previously a reporter with World Magazine.
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In the battle against fake news, Finland starts the fight in the classrooms. For decades, the Nordic nation and neighbour to Russia has woven media literacy - including the ability to analyse different kinds of media and recognize disinformation - into its national curriculum, starting from early preschool, at ages 3-4. But experts warn that with the development of artificial intelligence, it could become much more difficult.
Ten-year-old fourth grade student Ilo Lindgren works during a media literacy class at Tapanila Primary School in Tapanila, Finland, on Dec. 9, 2025. (AP Photo/James Brooks)
A young student works during a media literacy class at Tapanila Primary School in Tapanila, Finland, on Dec. 9, 2025. (AP Photo/James Brooks)
Tapanila Primary School teacher and vice-principal Ville Vanhanen speaks to the fourth grade students during a media literacy class in Tapanila, Finland, on Dec. 9, 2025. (AP Photo/James Brooks)
HELSINKI (AP) — The battle against fake news in Finland starts in preschool classrooms.
For decades, the Nordic nation has woven media literacy, including the ability to analyze different kinds of media and recognize disinformation, into its national curriculum for students as young as 3 years old. The coursework is part of a robust anti-misinformation program to make Finns more resistant to propaganda and false claims, especially those crossing over the 1,340-kilometer (830-mile) border with neighboring Russia.
Now, teachers are tasked with adding artificial intelligence literacy to their curriculum, especially after Russia stepped up its disinformation campaign across Europe following its full-scale invasion of Ukraine nearly four years ago. Finland's ascension into NATO in 2023 also provoked Moscow's ire, though Russia has repeatedly denied it interferes in the internal affairs of other countries.
“We think that having good media literacy skills is a very big civic skill,” Kiia Hakkala, a pedagogical specialist for the City of Helsinki, told The Associated Press. “It's very important to the nation's safety and to the safety of our democracy.”
At Tapanila Primary School, in a quiet neighborhood north of Helsinki, teacher Ville Vanhanen taught a group of fourth graders how to spot fake news. As a TV screen beamed a “Fact or Fiction?” banner, student Ilo Lindgren evaluated the prompt.
“It is a little bit hard,” the 10-year-old admitted.
Vanhanen said his students have been learning about fake news and disinformation for years, beginning with reading headlines and short texts. In a recent class, the fourth graders were tasked with coming up with five things to look out for when consuming online news to ensure it's trustworthy. Now they are moving onto AI literacy, which is quickly becoming a vital skill.
“We've been studying how to recognize if a picture or a video is made by AI,” added Vanhanen, a teacher and vice principal at the school.
Finnish media also play a role, organizing an annual “Newspaper Week,” where papers and other news are sent to young people to consume. In 2024, Helsinki-based Helsingin Sanomat collaborated on a new “ABC Book of Media Literacy,” distributed to every 15-year-old in the country as they began upper secondary school.
“It's really important for us to be seen as a place where you can get information that's been verified, that you can trust, and that's done by people you know in a transparent way,” Jussi Pullinen, the daily newspaper's managing editor, said.
Media literacy has been part of the Finnish educational curriculum since the 1990s, and additional courses are available for older adults who might be especially vulnerable to misinformation.
The skills are so ingrained into the culture that the Nordic nation of 5.6 million people regularly ranks at the top of the European Media Literacy Index. The index was compiled by the Open Society Institute in Sofia, Bulgaria, between 2017 and 2023.
“I don't think we envisioned that the world would look like this,” Finnish Education Minister Anders Adlercreutz said. “That we would be bombarded with disinformation, that our institutions are challenged — our democracy really challenged — through disinformation.”
And with the rapid advancement of AI tools, educators and experts are rushing to teach students and the rest of the public how to tell what's fact and what's fake news.
“It already is much harder in the information space to spot what's real and what's not real,” Martha Turnbull, director of hybrid influence at the Helsinki-based European Centre of Excellence for Countering Hybrid Threats, said. “It just so happens that right now, it's reasonably easy to spot the AI-generated fakes because the quality of them isn't as good as it could be.”
She added: “But as that technology develops, and particularly as we move toward things like agentic AI, I think that's when it could become much more difficult for us to spot.”
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Scores of foreign nationals who traveled to a remote Indian Ocean island seeking adventure have become stranded there as simmering tensions between warring Yemeni parties and their backers disrupt travel.
European and American tourists who spoke to CNN said that up to “hundreds” are stuck on the Yemeni island of Socotra, which sits between the Gulf of Aden, the Guardafui Channel and the Arabian Sea, following a state of emergency that led to the closure of all ports of entry.
While CNN cannot independently verify how many tourists are stranded on Socotra Island, it understands them to number scores at least.
Known for its unique biodiversity, the island is a classified UNESCO World Heritage Site and has become a regional hub for adventure tourism, especially among expats flying from the nearby United Arab Emirates. Visitors can expect to see dramatic cliffs, pristine white sand beaches and exotic flora like the dragon's blood tree.
These dragon's blood trees exist in only one place on Earth. Now their survival is under threat
Its distance from the mainland has shielded Socotra from the worst of Yemen's long-running conflict. But regional tensions that last week culminated in Saudi strikes on a UAE-linked shipment in Yemen have now had an impact.
Last week, the United States Department of State said it had received reports of “closures, cancelations and redirected flights on commercial airline travel to and from the island of Socotra” to nearby airports.
The State Department advised against all travel to Yemen, adding that “the US government is unable to provide emergency or routine consular services to US citizens in Yemen, including Socotra.”
One American citizen in Socotra, who spoke to CNN on condition of anonymity due to security concerns, said that while tourists are physically safe, they are unsure when they might be able to return home.
“There's a lot (of tourists),” the American tourist said, adding that his group had started making contact with others in neighboring camp sites.
“There's all sorts of Westerners here. There's hundreds of them.”
Rocky Road Travel, a Berlin-based tourism agency with at least 14 people stuck in Socotra, said it had contacted US embassies in Abu Dhabi and Riyadh, as well as multiple European missions in both the UAE and Saudi Arabia, for assistance.
Tourists on the island told CNN that embassies have been able to provide little help so far. The ongoing conflict means few Western nations have a diplomatic presence in Yemen, with most handling its concerns from nearby capitals.
Saudi Arabia's dispute with the UAE exposes a deeper regional power struggle
CNN has reached out to the UAE and Saudi Arabian foreign ministries, as well as the US embassy in Riyadh, under which Yemen falls, for comment.
Gerrit van Wijngaarden, a Dutch-Polish national who is in Socotra with his wife, their three children and a grandchild, had planned to stay on the island for a week, but has been there for 11 days, he said.
“A lot of planes came, but no planes are leaving anymore. There are a lot of people on this island at the moment,” he told CNN, adding that embassies “unfortunately they cannot do anything because they don't have any offices in Yemen.”
Van Wijngaarden said there are up to 100 Polish tourists on the island. The Polish embassy in Saudi Arabia, which handles the concerns of Polish citizens in Yemen, has not yet responded to CNN's request for comment.
Amid flight cancellations, some tourists have been advised to take commercial ships from the island to Oman, and then fly back to Europe or the US, Van Wijngaarden said, adding that he himself has not made any arrangements to travel by boat.
Socotra island has been controlled by Yemen's UAE-backed separatist Southern Transitional Council (STC) since 2020. The UAE maintains significant economic influence over the island, however, which some analysts say amounts to de facto control over the area.
Tensions have flared over recent weeks in Yemen, after the STC overran the south of the country in early December, taking swathes of territory and expelling Saudi-backed Yemeni government forces from those areas.
A regional feud then erupted into public view, as Saudi Arabia bombed the war-torn country's port city of Mukalla following accusations that two ships from the UAE had delivered weapons and combat vehicles to the separatist forces.
Two of the Middle East's most powerful countries are facing off in Yemen. Here's what to know
The UAE has since announced a withdrawal of its forces from Yemen, but the situation remains volatile, especially after the STC announced it would hold an independence referendum in two years to help “exercise the right of self-determination for the Southern people.” That would include the island of Socotra.
Flights are expected to resume this week, but it remains unclear when. For now, scores of visitors are waiting to return home.
There's no shortage of food or other supplies, they say, but the situation is still frustrating. “We hope that somebody is doing something,” van Wijngaarden said.
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Sen. Rick Scott, R-Fla., joins 'Fox & Friends Weekend' to weigh in on the arrest of Nicolás Maduro, the transition of power and the ripple effects for Cuba.
Cuba acknowledged that 32 of its citizens — described by the government as members of the island's armed forces and intelligence services — were killed during the U.S. operation that seized Venezuelan leader Nicolás Maduro in Caracas, declaring two days of national mourning in their honor.
Havana did not specify where the personnel were stationed during the raid. But their deaths have renewed scrutiny of years of reporting and international investigations documenting Cuba's deep and covert involvement inside Venezuela's military and intelligence structures.
Jorge Jraissati, a Venezuelan political analyst, said Cuba's intelligence role was critical to the consolidation of power first under Hugo Chávez and later under Maduro. "Experts usually link Cuba as the most important intelligence provider of Venezuela. This includes issues like running elections, building diplomatic leverage with other countries and keeping the security forces in check, among others," he told Fox News Digital.
TRUMP VOWS US WILL 'RUN' VENEZUELA UNTIL 'SAFE' TRANSITION OF POWER
Cubans hold a Venezuelan national flag with a Cuban one during a gathering in support of Venezuelan leader Nicolás Maduro in Havana on Jan. 3, 2026, after U.S. forces captured him. President Donald Trump said Saturday that U.S. forces had captured Venezuela's leader Nicolás Maduro after bombing the capital Caracas and other cities in a dramatic climax to a monthslong standoff between Trump and his Venezuelan arch-foe. (Adalberto Roque / AFP via Getty Images)
Jraissati said any transition in Venezuela "would require the American government, in partnership with the Venezuelan people, to work together on minimizing the Cubans' influence over Venezuela's state apparatus and society at large."
A Reuters investigation published in August 2019 found that two confidential agreements signed in 2008 granted Cuba sweeping access to Venezuela's armed forces and intelligence services. Under those agreements, Cuban officials were authorized to train Venezuelan troops, restructure intelligence agencies and help build an internal surveillance system focused on monitoring Venezuela's own military, according to the report.
Those arrangements played a central role in transforming Venezuela's military counterintelligence agency — the General Directorate of Military Counterintelligence (DGCIM) — into a force designed to detect dissent, instill fear within the ranks and ensure loyalty to the government, the investigation found.
VENEZUELAN LEADER MADURO LANDS IN NEW YORK AFTER BEING CAPTURED BY US FORCES ON DRUG CONSPIRACY CHARGES
Nicolas Maduro, Venezuela's president, right, greets Miguel Diaz-Canel, Cuba's president, during the 23rd States of the Bolivarian Alliance for the Peoples of Our America People's Trade Treaty (ALBA-TCP) Summit at Miraflores Palace in Caracas, Venezuela, on Wednesday, April 24, 2024. The alliance of leftist countries in the region are meeting to reject the U.S.' reimposed oil sanctions on Venezuela, ending a six-month reprieve for the Maduro regime.
The findings were later echoed by the United Nations Independent International Fact-Finding Mission on Venezuela, which said it reviewed a 2008 memorandum of understanding between Cuba and Venezuela. The U.N. mission reported that the agreement provided for Cuban advisory oversight in the restructuring of Venezuelan military intelligence, including the creation of new agencies, training of counterintelligence officers and assistance with surveillance and infiltration techniques.
Former Venezuelan officials cited by Havana Times and El Toque have described Cuban advisers embedded across some of the country's most sensitive institutions, including the civilian intelligence service SEBIN, DGCIM, the defense ministry, ports and airports, and Venezuela's national identification system.
Human rights organizations and international investigators say those structures were central to the government's response to mass protests in 2014 and 2017, when Venezuelan security forces carried out widespread arrests and deadly crackdowns on demonstrators.
The U.N. fact-finding mission documented patterns of extrajudicial executions, arbitrary detention and torture, and reported that Cuban advisers helped train Venezuelan personnel in methods used to track, interrogate and repress political opponents.
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Experts say Cuba's admission that its military and intelligence personnel were killed during a U.S. operation inside Venezuela has sharpened focus on the alliance's true depth, turning years of documentation into an immediate geopolitical issue.
Efrat Lachter is an investigative reporter and war correspondent. Her work has taken her to 40 countries, including Ukraine, Russia, Iraq, Syria, Sudan and Afghanistan. She is a recipient of the 2024 Knight-Wallace Fellowship for Journalism. Lachter can be followed on X @efratlachter.
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Secretary of Defense Pete Hegseth announced Monday that the Pentagon is taking administrative action to punish Sen. Mark Kelly, a retired Navy captain, by moving to cut his retirement pay for participating in a video where he and other Democratic lawmakers reminded US service members of their duty to refuse illegal orders.
Hegseth said in a post on X that the US military has initiated proceedings to reduce the amount of retirement pay Kelly receives and has issued a secretarial letter of censure, which would stand as a written reprimand but have no practical consequences for the Arizona Democrat.
“In response to Senator Mark Kelly's seditious statements — and his pattern of reckless misconduct — the Department of War is taking administrative action against Captain Mark E. Kelly, USN (Ret),” Hegseth posted on X. “The department has initiated retirement grade determination proceedings under 10 U.S.C. § 1370(f), with reduction in his retired grade resulting in a corresponding reduction in retired pay.”
Kelly responded later Monday morning, saying he wouldn't be intimidated and intended to fight the action.
“If Pete Hegseth, the most unqualified Secretary of Defense in our country's history, thinks he can intimidate me with a censure or threats to demote me or prosecute me, he still doesn't get it. I will fight this with everything I've got — not for myself, but to send a message back that Pete Hegseth and Donald Trump don't get to decide what Americans in this country get to say about their government,” he said in a post on X.
Hegseth's letter of censure for Kelly, a copy of which was obtained by CNN, includes an apparent threat of criminal prosecution if he engages in similar conduct going forward.
“If you continue to engage in conduct prejudicial to good order and discipline, you may subject yourself to criminal prosecution or further administrative action,” the letter from Hegseth says.
It also describes Kelly's “pattern” of alleged misconduct that represents a serious “breach” of standards for a retired military officer.
“When viewed in totality, your pattern of conduct demonstrates specific intent to counsel servicemembers to refuse lawful orders. This pattern demonstrates that you were not providing abstract legal education about the duty to refuse patently illegal orders. You were specifically counseling servicemembers to refuse particular operations that you have characterized as illegal,” Hegseth wrote.
“Your conduct has had, and continues to have, a detrimental impact on military discipline and good order,” Hegseth added. “For the reasons stated above, I hereby formally CENSURE you for conduct prejudicial to good order and discipline in the armed forces and conduct unbecoming an officer.”
Behind closed doors, Hegseth has been weighing his options to punish Kelly for participating in the video, ranging from reducing the retired US Navy captain's rank and pension to prosecuting him under military law, CNN has reported.
In the video that triggered the Trump administration's calls for consequences, six Democratic lawmakers said that “threats to our Constitution” are coming “from right here at home,” and repeatedly urged the military and intelligence community to “refuse illegal orders.”
Although the video didn't reference what orders service members might be receiving that would potentially be illegal, lawmakers on both sides of the aisle have raised concerns repeatedly about the legality of US military strikes against suspected drug boats in the Caribbean and the US military's deployment to cities over the protest of governors.
Mississippi Sen. Roger Wicker, a Republican who chairs the Senate Armed Services Committee, said last month it's not appropriate for the military to try to punish Kelly.
Asked by CNN if it's appropriate to do so, Wicker shook his head. And after a follow up question, he replied, “You asked me that question, and my answer is no.”
In November, Hegseth requested advice from the Navy secretary, who oversees the military branch Kelly served in for more than two decades, on how to proceed to potentially punish him for participating in the video, which Hegseth has claimed amounted to serious violations of the military's code of justice.
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Since the seizure of Venezuelan President Nicolás Maduro by US forces at the weekend, US President Donald Trump and members of his administration have issued warnings to several other countries and territories – including Colombia, Cuba, Mexico, Iran and Greenland, a self-governing territory of Denmark.
Trump said Sunday: “We are in the business of having countries around us that are viable and successful and where the oil is allowed to freely come out.”
“American dominance in the Western hemisphere will never be questioned again,” Trump said.
Here's what to know about what Trump has said in the last two days, and how some of those governments have responded.
Trump repeated on Sunday that the US needs the huge north Atlantic island of Greenland “from the standpoint of national security.”
“We need Greenland. … It's so strategic right now. Greenland is covered with Russian and Chinese ships all over the place,” Trump told reporters aboard Air Force One. “We need Greenland from the standpoint of national security, and Denmark is not going to be able to do it.”
Responding to Trump's latest comments, Greenland's Prime Minister Jens Frederik Nielsen said Monday that “the current and repeated rhetoric coming from the United States is entirely unacceptable. When the President of the United States speaks of ‘needing Greenland' and links us to Venezuela and military intervention, it is not only wrong. It is disrespectful.”
“Our country is not an object in great-power rhetoric. We are a people. A country. A democracy,” Nielsen added.
Trump has repeatedly stated that he wants to annex Greenland — a huge, resource-rich 836,000 square miles (2,166,000 square kilometer) island in the Atlantic and self-governing territory of Denmark — claiming that this is needed for American security purposes.
Both Greenland and Denmark, a NATO ally of the US, are staunchly opposed to the idea.
Trump had harsh words for Colombian President Gustavo Petro on Sunday, describing him as “a sick man who likes making cocaine and selling it to the United States, and he's not going to be doing it very long.”
When pressed by a reporter if those comments meant there could be an “operation” in Colombia in the future, Trump responded, “sounds good to me.”
Petro defended his government's track record on combatting drug trafficking in a near 700-word post on X, including what he described as “the largest cocaine seizure in the world's history.”
He added: “I am not illegitimate, nor am I a narco, I only have as assets my family home that I still pay for with my salary.”
Petro said he has ordered targeted bombings against drug-linked armed groups while adhering to humanitarian law.
However, cocaine production in Colombia has reach record highs, according to the the United Nations Office on Drugs and Crime.
Petro, a former member of the M19 guerilla group, said later Monday that he would himself fight to defend Colombia.
“I swore not to touch a weapon again … but for the homeland I will take up arms again,” he said.
Petro angered the Trump administration and had his US visa canceled in September after calling on US soldiers to disobey orders.
Trump said Sunday that military intervention was unnecessary in Cuba, a key ally of Venezuela, because it was “ready to fall.”
“I don't think we need any action,” Trump said. “It looks like it's going down.”
“I don't know if they're going to hold out, but Cuba now has no income,” he added. “They got all their income from Venezuela, from the Venezuelan oil.”
But his secretary of state, Marco Rubio, called the Cuban government “a huge problem.”
“I think they're in a lot of trouble, yes,” Rubio told NBC's “Meet the Press” on Sunday.
“I'm not going to talk to you about what our future steps are going to be and our policies are going to be right now, in this regard, but I don't think it's any mystery that we are not big fans of the Cuban regime.”
“If I lived in Havana and I worked in the government, I'd be concerned,” Rubio said.
At a rally Saturday in front of the US Embassy in Havana, Cuban President Miguel Díaz-Canel promised not to let the Cuba-Venezuela alliance go down without a fight.
“For Venezuela, of course for Cuba, we are willing to give even our own life, but at a heavy cost,” Díaz-Canel proclaimed.
Trump has frequently accused Mexico of not doing enough to clamp down on drug cartels.
On Sunday, he said drugs were “pouring” through Mexico and that “we're going to have to do something.”
Trump added that the cartels in Mexico were “very strong” and “Mexico has to get their act together.”
In a phone interview with Fox News, Trump said he had asked Mexican President Claudia Sheinbaum if she wanted the US military's help in rooting out drug cartels.
Sheinbaum again rejected the US intervention in Venezuela and the seizure of Maduro on Monday.
“Mexico reaffirms a principle that is neither new nor open to ambiguity: We categorically reject intervention in the internal affairs of other countries.”
Responding to Trump's accusations that Mexico has not done enough to combat drug trafficking cartels, Sheinbaum asserted: “Mexico cooperates with the United States, including for humanitarian reasons, to prevent fentanyl and other drugs from reaching its population, especially young people.”
“We do not want fentanyl or any drug to get near any young person — whether in the United States, in Mexico, or anywhere else in the world.”
Again rejecting the notion of US military action on Mexican soil, Sheinbaum said she did not think an invasion of Mexico was something the US was taking seriously.
Trump also repeated his warning to Iran, where anti-government protests are into their second week.
“If they start killing people like they have in the past, I think they're going to get hit very hard by the United States,” Trump told reporters Sunday.
Last week, Trump said that if Iran “kills peaceful protesters, which is their custom, the United States of America will come to their rescue. We are locked and loaded and ready to go.”
One Iranian human rights group estimated Sunday that 16 people had been killed in the protests so far. CNN cannot verify that tally.
At the end of last month, Trump warned Iran against any attempt to rebuild its nuclear and ballistic missile programs. After meeting with Israeli Prime Minister Benjamin Netanyahu, Trump said he had heard Iran is “behaving badly … I hear that Iran is trying to build up again, and if they are, we're going to have to knock them down.”
Iran's supreme leader Ayatollah Ali Khamenei said Sunday the Islamic Republic “will not yield to the enemy” and rioters should be “put in their place.”
The US bombed several of Iran's key nuclear facilities in June, amid Israel's 12-day war against the country. The attack ended what had been a stuttering process of bilateral US-Iran talks designed to rein in its nuclear program.
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Meyer Resources CEO Cornelia Meyer joins CNN's Rahel Solomon to discuss oil and what US companies might need if they invest in Venezuela.
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President Donald Trump on Sunday told reporters that U.S. officials have determined that Ukraine did not target a residence belonging to Russian President Vladimir Putin in a drone attack last week.
President Donald Trump departs on Air Force One from Palm Beach International Airport, Sunday, Jan. 4, 2026, in West Palm Beach, Fla. (AP Photo/Alex Brandon)
ABOARD AIR FORCE ONE (AP) — President Donald Trump on Sunday told reporters that U.S. officials have determined that Ukraine did not target a residence belonging to Russian President Vladimir Putin in a drone attack last week, disputing Kremlin claims that Trump had initially greeted with deep concern.
Russian Foreign Minister Sergey Lavrov last week said Ukraine launched a wave of drones at Putin's state residence in the northwestern Novgorod region that the Russian defense systems were able to defeat. Lavrov also criticized Kyiv for launching the attack at a moment of intensive negotiations to end the war.
The allegation came just a day after Ukrainian President Volodymyr Zelenskyy had traveled to Florida for talks with Trump on the U.S. administration's still-evolving 20-point plan aimed at ending the war. Zelenskyy quickly denied the Kremlin allegation.
Trump said that “something happened nearby” Putin's residence but that Americans officials didn't find the Russian president's residence was targeted.
“I don't believe that strike happened,” Trump told reporters as he traveled back to Washington on Sunday after spending two weeks at his home in Florida. “We don't believe that happened, now that we've been able to check.”
Trump addressed the U.S. determination after European officials argued that the Russian claim was nothing more than an effort by Moscow to undermine the peace effort.
But Trump, at least initially, had appeared to take the Russian allegations at face value. He told reporters last Monday that Putin had also raised the matter during a phone he had with the Russian leader earlier that day. And Trump said he was “very angry” about the accusation.
By Wednesday, Trump appeared to be downplaying the Russian claim. He posted a link to a New York Post editorial on his social media platform that raised doubt about the Russian allegation. The editorial lambasted Putin for choosing “lies, hatred, and death” at a moment that Trump has claimed is “closer than ever before” to moving the two sides to a deal to end the war.
The U.S. president has struggled to fulfill a pledge to quickly end the war in Ukraine and has shown irritation with both Zelenskyy and Putin as he tried to mediate an end to a conflict he boasted on the campaign trail that he could end in one day.
Both Trump and Zelenskyy said last week they made progress in their talks at Trump's Mar-a-Lago resort.
But Putin has shown little interest in ending the war until all of Russia's objectives are met, including winning control of all Ukrainian territory in the key industrial Donbas region and imposing severe restrictions on the size of Ukraine's post-war military and the type of weaponry it can possess.
___
Madhani reported from Washington.
Copyright 2026 The Associated Press. All Rights Reserved.
The Justice Department has requested a weeklong delay in returning a group of Venezuelan nationals deported under the Alien Enemies Act to the United States, citing the recent U.S. military operation in Venezuela.
Defendants for the Trump administration have been facing a Monday deadline imposed by U.S. District Judge James Boasberg to either “facilitate the return” of the Venezuelan nationals to the U.S. or “otherwise provide them with hearings that satisfy the requirements of due process.” The Venezuelans in question were deported in March 2025 to a megaprison in El Salvador due to their alleged ties to the Tren de Aragua gang, before being transferred to Venezuela under a prisoner exchange.
In a last-minute plea on Sunday night, DOJ lawyers said the extension is necessary because the military operation over the weekend has led to “substantial changes” in the country, most notably the arrest of now-former President Nicolas Maduro.
“Over the weekend, the United States apprehended Nicolas Maduro,” the one-page court filing reads. “As a result, the situation on the ground in Venezuela has changed dramatically. Defendants thus need additional time to determine the feasibility of various proposals. Defendants therefore request a 7-day extension to evaluate and determine what remedies are possible.”
Boasberg has yet to respond to the request, though the toppling of Maduro's government has added a wrinkle to the case that now threatens to drag on even further.
VENEZUELANS POUR INTO STREETS TO CELEBRATE MADURO'S FALL
Maduro, who is now detained in New York City and will appear in court on Monday, was sympathetic toward the alleged gang members' detention in El Salvador, previously referring to them as “kidnapped brothers” and demanding their return to Venezuela.
With Maduro gone and many of the former detainees since released into the country after the prisoner swap, it is unclear where they are or what their status would now be.
The morning after US forces bombed Caracas, dragged President Nicolás Maduro out of bed, carted him over the Caribbean and installed him in a Brooklyn jail, many Venezuelans hurried to the grocery store.
“Why did I have to go out?” said Judith Ledezma. “I have a pet that needs exercise and I was really stressed out staying indoors.”
Her orange dog sat beside her on a park bench in Caracas, along with numerous shopping bags. Ledezma, who lives near one of the airbases hit by US airstrikes, told CNN the noise from the attack woke her up.
“I thought it was an earthquake,” Ledezma said. “I got scared and came running out with my daughter and the dog.”
“We have no idea what our fate will be now with this new situation,” Ledezma continued. “I am completely in the dark. I have no idea what is going to happen to the country, to us.”
The government in Caracas wants Venezuelans out and about, though the streets are quiet, apart from a few militia members mustering with their motorcycles. Defense Minister Vladímir Padrino Lopez told people Sunday to “resume their economic activities, work, and all other types of activities, including educational activities, in the coming days.”
Olga Jimenez told CNN she finally left her house on Sunday after staying in all of Saturday. Maduro or no Maduro, Jimenez said, she doesn't expect much to change in Venezuela – except maybe the lines at the shops.
“I've been glued to the TV, watching to see what's going on, and what there is is uncertainty,” Jimenez said. “You don't feel a change of government because everything is the same. The only thing is that we don't know.”
Venezuelans lose their homes after US strikes
“What's happening to us is that places aren't open, and you have to line up for everything, as if we were going backwards to the Chávez era, when you had to line up everywhere just to buy things,” Jimenez added. “I don't know how to put it – it was Maduro's government, and they should have taken them all, not just Maduro.”
Maria Azocar, meanwhile, told CNN that “having lived through so much, nothing really worries me anymore.”
“As I say, this is for the history books,” Azocar said, before listing the names of past Venezuelan leaders: “(Marcos) Pérez Jiménez, (Isaías Medina) Angarita, Rómulo Gallegos, Juan Vicente Gómez – people who, in their time, were overthrown or displaced.”
“I'll tell you something straight: It was really an abuse on the part of the Americans,” Azocar said of the attack, “because they intimidated the people with their missiles. That says it all.”
Acting President Delcy Rodríguez (whom Azocar said US President Donald Trump “appointed” to lead the country) is “a woman of real strength,” she added.
“I think with her, it eases people's hearts a little, on one side and the other,” Azocar said.
The United States is apparently tolerating having Rodríguez in charge, for now. Saturday, Trump told reporters he thought opposition leader María Corina Machado didn't have the “respect' or “support” to lead the country.
Resident Mario Valdez told CNN he thought an immediate, forceful transition to opposition rule “could lead us into violence.”
“It would mean the reds leave only for the blues to take over,” Valdez said, referring to the left and right respectively, “in a country which, at this moment, after 26 years of a Chavista government, can't handle, because it would lead to another bloodbath, like we've had in the past.”
Still, Valdez said he is hopeful for a democratic transition, eventually.
“I believe this democratic transition must take place, and we will all take part in it,” Vladez said. “The first thing the president of the Republic must do is release the political prisoners – all of them. There is no reason whatsoever for them to remain imprisoned.”
Valdez said he also hopes international oil companies will return to Venezuela. His country has been plundered for years by Russia, China and Iran, he said, which provided nothing in return for Venezuela's vast oil wealth.
“They stole all the money from this country to build major projects and did absolutely nothing,” Valdez said. “The motorways are unfinished.”
Trump wants the US oil industry to thrive in Venezuela again. That won't be easy
All told, Valdez said, he was unsurprised by Maduro's abduction. “President Maduro should have been prudent and accepted one of the offers that were made to him; he was made multiple offers.”
“He should have called new elections,” Valdez said, referring to the 2024 election that most observers say Maduro lost, despite clinging to power. “That is what I would have done: called new elections with a new National Electoral Council, changed things and summoned in the country a spirit of concord, where all organizations could take part.”
“But that didn't happen, and so there are consequences – without making value judgments about whether all that was right or wrong.”
CNN's Mary Triny Mena reported from Caracas and Max Saltman wrote from Atlanta. CNN's Harry Ungoed contributed to this report.
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President Donald Trump's defenders had it half right.
The US overthrow of Venezuelan President Nicolás Maduro isn't an exact copy of the haunted regime change that gutted Iraq's government and civil society.
The emerging White House strategy instead looks more like a regime decapitation that is evolving into coercion of Maduro's left-behind lieutenants. The administration is demanding acquiescence to Trump's dream of an obedient, MAGAfied Western Hemisphere.
The focal point of the effort is Venezuelan Vice President Delcy Rodríguez, the interim leader in Caracas since a spectacular US special forces operation spirited Maduro out of his bed and to New York, where he'll appear in court Monday.
Trump declared Sunday evening that the US was running Venezuela through its pressure on Rodríguez, now the acting president. “Don't ask me who's in charge, because I'll give you an answer, and it'll be very controversial,” he told reporters. “It means we're in charge. We're in charge.”
The spectacle of an American president claiming to be “in charge” of a sovereign nation around 1,000 miles from the US mainland — even if it is not strictly true — shows just how fundamentally Trump has hardened the country's posture to the rest of the world and reveals his ambition to wield expansive power. And Trump apparently feels emboldened by the Venezuela raid, telling reporters Sunday that Colombia is “very sick” and that “Mexico has to get their act together.”
Co-opting Maduro's remnant regime would require less US blood and treasure than failed nation-building efforts in the post-9/11 wars. But that route brings its own complications and has uncertain odds given the volatile political landscape. And it could create an unexpected and immediate consequence of Maduro's fall: a counterintuitive US turn away from Venezuela's democracy movement.
Hurried efforts in Washington to piece together a viable path forward in Venezuela coincided Sunday with rising fury among Democrats over Trump's failure to seek congressional authorization for what looked like an act of war. Early signs indicate that Republicans are standing firm behind a president they've rarely challenged. But it will take time to gauge whether yet another foreign policy adventure will widen splits in Trump's MAGA movement.
The Trump administration is now wrestling with the complex aftermath of their boss's headline-grabbing order of a daring military raid. It is walking a fine line in seeking to secure a stable source of authority in Caracas. And it's looking to avoid the kind of purges of top officials that could bring the government crashing down and lead to civil strife, which could turn Trump's latest triumph into a political disaster in a midterm election year in the United States.
Trump created a storm Saturday when he said the US would “run” Venezuela ahead of a political transition. He also fueled fears of 21st century imperialism by fixating on getting the US a piece of Venezuela's vast oil reserves.
Secretary of State Marco Rubio appeared on Sunday news shows to dispel comparisons to Iraq from what he called “clown-hour” analysts.
He said the US would maintain its “quarantine” oil embargo to force Venezuela's remaining leaders to obey Trump's orders. The freshly demonstrated might of the US military is also supposed to concentrate minds in the Venezuelan capital.
“We want drug trafficking to stop. We want no more gang members to come our way. We don't want to see the Iranian and, by the way, Cuban presence in the past,” Rubio said on CBS' “Face the Nation”
“We want the oil industry in that country not to go to the benefit of pirates and adversaries of the United States, but for the benefit of the people. … We insist on seeing that happen,” Rubio said.
Republican Sen. Tom Cotton, a key Trump ally, summed up the thrust of the strategy on CNN's “State of the Union.” He told Dana Bash, “When the president said that the United States is going to be running Venezuela, it means that the new leaders of Venezuela need to meet our demands.”
In short, Trump's plan for Venezuela is to coerce its acting president to become a vessel for his power inside her own country. As Defense Secretary Pete Hegseth told CBS News on Saturday, “President Trump sets the terms. … (He) has shown American leadership and he will be able to dictate where we go next.”
The spectacular special forces smash-and-grab raid that captured Maduro and his wife looks in the immediate aftermath like one of the more successful CIA and US military attempts to shape the geopolitics of America's backyard — a preoccupation of presidents for more than 200 years.
If Trump succeeds after years of Washington neglecting Latin America, he may turn an enemy into a pliant state and advance his effort to shape the Western Hemisphere into a region of pro-US powers. He might ease deprivation in the Venezuelan economy by getting oil revenues flowing; disrupt drug cartels; and drive out Russian and Chinese influences that threaten US national security.
Washington wants a partner in Caracas to do the deals at which Maduro balked. “We just could not work with him. He is not a person that had ever kept any of the deals he made,” Rubio told CBS.
The assumption that Rodríguez or another regime survivor will help the US is fine in theory. Outsiders are not privy to conversations and behind-the-scenes work from American diplomats and intelligence agencies with regime figures. Sources told CNN that Rodríguez had been identified as potentially providing more stable governance than Maduro.
Yet the vice president has been publicly scathing about Maduro's ouster, and other key figures have vowed to stand behind the regime. Rodríguez may need to avoid any public show of betrayal to keep herself safe in Venezuela. But after portraying her as cooperative on Saturday, Trump issued a dark threat on Sunday. “If she doesn't do what's right, she is going to pay a very big price, probably bigger than Maduro,” he told The Atlantic.
On Sunday evening, Rodríguez issued a more conciliatory statement offering an “agenda of cooperation” with the US.
Trump and several key members of his administration have warned that if Venezuelan officials don't play ball, they could court another, bigger US attack. But their threats raise a key question: Can Washington really force Venezuelan leaders to comply through the leverage of an offshore naval armada, special forces raids, intelligence operations or the threat of air attacks?
Ivo Daalder, a former US ambassador to NATO, told CNN on Sunday that it was impossible for the Trump administration to “run” Venezuela without committing the resources needed to properly govern it.
“This disconnect between the means that we have deployed and the goals that we have set is going to come and bite us in the back,” Daalder said.
It already looks like the US risks falling yet again into one of the recurring traps of its modern foreign policy — creating plans that seem sound in Washington but that dissolve on contact with the reality of a foreign nation.
Rodríguez might seem like a stabilizing force to US officials. As a former diplomat, she has good contacts abroad and in the oil industry.
But she's long been a key face of the Maduro regime and that of his predecessor Hugo Chávez. There's been no sign that she's renounced the far-left ideology of the revolution. And Rodríguez herself may have limited room for maneuver or cooperation with the US in the snake pit of competing currents and strongmen that characterize the inner sanctums of the regime in Caracas.
“She doesn't have the support among the various armed actors,” Daniel Lansberg-Rodriguez, a geopolitical risk consultant, told CNN's Boris Sanchez on Sunday. “She's going to have to straddle keeping the people who do have good contacts there, keeping them balanced with whatever instructions she is supposedly getting from DC.”
The acting president's emerging importance to the administration means she risks becoming a fragile platform for Trump's entire gamble in Venezuela.
“Delcy Rodríguez is a very powerful figure in her own right, handpicked by Maduro,” Democratic Sen. Chris Murphy said on “State of the Union.”
“There's really no explanation for how American interests are changed at all with a Rodríguez administration that right now seems to be intent on carrying through and carrying forward the policies of Nicolás Maduro,” Murphy said.
Even Cotton will wait and see. “I don't think that we can count on Delcy Rodríguez to be friendly to the United States until she proves it,” he told CNN's Bash.
Perhaps the most shocking moment in Trump's Saturday news conference at Mar-a-Lago was the president's dismissal of María Corina Machado. The Nobel Peace laureate is credited with masterminding the campaign of opposition candidate Edmundo González, who is regarded as the winner of last year's election — a result Maduro refused to recognize.
The US government has consistently said that González is the rightful president of Venezuela. Many people assumed that any US ouster of Maduro would swiftly lead to González's installation as president.
But Trump said Machado “doesn't have the support within or the respect within the country. She's a very nice woman, but she doesn't have the respect.”
The administration's shift away from the democratic movement and engagement with regime remnants is a blow to Venezuelans hoping their long political torment would end.
Rubio, who has long supported Machado and democratic movements across Latin America, tried to square a politically uncomfortable circle. “There has to be a little realism here,” he told CBS.
“They've had this regime … in place for 15 or 16 years and everyone's asking why 24 hours after Nicolás Maduro was arrested there isn't an election scheduled for tomorrow. That's absurd,” Rubio said.
Rubio argued that “these things take time” and that while he hoped to see Venezuela transition to a democracy, US national interests were the immediate concern.
This Trump administration pragmatism is fueling anger on Capitol Hill.
“My God, we're the United States of America, right?” Rep. Jim Himes, the top Democrat on the House Intelligence Committee, said on “State of the Union.”
“We care — or at least we used to care — about democratic norms. We used to care about the idea that the people ought to have a little something to say about who governs them,” Himes said.
Trump is clearly rushing for Venezuelan oil — and he wants to dominate the Western Hemisphere. But in courting Maduro's regime remnants, the US risks becoming complicit in the repression imposed by a government it has long reviled.
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Regime change in Venezuela could pave the way for the return of U.S. oil majors to the South American nation, which has the largest proven crude oil reserves in the world.
President Donald Trump called for U.S. oil companies to invest billions of dollars in Venezuela's energy sector, hours after U.S. forces captured President Nicolas Maduro and his wife.
"We're going to have our very large United States oil companies — the biggest anywhere in the world — go in, spend billions of dollars, fix the badly broken infrastructure, the oil infrastructure," Trump said in a press conference Saturday from his Mar-a-Lago residence in Palm Beach, Florida.
The oil majors have largely been silent since Maduro's overthrow as the situation on the ground in Venezuela remains uncertain. But shares of Chevron, Exxon Mobil and ConocoPhillips are rising as investors bet that the three largest U.S. oil companies will cash in after the U.S. military action.
Venezuela's oil reserves are estimated at 303 billion barrels or about 17% of the global total, according to the U.S. Energy Information Administration.
The country's production peaked at 3.5 million barrels per day in the late 1990s but has declined significantly since then, according to energy consulting firm Kpler. Venezuela's production currently stands at around 800,000 bpd, Kpler data shows.
Its reserves, located mostly in the Orinoco Belt in the eastern part of the country, are extra-heavy crude oil that require a greater level of technical expertise to extract, according to the EIA.
Former President Hugo Chavez seized assets from U.S. oil majors in 2007. Chevron is the only U.S. oil major operating in Venezuela. Exxon and Conoco have billions of dollars in outstanding claims against Caracas from Chavez's nationalization.
It will take more than just easing U.S. sactions against Venezuela to encourage new investment in the country, Morgan Stanley analyst Devin McDermott told clients in a Monday note. Trump said over the weekend that the U.S. embargo of Venezuelan oil remains in full effect.
U.S. producers would need to see a path to recover their claims from Caracas and have confidence in the stability of the government in Venezuela, McDermott said.
Trump railed against Venezuela's oil nationalization, describing it as "one of the largest thefts of American property in the history of our country."
"The oil companies are going to go in, they're going to spend money, we're going to take back the oil that, frankly, we should have taken back a long time ago," the president said.
The administration will discuss plans with oil executives to expand in the country, a U.S. official told CNBC.
Chevron is best positioned to scale up production quickly if conditions allow, McDermott said. It exported about 140,000 barrels per day in the fourth quarter of 2025, Kpler data shows.
Chevron has a significant resource base in Venezuela, JPMorgan analyst Arun Jayaram told clients Monday. It has joint ventures with state-owned oil company Petróleos de Venezuela (PDVSA) that are responsible for 23% of the South American nation's output, Jayaram said.
Chevron said it "remains focused on the safety and wellbeing of our employees, as well as the integrity of our assets" in the wake of Maduro's overthrow. "We continue to operate in full compliance with all relevant laws and regulations," the oil major said in a weekend statement.
The Biden administration issued a license in 2022 that allowed Chevron's joint venture with PDVSA to produce and export oil. The Trump administration granted the oil major a restricted license in July 2025 that allowed it to pump but banned proceeds from going to the Maduro government.
Conoco and Exxon participated in Venezuela's "oil opening" policy in the 1990s, which invited foreign investment to develop resources in the Orinoco Belt. They exited the country after Chavez's nationalization and filed arbitration claims against Caracas.
Conoco has oustanding claims from abitration cases against the Venezuela approaching $10 billion, Jayaram said. Exxon's claims are around $2 billion, he said.
Conoco is "monitoring developments in Venezuela and their potential implications for global energy supply and stability," spokesperson Dennis Nuss said in a weekend statement. "It would be premature to speculate on any future business activities or investments."
Exxon has not responded to requests for comment.
Rebuilding Venezuela's oil infrastructure will likely cost billions. Investors were speculating the work could boost business for oil services companies, with shares of Slb up more than 10%, Halliburton gained 9%, while Baker Hughes added 4% in trading Monday.
The future of Venezuelan production depends on how the security situation on the ground evolves, said Helima Croft, head of global commodity strategy at RBC Capital Markets, in a Saturday note to clients.
Oil executives operating in Venezuela say it will cost $10 billion annually to turn production around and a stable security environment is essential to grow production back to historic levels, Croft said.
Venezuela production could grow by several hundred thousand barrels per day over the next 12 months if the Trump administration provides full sanctions relief and there is an orderly transition of power, she said.
"However, all bets are off in a chaotic change of power scenario like what occurred in Libya or Iraq," Croft told clients.
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Amazon on Monday launched an Alexa+ website that lets some users chat with its assistant via their browser, putting it in more direct competition with OpenAI's ChatGPT.
The Alexa.com website is only available to users of Alexa+, its revamped artificial intelligence assistant that debuted last February and remains in early access. Users have to join a waitlist to gain access to the service or purchase newer devices.
Amazon says consumers can use Alexa.com to "get quick answers, explore complex topics, create content, plan trip itineraries and get help with homework." Users can also manage their smart home gadgets within the Alexa+ chat window, the company said.
By launching a browser-based version of Alexa, Amazon wants to make sure users can interact with its AI assistant across different interfaces.
Previously, Alexa+ was only available via a mobile app or some Echo devices.
It also puts Amazon's service more in line with popular AI chatbots made by the likes of OpenAI, Google, Anthropic and Perplexity, all of which are frequently accessed via web browsers.
Amazon has faced growing pressure to update its hardware and software for the generative AI age following the success of ChatGPT, Google's Gemini and others.
Alexa+ has gradually rolled out to users since its debut, and the company has said tens of millions of people now have access to the service.
Amazon previewed Alexa.com when it launched Alexa+ last year, saying at the time that the website would launch in the coming months. The company told the Washington Post last July that the feature would be available for early access users in the summer.
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The Pentagon will cut the military retirement pay of Sen. Mark Kelly for what Defense Secretary Pete Hegseth called the Arizona Democrat's "seditious" statements on a video with other members of Congress telling service members they have the right to refuse to execute illegal orders.
Hegseth also issued a formal letter of censure against Kelly, which the Defense secretary said details "reckless misconduct" by the retired Navy captain and astronaut.
Hegesth said the Defense Department has begun a proceeding aimed at reducing Kelly's rank in retirement, which would in turn lead to a decrease in retirement pay.
"Six weeks ago, Senator Mark Kelly — and five other members of Congress — released a reckless and seditious video that was clearly intended to undermine good order and military discipline," Hegseth said in a statement on X.
"As a retired Navy Captain who is still receiving a military pension, Captain Kelly knows he is still accountable to military justice. And the Department of War — and the American people — expect justice," Hegseth said.
Kelly has 30 days to file a response to the decision to cut his rank and retirement pay, according to Hegseth's tweet.
The Pentagon in November announced a probe of Kelly for his involvement with the video, and said that further actions could include a recall to active duty and a court-martial proceeding.
Hegeth's statement on Monday suggests that the Pentagon has ruled out that more severe option.
But, in his tweet, Hegseth warned, "Captain Kelly's status as a sitting United States Senator does not exempt him from accountability, and further violations could result in further action."
Kelly, in a statement on X, vowed to fight the disciplinary action "with everything I've got," and called Hegseth "the most unqualified Secretary of Defense in our country's history."
"Over twenty-five years in the U.S. Navy, thirty-nine combat missions, and four missions to space, I risked my life for this country and to defend our Constitution – including the First Amendment rights of every American to speak out," Kelly wrote. "I never expected that the President of the United States and the Secretary of Defense would attack me for doing exactly that."
"My rank and retirement are things that I earned through my service and sacrifice for this country. I got shot at. I missed holidays and birthdays. I commanded a space shuttle mission while my wife Gabby recovered from a gunshot wound to the head– all while proudly wearing the American flag on my shoulder," Kelly wrote. "Generations of servicemembers have made these same patriotic sacrifices for this country, earning the respect, appreciation, and rank they deserve.
"Pete Hegseth wants to send the message to every single retired servicemember that if they say something he or Donald Trump doesn't like, they will come after them the same way," the senator said. "It's outrageous and it is wrong. There is nothing more un-American than that."
The video that Kelly spoke on was made in response to the U.S. military conducting 20 airstrikes on boats in the Caribbean and eastern Pacific Ocean against purported drug smugglers, killing scores of people.
The legality of those strikes, which were made without authorization from Congress, has been questioned.
In the video, which was posted on X on Nov. 18, Kelly says, "Our laws are clear: you can refuse illegal orders."
The five other Democratic members of Congress who delivered similar messages on the same video are Michigan Sen. Elissa Slotkin, House Reps. Jason Crow of Colorado, Maggie Goodlander of New Hampshire, and Chris Deluzio and Chrissy Houlahan, both of Pennsylvania.
Slotkin is a former CIA analyst. Deluzio and Goodlander are former Navy officers, and Houlahan is a former Air Force officer.
But unlike Kelly, the other three veterans on the video separated from their service branches rather than retiring from them. As a result, they are not subject to the Uniform Code of Military Justice, as Kelly is.
Hegseth, in his statement on Monday, said about the Pentagon's move to discipline Kelly: "These actions are based on Captain Kelly's public statements from June through December 2025 in which he characterized lawful military operations as illegal and counseled members of the Armed Forces to refuse lawful orders."
"This conduct was seditious in nature and violated Articles 133 and 134 of the Uniform Code of Military Justice, to which Captain Kelly remains subject as a retired officer receiving pay," Hegseth said.
Senate Minority Leader Chuck Schumer condemned the Pentagon's action on Monday.
"Mark Kelly is a hero and a patriot committed to serving the American people," Schumer, D-N.Y., wrote in a tweet responding to Hegseth.
"Pete Hegseth is a lap dog committed to serving one man – Donald Trump. This is a despicable act of political retribution," Schumer wrote. "I stand with Sen. Kelly, who will always do the right thing no matter the consequences."
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Democratic Gov. Tim Walz of Minnesota is dropping his bid for reelection, he announced Monday morning.
The announcement came as Walz, who was Kamala Harris' vice presidential pick for her failed 2024 White House bid, continues to weather heated criticism over a sweeping fraud scandal in his state.
"As I reflected on this moment with my family and my team over the holidays, I came to the conclusion that I can't give a political campaign my all," Walz said in a statement.
"Every minute I spend defending my own political interests would be a minute I can't spend defending the people of Minnesota against the criminals who prey on our generosity and the cynics who prey on our differences," he said.
"So I've decided to step out of the race and let others worry about the election while I focus on the work," the governor said.
Walz read the same statement during a brief news conference later Monday. He took no questions.
Sen. Amy Klobuchar, who ran for the Democratic presidential nomination in 2020, is weighing a Minnesota gubernatorial bid in light of Walz bowing out, The New York Times reported Monday. Walz and Klobuchar spoke over the weekend, multiple outlets reported.
Walz had announced in September that he would seek a third term in office. But his plans were soon upended by damning reports on the social services fraud scams that have blossomed in Minnesota in the years since the Covid-19 pandemic, while Walz led the state.
A federal prosecutor in Minnesota last month estimated that the fraud schemes may have totaled more than $9 billion, though Walz has called that number "sensationalized."
The scandal has put focus on the state's Somali community, where the majority of people so far charged by the Department of Justice in connection with the fraud have come from.
President Donald Trump has responded to the fraud reports with vehemently anti-Somali rhetoric and renewed attacks against Democratic Rep. Ilhan Omar, the first Somali American member of Congress.
The Trump administration's Health and Human Services Department last week announced it would freeze all federal child-care payments to Minnesota.
Walz, in Monday's statement, defended Minnesota's Somalian population while acknowledging that the fraud in the state must be addressed.
"Make no mistake: We should be concerned about fraud in our state government. We cannot effectively deliver programs and services if we can't earn the public's trust," Walz said, listing the steps his administration has already taken.
"But the political gamesmanship we're seeing from Republicans is only making that fight harder to win," he said.
"We've got the President of the United States demonizing our Somali neighbors and wrongly confiscating childcare funding that Minnesotans rely on."
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Versant Media Group, the portfolio of cable TV networks and digital assets spun off by Comcast, joined the small cohort of public media companies Monday as the industry reckons with ongoing disruption.
Versant began trading on the Nasdaq under the ticker symbol "VSNT," opening at $45.17 per share.
The company's so-called when-issued stock — a security that is expected to be issued and has been authorized to trade on a conditional basis to give investors an early chance to buy shares — initially began trading on Dec. 15 at $55 per share and ended trading Friday at $46.65 per share.
As of mid-morning Monday, Versant shares had fallen to roughly $40 per share, down 14% on the day.
The company's market capitalization stands at roughly $6.5 billion with shares outstanding of 145.76 million based on the spinoff ratio. As part of the spinoff, Comcast shareholders received one share of Versant stock for every 25 shares of Comcast stock they owned.
"It's been a year in the making," said Mark Lazarus, Versant CEO, on CNBC's "Squawk Box" on Monday.
In November 2024, Comcast announced its intention to separate out the bulk of NBCUniversal's cable TV networks, including MS Now (formerly MSNBC), CNBC, Golf Channel, USA, E!, Syfy and Oxygen, as well as digital properties Fandango, Rotten Tomatoes, GolfNow and Sports Engine.
"As part of Comcast and NBCU we had other priorities as a company," Lazarus said. "We made different decisions, because we had a different company and a different strategy. Now we're bringing these [assets] into their own company, we're going to be able to invest into them. We'll invest organically ... and hopefully the market is listening to what we're saying."
Lazarus said "vertical scale" is necessary to diversify the business away from a dependence on pay TV.
"While that's still a big, profitable part for us, it's not going to be the end game," he said.
There are few traditional media companies that have gone public in recent years — namely because of the significant challenges the industry has been facing due to the shift away from the TV bundle and toward streaming.
In 2025, Newsmax, the conservative cable news network, went public on the New York Stock Exchange and quickly saw its shares soar from its $14 per share opening price. It has fallen precipitously since its debut.
Instead, the media sector has been marked by a rush for consolidation and fresh M&A deals. Paramount Skydance completed its merger last year, and since then CEO David Ellison has been acquisitive. Warner Bros. Discovery, itself formed following a merger in 2022, last year kicked off a sale process that resulted in a proposed deal with Netflix. Paramount has since made a hostile offer to WBD shareholders to upend the proposed transaction with Netflix.
The Versant spinoff was likewise a result of the disruptive media landscape. Its executives, led by CEO Lazarus, former chairman of NBCUniversal's media group, spent the final months of 2025 convincing Wall Street investors that the future of the business would be focused on growing the digital presence of its portfolio.
The company has also highlighted its strength in news and sports, the two categories of programming that still receive the bulk of TV viewers. Although networks like those in Versant's portfolio are seeing declines in financials, they are still profitable and beckon ad dollars.
On Monday, Lazarus once again pointed to Versant's weight in sports and news, saying 62% of the portfolio is in those two content areas.
"We have a really strong position," Lazarus said.
In September Versant reported declining revenue in recent years as consumers exit the cable TV bundle.
According to a filing with the Securities and Exchange Commission ahead of going public, Versant's assets generated $7.1 billion in revenue in 2024 , down from $7.4 billion in 2023 and $7.8 billion in 2022. The company said its net income attributable to Versant was $1.4 billion in 2024, down from $1.5 billion in 2023 and $1.8 billion in 2022.
Shortly after, ratings agencies S&P Global and Fitch Ratings each issued BB credit ratings on the company's debt noting stable outlooks, placing the company's rating in junk territory. This was based on Versant's plans to issue $2.75 billion of new senior secured debt to fund a one-time $2.25 billion cash distribution to Comcast and add $500 million to its balance sheet, according to S&P.
Versant's low debt levels have boded well for the company with both ratings agencies and have been a highlight in its pitch to Wall Street investors. Media peers like Warner Bros. Discovery have grappled with heavy debt loads while also contending with the decline of cable TV subscribers and lower ad revenue.
Both ratings agencies noted the headwinds facing the traditional TV landscape, which S&P said "offset the strength of [Versant's] portfolio," noting that revenue from linear distribution and advertising from its networks accounted for more than 80% of total revenue.
Fitch said "the strong viewer loyalty and engagement" with Versant's TV networks, as well as its conservative debt structure, bodes as a positive for the company.
Versant executives said at a recent investor day presentation that the company intends to grow its digital business through acquisitions and investments.
— CNBC's Gina Francolla contributed to this article.
Disclosure: Versant is the parent company of CNBC.
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This is CNBC's Morning Squawk newsletter. Subscribe here to receive future editions in your inbox.
Good morning. It was anything but a quiet weekend for news, so I'll cut to the chase.
S&P 500 futures are up slightly this morning. The market is coming off a losing week.
Here are five key things investors need to know to start the trading day:
President Donald Trump said early Saturday that the U.S. carried out a large-scale strike on Venezuela. Venezuelan President Nicolas Maduro and his wife were captured and taken to New York to be indicted for narco-terrorism.
Here's what to know:
Oil prices and stocks are being closely watched this morning as investors wonder what the shakeup in Venezuela would mean for the market structure.
As CNBC's Spencer Kimball notes, Venezuela has the largest proven crude oil reserves in the world. Still, analysts say the energy market is unlikely to see big swings in the near term as a result of the strike. Petroleum-focused intergovernmental group OPEC+ kept its oil output unchanged yesterday.
Shares of oil stocks such as Chevron and Exxon Mobil jumped in premarket trading today. Follow live markets updates here.
"Do more with less." This phrase-turned-governing principle has been a bedrock for Anthropic president and co-founder Daniela Amodei.
As CNBC's MacKenzie Sigalos reports, the buzzy artificial intelligence startup has been disciplined when it comes to spending. This strategy stands in stark contrast to other major AI players, who have raced to ink billion-dollar deals to bolster their leadership on the technology.
As Amodei puts it: "Anthropic has always had a fraction of what our competitors have had in terms of compute and capital, and yet, pretty consistently, we've had the most powerful, most performant models for the majority of the past several years." Read and watch the full interview here.
CNBC's Morning Squawk recaps the biggest stories investors should know before the stock market opens, every weekday morning.
Subscribe here to get access today.
Tesla lost its spot as the world's largest electric vehicle maker for the first time last week.
The company reported 418,227 deliveries in the fourth quarter on Friday, missing Wall Street's forecast and marking a 16% decline from a year ago. Tesla's 2025 calendar year total of 1.64 million placed it behind China-based company BYD, which sold 2.26 million vehicles in the year.
Users also criticized Musk's xAI company last week over recent Grok chatbot posts showing AI-generated, sexualized images of children shared on X. Meanwhile, Musk's Starlink business said it would provide free broadband internet service to Venezuela users until early February following the U.S. strike.
Chick-fil-A is ringing in its 80th anniversary with its biggest marketing campaign ever.
As CNBC's Amelia Lucas found, the fast-food chain is dishing out retro packaging, collectible cups, special merchandise and freebies to mark the occasion. The company said the theme at the heart of the campaign is "newstalgia" — a combination of the words new and nostalgia.
Chick-fil-A's marketing blitz comes as the restaurant industry grapples with sliding traffic. The company's franchise disclosure documents show system sales growth came in at 5.4% in 2024, which marked the first year in more than a decade with an increase in the single digits.
Here's what we're keeping an eye on this week:
CNBC Pro subscribers can see a calendar and rundown for the week here.
CNBC's Spencer Kimball, Victor Loh, Dan Mangan, Justin Papp, Hayley Cuccinello, Jessica Dickler, Leslie Josephs, MacKenzie Sigalos, Sam Meredith, Lora Kolodny, Samantha Subin, Amelia Lucas and Sarah Min contributed to this report. Melodie Warner edited this edition.
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Novo Nordisk will start rolling out the first-ever GLP-1 pill for weight loss in the U.S. on Monday, the company announced, marking a new chapter of obesity treatment in the U.S.
The drug's cash prices are among the lowest on the market, ranging from $149 to $299 per month, depending on the dose. That fuels hopes that pills could help address the long-standing affordability hurdles tied to the weekly injections dominating the weight loss drug market.
The official launch of the oral drug, called the Wegovy pill, comes just two weeks after U.S. regulators cleared the treatment.
The starting dose of 1.5 milligrams is available at more than 70,000 U.S. pharmacies such as CVS and Costco, as well as select telehealth providers, including Ro, LifeMD, Weight Watchers, GoodRx and Novo Nordisk's NovoCare Pharmacy. The higher, remaining doses of the pill will be available to patients by the end of the week, Novo Nordisk said.
Cash-paying patients can pay $149 per month for the starting dose. The 4-milligram dose of the pill will also be available for $149 per month through April 15, then $199 per month after that.
The highest doses of the Wegovy pill – 9 milligrams and 25 milligrams – will be available for $299 per month. Patients with insurance coverage for the drug can pay as little as $25 per month for the treatment.
Cash-paying patients will also be able to access the starting dose of the pill for $149 per month on President Donald Trump's direct-to-consumer website, TrumpRx, under a deal Novo Nordisk struck with his administration in November. The site also launches in January, though it's unclear when.
Novo Nordisk on Monday said the pill's availability "opens new possibilities" for the more than 100 million Americans living with obesity.
Injections from Novo Nordisk and its chief rival, Eli Lilly, carry a list price of roughly $1,000 per month. But both companies offer lower cash-pay prices for their shots that range from $299 to $499 monthly, depending on the dose.
Pills are the next battleground for the two companies, which established the booming GLP-1 space that some analysts say could be worth roughly $100 billion by the 2030s. Goldman Sachs analysts said in August that oral drugs could capture a 24% share — or around $22 billion — of the 2030 global weight loss drug market.
The launch of Novo Nordisk's daily oral drug on Monday gives the company a clear head start. The Food and Drug Administration approved the treatment on Dec. 22 and will decide whether to clear a rival pill from Eli Lilly later this year.
The FDA also approved Novo Nordisk's pill for use to reduce the risk of major cardiovascular events, such as death, heart attack or stroke, in adults with obesity and established cardiovascular disease.
That's consistent with the approval label of the company's blockbuster weight loss drug Wegovy, which shares the same active ingredient, semaglutide. Both work by mimicking the gut hormone GLP-1 to suppress appetite.
"This moment is about changing what's possible in weight management, and to make that possible, we have worked to ensure [the Wegovy pill] is affordable and accessible to those who need it, however they choose to receive their care," said Ed Cinca, Novo Nordisk's senior vice president of marketing and patient solutions, in a release.
People who take Novo Nordisk's pill have to wait 30 minutes before eating or drinking each day.
In a phase three trial that followed more than 300 adults with obesity and not diabetes, the highest dose of Novo Nordisk's oral semaglutide helped patients lose up to 16.6% of their weight on average after 64 weeks. That weight loss was 13.6% when the company analyzed all patients regardless of whether they stopped the drug.
The pill appears to be slightly more effective than Eli Lilly's experimental oral drug, which does not have dietary restrictions.
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For Chick-fil-A's 80th anniversary, the chicken chain is going all out: retro packaging, collectible cups, themed merch and even the chance to win free food for a year.
The chain's anniversary comes as the restaurant industry struggles with declining traffic. To win back diners, many restaurants have leaned into deals, buzzy promotions and larger marketing budgets.
As a privately held company, Chick-fil-A does not disclose quarterly financial results, but franchise disclosure documents show that the company's system sales growth slowed to 5.4% in 2024, making it the first year in more than a decade with less than double-digit sales growth.
Chick-fil-A has stayed out of the so-called value wars other restaurants have leaned into to compete, but the anniversary gives the chain the opportunity to attract more customers to its restaurants. The yearlong marketing campaign kicks off on Monday and represents the biggest promotional push ever for Chick-fil-A. Khalilah Cooper, Chick-fil-A's vice president of brand strategy, advertising and media, told CNBC that new advertising will spotlight the anniversary in both national TV spots and on social media.
At the center of the campaign is what the company is calling "newstalgia," a portmanteau of "new" and "nostalgia."
"We've thought about this as a way to celebrate our heritage with customers who've been with us, potentially for decades, for all 80 years, or whether they've been with us for eight days or have never tried Chick-fil-A before," Cooper said.
While Chick-fil-A's growth is slowing, its sales are still rising even as the broader restaurant industry struggles with more budget-conscious consumers who are eating out less often and spending less, leading to shrinking traffic to eateries. In 2025, July was the only month with increasing restaurant visits compared with the year-ago period, according to Black Box Intelligence. Monthly traffic hit a low point in February, with the firm reporting a 5.7% fall from a year earlier.
Chains like Chipotle Mexican Grill, Papa John's and Wendy's have reported declining traffic and falling same-store sales. Hundreds of restaurant locations, from the likes of Starbucks and Jack in the Box, permanently closed in 2025 due to weak traffic.
To start, Chick-fil-A is also rolling out four retro collectible cup designs every few weeks, inspired by the company's archives and the shape of its 32-ounce cup. The chain is selling the cups for $3.99 at restaurants nationwide.
Plus, Chick-fil-A has come up with its own riff on Willy Wonka's famous golden ticket: the Golden Fan Cup. The 3,000 customers who buy a collectible cup and receive the Golden Fan Cup will receive free Chick-fil-A for a year.
The chain will also give its iconic chicken sandwich limited-time, vintage-inspired packaging.
Chick-fil-A plans to sell themed merch through its website over the course of the year. Customers who visit its restaurants will also be able to purchase limited-edition designs of its stuffed cows.
Also as part of the campaign, Chick-fil-A is adding its frosted sodas and floats to its menu permanently, starting Monday. Customers can also expect to see more limited-time menu items throughout the year than Chick-fil-A typically offers, according to Cooper.
The focus on "newstalgia" will also be front and center at the Chick-fil-A Peach Bowl on Friday, when the Oregon Ducks face off against the Indiana Hoosiers in the College Football Playoff semifinal.
Chick-fil-A traces its roots to 1946, when S. Truett Cathy and his brother opened a restaurant called The Dwarf Grill in Hapeville, Georgia, a suburb of Atlanta. More than two decades later, Cathy opened the first Chick-fil-A location, with its trademark chicken sandwich. The business is still family owned, and Cathy's grandson Andrew serves as its CEO.
The privately held chain's system sales reached $22.74 billion in 2024, making it the third-largest restaurant chain in the U.S., trailing only McDonald's and Starbucks. Over the past decade, Chick-fil-A has expanded far beyond its Southeastern stronghold, opening locations all across the U.S. and planning to expand its international business into the United Kingdom and Singapore.
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Deposed Venezuelan leader Nicolas Maduro appeared in a New York court on Monday afternoon, saying he had been "kidnapped" with his wife by U.S. forces from their home in Caracas, and that he was a "prisoner of war," as he pleaded not guilty to drug-trafficking charges
Maduro and his wife, Cilia Flores, who is also charged in the case, have been held since they were taken from Venezuela on Saturday after a U.S. strike on the country at the orders of U.S. President Donald Trump. Flores also pleaded not guilty.
"I'm innocent. I am not guilty of anything," Maduro repeatedly said through a translator to Judge Alvin Hellerstein during his appearance in U.S. District Court in Manhattan.
Flores said, "I am first lady of the Republic of Venezuela."
"Not guilty. Completely innocent," Flores replied when asked for her plea.
Flores had a large bruise on her forehead. Her attorney requested that she get medical attention from jail officials for injuries she sustained during her capture Saturday, including an X-ray for her ribs, which are believed to be broken or severely bruised.
The couple agreed to remain in jail without bail for now, but could submit a bail application in the future.
Hellerstein set the next court date for the case on March 17.
Manhattan U.S. Attorney Jay Clayton, whose office is prosecuting the couple, during an interview Monday morning on CNBC's "Squawk Box," said, "From the perspective of where I sit, my people and I are completely comfortable with this prosecution."
Defense lawyer Barry Pollack represented Maduro at the hearing.. Pollack previously represented WikiLeaks founder Julian Assange in Assange's federal criminal case.
Pollack said during the hearing said Maduro "is head of a sovereign state and entitled to the privilege" from that status. Pollack also said there were "questions about the legality of his military abduction" and that there would be "voluminous" court filings addressing that issue.
Flores is being represented by Mark Donnelly, a former federal prosecutor in Texas.
Maduro, 63, is charged in a federal indictment with narco-terrorism conspiracy, cocaine importation conspiracy, possession of machine guns and destructive devices, and conspiracy to possess machine guns and destructive devices. He has previously denied the allegations.
Flores, 69, is charged with the cocaine conspiracy and weapons counts.
Maduro, whom the indictment refers to as the "illegitimate ruler" of Venezuela as a result of fraudulent election results, is accused of partnering with co-conspirators, narcotics traffickers, and narco-terrorist groups to import tons of cocaine into the United States.
Maduro and his wife appeared at around noon before Judge Hellerstein.
"Nicolas Maduro Moros, the defendant, now sits atop a corrupt, illegitimate government that, for decades, has leveraged government power to protect and promote illegal activity, including drug trafficking," the 25-page indictment alleges.
"This cycle of narcotics-based corruption lines the pockets of Venezuelan officials and their families while also benefiting violent narco-terrorists who operate with impunity on Venezuelan soil and who help produce, protect, and transport tons of cocaine to the United States," the indictment says.
Among the alleged overt acts detailed in the indictment is a meeting that Flores attended in approximately 2007, in which she purportedly "accepted hundreds of thousands of dollars in bribes to broker a meeting between a large-scale drug trafficker and the director of Venezuela's National Anti-Drug Office, Nestor Reverol Torres."
"The drug trafficker later arranged to pay a monthly bribe to Reverol Torres, in addition to approximately $100,000 for each flight that was transporting cocaine to ensure the flight's safe passage, a portion of which was then paid to Flores de Maduro," the indictment alleges.
"Reverol Torres was charged with narcotics offenses in the Eastern District of New York and is a fugitive."
The other defendants charged in the same indictment are not in U.S. custody.
Those defendants are Maduro's son, Nicolas Ernesto Maduro Guerra; Diosdado Cabello Rondon; Ramon Rodriguez Chacin; and Hector Rusthenford Guerrero Flores.
Cabello is Venezuela's interior minister, a post previously held by Rodriguez.
Guerrero has been identified as the leader of the Venezuelan gang Tren de Aragua.
The Trump administration has faced questions about Maduro's apprehension in his own country, given Trump's recent pardon of former Honduran President Juan Orlando Hernandez, who was convicted in 2024 of conspiring with drug traffickers and using his government position to help hundreds of tons of cocaine enter the United States.
This is developing news. Check back for updates.
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Deposed Venezuelan leader Nicolas Maduro appeared in a New York court on Monday afternoon and pleaded not guilty to drug-trafficking charges two days after their dramatic capture by U.S. forces in their home country, according to media reports.
Maduro and his wife, Cilia Flores, who is also charged in the case, have been held since they were taken from Venezuela after a U.S. strike on the country at the orders of U.S. President Donald Trump. Flores also pleaded not guilty, according to reports.
"I'm innocent. I am not guilty. I am a decent man, the president of my country," Maduro told Judge Alvin Hellerstein during his appearance Monday in U.S. District Court in Manhattan, according to the Associated Press.
Flores said, "I am first lady of the Republic of Venezuela," according to the AP.
"Not guilty. Completely innocent," Flores reportedly replied when asked her plea.
The couple reportedly agreed to remain in jail without bail pending a possible detention hearing. Hellerstein set the next court date for the case on March 17.
Manhattan U.S. Attorney Jay Clayton, whose office is prosecuting the couple, during an interview Monday morning on CNBC's "Squawk Box," said, "From the perspective of where I sit, my people and I are completely comfortable with this prosecution."
Court filings on Monday morning show that defense lawyer Barry Pollack entered an appearance to represent Maduro. Pollack previously represented WikiLeaks founder Julian Assange in Assange's federal criminal case.
Pollack reportedly said during the hearing said Maduro "is head of a sovereign state and entitled to the privilege" from that status. Pollack also said there were "questions about the legality of his military abduction" and that there would be "voluminous" court filings addressing that issue.
Flores is being represented by Mark Donnelly, a former federal prosecutor in Texas.
Maduro, 63, is charged in a federal indictment with narco-terrorism conspiracy, cocaine importation conspiracy, possession of machine guns and destructive devices, and conspiracy to possess machine guns and destructive devices. He has previously denied the allegations.
Flores, 69, is charged with the cocaine conspiracy and weapons counts.
Maduro, whom the indictment refers to as the "illegitimate ruler" of Venezuela as a result of fraudulent election results, is accused of partnering with co-conspirators, narcotics traffickers, and narco-terrorist groups to import tons of cocaine into the United States.
Maduro and his wife appeared at around noon before Judge Hellerstein.
"Nicolas Maduro Moros, the defendant, now sits atop a corrupt, illegitimate government that, for decades, has leveraged government power to protect and promote illegal activity, including drug trafficking," the 25-page indictment alleges.
"This cycle of narcotics-based corruption lines the pockets of Venezuelan officials and their families while also benefiting violent narco-terrorists who operate with impunity on Venezuelan soil and who help produce, protect, and transport tons of cocaine to the United States," the indictment says.
Among the alleged overt acts detailed in the indictment is a meeting that Flores attended in approximately 2007, in which she purportedly "accepted hundreds of thousands of dollars in bribes to broker a meeting between a large-scale drug trafficker and the director of Venezuela's National Anti-Drug Office, Nestor Reverol Torres."
"The drug trafficker later arranged to pay a monthly bribe to Reverol Torres, in addition to approximately $100,000 for each flight that was transporting cocaine to ensure the flight's safe passage, a portion of which was then paid to Flores de Maduro," the indictment alleges.
"Reverol Torres was charged with narcotics offenses in the Eastern District of New York and is a fugitive."
The other defendants charged in the same indictment are not in U.S. custody.
Those defendants are Maduro's son, Nicolas Ernesto Maduro Guerra; Diosdado Cabello Rondon; Ramon Rodriguez Chacin; and Hector Rusthenford Guerrero Flores.
Cabello is Venezuela's interior minister, a post previously held by Rodriguez.
Guerrero has been identified as the leader of the Venezuelan gang Tren de Aragua.
The Trump administration has faced questions about Maduro's apprehension in his own country, given Trump's recent pardon of former Honduran President Juan Orlando Hernandez, who was convicted in 2024 of conspiring with drug traffickers and using his government position to help hundreds of tons of cocaine enter the United States.
This is developing news. Check back for updates.
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Foxconn, a major partner for Nvidia, has reported a 22% surge in revenues in the final quarter of 2025, as tech firms continue to ramp up spending on AI infrastructure.
Also known as Hon Hai, Foxconn reported revenues of 2.6 trillion Taiwan dollars ($83 billion) in the quarter up to December, as its components and cloud businesses demonstrated strong growth, the company said.
The figure tops analyst expectations of NT$2.4 trillion ($77 billion), according to LSEG estimates.
Foxconn is the world's largest contract electronics manufacturer and makes the servers that hold chips in data centers. It also assembles Apple's iPhone.
The company has emerged as a key player in AI as companies race to build out infrastructure for the technology. Its share price rose 25% across 2025, following a 76% uptick over the previous year.
"Revenue in the fourth quarter of 2025 achieved strong growth both QoQ and YoY, exceeding our expectation of significant growth, causing a high base for the first quarter," the company said in a statement.
Foxconn signed a partnership with OpenAI in November to collaborate on designs for next-generation AI infrastructure hardware.
In May, it was announced that the company would partner with Nvidia and the Taiwanese government to provide infrastructure to a major AI factory in Taiwan.
also announced in July that it was taking a stake in data center construction company TECO Electric & Machinery Co.
Foxconn said it expected earnings to be near the upper end of the past five-year range thanks to the continued rise in AI rack shipments, despite entering the "traditional off-season" for ICT products in the first quarter of the year.
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Russia's reaction to the ousting of Venezuelan President Nicolas Maduro has been cautious, with Moscow weighing up the potential geopolitical benefits and opportunities of the U.S.' unilateral action against the loss of an important regional ally in Latin America.
Moscow initially condemned U.S. strikes on Venezuela on Saturday, and the subsequent capture of Maduro and his wife, Cilia Flores.
Russia's Foreign Ministry decried the U.S.' "aggressive actions," saying they constituted "an unacceptable infringement on the sovereignty of an independent state." But the Kremlin has not issued an official response on the ousting, nor has Russian President Vladimir Putin.
Maduro was an ally of Putin and Venezuela has long-standing ties with Russia; Caracas backed Russia's invasion of Ukraine, and the two countries shared energy ties and military cooperation. The allies also had a shared interest in counteracting the U.S.' geopolitical, military and economic influence in the region.
Still, Maduro's removal is not all bad news for Russia, and Moscow is likely to be looking at ways it can leverage the crisis in Venezuela to its own benefit.
For a start, the Venezuela crisis comes at a delicate moment in Moscow's own relations with Washington. It's likely to be wary of burning bridges with the White House at a time when it's trying to curry favor with the administration to get the most favorable terms from a prospective Ukraine peace deal.
But events in Venezuela provide a welcome distraction on that front, with Russia benefiting from any relaxation of efforts — or pressure — to reach a peace deal with Ukraine, or to enter into a ceasefire as part of any agreement.
While Russian forces are seen to have an advantage on the battlefield, not least in terms of manpower, and are making incremental progress in eastern Ukraine, a ceasefire is not seen to be in Russia's interests.
"The Kremlin's response to the U.S. operation in Venezuela has been boilerplate thus far," analysts at the Institute for the Study of War, noted Sunday, adding that the Kremlin "will likely have to balance its responses between maintaining its credibility as a partner to other states with its continued efforts to cater to the Trump administration."
Analysts have also expressed concern that Trump's capture of Maduro, and the criminal charges levelled against him, could give Russia carte blanche to do the same to Ukrainian President Volodymyr Zelenskyy, who Moscow frequently describes as a "criminal" without presenting evidence to back up its accusations.
"He [Trump] is giving Putin permission to go as far as he wants with Zelenskyy," Sarah Lenti, political consultant and former director on the National Security Council at the White House, told CNBC on Monday.
"The president saying Maduro was a criminal, therefore he had the right to take [and] capture him. And we know that President Putin has often called Zelenskyy, wrongly, I believe, a criminal. And so he's setting a precedent and saying that it's OK for countries to go against the political sovereignty of another nation," she said in comments to CNBC's "Europe Early Edition."
"I think this is setting a very bad precedent for countries that China and Russia are looking to infringe upon, whether that's Taiwan or whether it's Ukraine," Lenti added.
On an ideological level, Trump's intervention in Venezuela and the foreign policy stance underpinning it — a desire to reassert the U.S.' power and dominance in the Western Hemisphere — chimes with Russia.
Putin is also widely seen as wanting to reestablish Russia's sphere of influence in Europe and Central Asia, which was lost following the collapse of the Soviet Union in 1991, an event that Putin described as the "greatest geopolitical catastrophe" of the 20th century.
There has been speculation that Trump's newfound focus on reestablishing American hegemony in the West could allow Russia to do the same in its own backyard. But several analysts commented to CNBC that the U.S.' intervention in Venezuela showed countries like Russia and Iran that Trump was ready to act if it was deemed to be in the U.S.' interests.
"What he is doing in Venezuela is definitely going to be seen and heard very clearly in Iran, and in Russia," Amrita Sen, founder of Energy Aspects, told CNBC on Monday,
"Whether that's in terms of needing to take Trump seriously, or in terms of, 'Don't dismiss it when he says, "I am going to be doing X,"' and I think that's something that world leaders will be very careful about," she told CNBC's "Squawk Box Europe."
Marko Papic, strategist at BCA Research, contended that Russia had no bargaining power with the U.S. when it came to allies like Venezuela.
"If the U.S. gets a free rein in the sphere of influence, do other great powers get a free rein in theirs? The answer is 'no.' There is nothing that Russia could have given America in Venezuela. ... There was no need for any kind of a bargain between Russia and the U.S. [as] the U.S. has free rein in its Western hemisphere," he noted.
Analysts are keen to stress that Maduro's ousting won't be actively welcomed in Moscow, as it removes an important ally and a bulwark against U.S. influence and aspirations in Latin America.
"With Maduro's fall, another Russian client state bites the dust, reducing the value of a Kremlin security guarantee to slightly better than zero," Tina Fordham, founder of Fordham Global Foresight, stated in analysis on Monday.
"To make matters worse from the Kremlin's perspective, the U.S. operation effortlessly cut through the much-vaunted S-300 Russian air defence systems that had been installed in Venezuela, after having also failed to deliver air protection in Syria and Iran," she noted.
Correction: Tina Fordham is founder of Fordham Global Foresight. An earlier version misstated the firm's name.
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Deborah Carrillo made a classic lawyer pivot. After a decade at a white-shoe firm, she left to join one of her clients, the venture capital firm Menlo Ventures.
What came next is far less common. Menlo has elevated Carrillo, its general counsel and only in-house lawyer, to partner after nearly six years with the firm — a rare distinction inside a venture fund.
Carrillo's promotion suggests the role of the legal department is shifting in the venture industry. Carrillo said she's at the table for weekly partner meetings where they pitch deals and bat around ideas.
"My voice is valued," she said.
Lawyers who go in-house often swap the prestige of firm life for steadier hours and a different kind of influence. At venture firms, general counsels typically haven't been on a path to ownership. Carrillo's new title puts her closer to the upside, giving her a larger claim on future profits.
Menlo Ventures is one of the oldest investment shops in Silicon Valley, with $6.8 billion in assets under management. It backed Anthropic early on and counts Lovable, Chime, and Carta among its breakout investments.
Other firms that have granted the partner title to general counsels over the years include Lightspeed and Bessemer Venture Partners.
Before joining Menlo, Carrillo was a partner at the New York law firm Pillsbury Winthrop Shaw Pittman LLP, where she advised startups and venture firms. She previously taught math in public schools.
As the firm's one-person legal shop, Carrillo helps structure investments and funds and keeps the machinery of compliance running smoothly.
Increasingly, that means translating geopolitics into go or no-go calls: flagging risks that could trigger blowback from the government, and, amid new federal restrictions on foreign investments, digging into whether a portfolio company's ownership traces back to Chinese nationals.
"I help people make the best decision and execute on those decisions," Carrillo said.
Carrillo's advice for young lawyers looking to make a move in-house: "Follow people and follow joy."
Have a tip? Contact this reporter via email at mrussell@businessinsider.com or Signal at @MeliaRussell.01. Use a personal email address and a non-work device; here's our guide to sharing information securely.
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Jason Lemkin, known to some as the Godfather of SaaS, says the time has come to push the limits of AI in the workplace.
In practice, Lemkin, the founder of SaaStr, the world's largest community of business-to-business founders, said on Lenny's Podcast recently that this means he will stop hiring humans in his sales department.
Instead, SaaStr is going all in on agents, which are commonly defined as virtual assistants that can complete tasks autonomously. They break down problems, outline plans, and take action without being prompted by a user.
He said the company now has 20 AI agents automating tasks once handled by a team of 10 sales development representatives and account executives.
That move from an entirely human workforce to an agent-based workforce was rapid.
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In May, SaaStr had just one AI agent in production that it used for various digital tasks, Lemkin said. That month, though, during the SaaStr Annual — its yearly gathering of over 10,000 founders, executives, and VCs — two of its high-paid sales representatives abruptly quit.
Lemkin said he turned to his chief AI officer and said, "We're done with hiring humans in sales. We're going to push the limits with agents."
Lemkin's calculus was that it just wasn't worth the cost of hiring another junior sales representative for a $150,000 a year position who would eventually quit, when he could use a loyal AI agent instead.
Amelia Lerutte, SaaStr's chief AI officer, told Business Insider by email that by June, the company began ramping up the number of agents it had in production.
"We had only 1 non-core agent at the time with Delphi, but didn't go deep on 2 to 20+ until the beginning of June," she said. "It was a conscious choice after their departure to reallocate some (but not all) head count spend to agents."
At the SaaStr office, the 10 desks that once belonged to humans on the go-to-market team are now labeled with the names of agents, like "Quali for qualified," "Arty for artisan," and "Repli for Replit," Lemkin said.
Lemkin said SaaStr is training its agents on its best humans.
"Train an agent with your best person, and best script, then that agent can start to become a version of your best salesperson," he said.
SaaStr's process is similar to how Vercel, the cloud-based platform for developers, trained a sales agent off its top performer for six weeks by documenting every step of their work, and then building an agent to mimic their process.
Many companies are experimenting with AI agents, but risks remain. One of the big ones is the threat of data leaks and cybercrime.
"AI agents, in order to have their full functionality, in order to be able to access applications, often need to access the operating system or the OS level of the device on which you're running them," Harry Farmer, a senior researcher at the Ada Lovelace Institute, recently told Wired.
All of that access creates more potential attack points for cybercriminals.
Security threats aside, Lemkin said that the net productivity of agents is about the same as humans. However, he said, agents are more efficient and can scale — just like software.
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BEIJING — Even as China eyes new opportunities to build global influence in the wake of the U.S. attack on Venezuela, Beijing's immediate priority is protecting its economic interests, analysts said.
China reacted swiftly to the military strike on Saturday night, expressing shock and condemnation. Beijing subsequently called on the U.S. to release the ousted Venezuelan president Nicolás Maduro and his wife, and urged Washington to resolve the crisis through dialogue.
China's Foreign Ministry spokesperson Lin Jian said at a press briefing Monday that China maintains "positive communication and cooperation" with the Venezuelan government and that its willingness to deepen cooperation, including on oil exports, would not change regardless of how the situation evolves.
He added that Chinese interests in Venezuela would be protected under the law.
The U.S. attack on Venezuela helps China bolster its position as a "force for stability" in the world, said Zichen Wang, a research fellow at the Beijing-based think tank Center for China and Globalization.
But Wang said the situation raises concerns for Beijing because of China's exposure in the country.
"How this unfolds in the future is also very concerning, because China has a lot of commercial interests there," he said, adding that the uncertainty could spill over to Chinese business across Latin America and beyond.
Beijing has made significant inroads in Latin America over the past two decades, persuading several countries, including Panama, Costa Rica, the Dominican Republic and El Salvador, to shift diplomatic recognition from Taiwan to China.
Chinese companies, mostly state-owned, have invested $4.8 billion in Venezuela over the last two decades, according to data compiled by the U.S.-based research firm Rhodium Group. Most of the deals occurred in the decade following the global financial crisis — and during the final years of former President Hugo Chávez's rule — with a focus on energy projects.
State-owned oil giant China National Petroleum Corporation has joint ventures with its Venezuelan counterpart, Petróleos de Venezuela. In August, privately held China Concord Resources Corp. announced rare plans to invest more than $1 billion in a Venezuelan project, targeting production of 60,000 barrels of crude oil a day by the end of 2026, according to Reuters.
Protecting Chinese nationals and Chinese companies remains Beijing's top priority, said Dong Shaopeng, a senior researcher at Renmin University of China. China's Foreign Ministry said Monday it has received no reports of Chinese citizens being harmed by the U.S. strike.
Beijing also criticized what it described as bullying actions that violate another country's sovereignty and said it opposes interference in the internal affairs of Latin American nations for any reason.
China said it follows a noninterference policy and will remain a "good friend" to countries in Latin America and the Caribbean "and does not draw ideological lines."
"China never seeks spheres of influence, nor does it target any third party," Lin added.
China is the top destination for Venezuela crude, according to S&P Global.
But Venezuela accounted for only 2% of China's crude oil and condensate imports in 2024, with the majority coming from the Middle East, according to figures published by the U.S. Energy Information Administration.
Imports from Iran and Iraq increased between 2023 and 2024, while those from Venezuela fell, the data showed.
"China is likely to be wary of being dragged into this conflict, as Venezuela carries limited economic significance for China and little geopolitical proximity," said Yue Su, principal economist, China, at The Economist Intelligence Unit.
"Rather than choosing sides decisively, China's priority has been to protect its interests, so long as partner countries do not take an explicit stance on Taiwan," she said.
China's broader geopolitical posture remains unchanged, analysts added, including its approach to Taiwan, which Beijing considers part of its territory.
China staged live-fire drills around Taiwan last week in a massive military display, days after the U.S. announced a record-size arms package to Taiwan.
"This Venezuela episode is quite a big crisis, but it doesn't change China's playbook on Taiwan. It doesn't change the expectation on what will happen between China and the U.S.," Dan Wang, a director on Eurasia Group's China team, said Monday on CNBC's "Squawk Box Asia."
What may change, she said, is Beijing's thinking on the need to establish a legal framework for taking Taiwan, similar to how the U.S. justified Maduro's capture with drug trafficking charges.
Against the backdrop of the U.S. attack on Venezuela, China's high-level diplomacy continued in earnest on Monday.
Chinese President Xi Jinping met with Ireland's Prime Minister Michael Martin — the first visit by an Irish leader in 14 years — and was set to host South Korea's President Lee Jae Myung later in the day.
"China pulled from 6% to more than 20% of world GDP (PPP) in 15 years," Nassim Nicholas Taleb, author of "The Black Swan," wrote back in September. "So consider what the state of geopolitics would be in 2035."
"In the future, discussions about war might need to happen in Beijing, not Washington."
— CNBC's Victoria Yeo contributed to this report.
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Shares of U.S. oil companies soared in premarket trade on Monday, as investors scrutinize the fallout from the Trump administration's surprise military operation in Venezuela.
Chevron shares rose 6.4% at 7:40 a.m. ET, with Exxon Mobil up 3%, exploration and production company ConocoPhillips advancing 5.5% and oilfield services giant SLB climbing 8.5%.
The moves come after the U.S. conducted a major military operation in Venezuela over the weekend, capturing Venezuelan President Nicolas Maduro and his wife, Cilia Flores, in an audacious intervention that has sent shockwaves across the globe.
U.S. President Donald Trump has since said the White House will "run" the South American country until such a time that "a safe, proper and judicious transition" can take place.
Venezuela is a founding member of OPEC, an influential energy alliance, and sits on the largest proven crude oil reserves in the world at 303 billion barrels, according to the U.S. Energy Information Administration. That represents roughly 17% of global oil reserves.
Trump has said U.S. investment in Venezuela's energy sector is now a core objective for his administration.
"We're going to have our very large United States oil companies — the biggest anywhere in the world — go in, spend billions of dollars, fix the badly broken infrastructure, the oil infrastructure," Trump said in a press conference from his Mar-a-Lago residence in Palm Beach, Florida.
"Let's start making money for the country," Trump said on Saturday.
Oil prices were last seen trading slightly higher on Monday.
International benchmark Brent crude oil futures with March delivery were up 0.5% at $61.03 per barrel, while U.S. West Texas Intermediate futures with February delivery stood 0.6% higher at $57.64.
Allen Good, director of equity research at Morningstar, said Chevron appeared to be best positioned among the oil majors to benefit from U.S. involvement in Venezuelan crude restoration projects, highlighting the firm's significant presence in the country.
The Trump administration's intervention in Venezuela could also allow for Exxon and ConocoPhillips to re-enter the country, Good said, although he warned that Venezuela's oil industry "will require tens of billions in investment" to meaningfully lift production.
"Oil companies will need to be cautious about deploying capital until there is greater regulatory and contractual certainty," Good said.
"While Chevron may be able to add incremental production in the near term with US approval, meaningful volume increases are likely years away. With this in mind, the possibility of US companies developing Venezuela's oil reserves remains far from certain," he added.
Neil Atkinson, an independent energy analyst and former London-based employee of Venezuela's state-owned oil company PDVSA, said there are several challenges to address when it comes to fixing Venezuela's oil industry.
"Look at it cynically, you want to get Venezuela's oil industry back up and running. If you want to do that, you can only do it if you have stability, and that means you have to ensure that there is law and order, which there isn't now," Atkinson told CNBC's "Squawk Box Europe" on Monday.
"You have to ensure that there is stable electricity supplies, which there isn't now. You have to ensure that food and fuel supplies are reliable, where they are not now. So, a lot has to happen and it cannot happen without the consent of the Venezuelan people," he added.
Asked whether American oil companies would want to go into Venezuela given relatively low oil prices, Atkinson said, "Well, I would think for long-term strategic reasons, yes. But, as you say, the price is low currently."
He added: "There are special issues in terms of increasing oil production in Venezuela, the type of oil that it is, the cost and complexity of processing it. But for them, it would be a long-term play. That, to me, is the main reason why investors might feel more positive toward those companies."
— CNBC's Spencer Kimball contributed to this report.
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Defense stocks in Europe and Asia surged on Monday as investors assessed how the dramatic overthrow of Venezuelan leader Nicolas Maduro could herald a significant geopolitical shift that will boost the rearmament trade in the long run.
Rheinmetall, Germany's largest arms manufacturer, gained over 9.3% by the closing bell in London, while military technology and surveillance specialist Hensoldt rose more than 8.2%. Italy's Leonardo added more than 6.3%, while German counterpart Renk added around 8%.
Swedish fighter jet maker Saab added more than 6%.
Earlier, Japan's IHI Corp led Asian defense stocks' gains, advancing about 9%, followed closely by Mitsubishi Heavy Industries, which rose more than 8%. Kawasaki Heavy Industries, meanwhile, was up nearly 8%. In South Korea, Hanwa Aerospace closed 7% higher, while shares in Poongsan gained more than 2%.
In the U.S., meanwhile, fighter jet giant Lockheed Martin and military aircraft maker Northrop Grumman both advanced more than 2%. The iShares U.S. Aerospace & Defense ETF (ITA) rose more than 1%, notching a new all-time intraday record.
Fawaz Chaudhry, chief investment officer at Fulcrum Asset Management, said Maduro's overthrow is a "signaling exercise" that will reshape geopolitics.
"As President Trump invoked the Monroe Doctrine, he's talking about the near sphere in America taking control through hard power, through hard power assets," Chaudhry told CNBC's "Europe Early Edition" on Monday.
"We're talking about a world trying to shift to a new era, where we will basically [have] hard power military assets, and go and take control, which basically is a different policy from before."
Chaudhry expects that this more assertive U.S. foreign policy approach will mean "more rearmament of Europe, rearmament of Asia," in the longer term, adding that defense stocks and military spending will continue to rise.
"What President Trump and what America just did in Venezuela will actually reinforce that. More military spending, more rearmament, of Europe, of Asia, so that trend will continue," he explained.
The gains made by European defense names mark a sharp reversal for the sector, which has struggled in recent weeks amid the prospect of a potential peace agreement between Ukraine and Russia.
Aoifinn Devitt, senior investment advisor at Moneta, expects defense spending to surge as a result of U.S. exceptionalism and the "gunboat diplomacy" theme on display in recent days.
"We know that the defense stocks did wobble when it looked like there might be peace in Ukraine. But ironically that theme, if anything, is going to be underscored especially [by] this rhetoric that is spreading things around to the neighboring countries," Devitt told CNBC's "Squawk Box Europe" on Monday.
More broadly, defense has several key structural tailwinds behind it, Devitt said, highlighting a ramp-up in Germany's military spending, which has been "endorsed wholeheartedly" by the current German administration.
"New year, new world order – I think we all have to accept that. That will drive precautionary spending on defense," Devitt observed. "Do we think that's a productive use of funds, where we will actually generate jobs and generate long-term economic growth? Probably not. But it is actually where we need to go."
Stephen Dover, chief market strategist and head of Franklin Templeton Institute, said that other countries with territorial interests elsewhere could be emboldened by the Trump administration's unilateral use of force.
This action will also likely add to the uncertainty of the dollar's role as a safe haven, Dover said in a note, "while raising further questions about deterioration of international institutional pillars."
"The U.S. military's recent action is therefore likely to reinforce the trend, well underway, for various countries worldwide to invest more in their national security. That has been one of our key investment themes since the Russian invasion of Ukraine."
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President Donald Trump on Saturday announced that the US had conducted a raid on Venezuela, resulting in the capture of Venezuelan President Nicolás Maduro and his wife, and big names in business and foreign policy have been reacting as the aftermath unfolds.
Here's what they've been saying:
Myers, chairman of political risk consulting firm Signum Global Advisors, told Business Insider that foreign investment in oil, tourism, and construction will be the "centerpiece" of Venezuela's financial recovery going forward, adding that he expects the country's economy will grow "faster over the next two years than people anticipate because of the extent or scale of foreign investment."
Myers, also a former head of investment advisory firm Evercore, is planning a trip of 15-20 investors to visit Venezuela in March to identify investment opportunities. Signum Global Advisors has hosted similar trips for investor groups in Syria and Ukraine.
Bremmer, founder of the political risk research and consulting firm, Eurasia Group, in a post on LinkedIn, wrote that the "US presumption is next Venezuelan leaders will now do what the Americans want because they've just seen the 'or else.'"
Accompanying the post was a photo of a drawing of a horse. The hindquarters of the horse were drawn in intricate detail, and labeled "SOF operation to capture Maduro," referencing the special operations forces mission that was executed early Saturday. The horse's head was depicted as a rudimentary children's drawing, captioned "plans for future of Venezuela."I wouldn't exactly call it a plan," Bremmer added.
In a separate post, he wrote: "The law of the jungle is dangerous. What applies to your enemies one day can apply to you the next. Make no mistake where the world is heading here."
The billionaire hedge fund manager wrote in a post on X that "The removal of Maduro will lower oil prices, which is good for America and very bad for Russia. A weaker Russian economy will increase the probability that the war in Ukraine ends sooner and on more favorable terms for Ukraine. And Putin will be sleeping in his safe room from this point going forward."
Gao is a senior fellow at the Center for International Governance Innovation and a law professor at Singapore Management University. In a series of posts on X, he said the raid on Caracas ushered in "the brave new world of international law."
"Maduro's capture has triggered the biggest revival of international law since Grotius — and overnight turned everyone on X into an international law wonk, eager to compare Venezuela to Taiwan," he wrote.
"But China has never treated the Taiwan issue as a matter of international law," he continued. "It has always been framed as an internal affair, with Taiwan regarded as a renegade province. The reason China has not acted is not because it lacks legal justification, but because it lacks the capability. Thus, US ops in Venezuela provide China with no additional legal justification."
The Democratic senator from Massachusetts is a former Harvard Law professor who holds deep expertise in bankruptcy and consumer finance. In a post on X, she wrote that Trump's action to seize Maduro, "no matter how terrible a dictator he is — is unconstitutional and threatens to drag the US into further conflicts in the region."
"What does it mean that the US will 'run' Venezuela, and what will Trump do next around the world?" Warren wrote. "The American people voted for lower costs, not for Trump's dangerous military adventurism overseas that won't make the American people safer."
The Tesla and SpaceX CEO spent most of Saturday posting praise for the Trump administration and the military operations in Venezuela, posting that it was "heartwarming to see so many Venezuelans celebrating their country freed from a brutal tyrant."
In another post, Musk retweeted a White House image of Maduro aboard the USS Iwo Jima after being apprehended, with the caption "Congratulations, President Trump! This is a win for the world and a clear message to evil dictators everywhere."
Musk and Trump have had a tumultuous relationship over the years, alternating between appearing to be close allies and trading sharp criticisms in the media.
Writing on X, the British billionaire and founder of the Virgin Group said Maduro's "corrupt and inept reign" had "caused endless suffering for the Venezuelan people and brought this beautiful country to the verge of economic and social collapse."
"He will not be missed," he wrote.
Branson added that a "just and fair transition means handing power to Venezuelans, and especially to those with a clear mandate to lead."
Washington's effective control of Venezuela would hand the US a major energy advantage, according to Vishnu Varathan, Mizuho's head of macro research for Asia ex-Japan.
The first advantage is practical and industrial: Venezuela's heavy crude is well suited to US refining capacity. The second advantage is strategic: Access to Venezuela's vast oil reserves would give the US a decisive energy edge in the AI race, particularly relative to China.
Finally, Varathan highlighted a shipping advantage. Proximity gives the US a logistical edge to Venezuelan oil supply, while the loss of access leaves China's remaining oil imports increasingly vulnerable to major maritime chokepoints.
"China's energy security is compromised at the margin whilst the US gains significant energy dominance advantage," Varathan wrote.
Panikoff, director of the Scowcroft Middle East Security Initiative at the Atlantic Council and a former deputy national intelligence officer at the Office of the Director of National Intelligence, pushed back on the idea that Trump's raid was primarily about oil.
In an X post on Saturday, he said that while Venezuela holds an estimated 17% to 18% of global oil reserves, it accounts for just 1% to 1.5% of global production, calling oil a "secondary benefit" rather than the main motivation.
Panikoff said the move reflects Trump's long-held view that the US should assert dominance in the Western Hemisphere and push out the influence of China, Russia, Iran, and Cuba.
"America First requires American dominance in the Western Hemisphere," he wrote, adding that the operation looked more like a revival of the Monroe Doctrine than a traditional war-on-drugs effort.
Haass, president emeritus of the Council on Foreign Relations think tank, said Maduro's removal may be widely welcomed, but that the operation was not strategically wise.
Writing in his "Home & Away" newsletter, Haass called the raid a "military operation of choice, not of necessity," saying that Maduro "hardly posed an imminent threat to the United States."
He said that removing a leader is far easier than replacing a regime, invoking former Secretary of State Colin Powell's "Pottery Barn rule" — the idea that if you break a country, you own the consequences.
"We broke it, so now we own it," Haass wrote.
Haass also said that the operation could set a dangerous precedent, potentially emboldening Russia and China to justify interventions in Ukraine and Taiwan under similar logic.
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The big presale crypto market is becoming more selective as buyers focus less on promises and more on proof of participation. Instead of betting on roadmaps alone, attention is shifting toward presales that show live activity, transparent token distribution, and visible growing demand. This change has pushed a few names into focus as buyers rush to secure early positions before conditions tighten.
What stands out across today's big presale crypto projects is urgency. Live presale auctions, rising participation, and parallel demand for infrastructure are reshaping how early exposure is evaluated. Below are the four leading presale cryptos, including Zero Knowledge Proof, IPO Genie, Digitap, and Best Wallet, which are currently drawing strong interest, each for different reasons.
Zero Knowledge Proof sits at the high position of the leading presale crypto list because it's fully live and actively reshaping buyer behavior. Instead of a static sale with fixed pricing, ZKP runs a daily presale auction that refreshes every 24 hours. Each window resets allocation and pricing based on demand, which has created visible urgency as missed days cannot be reclaimed.
Participation has been accelerating as buyers rush to secure positions before the daily supply tightens. This pressure is not coming from a single source. Contributors are entering consistently across presale auction windows, signaling sustained interest rather than short-term spikes. That flow has turned the presale auction into a live signal of demand.
What amplifies this urgency is that buyers are not limiting themselves to token exposure. Proof Pods are being purchased alongside auction participation. These devices allow users to operate inside the network by running verifiable compute and earning ZKP through real workload contribution. This dual demand shows that participants are positioning for both ownership and activity.
Momentum strengthened further after confirmation that the first Proof Pod has already been delivered to Australia. That milestone reinforced confidence that infrastructure is already moving into deployment while the presale auction is still open. For many buyers, that combination is what places Zero Knowledge Proof at the top of the leading presale crypto discussion right now.
IPO Genie has carved out a different lane within the big presale crypto space by focusing on tokenized access to private and pre-IPO investments. This is a segment traditionally reserved for institutions, and IPO Genie positions itself as a structured gateway rather than a speculative play.
Its presale follows a tiered pricing model that reflects gradual expansion rather than sharp jumps. From Stage 1 at $0.0001000 to Stage 24 at $0.00010830, growth has remained controlled, reinforcing the project's long-term framing. Utility is centered on governance participation, staking rewards, and direct deal access, which supports holding rather than fast exits.
For buyers comparing the popular presale crypto options, IPO Genie stands out for combining private market access with mainstream visibility while still in its presale phase.
Digitap approaches the big presale crypto conversation from a utility-first angle. The project is designed to integrate crypto wallets with traditional banking infrastructure via a phased deployment strategy and growing fiat on-ramp partnerships.
Payment and banking infrastructure projects tend to follow steadier adoption curves, which has attracted attention from buyers seeking measured growth rather than sharp volatility. Digitap's roadmap emphasizes integration over experimentation, aligning with broader fintech trends rather than short-term narratives.
As regulatory clarity improves across regions, crypto-fiat bridges continue to draw long-term interest. Digitap benefits from this backdrop by positioning itself as a functional layer rather than a speculative token. This framing places it among analyst-watched presales where progress is expected to compound over time.
For participants scanning the big presale crypto market for practical exposure, Digitap offers a quieter but structured alternative centered on real-world usage.
Best Wallet rounds out the list by focusing on access rather than assets alone. The project operates as a multi-chain mobile wallet designed to surface upcoming presales directly inside the user experience.
Wallet platforms have historically scaled in parallel with ecosystem growth, particularly during early access phases. Best Wallet ties its utility directly to onboarding users into presales and early token opportunities, making discovery part of the product rather than an external process.
The focus on simplicity and visibility supports sustained engagement rather than short-term trading behavior. Instead of chasing individual launches, users are positioned to remain connected to the presale pipeline itself.
Within the popular presale crypto space, Best Wallet stands out as an infrastructure play that benefits from continued presale activity across the market rather than dependence on a single token narrative.
The leading presale crypto is the one that shows live participation, clear structure, and visible demand while access is still open. Zero Knowledge Proof leads on that front with a live presale auction and rising Proof Pod purchases, creating urgency that builds day by day.
Other presale cryptos also bring unique opportunities, but they aren't as exciting as what ZKP offers. IPO Genie brings institutional-style access and real-world exposure, Digitap focuses on steady crypto-fiat infrastructure, and Best Wallet simplifies presale discovery at the wallet level.
Together, these projects show how crypto presales are shifting away from static fundraising toward active ecosystems where timing, structure, and participation shape early opportunity.
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Bitcoin and the wider crypto market has started to wake up recently, but underlying liquidity conditions appear strikingly weak, according to onchain analytics firm Glassnode — a dynamic that echoes concerns raised in a CoinDesk analysis in November on hollow crypto market liquidity following the October crash.
Glassnode's latest data shows that both bitcoin spot trading volume and aggregate altcoin spot volume have sunk to their lowest readings since November 2023, even as prices have climbed — a divergence that typically points to thinning market participation and fragile demand underneath the recent strength.
Spot volume is a metric that assesses actual buying and selling activity on exchanges, a barometer of real trading interest.
Traditionally, healthy price advances are supported by rising volumes, as fresh capital and buyers enter the market. But in this case, spot volumes have not only failed to increase alongside prices, they've fallen to year-long lows, underscoring a lack of broad participation behind the moves.
This assessment reiterates issues raised in a CoinDesk research piece published in November, which documented how liquidity across centralized exchanges — including bitcoin and ether market depth — failed to recover fully after the October liquidation cascade.
The research highlighted that post-crash, order-book depth remained structurally lower than before the sell-off, suggesting a new, thinner baseline of liquidity that leaves markets more vulnerable to exaggerated price reactions.
The October event, which resulted in $19 billion worth of leveraged positions being wiped out in a matter of hours, did more than unwind overextended bets. It reshaped the market's underlying structure, leading to a sustained pullback in resting liquidity as market-making firms and liquidity providers pulled back, making markets shallower and less capable of absorbing large trades without meaningful price impact.
Bitcoin is currently trading at $93,500 after rising by 7.5% since Jan. 1, but the move on minimal volume is presenting traders with a number of warning signs.
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KuCoin Hits Record Market Share as 2025 Volumes Outpace Crypto Market
KuCoin captured a record share of centralised exchange volume in 2025, with more than $1.25tn traded as its volumes grew faster than the wider crypto market.
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Famed Coinbase backer Fred Wilson predicts 2026 UX pivot for crypto
The VC mogul has previously said crypto apps must hide blockchain complexity or risk missing mass-market adoption.
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Disclosure & Polices: CoinDesk is an award-winning media outlet that covers the cryptocurrency industry. Its journalists abide by a strict set of editorial policies. CoinDesk has adopted a set of principles aimed at ensuring the integrity, editorial independence and freedom from bias of its publications. CoinDesk is part of Bullish (NYSE:BLSH), an institutionally focused global digital asset platform that provides market infrastructure and information services. Bullish owns and invests in digital asset businesses and digital assets and CoinDesk employees, including journalists, may receive Bullish equity-based compensation.
$BTC and aggregate altcoin spot volumes printed their lowest levels since Nov 2023. This weakening demand contrasts sharply with upside moves across the market, highlighting increasingly thin liquidity conditions behind recent price strength.📈https://t.co/WEAmnNjNOx pic.twitter.com/0Aw1DVFbSv
The Bitcoin network hashrate, a metric measuring mining competition, declined for a second consecutive month in December, according to a report released by Wall Street giant JPMorgan (JPM) on Monday.
"The monthly average network hashrate, a proxy for industry competition, declined 30 EH/s (-3%) m/m to an average of 1,045 EH/s in December," analysts Reginald Smith and Charles Pearce wrote.
The hashrate refers to the total combined computational power used to mine and process transactions on a proof-of-work blockchain, and is measured in exahashes per second.
Despite the lower competition for the miners, mining profitability also fell. The analysts estimated that miners earned an average of $38,700 per EH/s in daily block reward revenue last month, "down 7% from November and 32% y/y, representing the lowest level on record." Daily block reward gross profit also declined last month, dropping 9% to $17,100 per EH/s, the report said.
While the bank didn't go into detail about why mining profitability is falling, lower bitcoin prices since October have likely added to the margin squeeze for miners who are already feeling the pain from the most recent halving and higher energy prices.
Although it's not all doom-and-gloom. The combined market cap of the 14 U.S.-listed bitcoin miners and data center operators that the bank tracks rose to $48 billion by the end of 2025, up 73% for the year. Hut 8 (HUT) was the best performer of the group last month with a 2% gain, while CleanSpark (CLSK) underperformed with a 33% decline.
While only two of the companies outperformed bitcoin in December, 9 of the 14 beat the largest cryptocurrency over the course of the year, led by IREN (IREN) and Cipher Mining (CIFR), the report added.
Read more: Bitcoin Mining Profitability Fell for Fourth Consecutive Month in November: JPMorgan
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KuCoin captured a record share of centralised exchange volume in 2025, with more than $1.25tn traded as its volumes grew faster than the wider crypto market.
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Famed Coinbase backer Fred Wilson predicts 2026 UX pivot for crypto
The VC mogul has previously said crypto apps must hide blockchain complexity or risk missing mass-market adoption.
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Disclosure & Polices: CoinDesk is an award-winning media outlet that covers the cryptocurrency industry. Its journalists abide by a strict set of editorial policies. CoinDesk has adopted a set of principles aimed at ensuring the integrity, editorial independence and freedom from bias of its publications. CoinDesk is part of Bullish (NYSE:BLSH), an institutionally focused global digital asset platform that provides market infrastructure and information services. Bullish owns and invests in digital asset businesses and digital assets and CoinDesk employees, including journalists, may receive Bullish equity-based compensation.
Tom Lee Predicts $250K Ethereum Price as BitMine Adds to $13 Billion Stash
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Ethereum treasury firm BitMine Immersion Technologies added 32,977 ETH valued around $104 million during the final week of 2025, the firm announced on Monday.
The latest purchase brings its total holdings to more than 4.14 million ETH, worth more than $13 billion as of this writing. Its holdings now represent around 3.4% of the circulating ETH supply, leaving BitMine about 1.9 million ETH shy of its stated goal of 5% of the total circulating supply.
"In the final week of 2025, total equity and crypto activity slowed, and yet we acquired 32,977 ETH in the past week," said Bitwise Chairman Tom Lee, in a statement.
“Our analysis shows that BitMine has continued to accumulate ETH at an accelerated pace versus other Ethereum [digital asset treasuries]. We remain the largest 'fresh money' buyer of ETH in the world."
The firm's purchase announcement follows aggressive forecasting for the price of Ethereum and shares in BitMine (BMNR) as part of Lee's latest chairman's message. In his Friday remarks, Lee predicted a move to $250,000 for ETH—a roughly 7,760% increase from the recent trading price of $3,180. ETH is up nearly 9% over the last week.
Lee also predicted a future price of $5,000 per share for BMNR based on its relationship to the price of Ethereum. But that mark is without any stock splits, a major focus for the firm as it seeks shareholder approval to increase the authorized share count from 500 million to 50 billion.
"BitMine needs the increase in authorized shares primarily to allow the company to selectively issue shares for capital market activities, accommodate future share splits (as ETH moves to our long-term targets), and enable us to consider selective acquisitions," Lee said.
The firm cited stock splits as the most important reason for the share increase, highlighting a focus on keeping the stock price accessible to the public and around $25. Lee's message urged all shareholders to vote yes on the proposal by January 14.
Other proposals ahead of its annual meeting include electing eight directors and implementing special compensation and incentive plans.
Shares in the Ethereum treasury firm are up around 4% on Monday, recently changing hands at $32.49 and up nearly 14.8% in the last five trading days, according to data from Yahoo Finance.
The company remains the largest Ethereum treasury firm and is the second-largest publicly traded crypto treasury overall, trailing only Strategy, the Bitcoin treasury firm that holds around $63 billion in BTC.
In addition to its $13 billion in ETH, BitMine holds around $915 million in cash and 192 Bitcoin valued near $18 million.
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Banking-focused crypto is quietly re-entering investor conversations as investors seek the best altcoins to buy now, particularly those focused on payments, settlement, and real financial infrastructure rather than speculative narratives. Not to replace banks overnight fantasy, but the boring part that actually matters: moving money, settling payments, and bridging cash with stablecoins.
Digitap ($TAP) focuses on the consumer banking layer, where users convert, spend, and settle crypto rather than speculate on price moves. It is designed for low-liquidity market conditions where fast conversion and predictable settlement matter more than upside volatility.
The list below focuses on altcoins to watch that are connected to payments, settlement rails, and financial infrastructure, plus one early-stage banking presale designed around capital protection.
Digitap is a consumer-facing banking app that prioritizes settlement reliability and conversion speed in volatile markets. When markets are fearful and liquidity is thin, number-go-ups become unreliable, and working financial tools become more valuable.
Digitap supports real-time crypto-to-fiat conversion, allowing users to convert supported assets into fiat quickly within the same platform. Digitap offers a no-KYC wallet setup, with additional verification requirements applying to expanded banking features.
On the token side, $TAP is framed around a fixed supply (2B) and deflationary mechanics. The model is designed to use app-generated revenue for token buybacks, with a portion of those tokens permanently removed from circulation over time.
Staking and rewards also matter here, and $TAP holders can currently earn 124% APY. Digitap's native $TAP token is currently priced at $0.0411, with the next step at $0.0427 coming soon. The project reports Round 3 as nearly sold out, with approximately $3.5 million raised.
XRP remains one of the most visible banking-adjacent assets because the broader Ripple ecosystem focuses on enterprise payments infrastructure. In July 2025, OpenPayd announced a partnership with Ripple to provide stablecoin and payments infrastructure for businesses, combining OpenPayd's fiat rails with Ripple Payments and stablecoin liquidity access.
OpenPayd and Ripple are working together to integrate stablecoin liquidity and payment rails into enterprise banking systems. (Source: OpenPayd)
That type of integration matters because it pushes crypto payment rails closer to the systems businesses already use: treasury flows, cross-border settlements, and multi-currency operations.
Why XRP ranks behind Digitap in this list: XRP is mostly payment infrastructure and network positioning, not a consumer banking surface where token value capture is directly tied to app usage and defensively framed tokenomics.
Stellar's strongest banking angle is real-world access. MoneyGram Ramps is designed to connect cash and digital dollars through a single integration, enabling cash-in and cash-out in many countries without requiring a bank account.
For beginners, the plain-English value is simple: stablecoins become more useful when converting between cash and digital dollars is easier. Stellar sits inside that on/off ramp layer, where utility matters more than memes.
Why XLM ranks behind Digitap: Stellar is a payment rails and distribution infrastructure, while Digitap focuses on being the direct consumer layer for spending, conversion, and settlement, plus a presale structure designed around asymmetric entry and value capture.
Quant's banking relevance is tied to interoperability and regulated finance projects. In September 2025, Quant stated it was selected by UK Finance and a consortium of commercial banks to provide technology underpinning the UK's tokenised sterling deposits (GBTD) project, running until mid-2026.
Tokenised deposits are essentially digital representations of commercial bank money, designed to keep the trust and regulatory protections of traditional deposits while adding programmability and speed.
Why QNT ranks behind Digitap: Quant is institutional plumbing, not a beginner-friendly banking product layer. It can matter massively for finance infrastructure, but it does not offer the same direct consumer utility and presale asymmetry that Digitap is selling for 2026.
XDC Network is built around trade finance, real-world asset tokenization, and enterprise use cases. The ecosystem around TradeFinex describes an ISO 20022-aligned trade finance protocol with industry partners, which is part of why XDC is often discussed in banking rails circles.
This is less about retail trading and more about modernizing the settlement and documentation side of global trade, where slow processes and fragmented systems cost real money.
Why XDC ranks behind Digitap: XDC is infrastructure-first and enterprise-oriented. Digitap is designed as a consumer-facing app focused on spending, conversion, and crypto-to-fiat access, plus a token model explicitly pitched as defensive during drawdowns.
XRP, Stellar, Quant, and XDC each connect to real payment or settlement narratives, but most of that value lives in rails, partnerships, and infrastructure layers.
Digitap is different: a live app that turns those banking crypto ideas into something usable at the consumer level, and a token system designed to behave like a defensive tool rather than a hype vehicle. This matters as global remittance fees still average around 6%, while crypto-native banking tools aim to significantly reduce those costs compared to traditional remittance channels.
This approach fits cleanly into a bear-market environment: fixed supply, buyback-and-burn mechanics, stable settlement, and practical tools for converting and spending value when charts are unstable. Presale mechanics also matter when evaluating the best crypto presales 2025, because Digitap's price steps are programmed and time-boxed rather than driven by market hype.
Banking altcoins are not exciting in a loud way. The projects above are connected to settlement rails, cash access, tokenized deposits, and trade finance infrastructure, all areas that tend to grow quietly and matter later.
For users searching for the best crypto to buy right now, Digitap stands out by combining a working banking layer with a value-capture token model.
Discover how Digitap is unifying cash and crypto by checking out their project here:
Presale: https://presale.digitap.app
Website: https://digitap.app
Social: https://linktr.ee/digitap.app
Win $250K: https://gleam.io/bfpzx/digitap-250000-giveaway.
Disclaimer:
AMBCrypto's content is meant to be informational in nature and should not be interpreted as investment advice. Trading, buying or selling cryptocurrencies should be considered a high-risk investment and every reader is advised to do their own research before making any decisions.
© 2026 AMBCrypto
BREAKING: Oil Stocks Rally On Venezuela Oil Industry Takeover
Bitcoin and cryptocurrency prices traded higher early Monday, continuing their weekend climb following the U.S. capture and extraction of Venezuela President Nicolas Maduro. President Donald Trump on Saturday announced the U.S. is "going to run" Venezuela until there is an opportunity for a "safe, proper and judicious transition," after detaining Maduro on drug and weapons charges. Trump also said that…
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Strategy (MSTR), the world's largest publicly traded holder of bitcoin, in the final days of 2025 and early days of 2026 lifted both its bitcoin holdings and cash reserve.
Led by Executive Chairman Michael Saylor, the company added 1,287 bitcoin for just over $116 million, or an average price of about $90,000 each. Firm holdings are now 673,783 bitcoin purchased for $50.55 billion, or an average price of $75,026 each.
The company last week also added $62 million to its cash reserves, bringing that total to $2.25 billion.
The boosts to both the cash and BTC reserves were funded through the sales of common stock.
The cash reserve is intended to fund dividend payments on the company's perpetual preferred equity. At current levels, Strategy has enough cash on hand to fund 32.5 months of dividend coverage, according to the company dashboard.
Alongside news of the balance sheet additions, the company disclosed $17.44 billion in unrealized losses on its bitcoin holdings in the fourth quarter — not surprising given BTC's decline from the $120,000 area at the start of October to $88,000 to close the year.
MSTR shares were up 4.5% in premarket action alongside a weekend rise in the price of bitcoin to the current $92,900.
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KuCoin Hits Record Market Share as 2025 Volumes Outpace Crypto Market
KuCoin captured a record share of centralised exchange volume in 2025, with more than $1.25tn traded as its volumes grew faster than the wider crypto market.
Yang perlu diketahui:
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Famed Coinbase backer Fred Wilson predicts 2026 UX pivot for crypto
The VC mogul has previously said crypto apps must hide blockchain complexity or risk missing mass-market adoption.
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Disclosure & Polices: CoinDesk is an award-winning media outlet that covers the cryptocurrency industry. Its journalists abide by a strict set of editorial policies. CoinDesk has adopted a set of principles aimed at ensuring the integrity, editorial independence and freedom from bias of its publications. CoinDesk is part of Bullish (NYSE:BLSH), an institutionally focused global digital asset platform that provides market infrastructure and information services. Bullish owns and invests in digital asset businesses and digital assets and CoinDesk employees, including journalists, may receive Bullish equity-based compensation.
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Yoshitaka Kitao, CEO of SBI Holdings, has shared a thoughtful message linking ancient history with modern technology, as Japan prepares for the rare “Fire Horse” year of 2026, a cycle that appears only once every 60 years. In his remarks, Kitao opened up about how this period is often seen as powerful but demanding, especially for businesses enjoying success.
Kitao explained that even when a company is doing well, danger can quietly build up. He warned that arrogance and overconfidence are the biggest threats during periods of growth. According to him, strong leadership requires clear judgment and courage, especially when things seem to be going smoothly.
Looking beyond 2026, Kitao stressed the importance of thinking in decades, not quarters. He reminded readers that as far back as 2018, SBI identified AI and blockchain as the technologies that would drive the biggest changes in society. Since then, the group has consistently invested in these areas and built a full crypto ecosystem.
Additionally, Ripple Labs received a special mention. Kitao revealed that SBI invested in Ripple around ten years ago, acquiring roughly 10% of the company. Today, that early decision has paid off, with blockchain and crypto-related businesses becoming a major source of revenue for the SBI Group. This long-term partnership shows how early belief in blockchain technology is now shaping real-world financial systems.
“Furthermore, it was about ten years ago that we invested in Ripple Labs in the U.S. and acquired approximately 10% of its shares. Needless to say, these fields currently play a major role in the SBI Group's revenue stream,” he wrote.
The SBI chief also described 2026 as a year when hidden problems come into the open. Long-ignored issues, he said, will become impossible to ignore. He pointed to recent global and Japanese examples where long-standing allegations are now being exposed. His message was simple: businesses must stay honest, disciplined, and careful in their actions.
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Ethereum co-founder Vitalik Buterin said the network is approaching a turning point as two major upgrades, PeerDAS and zkEVMs, move from research to working code.
In a post on X, Buterin argued that the combination could shift Ethereum into “a fundamentally new and more powerful kind of decentralized network,” because it targets the core tradeoff that has historically limited blockchains where a system can be decentralized and have consensus, but bandwidth and throughput stay low.
He framed the problem through two internet-era models. Systems like BitTorrent can move enormous amounts of data in a decentralized way, but they do not need consensus. Bitcoin has strong decentralization and consensus, but it stays low-bandwidth because every node effectively re-checks the same work instead of dividing it up.
Ethereum's next phase, he said, is about getting all three at once.
The first leg is already live. PeerDAS (data availability sampling) is now on Ethereum mainnet, letting nodes verify that data is available without downloading the full dataset.
PeerDAS is a prototype for Data Availability Sampling (DAS), which is essential for Ethereum's scaling via sharding. It allows light clients to check if all shard data has been published by sampling small portions, greatly enhancing scalability while maintaining decentralization and security.
The second leg, zkEVMs, is now “production-quality on performance,” Buterin said, meaning the remaining work is safety and proving robustness at scale.
Buterin described this as a practical step toward solving the so-called “blockchain trilemma,” not as a theory, but through “live running code," adding that zkEVM nodes could start appearing in limited form in 2026.
A longer-term goal is “distributed block building,” Buterin added, where no single party assembles the full block in one place, reducing censorship risks and improving geographic fairness.
The message is that Ethereum's scaling roadmap is increasingly about splitting verification work across the network, rather than asking every node to replicate everything.
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Disclosure & Polices: CoinDesk is an award-winning media outlet that covers the cryptocurrency industry. Its journalists abide by a strict set of editorial policies. CoinDesk has adopted a set of principles aimed at ensuring the integrity, editorial independence and freedom from bias of its publications. CoinDesk is part of Bullish (NYSE:BLSH), an institutionally focused global digital asset platform that provides market infrastructure and information services. Bullish owns and invests in digital asset businesses and digital assets and CoinDesk employees, including journalists, may receive Bullish equity-based compensation.
Now that ZKEVMs are at alpha stage (production-quality performance, remaining work is safety) and PeerDAS is live on mainnet, it's time to talk more about what this combination means for Ethereum.These are not minor improvements; they are shifting Ethereum into being a…
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Bitmine releases Special Chairman's Message related to upcoming Annual Stockholder Meeting
Bitmine staked ETH stands at 659,219 and MAVAN staking solution on track to launch Q1 2026
Bitmine remains the largest 'fresh money' buyer of ETH in the world
Bitmine now owns 3.43% of the ETH token supply, two-thirds of the way to the 'Alchemy of 5%'
Bitmine Crypto + Total Cash Holdings + "Moonshots" total $14.2 billion, including 4.144 million ETH tokens, total cash of $915 million, and other crypto holdings
Bitmine will hold its Annual Stockholder Meeting at the Wynn Las Vegas on January 15, 2026
Bitmine leads crypto treasury peers by both the velocity of raising crypto NAV per share and by the high trading liquidity of BMNR stock
Bitmine is the 44th most traded stock in the US, trading $1.1 billion per day (5-day avg)
Bitmine remains supported by a premier group of institutional investors including ARK's Cathie Wood, MOZAYYX, Founders Fund, Bill Miller III, Pantera, Kraken, DCG, Galaxy Digital and personal investor Thomas "Tom" Lee to support Bitmine's goal of acquiring 5% of ETH
LAS VEGAS, Jan. 5, 2026 /PRNewswire/ -- (NYSE AMERICAN: BMNR) Bitmine Immersion Technologies, Inc. ("Bitmine" or the "Company") a Bitcoin and Ethereum Network Company with a focus on the accumulation of crypto for long term investment, today announced Bitmine crypto + total cash + "moonshots" holdings totaling $14.2 billion.
As of January 4th at 9:00pm ET, the Company's crypto holdings are comprised of 4,143,502 ETH at $3,196 per ETH (Coinbase), 192 Bitcoin (BTC), $25 million stake in Eightco Holdings (NASDAQ: ORBS) ("moonshots") and total cash of $915 million. Bitmine's ETH holdings are 3.43% of the ETH supply (of 120.7 million ETH).
As of January 4th at 9:00pm ET, the Company's crypto holdings are comprised of 4,143,502 ETH at $3,196 per ETH (Coinbase), 192 Bitcoin (BTC), $25 million stake in Eightco Holdings (NASDAQ: ORBS) ("moonshots") and total cash of $915 million. Bitmine's ETH holdings are 3.43% of the ETH supply (of 120.7 million ETH).
"We are excited about the prospects for Ethereum in 2026 given the multiple tailwinds of US government support for crypto, Wall Street embracing stablecoins and tokenization, the rising need for authentication and proof of provenance in an increasingly complex AI world and the rising adoption of crypto among younger generations," said Thomas "Tom" Lee of Fundstrat, Chairman of Bitmine. "Moreover, the surge in commodity and precious metals in 2025 bodes well for crypto prices in 2026, which tend to follow metal price moves."
"In the final week of 2025, total equity and crypto activity slowed, and yet we acquired 32,977 ETH in the past week," continued Lee. "Our analysis shows that Bitmine has continued to accumulate ETH at an accelerated pace versus other Ethereum DATs. We remain the largest 'fresh money' buyer of ETH in the world."
Bitmine released a special Chairman's message (link) explaining why Bitmine stockholders should vote to support the amendment to increase authorized shares ahead of the upcoming annual stockholder meeting on January 15, 2026 (the "Annual Meeting"). "BitMine needs the increase in authorized shares primarily to allow the company to selectively issue shares for capital market activities, accommodate future share splits (as ETH moves to our long-term targets) and enable us to consider selective acquisitions," said Tom Lee. "Bitmine sole focus remains creating stockholder value, achieving this by accretively acquiring ETH per share, optimizing yield and income on its ETH holdings, and strategically investing the balance sheet on 'moonshots' and leveraging the company's strong community and market position to generate additional returns."
As of January 4, 2026, Bitmine total staked ETH stands at 659,219 ($2.1 billion at $3,196 per ETH). This is an increase of 250,592 in the past week. This is a fraction of the 4.11 million ETH held by Bitmine. The CESR (composite Ethereum staking rate, administered by Quatrefoil) is 2.81%. Bitmine is currently working with 3 staking providers as the company moves towards unveiling its commercial MAVAN (Made in America VAlidator Network) in 2026. "At scale (when Bitmine's ETH is fully staked by MAVAN and its staking partners), the ETH staking fee is $374 million annual (using 2.81% CESR), or greater than $1 million per day," stated Tom Lee.
"We continue to make progress on our staking solution known as The Made in America Validator Network (MAVAN). This will be the 'best-in-class' solution offering secure staking infrastructure and will be deployed in early calendar 2026," continued Lee.
Bitmine crypto holding reigns as the #1 Ethereum treasury and #2 global treasury, behind Strategy Inc. (MSTR), which owns 672,497 BTC valued at $61 billion. Bitmine remains the largest ETH treasury in the world.
Bitmine is now one of the most widely traded stocks in the US. According to data from Fundstrat, the stock has traded average daily dollar volume of $980 million (5-day average, as of January 2, 2026), ranking #44 in the US, behind IBM (rank #43) and ahead of Home Depot (rank #45) among 5,704 US-listed stocks (statista.com and Fundstrat research).
Bitmine will hold its Annual Meeting at the Wynn Las Vegas on January 15, 2026. The company encourages stockholders to vote and attend its in-person Annual Meeting. Details and the agenda for the Annual Meeting can be found below:
Bitmine's Annual Meeting:
The Annual Meeting will be livestreamed on Bitmine's X account: https://x.com/bitmnr
The GENIUS Act and SEC's Project Crypto are as transformational to financial services in 2025 as US action on August 15, 1971 ending Bretton Woods and the USD on the gold standard 54 years ago. This 1971 event was the catalyst for the modernization of Wall Street, creating the iconic Wall Street titans and financial and payment rails of today. These proved to be better investments than gold.
The Fiscal Full Year 2025 Earnings presentation and corporate presentation can be found here: https://bitminetech.io/investor-relations/
The Chairman's message can be found here:https://www.bitminetech.io/chairmans-message
To stay informed, please sign up at: https://bitminetech.io/contact-us/
About BitmineBitmine is a Bitcoin and Ethereum Network Company with a focus on the accumulation of Crypto for long term investment, whether acquired by our Bitcoin mining operations or from the proceeds of capital raising transactions. Company business lines include Bitcoin Mining, synthetic Bitcoin mining through involvement in Bitcoin mining, hashrate as a financial product, offering advisory and mining services to companies interested in earning Bitcoin denominated revenues, and general Bitcoin advisory to public companies. Bitmine's operations are located in low-cost energy regions in Trinidad; Pecos, Texas; and Silverton, Texas.
For additional details, follow on X:https://x.com/bitmnr https://x.com/fundstrat https://x.com/bmnrintern
Forward Looking StatementsThis press release contains statements that constitute "forward-looking statements." The statements in this press release that are not purely historical are forward-looking statements which involve risks and uncertainties. This document specifically contains forward-looking statements regarding progress and achievement of the Company's goals regarding ETH acquisition and staking, the long-term value of Ethereum, continued growth and advancement of the Company's Ethereum treasury strategy and the applicable benefits to the Company. In evaluating these forward-looking statements, you should consider various factors, including Bitmine's ability to keep pace with new technology and changing market needs; Bitmine's ability to finance its current business, Ethereum treasury operations and proposed future business; the competitive environment of Bitmine's business; and the future value of Bitcoin and Ethereum. Actual future performance outcomes and results may differ materially from those expressed in forward-looking statements. Forward-looking statements are subject to numerous conditions, many of which are beyond Bitmine's control, including those set forth in the Risk Factors section of Bitmine's Form 10-K filed with the Securities and Exchange Commission (the "SEC") on November 21, 2025, as well as all other SEC filings, as amended or updated from time to time. Copies of Bitmine's filings with the SEC are available on the SEC's website at www.sec.gov. Bitmine undertakes no obligation to update these statements for revisions or changes after the date of this release, except as required by law.
SOURCE BitMine Immersion Technologies, Inc.
Bitmine Immersion Technologies, Inc. (NASDAQ: BMNR) gab heute die Veröffentlichung einer neuen Nachricht des Vorstandsvorsitzenden (Link) bekannt, in ...
Bitmine Immersion Technologies, Inc. (NASDAQ : BMNR) annonce aujourd'hui la publication d'un nouveau message du président (lien) expliquant pourquoi...
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Ethereum's price will surge 8,000% and trade at $250,000 per token, according to Bitmine chairman Tom Lee.
That surge would catapult the value of the second-largest crypto to about $30 trillion — more than Apple, Microsoft, Nvidia, Alphabet, Amazon, Meta, and Tesla combined.
In a message to Bitmine shareholders, Lee cites the six-figure target while proposing an increase in the company's authorised shares to grow 100-fold from 500 million to 50 billion in order to set the stage for a future stock split. He urges shareholders to vote by January 14.
Tom Lee Ethereum price targets (Credit: Tom Lee/Bitmine)
Bitmine's share price jumped 15% after Lee's proposal. This signalled investor confidence in the company and support for the strategy, which also includes “opportunistic acquisitions” and capital markets plays including “convertibles and warrants.”
The confidence bump comes as digital asset treasury firms like Bitmine is under pressure due to the crypto market having shaved roughly $1 trillion of its value since October.
This means that many of the public firms that have pivoted into becoming DATs are trading at lower values than their underlying assets, putting the viability of their business models into question.
This marks a dramatic change from the beginning of 2025 when a wave of companies pivoted into becoming DATs, spurred on by the Trump administration support of the crypto industry.
“The initial hype is over,” Brian Huang, co-founder of investment platform Glider, told DL News earlier in January.
Lee's bold call comes as Ethereum trades just above $3,100. That's less than half of Lee's prediction that the crypto's price would hit $7,500 by the end of 2025.
In recent weeks, Bitmine purchased $1.4 billion more of the crypto, bringing the firm's Ethereum holdings to over $12 billion.
Publicly-traded companies perform stock splits to lower the price of a single share. That will make it seem more affordable for regular investors to buy in without changing the company's actual total value.
By increasing the number of shares available at a lower price, the company also makes its stock easier to trade on the market.
Backed by top institutional investors — including Peter Thiel's Founders Fund and Cathie Wood's ARK Invest — Bitmine now owns over 3.4% of Ethereum's circulating supply and is aiming for 5%.
Lee argues that a stock split will be necessary because Bitmine's “stock price follows Ethereum price,” and projects the company's stock trading at $5,000 per share when Ethereum reaches $250,000.
He did not offer a timeframe for any of his targets.
To be sure, Lee is far from the only one with grand plans for Ethereum.
Vitalik Buterin, the blockchain network's co-founder, described the technology as “civilisational infrastructure” on the first day of 2026.
Commenting on the development of new ZKEVM technology, Buterin said “they are shifting Ethereum into being a fundamentally new and more powerful kind of decentralised network.”
“Over the next four years, expect to see the full extent of this vision roll out.”
Lance Datskoluo is DL News' Europe-based markets correspondent. Got a tip? Email at lance@dlnews.com.
The retail digital yuan is no longer a central bank digital currency. China's version 2.0 upgrade, launched 1 January 2026, has transformed it into a commercial bank deposit solution where retail balances become liabilities of the holding institution – whether a bank or non-bank payment provider. Banks can now use these deposits for fractional reserve banking with balances covered by deposit insurance, while non-bank providers must hold full reserves. The fundamental pivot, positions the approach as a more financially stable alternative to stablecoins.
The major state-owned banks and others have issued announcements stating they now pay interest on digital RMB deposits at the same rate as existing demand deposits. In the case of many banks that rate is just 0.05%.
In an article published in the Financial News, the deputy governor of the People's Bank of China, Lu Lei, outlined that this approach addresses the risks of stablecoins. That's partly because stablecoins could result in outflows from banks, but also because it avoids the volatility in the valuation of stablecoin backing assets (such as Treasury bonds) and supports full integration with current systems. Ledger Insights anticipated this direction following remarks by Mu Changchun the leader of the Digital Currency Research Institute at the People's Bank of China in September 2025, though the latest announcement provides the first official confirmation of the transformation.
Article continues …
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Copyright © 2018 - 2025 Ledger Insights Ltd.
The retail digital yuan is no longer a central bank digital currency. China's version 2.0 upgrade, launched 1 January 2026, has transformed it into a commercial bank deposit solution where retail balances become liabilities of the holding institution – whether a bank or non-bank payment provider. Banks can now use these deposits for fractional reserve banking with balances covered by deposit insurance, while non-bank providers must hold full reserves. The fundamental pivot, positions the approach as a more financially stable alternative to stablecoins.
The major state-owned banks and others have issued announcements stating they now pay interest on digital RMB deposits at the same rate as existing demand deposits. In the case of many banks that rate is just 0.05%.
In an article published in the Financial News, the deputy governor of the People's Bank of China, Lu Lei, outlined that this approach addresses the risks of stablecoins. That's partly because stablecoins could result in outflows from banks, but also because it avoids the volatility in the valuation of stablecoin backing assets (such as Treasury bonds) and supports full integration with current systems. Ledger Insights anticipated this direction following remarks by Mu Changchun the leader of the Digital Currency Research Institute at the People's Bank of China in September 2025, though the latest announcement provides the first official confirmation of the transformation.
Article continues …
Want the full story? Pro subscribers get complete articles, exclusive industry analysis, and early access to legislative updates that keep you ahead of the competition. Join the professionals who are choosing deeper insights over surface level news.
Copyright © 2018 - 2025 Ledger Insights Ltd.
On Jan. 1, Vitalik Buterin announced a New Year's resolution for the blockchain he devised way back in 2013. It's time, he declared, for Ethereum to step up and deliver on its original mission: “To build the world computer that serves as a central infrastructure piece of a more free and open internet.”
Buterin's message is a timely one. For more than a decade now, Ethereum has offered the tantalizing promise of a global computer, available to anyone, that can be used to create decentralized alternatives to Big Tech's data-gobbling monopolies. The blockchain popularized smart contracts, and has been a springboard for thousands of projects backed by billions of dollars. It has also spawned legions of mostly fly-by-night imitators.
Despite all of this, the promise of Ethereum always seems just over the horizon. In recent years, the blockchain has come to resemble that can't-miss sports prospect who can't quite hack it in the big leagues. Instead of evolving into a popular global computer, Ethereum still feels like a sub-culture where cliques of insiders build esoteric applications for each other. In response, many in the crypto world started betting on other horses like Solana that promised to deliver practical results.
Ethereum's problem, ironically, has been its idealism. The blockchain has a core community that believes passionately in decentralization, and is mistrustful of anything resembling formal authority. That includes Buterin, who stepped back from his creation several years ago, preferring to let Ethereum find its own path forward.
All of this is admirable, especially in contrast to many recent arrivals on the crypto scene, whose first and only concern is to make a buck. Unfortunately, it has also led Ethereum developers to dither in the face of obvious problems, including congestion and high gas fees. To be fair, the blockchain has made some important fixes—but only after allowing piggy-back chains, known as layer 2s, to siphon off large amounts of revenue and make the crypto landscape painfully complicated.
Now, though, change could be in the air. In the last two years, both BlackRock and JPMorgan Chase have launched tokenized assets that settle directly to the main Ethereum blockchain. This is a testament to how Ethereum remains the gold standard for security and points to a future where it will be the backbone of global finance. The tokenized transactions also legitimize Ethereum's claim to be a universal computer, and could spur the mainstream adoption of other decentralized applications for social media, identity, and more.
For this to happen, though, the Ethereum community will require Buterin's ongoing leadership. That's why his New Year's Day post is a welcome development. The piece reinforced the primacy of decentralization as Ethereum's paramount value: “We're building decentralized applications. Applications that run without fraud, censorship or third-party interference. Applications that pass the walkaway test: they keep running even if the original developers disappear.”
But it also delivered a pragmatic piece of advice to the community seeking to build this decentralized future: Get on with it, already.
Jeff John Roberts jeff.roberts@fortune.com@jeffjohnroberts
Trump airdrop coming: Yet another Trump token is on the way as Truth Social announced an upcoming drop to its shareholders via Crypto.com. The company added the token will not be transferable and “cannot be exchanged for cash” but could become redeemable for Trump Media discounts. (FT)
Memecoin misery: In a year that saw silver outperform every other asset, Bitcoin notched a 5% decrease in 2025. But the biggest losers of 2026 were memecoins with Dogwifhat down 91%, $TRUMP down 93% and Milei's $LIBRA down 99%. (WSJ)
Better late than never: The U.S. head of PWC, echoing earlier statements from its Big 4 peers, says the consulting firm decided to “lean in” to crypto in light of the new regulatory environment. The firm is actively providing audits and advice to clients. (FT)
Bitcoin bounces back: The crypto market is off to a strong start in 2026 as Bitcoin climbed over $93,000 and altcoins posted gains even as the economic impact of events in Venezuela remain uncertain. (Bloomberg)
Counting coins: In a key development in corporate accounting, the standard setting body FASB will formally explore whether firms can treat stablecoins as cash equivalents. (WSJ)
Ilya Lichtenstein, the mastermind behind the multi-billion dollar Bitfinex hack, is the latest crypto criminal to walk free. He now faces a fate many would regard as worse than prison—resuming domestic life with his rapper wife Razzlekhan.
It was once fashionable for journalists to seize on price slumps in order to write sneering columns predicting Bitcoin's demise. These “Bitcoin obituaries” persisted well after the currency's viability became clear, but now appear to have finally faded altogether.
Jeff John Roberts is the Finance and Crypto editor at Fortune, overseeing coverage of the blockchain and how technology is changing finance.
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(2026)Cite this article
Blood biomarkers have emerged as accurate tools for detecting Alzheimer's disease (AD) pathology, offering a minimally invasive alternative to traditional diagnostic methods such as imaging and cerebrospinal fluid (CSF) analysis. Yet, the logistics surrounding venipuncture for blood collection, although considerably simpler than the acquisition of imaging and CSF, require precise processing and storage specific to AD biomarkers that are still guided by medical personnel. Consequently, limitations in their widescale use in research and broader clinical implementation exist. The DROP-AD project investigates the potential of dried plasma spot (DPS) and dried blood spot (DBS) analysis, derived from capillary blood, for detecting AD biomarkers, including phosphorylated tau at amino acid 217 (p-tau217), glial fibrillary acidic protein and neurofilament light. Here, 337 participants from 7 centers were included, with 304 participants providing paired capillary DPS or DBS and venous plasma samples. We observed strong correlations between DPS p-tau217 and venous plasma p-tau217 (rS = 0.74, P < 0.001). DPS p-tau217 progressively increased with increasing disease severity, and showed good accuracy in predicting CSF biomarker positivity (area under the curve = 0.864). Similarly, we demonstrated the successful detection of glial fibrillary acidic protein and neurofilament light with strong correlations between DBS and DPS, respectively, using paired venous plasma samples. Notably, the method was also effective in individuals with Down syndrome, a population at high genetic risk for AD but in whom standard blood sampling by venipuncture may be more complicated, revealing elevated biomarkers in those with dementia compared with asymptomatic individuals. The study also explored unsupervised blood collection, finding high concordance between supervised and self-collected samples. These findings underscore the potential of dried blood collection and capillary blood as a minimally invasive, scalable approach for AD biomarker testing in research settings. Yet, further refinement of collection and analytical protocols is needed to fully translate this approach to be viable and useful as a clinical tool.
In less than a decade, the development of blood biomarkers for the identification of AD pathology has transitioned from a promising research endeavor to a valued tool that is now included in research diagnostic criteria1 and is increasingly being adopted in clinical practice. Phosphorylated tau at amino acid 217 (p-tau217) has emerged as an early and accurate AD blood biomarker2,3, offering higher accuracy compared with other putative blood biomarkers for detecting cerebral amyloid-β (Aβ) pathology4, a required hallmark for an AD diagnosis5,6. Several blood p-tau217 assays, spanning different immunological detection methods and mass spectrometry techniques7 are now available with some—but not all—meeting the recommended criteria for clinical usefulness, approved for clinical use, or currently under regulatory evaluation8. Thus, a cost-effective and timely tool is now available to identify individuals who may benefit from approved and emerging treatments or to monitor disease progression9. Specifically, the most likely clinical applications of blood p-tau217 will be based on a two-cutoff approach10 aimed at identifying people at either very high or very low risk of brain amyloidosis and for whom additional biomarker investigations are unnecessary, thereby lowering the need for positron emission tomography (PET) or CSF testing11. Other supportive blood biomarkers also offer insights into disease pathophysiology. Specifically, glial fibrillary acidic protein (GFAP), a marker of astrogliosis, has been associated with the onset of Aβ deposition12,13; and neurofilament light (NfL), a marker for axonal degeneration across neurodegenerative diseases14, has also been developed and is widely deployed in research and some clinical and therapeutic settings.
Although current guidelines recommend AD blood biomarker testing for symptomatic individuals15, there is also the potential to screen cognitively unimpaired (CU) older adults using a simplified test in a research setting and prevention strategies. This is because of the expectation of improved effectiveness of disease-modifying therapies targeting amyloid pathology in earlier disease stages, with trials currently ongoing16. Moreover, broader implementation of blood biomarkers will likely substantially advance the treatment, management and biological understanding of AD and related disorders in populations and communities currently underrepresented in research; for example, in individuals with Down syndrome (DS).
Substantial efforts have been made to ensure that blood tests become widely accessible, rather than confined to specialized laboratories. A major advancement in this area is the development of high-performing commercial and fully automated immunoassays for AD blood biomarkers, in particular p-tau21717. These fully automated immunoassays demonstrate performance identical or almost identical to immunoprecipitation mass spectrometry, as shown in a series of papers17,18,19,20,21. Although immunoprecipitation mass spectrometry remains difficult for widespread research and clinical implementation because of its high costs and limited instrument availability, automated immunoassays offer reliable and scalable solutions that address these limitations. Yet, for their global adoption to be fully realized, logistical challenges surrounding blood collection—such as the need for timely and standardized sample handling and storage22, as well as limited access to phlebotomy services—must be overcome to avoid constraining the impact of blood-based biomarker testing.
The DROP-AD project aims to streamline blood sample collection for larger-scale research, therapeutic trial enrollment and, potentially, clinical care, by introducing an alternative method that addresses the logistical challenges of traditional venipuncture blood collection and processing. By using capillary blood collected on DBS or DPS cards, the latter needed for p-tau217, reliance on guided venipuncture, immediate centrifugation and temperature-controlled shipment is eliminated. This approach enables a simplified, and potentially self-administered, protocol using fingertip blood collection. We have previously demonstrated the feasibility of measuring AD biomarkers from dried blood spots23, with the blood source being venous, followed by manual transfer onto a card for shipping and storage advantages. Here we extend this previous work by evaluating the feasibility of remote biomarker assessment using capillary blood, obtained by fingerstick collection, thus potentially self-collected and remote. A total of 337 participants were recruited across 7 European centers to assess the quantification of key AD pathology and neurodegeneration biomarkers—plasma p-tau217, NfL and GFAP—from capillary-derived blood collected from the finger. These values were directly compared with those obtained by standard venous plasma sampling, as well as to CSF biomarker concentrations routinely used in clinical diagnostics.
We recruited 337 participants (mean (s.d.) age, 70.8 (11.7) years; 167 women (53.4%) (Table 1) from 7 centers. Depending on the research site, and the evolution of the DROP-AD project, participants followed different capillary blood collection and testing procedures, which are summarized in Fig. 1. Cohort characteristics are shown in Supplementary Table 1.
a, Collection and processing of venous plasma and capillary DPS and DBS samples. For DPS and DBS sample collection, a finger prick was carried out by trained study personnel and a few drops of capillary blood were spotted onto DPS and DBS collection devices. DPS and DBS were collected via semi-automated spot collectors and incubated with analyte-specific extraction buffer in a 96-well filter plate. After incubation and centrifugation, the eluate was immediately measured using ultrasensitive immunoassays on the single molecule array platform. b–f, Participant numbers and collection device numbers per cohort: capillary p-tau217 (b), capillary GFAP (c), capillary NfL (d), DS cohort (e) and self-sampling cohort (f). Panel a created using BioRender.com.
Source data
In total, 252 participants (mean (s.d.) age, 72.7 (9.0) years; 143 women (56.7%)) provided paired capillary DPS samples and venous plasma samples. We found a high correlation between DPS p-tau217 and venous plasma p-tau217 across all merged cohorts (Spearman's rank correlation (rS) = 0.74, 95% confidence interval (CI) 0.678–0.791; P < 0.001) (Fig. 2a). The strength of this correlation varied among participating centers (Extended Data Fig. 1) and was highest in the Gothenburg cohort (rS = 0.904, 95% CI 0.731–0.968; P < 0.0001) and the Brescia cohort (rS = 0.838, 95% CI 0.694–0.917; P < 0.0001), followed by the Exeter (rS = 0.765, 95% CI 0.530–0.891; P < 0.0001) and Barcelona (rS = 0.735, 95% CI 0.646–0.805; P < 0.0001) cohorts, and the Malmö cohort (rS = 0.429, 95% CI 0.159–0.640; P < 0.001), the only cohort in which a different assay (Lilly2) for venous plasma was used. To further demonstrate the strength the relationship between capillary and venous blood, we stratified plasma p-tau217 concentrations into tertiles and computed Spearman correlations in each tertile, allowing us to assess agreement at low, medium and high concentrations (Extended Data Fig. 2). Significant correlations were observed for p-tau217 concentrations in tertile two (rS = 0.51; P < 0.0001) and tertile three (rS = 0.62; P < 0.0001), but no relationship in tertile one, where all participants were CSF Aβ42/p-tau181 negative. The strength of the relationship between capillary and venous blood was not confounded by age or sex (Supplementary Table 2).
a, Correlation between capillary p-tau217 and venous plasma p-tau217 (n = 252). Dots correspond to individual data points. b, Correlation between capillary p-tau217 and MMSE (n = 209). Left: capillary p-tau217. Right: venous plasma p-tau217. c, Correlation between capillary p-tau217 and age (n = 249). Left: capillary p-tau217. Right: venous plasma p-tau217. A mean regression line is presented in all panels, with ribbons representing 95% CI. For numerical representation of the correlation, we present Spearman coefficients alongside their P values. Statistical tests were two-sided.
Source data
Next, we investigated the association of capillary biomarkers with cognitive testing. DPS p-tau217 showed significant correlations with both Mini Mental State Evaluation (MMSE) (n = 209; rS = −0.374, 95% CI −0.485 to −0.251; P < 0.0001) (Fig. 2b) and age (n = 249; rS = 0.334, 95% CI 0.219–0.440; P < 0.0001) (Fig. 2c), which were similar to the correlations of venous plasma p-tau217 with MMSE (n = 209; rS = −0.410, 95% CI −0.517 to −0.290; P < 0.0001) (Fig. 2b) and age (n = 249; rS = −0.317, 95% CI 0.200 to 0.424; P < 0.0001) (Fig. 2c).
DPS p-tau217 was significantly increased in clinically defined mild cognitive impairment (MCI) and AD (no biomarker classification) compared with CU participants and clinically defined non-AD dementias (Fig. 3a). Next, we investigated the discriminative accuracy of DPS p-tau217 to detect abnormal CSF biomarkers. In participants with DPS p-tau217, venous plasma p-tau217 and CSF Aβ42/p-tau181 (n = 176; mean (s.d.) age, 74.6 (7.9) years; 102 women (58.0%)), capillary DPS p-tau217 was significantly increased (+198%; P < 0.001) in the AD CSF biomarker-positive group (Fig. 3b). DPS p-tau217 had an area under the curve (AUC) of 0.863 (95% CI 0.809–0.917); however, this was significantly lower than venous plasma p-tau217 which had an AUC of 0.982 (95% CI 0.968–0.996; P < 0.0001) (Extended Data Fig. 3) in the same participant subsample. We also show the distribution of capillary p-tau217 across clinico-biological diagnostic groups (Fig. 3c), which shows a similar pattern to venous derived p-tau217, with similar statistical significance across groups (Extended Data Fig. 4). Results demonstrating DPS p-tau217 against CSF Aβ42/Aβ40 as the standard of truth are shown in Extended Data Fig. 5. Next, we tested the accuracy of capillary DPS p-tau217 to determine abnormal venous plasma p-tau217 (n = 252), which had predetermined cutoff validated against Aβ-PET (ALZpath single molecule array (Simoa) > 0.42 pg ml−1)3. DPS p-tau217 was more concordant with venous plasma p-tau217 and was increased by 217% in individuals with venous plasma p-tau217 > 0.42 pg ml−1, compared with individuals with venous plasma p-tau217 ≤ 0.42 pg ml−1, and had a discriminative accuracy to detect abnormal venous plasma p-tau217 of 0.868 (95% CI 0.825–0.911) (Extended Data Fig. 6).
a, Relationship between capillary p-tau217 level and diagnostic groups (CU, n = 37; MCI, n = 92; AD, n = 45; non-AD, n = 30). Horizontal solid-line bars represent group-wise comparisons alongside P values, obtained from post-hoc contrasting of a linear model adjusted for age and sex. b, Relationship between capillary p-tau217 level and CSF p-tau181/Aβ42 status (CSF-negative, n = 71; CSF-positive, n = 93). In addition to the P value, the mean fold-change between groups is presented. c, Relationship between capillary p-tau217 level and clinico-biological groups (CU Aβ−, n = 13; CU Aβ+, n = 1; MCI Aβ+, n = 49; AD Aβ+, n = 37; non-AD Aβ+, n = 6; MCI Aβ−, n = 39; AD Aβ−, n = 2; non-AD, n = 17), defined by clinical syndrome in conjunction with the CSF p-tau181/Aβ42 status, which is a validated metric for Aβ-positivity. In all panels, individual data points for each participant are shown and an overlaid boxplot represents group-wise distributions. Boxplots show the median (center line), interquartile range (IQR; box limits, 25th–75th percentiles), whiskers extending to the most extreme values within 1.5× IQR from the quartiles. A mean regression line is presented with ribbons representing 95% CI. Statistical tests were two-sided, and for group comparisons Tukey's adjustment was used.
Source data
Exploratory diagnostic accuracy metrics were derived in a subset of individuals (n = 176) with paired capillary and CSF Aβ42/p-tau181 metrics, at a prevalence of 56.3% of CSF biomarker positivity. A capillary p-tau217 cutoff of 0.01 pg ml−1, with 90% sensitivity for abnormal CSF Aβ42/p-tau181, led to a positive predictive value (PPV) of 0.738 (95% CI 0.653–0.808) and a negative predictive value (NPV) of 0.833 (95% CI 0.713–0.910), at a specificity of 58.4%. A capillary cutoff of 0.02 pg ml−1, with 90% specificity for abnormal CSF Aβ42/p-tau181, led to a PPV of 0.884 (95% CI 0.789–0.940) and an NPV of 0.645 (95% CI 0.551–0.729), at a sensitivity of 66.7%. A Youden's J statistic capillary cutoff (0.016 pg ml−1) led to a PPV of 0.849 (95% CI 0.758–0.909) and an NPV of 0.711 (95% CI 0.610–0.795), at a sensitivity of 73.7% and specificity of 83.2%. When combining the 90% sensitivity cutoff (0.01 pg ml−1) with the 90% specificity cutoff (0.02 pg ml−1) in a two-cutoff approach, the NPV of the lower cutoff was, as above, 0.833 (95% CI 0.713–0.910) and the PPV of the upper cutoff was 0.884 (95% CI 0.789–0.940), reaching an overall accuracy for those below the lower cutoff and above the upper cutoff of 86.2% (95% CI 78.8–91.7%), with 53 of the 176 individuals falling in the intermediate zone, which corresponded to 30.1% of the evaluated participants.
Based on 240 individuals (mean (s.d.) age, 69.9 (10.8) years; 99 women (48.8%)) measured using at least one of the three candidate DBS methods, we found that B50 and Telimmune collection cards were most compatible for GFAP and were combined for this analysis (Extended Data Fig. 7B). When comparing GFAP levels from capillary samples with venous plasma, a strong correlation was found (r = 0.773, 95% CI 0.710–0.823; P < 0.0001) (Fig. 4a). We also observed a similar correlation of capillary GFAP and venous plasma GFAP with age (capillary GFAP, r = 0.392, 95% CI 0.261–0.509; P < 0.0001; venous plasma GFAP, r = 0.276, 95% CI 0.135–0.405; P < 0.0001) (Fig. 4b) and MMSE (capillary GFAP, r = −0.448, 95% CI −0.558 to −0.324; P < 0.0001; venous plasma, r = −0.436, 95% CI −0.547 to −0.310; P < 0.0001) (Fig. 4c).
a, Association between venous plasma GFAP and capillary GFAP (n = 203). b,c, Association between MMSE score and blood GFAP (n = 181) (b), and between age and blood GFAP (n = 181) (c). Left: capillary GFAP levels. Right: venous plasma GFAP levels. d, Association between venous plasma NfL and capillary NfL for the Barcelona cohort (n = 71). e,f, Association between MMSE score and blood NfL (n = 71) (e), and between age and blood NfL (n = 71) (f). Left: capillary NfL levels. Right: venous plasma NfL levels. A mean regression line is presented in all panels, with ribbons representing 95% CI. For numerical representation of the correlation, we present Spearman coefficients alongside their P values. Statistical tests were two-sided, and for group comparisons Tukey's adjustment was used.
Source data
Based on a set with 237 individuals measured with at least one of the three DBS method candidates, only Telimmune DPS cards were useful in examining capillary NfL using our protocol (Extended Data Fig. 7C). Therefore, we examined 72 participants for NfL using Telimmune DPS cards (mean (s.d.) age, 76.4 (7.0) years; 45 women (62.5%)). When comparing NfL levels from capillary DPS to venous plasma, a strong correlation was observed (r = 0.83, 95% CI 0.743–0.892; P < 0.0001) (Fig. 4d). Similarly to GFAP, we observed similar correlations between DPS and venous plasma NfL in relation to age (capillary DPS, r = 0.429, 95% CI 0.219–0.601; P < 0.001; venous plasma, r = 0.524, 95% CI 0.333–0.674; P < 0.0001) (Fig. 4e) and MMSE (capillary DPS, r = −0.269, 95% CI −0.471 to −0.039; P = 0.02; venous plasma, r = −0.367, 95% CI −0.552 to −0.148; P < 0.001) (Fig. 4f).
We examined 31 participants with DS and DBS biomarker data. As with the euploid participants, we found a significant relationship between biomarkers measured in capillary blood and venous blood (p-tau217, r = 0.875, 95% CI 0.503–0.973 (Fig. 5a) GFAP, r = 0.629, 95% CI 0.347–0.806 (Fig. 5c)). Capillary biomarker levels were, as also shown in venous plasma (Fig. 5e,f), increased in DS with dementia (dDS), compared with DS without AD-related cognitive impairment (aDS), for both p-tau217 (Fig. 5b) and GFAP (Fig. 5d). Participants positive for CSF p-tau181/Aβ42 more often had higher levels of capillary GFAP (Fig. 5f), although there were not sufficient participants with DS and DBS p-tau217 and CSF biomarker data (n = 5, CSF-negative only). Telimmune cards were not collected in this study, so no NfL results were obtained.
a, Scatterplot representing the association between capillary and venous plasma p-tau217 in the DS Barcelona cohort, alongside their Spearman correlation coefficient and associated P value (n = 9). b, Boxplots of capillary p-tau217 based on cognitive diagnosis (aDS, n = 4; pDS, n = 1; dDS, n = 4). c, Scatterplot representing the association between capillary and venous plasma GFAP, with a Spearman correlation coefficient and its associated P value presented (n = 30). d, Boxplots of capillary GFAP based on cognitive diagnosis (aDS, n = 18; pDS, n = 2; dDS, n = 9). e, Boxplots of venous plasma GFAP based on cognitive diagnosis (aDS, n = 21; pDS, n = 3; dDS, n = 9). f,g, Boxplots of capillary GFAP (f) and venous plasma GFAP (g) based on CSF Aβ42/p-tau181 status (CSF-negative, n = 6; CSF-positive, n = 7). For scatterplots, a mean regression line is presented with 95% CI. All boxplots show the median (center line), IQR (box limits, 25th–75th percentiles), whiskers extending to the most extreme values within 1.5× IQR from the quartiles. When group comparisons are presented with boxplots, horizontal solid-line bars represent group-wise comparisons alongside P values, obtained from post-hoc contrasting of a linear model adjusted for age and sex. Statistical tests were two-sided, and for group comparisons Tukey adjustment was used.
Source data
In the previous result sections, all capillary DPS or DBS collection was supervised and guided by trained personnel. Here we evaluated the within-person difference if collection was supervised compared with unsupervised. In 30 participants, capillary blood guided by study personnel and self-collected unsupervised samples showed a very high concordance with little difference between timepoints (DPS p-tau217, 0.014 pg ml−1 versus 0.013 pg ml−1, P = 0.57 (Extended Data Fig. 8A); DBS GFAP, 10.1 pg ml−1 versus 11.0 pg ml−1, P = 0.26 (Extended Data Fig. 8B)). Because only one Telimmune card was sampled per participant dedicated to p-tau217 quantification, no NfL data were obtained.
The DROP-AD project, constituting an effort to assess biomarkers for AD-type pathology and neurodegeneration from capillary blood, showcases the capability of quantifying p-tau217, GFAP and NfL protein levels. The study evaluated straightforward capillary blood collection methods, a new extraction protocol and ultrasensitive immunoassay biomarker determination. Biomarker levels from capillary blood correlated well with conventional venipuncture-collected plasma measures, and in the case of p-tau217, predicted with good accuracy, abnormal AD CSF biomarkers, as demonstrated in individuals classified as asymptomatic, MCI, dementia, as well as in individuals with DS, who are at high-risk for AD.
In blood, p-tau217 is the principal blood biomarker for determining AD pathology8 and is increasingly adopted as a reliable metric in research, clinical trials and clinical practice. It has the capabilities of high diagnostic accuracy to detect AD pathology, primarily amyloid3,24, but is also tightly associated with severity of tau pathology assessed by tangle counts at post-mortem examination2 and by tau PET during life25 not only in the symptomatic phase of the disease4, but also in the asymptomatic phase26. Therefore, p-tau217 holds promise not only for clinical use, but also population-level screening, identifying at-risk individuals in preclinical phases and enabling early intervention strategies27. Plasma p-tau217 has already been used to assess outcomes in secondary preventive trials16,28. A drawback in expanding blood biomarker testing outside specialized centers, is the strict protocol and guided venipuncture collection, sample handling and shipment. Dried blood sampling23 overcomes this limitation by enabling simplified, minimally invasive and potentially, remote self-collection, reducing the need for specialized personnel and facilitating broader population access to biomarker testing.
The DROP-AD project, conducted across multiple centers, highlights the strong potential of using dried capillary blood samples to accurately quantify plasma p-tau217. We observed robust correlations between p-tau217 concentrations measured from DPS and matched venous plasma samples, although the strength of these correlations varied by site. Importantly, p-tau217 levels showed a stepwise increase across clinical stages—CU, MCI and AD—and demonstrated good accuracy in predicting CSF biomarker-confirmed AD pathology. In addition to p-tau217, we successfully quantified GFAP and NfL using DBS and DPS matrices, respectively. Both GFAP and NfL showed high concordance between capillary and venous samples, and were similarly associated with cognitive performance and age, reinforcing the validity of these remote sampling methods. Although our primary focus was on biomarkers of AD neuropathology, the reliable detection of NfL from DPS samples has broader implications. Given its established role as a diagnostic, prognostic and monitoring biomarker, capillary-based NfL measurement could be transformative for other neurodegenerative and neurological conditions—including frontotemporal dementia, atypical parkinsonian syndromes, multiple sclerosis, amyotrophic lateral sclerosis and acute neurological injuries. Biomarker levels extracted from DPS or DBS cards, for all analytes of interest, were substantially lower than those quantified from venous plasma, which we believe is attributable to the elution of dried blood or plasma with buffer, resulting in dilution. Protein concentrations were not adjusted using a uniform dilution factor, because we cannot currently estimate the volume of plasma that is dried onto a card. Attempts to measure Aβ42 and Aβ40 using this technique yielded mixed results. Although Aβ40 was readily quantifiable, Aβ42 levels were mainly below the limit of detection and could not be included in the analysis, limiting the utility of this approach for this biomarker.
Imaging, CSF and blood-based biomarkers for AD pathology have shown strong translational applicability in individuals with DS, which represents the most common genetically determined form of AD29. Given the near-universal risk of AD in this population, there is a critical need for scalable and accessible methods to enable longitudinal biomarker monitoring, particularly in the context of preventive and disease-modifying clinical trials. Collection of blood samples by standard venipuncture may be complicated in individuals with DS—for example, due to relatively high rates of institutionalization and a lack of professionals—and remote blood collection thus offers a promising solution by reducing reliance on in-clinic visits and facilitating broader participation across diverse spectrum of intellectual disability. To evaluate the feasibility of this approach, we conducted a pilot study in which capillary blood samples were successfully collected from individuals with DS across a spectrum of cognitive stages. Our results revealed significantly elevated levels of capillary-derived GFAP and p-tau217 in participants with symptomatic AD compared with those who were cognitively asymptomatic. Importantly, biomarker concentrations derived from capillary samples showed strong concordance with those obtained from matched venous plasma, supporting the reliability and translational potential of remote sampling for biomarker quantification and ultimately, AD diagnosis, in this high-risk population.
This study has limitations. First, we have indicated that capillary blood collection may be useful in an unsupervised fashion, remotely. This has not been fully examined in this proof-of-principle study, where all capillary sampling was performed in research centers guided by trained staff. To gain some initial insights, we conducted a pilot in 30 participants who provided two capillary samples: one sampled by research staff and one unsupervised—1 h later. These initial findings demonstrate the reproducibility of both the collection method and the laboratory extraction procedure. Further, our venous plasma analyses were performed in single-batch analysis for all study sites, and this is particularly important to consider when comparing results directly to capillary testing, which was analyzed prospectively in multiple batches (less than 4 weeks from collection) throughout the 24-month study period. The observed lower accuracies to determine AD pathology by capillary p-tau217 could be partially attributed to this key difference in analytical design. This 24-month period also reflects a time of protocol optimization, in sample collection at multiple study sites and biomarker determination in the laboratory. Despite this optimization, we do experience a proportion of unsuccessful collections of capillary samples because of insufficient capillary blood flow, coagulation or technical issues during plasma separation in 15–25% of cases. This may, in part, reflect the inherent challenges of fingertip capillary blood sampling in clinical practice, where achieving consistent blood flow from a fingerstick collection is difficult and often complicated by hemolysis or admixture of interstitial fluid due to external compression of the fingertip30. We believe that diligent training of the study personnel and patients and/or caregivers and the provision of informational material is essential for successful collection of dried blood; however, alternative capillary blood collection methods—other than fingerstick—should be considered and examined given the encouraging finding from this study. Moreover, studies with larger cohorts are needed to investigate the impact of confounders on DPS or DBS biomarker levels.
In conclusion, our findings demonstrate that dried blood analysis offers a feasible and scalable approach for detecting AD pathology, particularly in research, population-based and epidemiological contexts. This minimally invasive method has the potential to substantially broaden our understanding of the prevalence and distribution of AD pathology across the general population, while also facilitating the inclusion of historically underrepresented populations and geographically diverse regions in AD research. However, despite the promise shown, we do not currently recommend the use of dried blood analysis for clinical use, decision-making or patient management, because of observed differences in analytical performance and diagnostic accuracy between capillary-derived and venous blood samples. Further methodological refinement and validation will be essential before clinical translation can be considered.
To evaluate the feasibility of capillary-derived blood as a simplified collection method compatible with AD biomarker analysis, paired venous plasma and capillary blood samples obtained by fingerstick were collected from CU and cognitively impaired individuals across seven European study centers. Capillary blood collection was conducted by trained study personnel at each site. Dried blood cards were shipped without temperature control to the Neurochemistry Laboratory at the University of Gothenburg, Sweden, within 1–40 days of collection. In parallel, venous plasma samples were stored at −80 °C at the respective study sites and shipped on dry ice to the same laboratory at the end of the study. Complementary CSF data (total n = 227; Barcelona, n = 131; Barcelona (DS), n = 13; Brescia, n = 7; Gothenburg, n = 13; Malmö, n = 40; Copenhagen, n = 23) and cognitive assessments (total n = 244; Barcelona, n = 130; Brescia, n = 32; Copenhagen, n = 24; Gothenburg, n = 14; Malmö, n = 44) were obtained from each site as part of routine clinical evaluations or existing research protocols.
At each study site, all participants provided written informed consent before enrollment, and the studies were approved by local ethical review authorities. The inclusion criteria for each cohort are depicted below and summarized in Supplementary Table 1. Participants were not compensated for participation in this study. Biological sex was determined based on self-identification.
The Ace Alzheimer Center Barcelona, Spain (the ‘Barcelona' cohort) included participants under investigation for cognitive complaints recruited between September 2022 and April 2024. At Fundació ACE, clinical diagnosis was carried out through a comprehensive neuropsychological evaluation using the NBACE battery31, assessment of functional status with the Clinical Dementia Rating (CDR) scale, and supported by biological diagnosis through CSF biomarkers following the AT(N) classification framework32. Individuals with MCI and dementia were offered a voluntary (and informed consented) lumbar puncture in accordance with established consensus recommendations. Venous plasma, CSF and capillary DPS or DBS samples were collected on the same day under fasting conditions. All biospecimens obtained were part of the ACE collection, which was registered in Instituto de Salud Carlos III (ISCIII, Ministry of Health of Spain) under the code C.0000299. Capillary DPS and DBS samples were stored and shipped at room temperature between 1 and 3 days after the collection. The study was approved by the Ethics Committees of the Hospital Universitari de Bellvitge, Barcelona (Ref. PR148/22). The H70 Clinical Studies (the ‘Gothenburg' cohort) consecutively recruited participants under investigation for cognitive symptoms from the memory clinic at the Sahlgrenska University Hospital in Gothenburg, Sweden between June 2023 and April 2024. There were no exclusion criteria. Capillary DPS and DBS samples, venous plasma and CSF samples were collected at the same study visit. Cognitive testing (MMSE and CDR) was performed in each participant. Capillary DPS and DBS samples were stored at room temperature and delivered to the Neurochemistry Laboratory between 1 and 7 days after the collection. Ethical approval for H70 Clinical Studies was provided by The Swedish Ethical Review Authority (Etikprövningsmyndigheten; EPM: 2023-06137-02). In the BioFINDER Primary Care (NCT06120361) and BioFINDER Preclinical AD (NCT06121544) studies (the ‘Malmö' cohort), cognitively asymptomatic volunteers (asymptomatic AD or healthy controls) and individuals with cognitive symptoms undergoing cognitive diagnostic evaluation in primary care were included between December 2023 and November 2024. The exclusion criteria were (1) not undergoing CSF or blood sampling as part of clinical practice and (2) not undergoing cognitive testing as part of clinical practice. Cognitive testing (MMSE) and CSF samples were available for each participant. Capillary DPS and DBS were collected at the same day as venous plasma samples, stored at room temperature and shipped to the Neurochemistry Laboratory between 1 and 7 days after the collection. The studies were approved by Swedish Ethical Review Authority (Dnr. 2021-05724-01 and 2019-04320). Participants enrolled at the Center for Neurodegenerative Disorders at the University of Brescia, Italy (the ‘Brescia' cohort) met current clinical criteria for the diagnosis of fontotemperal dementia33,34 or AD35, or were healthy individuals recruited among spouses or family members. Consecutive recruitment took place between October 2023 and June 2024. Each participant underwent an extensive clinical and neuropsychological evaluation and simultaneous venous EDTA plasma and dried blood spot collection. Cognitive testing (MMSE and CDR) was available for each participant and CSF samples were collected in a subgroup. Capillary DPS and DBS samples were stored at room temperature and shipped to the Neurochemistry Laboratory between 1 and 30 days after the collection. The study was approved by the local ethics committee (NP2189 and NP1965). Participants enrolled at the University of Exeter Medical School (the ‘Exeter' cohort) were adults aged 50 years or above with a body mass index >25 kg m−2 and within 2 h travel of Exeter consecutively recruited from PROTECT-UK (Platform for Research Online to investigate Cognition and Genetics in Ageing) taking part in the DailyColors polyphenol supplement study in January 2024 (ref. 36). Exclusion criteria were the diagnosis of dementia and participation in an interventional clinical trial. Capillary dried blood samples and paired venous blood were collected at the same day. Capillary dried blood samples were stored at room temperature and shipped to the Neurochemistry Laboratory between 1 and 10 days after collection. This study was approved by the Ethics Committee of the University of Exeter, Faculty of Health & Life Sciences REC (Ref. 529634). Participants under investigation of a neurodegenerative disease from the memory clinic at Rigshospitalet, Copenhagen University Hospital (the ‘Copenhagen' cohort) were enrolled between May 2024 and July 2024. For each participant, paired capillary DPS and DBS and venous plasma, sampled on the same day, and CSF and MMSE data were available. Individuals were excluded if they did not consent to the Danish Dementia Biobank, if the lumbar puncture was unsuccessful, or if they were clinically evaluated as incapable of participating in the project. Capillary dried blood samples were stored at room temperature and shipped within 7–40 days after collection. This study was approved by the Danish Research Ethics Committee (Ref. H-23078392). For the Sant Pau cohort, participants with DS with (dDS or prodromal AD (pDS)) and without AD-related cognitive impairment (aDS) were consecutively recruited at the Sant Pau Memory Unit, Barcelona, Spain from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) study between May 2024 and November 2024. Capillary DPS and DBS samples were collected at the same day as venous EDTA plasma samples and stored at room temperature and shipped within 1–14 days after collection. This study was approved by the Sant Pau Ethics Committee. All participants or their legally authorized representative gave written informed consent before enrollment.
Three different dried blood spot collection devices were used in this study. Capitainer SEP-10 (Capitainer AB), Capitainer B50 (Capitainer AB) and Telimmune Plasma Separation Card (Novilytic). Capitainer SEP-10 and the Telimmune Plasma Separation Card were used interchangeably to measure p-tau217. Capitainer B50 and the Telimmune Plasma Separation Card were utilized for GFAP quantification. Telimmune Plasma Separation Cards alone were used for NfL measurements based on comparative studies (Extended Data Fig. 7). In all cohorts, capillary blood was collected by study personnel from the middle or index finger using a single-use lancet with a 1.5-mm wide and 2.0-mm deep cut. In the Exeter cohort, a secondary unsupervised capillary blood collection was carried out by all participants on the same day.
The Capitainer B50 and Capitainer SEP-10 cards collect 50 μl and 70 μl of capillary whole blood, respectively. In the SEP-10 cards, blood cells are separated from the whole blood generating 10 μl of a plasma-like sample. Whole blood and plasma-like spots are left to dry at room temperature for 30 min. The Telimmune Plasma Separation Card does not restrict blood volume and 50 μl of capillary whole blood, equivalent to 6 μl of plasma-like sample, was pipetted from the finger to the card to standardize collection volume. Telimmune Plasma Separation Cards were left to dry for 3 min, then the cell separation membrane layer was removed, and the samples were left to dry for additional 30 min. After drying, all cards were stored at room temperature and shipped without temperature control or cooling on a regular basis to the Neurochemistry Laboratory, Gothenburg, Sweden. Before analysis, one filter disk from Capitainer B50 and Capitainer SEP-10 cards and both filter disks from the Telimmune Plasma Separation Cards were removed from the card using a semi-automated spot collector (Capitainer AB), and transferred to a deep 96-well plate (Sirocco protein precipitation plate, Waters). Samples were then incubated shaking with 170–300 μl of protein extraction buffer depending on the analyte of interest and at 37 °C and 500 rpm for 30 min; for p-tau217 quantification, filter papers were eluted with 170 μl buffer for all card types (Quanterix, catalogue number 105909); for N2PE and N4PE assays, Capitainer B50 filter papers were eluted with 300 μL and Telimmune filter papers with 170 μl of analyte-specific buffer (Quanterix, catalogue numbers 103659 (N4PE) and 103516 (N2PB)). After incubation, the samples were centrifuged at 20 °C and 2,626g for 15 min and the eluate was collected in a conical 96-well plate (Quanterix). After spinning, the filter disks and protein precipitation plate were discarded, and the eluate was immediately used for biomarker analysis in singlecates by Simoa technology on the HD-X platform using a neat protocol (ALZpath Simoa pTau-217 v2 Assay3 (Quanterix, catalogue number 104371), Simoa Neurology 4-plex E (Quanterix, catalogue number 103607) or Simoa Neurology 2-plex B (Quanterix, catalogue number 103520).
Venous plasma samples collected by venipuncture and CSF collected by lumbar puncture are summarized for each cohort37,38,39,40,41,42. Before immunoassay procedures, venous EDTA plasma samples were thawed for 45 min at room temperature, vortexed for 30 s at 2,000 rpm and centrifuged at 4,000g and 20 °C for 10 min. Venous plasma samples were analyzed in singlecates with the same immunoassays using standard operating procedures, except for the Malmö cohort where venous plasma p-tau217 was quantified using an immunoassay on the Meso Scale Discovery platform developed by Lilly2. CSF biomarkers (Aβ42/Aβ40 or Aβ42/p-tau181) were analyzed by either Lumipulse G1200 (Fujirebio) or Elecsys e801 analyzers (Roche Diagnostics).
For the Gothenburg cohort, paired capillary blood extracts and venous plasma samples were measured in the same experiment. In all other cohorts, for logistic reasons, capillary blood extracts were measured prospectively with the accompanying venous plasma samples measured in a single batch at the end of the study. High and low dried blood quality controls were developed for p-tau217, GFAP and NfL on Capitainer SEP-10 filter disks. Dried blood quality controls were extracted on the day of each experiment and measured in duplicates at the beginning and end of each plate. Moreover, additional high and low venous plasma controls were run in duplicates at the beginning and end of each plate. Here, the inter-assay coefficient of variation (CV) was <17% for DPS and <15% for venous plasma p-tau217; the intra-assay CV was <15% for DPS p-tau217 and <7% for venous plasma p-tau217; the inter-assay CV for NfL and GFAP was <22% for DPS and <15% for venous plasma; and the intra-assay CV for NfL and GFAP was <11% for DPS and <10% for venous plasma (Supplementary Table 3).
To test the potential of capillary dried blood collection as self-sampling method, participants in the Exeter cohort underwent a second independently performed sampling session using Capitainer SEP-10, Capitainer B50 and Telimmune cards. During the first collection carried out by the study personnel, participants observed the sampling process and were handed written instructions (short text boxes and pictograms). Participants were then left alone with the instructions and performed the capillary dried blood collection independently (n = 44 pairs for DPS p-tau217; n = 18 pairs for DBS GFAP).
Demographic information from participants were summarized with descriptive statistics, with mean and s.d. for continuous variables and counts and percentages for categorical variables. For visualizing associations between capillary dried blood spot biomarkers and variables of interest, we used scatterplots and presented a mean linear regression line to represent trends in associations. To numerically quantify and compare these associations, we used Spearman's rho. To visualize between-group differences in DBS biomarkers, we plotted individual data points overlaid with boxplots. When group comparisons were made, we used linear models adjusted for age, sex and center (when applicable), and obtained P values from post-hoc Tukey contrasts between the levels of categorical variables. P values and 95% CIs were presented or described when appropriate. When evaluating biomarker discriminative ability for binary outcomes such as CSF biomarker positivity, we computed the AUC of receiver operating characteristics and used the DeLong test when receiver operating characteristic curves were compared. When evaluating diagnostic properties of DPS p-tau217, we assessed cutoffs derived with 90% sensitivity, 90% specificity or maximum Youdens' Index for CSF or venous plasma biomarker positivity and computed their respective NPV and PPV based on the prevalence of biomarker positivity in the subset of participants with available data for each analysis. Statistical significance was set as a two-sided alpha = 0.05. We did not control for multiple comparisons, and statistical significance was interpreted taking this into consideration. All analyses were performed in R v.4.2.1 (2022-06-23) on macOS 15.6.1.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
This study includes no data deposited in external repositories. Blinded and anonymized data can be shared with academic investigators, for the sole purpose of replicating procedures and results presented in the article, as long as data transfer agrees with local legislation and with the local Ethical Review Board of each cohort, which must be regulated in a material or data transfer agreement. Researchers interested in accessing the datasets should contact the corresponding author (Nicholas.Ashton@Bannerhealth.com) and provide a brief research proposal outlining the intended use of the data. Data requests will be evaluated based on scientific merit and compliance with ethical and legal requirements; requests are typically processed and accepted within 2–3 months. Data displayed in this paper have been provided in the source data file. Source data are provided with this paper.
All analyses were performed in R v.4.2.1 (2022-06-23) on macOS 15.6.1. The R code that supports the main results of this study is publicly available on GitHub (https://github.com/wsbrum/dropad_natmed). All models were built using publicly available packages and functions in the R programming language.
Jack, C. R. Jr et al. Revised criteria for the diagnosis and staging of Alzheimer's disease. Nat. Med. 30, 2121–2124 (2024).
Article
PubMed
PubMed Central
Google Scholar
Palmqvist, S. et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 324, 772–781 (2020).
Article
CAS
PubMed
Google Scholar
Ashton, N. J. et al. Diagnostic accuracy of a plasma phosphorylated tau 217 immunoassay for Alzheimer disease pathology. JAMA Neurol. 81, 255–263 (2024.
Article
PubMed
PubMed Central
Google Scholar
Palmqvist, S. et al. Blood biomarkers to detect Alzheimer disease in primary care and secondary care. JAMA 332, 1245–1257 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Jack, C. R. Jr et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 20, 5143–5169 (2024).
Article
PubMed
PubMed Central
Google Scholar
Dubois, B. et al. Alzheimer disease as a clinical–biological construct—an international working group recommendation. JAMA Neurol. 81, 1304–1311 (2024).
Article
PubMed
PubMed Central
Google Scholar
Ashton, N. J. et al. The Alzheimer's Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau round robin study. Alzheimers Dement. 21, e14508 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Schindler, S. E. et al. Acceptable performance of blood biomarker tests of amyloid pathology – recommendations from the Global CEO Initiative on Alzheimer's Disease. Nat. Rev. Neurol. 20, 426–439 (2024).
Article
CAS
PubMed
Google Scholar
Kirsebom, B. E. et al. Repeated plasma p-tau217 measurements to monitor clinical progression heterogeneity. Alzheimers Dement. 21, e70319 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Brum, W. S. et al. A two-step workflow based on plasma p-tau217 to screen for amyloid beta positivity with further confirmatory testing only in uncertain cases. Nat. Aging 3, 1079–1090 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Altomare, D. et al. Plasma biomarkers for Alzheimer's disease: a field-test in a memory clinic. J. Neurol. Neurosurg. Psychiatry 94, 420–427 (2023).
Article
PubMed
Google Scholar
Bellaver, B. et al. Astrocyte reactivity influences amyloid-beta effects on tau pathology in preclinical Alzheimer's disease. Nat. Med. 29, 1775–1781 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Pontecorvo, M. J. et al. Association of donanemab treatment with exploratory plasma biomarkers in early symptomatic Alzheimer disease: a secondary analysis of the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol. 79, 1250–1259 (2022).
Article
PubMed
PubMed Central
Google Scholar
Ashton, N. J. et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat. Commun. 12, 3400 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
Hansson, O. et al. The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease. Alzheimers Dement. 18, 2669–2686 (2022).
Article
CAS
PubMed
Google Scholar
Rafii, M. S. et al. The AHEAD 3-45 study: design of a prevention trial for Alzheimer's disease. Alzheimers Dement. 19, 1227–1233 (2023).
Article
CAS
PubMed
Google Scholar
Palmqvist, S. et al. Plasma phospho-tau217 for Alzheimer's disease diagnosis in primary and secondary care using a fully automated platform. Nat. Med. 31, 2036–2043 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Warmenhoven, N. et al. A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests. Brain 148, 416–431 (2025).
Article
PubMed
Google Scholar
Barthelemy, N. R. et al. Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests. Nat. Med. 30, 1085–1095 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Meyer, M. R. et al. Clinical validation of the PrecivityAD2 blood test: a mass spectrometry-based test with algorithm combining %p-tau217 and Aβ42/40 ratio to identify presence of brain amyloid. Alzheimers Dement. 20, 3179–3192 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Montoliu-Gaya, L. et al. Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study. Acta Neuropathol. 147, 5 (2023).
Article
PubMed
PubMed Central
Google Scholar
Verberk, I. M. W. et al. Characterization of pre-analytical sample handling effects on a panel of Alzheimer's disease-related blood-based biomarkers: results from the Standardization of Alzheimer's Blood Biomarkers (SABB) working group. Alzheimers Dement. 18, 1484–1497 (2022).
Article
CAS
PubMed
Google Scholar
Huber, H. et al. Biomarkers of Alzheimer's disease and neurodegeneration in dried blood spots—a new collection method for remote settings. Alzheimers Dement. 20, 2340–2352 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Mattsson-Carlgren, N. et al. Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease. Brain 143, 3234–3241 (2020).
Article
PubMed
PubMed Central
Google Scholar
Therriault, J. et al. Comparison of two plasma p-tau217 assays to detect and monitor Alzheimer's pathology. EBioMedicine 102, 105046 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Ashton, N. J. et al. Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer's trial selection and disease monitoring. Nat. Med. 28, 2555–2562 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
Aarsland, D. et al. Prevalence of Alzheimer's disease pathology in the community. Nature https://doi.org/10.1038/s41586-025-09841-y (2025).
Sims, J. R. et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 330, 512–527 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Fortea, J. et al. Alzheimer's disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol. 20, 930–942 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
Meites, S. Skin-puncture and blood-collecting technique for infants: update and problems. Clin. Chem. 34, 1890–1894 (1988).
Article
CAS
PubMed
Google Scholar
Alegret, M. et al. Cut-off scores of a brief neuropsychological battery (NBACE) for Spanish individual adults older than 44 years old. PLoS ONE 8, e76436 (2013).
Article
CAS
PubMed
PubMed Central
Google Scholar
Orellana, A. et al. Establishing in-house cutoffs of CSF Alzheimer's disease biomarkers for the AT(N) stratification of the Alzheimer Center Barcelona Cohort. Int. J. Mol. Sci. 23, 6891 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
Rascovsky, K. et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477 (2011).
Article
PubMed
PubMed Central
Google Scholar
Gorno-Tempini, M. L. et al. Classification of primary progressive aphasia and its variants. Neurology 76, 1006–1014 (2011).
Article
PubMed
PubMed Central
Google Scholar
McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 263–269 (2011).
Article
PubMed
Google Scholar
O'Leary, M. et al. Effects of the DailyColors polyphenol supplement on serum proteome, cognitive function, and health in older adults at risk of cognitive and functional decline. Food Funct. 16, 4505–4520 (2025).
Article
PubMed
Google Scholar
Cano, A. et al. Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinic. EBioMedicine 108, 105345 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Clemmensen, F. K. et al. Short-term variability of Alzheimer's disease plasma biomarkers in a mixed memory clinic cohort. Alzheimers Res. Ther. 17, 26 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Cotelli, M. S. et al. Predicting survival rate by plasma biomarkers and clinical variables in syndromes associated with frontotemporal lobar degeneration. Alzheimers Dement. 21, e14558 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Dittrich, A. et al. Evaluation of two plasma-based proteotyping assays against APOE epsilon4 genotyping in a memory clinic setting: The Gothenburg H70 Clinical Studies. Alzheimers Dement. 21, e14610 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Palmqvist, S. et al. Performance of fully automated plasma assays as screening tests for Alzheimer disease-related beta-amyloid status. JAMA Neurol. 76, 1060–1069 (2019).
Article
PubMed
PubMed Central
Google Scholar
Wangdi, J. T. et al. Tart cherry supplement enhances skeletal muscle glutathione peroxidase expression and functional recovery after muscle damage. Med. Sci. Sports Exerc. 54, 609–621 (2022).
Article
CAS
PubMed
Google Scholar
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H.H. has received grants from Demensförbundet, Adlerbertska forskningsstiftelsen, Anna-Lisa och Bror Björnssons Stiftelse and the German Research Foundation under Germany's Excellence Strategy (grant number EXC2151-390873048). L.M.-G. has received grants from Alzheimerfonden (grant numbers AF-1012339, AF-233060), Demensförbundet, Åhlen-Stiftelsen (grant numbers 233060, 243051), Gun och Bertil Stohnes Stiftelse (grant number 2024-037), Jerome Lejeune Foundation (grant number GRT-2023B–2303), Carin Mannheimer's prize 2023, Familjen Rönströms Stiftelse (grant number FRS-0012) and Stiftelsen Wilhelm och Martina Lundgrens vetenskapsfond (grant number 2025-SA-4922). A.D. was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (grant number ALFGBG-984092). M.C.I. reports grants from the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (grant numbers PI18/00335, PI22/00758, ICI23/00032) and the CIBERNED program (Program 1, Alzheimer Disease and SIGNAL study, www.signalstudy.es), partly jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa; Alzheimer's Association (grant number AARG-22-973966), Global Brain Health Institute (grant number GBHI_ALZ-18-543740), Jérôme Lejeune Foundation (grant number 1913 cycle 2019B) and Societat Catalana de Neurologia (grant number SCN2020). S.K. was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (grant numbers ALFGBG-1005471, ALFGBG-965923, ALFGBG-81392, ALFGBG-771071), the Alzheimerfonden (grant numbers AF-842471, AF-737641, AF-929959, AF-939825), the Swedish Research Council (grant numbers 2019-02075, 2019-02075_15), Stiftelsen Psykiatriska Forskningsfonden and The Swedish Brain Foundation FO2024-0097. A.C. and C.B. state that this paper represents independent research part-funded by the National Institute of Health Research (NIHR) Exeter Biomedical Research Centre, Maudsley–Exeter Health Technology Research Centre and Collaboration for Leadership in Applied Health Research and Care South-West Peninsula. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. K.B. is supported by the Swedish Research Council (grant numbers 2017-00915 and 2022-00732), the Swedish Alzheimer Foundation (grant numbers AF-930351, AF-939721, AF-968270 and AF-994551), Hjärnfonden, Sweden (grant numbers ALZ2022-0006, FO2024-0048-TK-130 and FO2024-0048-HK-24), the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (grant numbers ALFGBG-965240 and ALFGBG-1006418), the European Union Joint Program for Neurodegenerative Disorders (grant number JPND2019-466-236), the Alzheimer's Association 2021 Zenith Award (grant number ZEN-21-848495), the Alzheimer's Association 2022-2025 Grant (grant number SG-23-1038904 QC), La Fondation Recherche Alzheimer (FRA), Paris, France, the Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark, Familjen Rönströms Stiftelse, Stockholm, Sweden and an anonymous filantropist and donor. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (grant numbers 2023-00356, 2022-01018 and 2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement number 101053962, Swedish State Support for Clinical Research (grant number ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (grant numbers 201809-2016862), the AD Strategic Fund and the Alzheimer's Association (grant numbers ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C and ADSF-24-1284328-C), the European Partnership on Metrology, co-financed from the European Union's Horizon Europe research and innovation programme and by the participating States (NEuroBioStand, grant number 22HLT07), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (grant number FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (grant number JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL (grant number UKDRI-1003) and an anonymous donor. The BioFINDER study was funded by the National Institute of Aging (grant number R01 AG083740), the Alzheimer's Association (grant number SG-23-1061717), the Swedish Brain Foundation (grant number FO2024-0284), the Kamprad Foundation (grant number 20243058), the Family Rönström (grant numbers FRS-0011 and FRS-0004), the Swedish Alzheimer Foundation (grant number AF-1011949), Bundy Academy and MultiPark at Lund University. The DABNI study is funded by the Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España) through the projects INT21/00073, PI20/01473 and PI23/01786 to J.F.; PI18/00335, PI22/00758, ICI23/00032 to MCI; PI18/00435, PI22/00611, INT19/00016, INT23/00048 to D. Alcolea; and PI14/1561, PI20/01330 to A.L., the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas CIBERNED Program 1, partly jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una Manera de Hacer Europa. This work was also supported by the National Institutes of Health (grant numbers R01 AG056850 R21 AG056974, R01 AG061566, R01 AG081394 and R61AG066543 and 1RF1AG080769-01 to J.F.). It was also supported by Alzheimer's Association (grant number AARG-22-973966 to M.C.I.), Global Brain Health Institute (grant number GBHI_ALZ-18-543740 to M.C.I.), Jérôme Lejeune Foundation (grant number 1913 cycle 2019B to M.C.I.), Fundación Tatiana Pérez de Guzmán el Bueno (grant number IIBSP-DOW-2020-151 to J.F.) and Horizon 2020 research and innovation framework programme from the European Union (grant number H2020-SC1-BHC-2018-2020 to J.F.).
Open access funding provided by University of Gothenburg.
These authors contributed equally: Hanna Huber, Laia Montoliu-Gaya, Wagner S. Brum.
These authors jointly supervised this work: Kaj Blennow, Henrik Zetterberg, Nicholas J. Ashton.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
Hanna Huber, Laia Montoliu-Gaya, Wagner S. Brum, Jakub Vávra, Yara Yakoub, Haley Weninger, Luisa Sophie Braun-Wohlfahrt, Joel Simrén, Anna Dittrich, Ingmar Skoog, Silke Kern, Kaj Blennow, Henrik Zetterberg & Nicholas J. Ashton
German Center for Neurodegenerative Diseases, Bonn, Germany
Hanna Huber
University Hospital Bonn, Department of Old Age Psychiatry and Cognitive Disorders, Bonn, Germany
Hanna Huber
Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
Wagner S. Brum
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
Yara Yakoub
Research Center of the Douglas Mental Health University Institute, Montreal, Quebec, Canada
Yara Yakoub
Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain
Mercé Boada, Agustín Ruiz, Amanda Cano, Adelina Orellana, Sergi Valero, Laia Cañada, Natalia Tantinya, Ana Belen Nogales, Pilar Sanz-Cartagena & Xavier Morató
Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Mercé Boada, Agustín Ruiz, Amanda Cano, Adelina Orellana, Sergi Valero & Xavier Morató
Region Västra Götaland, Sahlgrenska University Hospital, Department of Neuropsychiatry, Mölndal, Sweden
Anna Dittrich, Ingmar Skoog & Silke Kern
College of Medicine and Health, University of Exeter, Exeter, UK
Millie Sander-Long, Clive Ballard, Megan Richards, Mary O'Leary & Anne Corbett
Danish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Frederikke Kragh Clemmensen, Hannah H. D. Wandall & Anja Hviid Simonsen
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
Daniele Altomare, Valentina Cantoni & Barbara Borroni
Competence Centre on Ageing (CCA), Department of Business Economics, Health and Social Care (DEASS), University of Applied Sciences and Arts of Southern Switzerland (SUPSI), Manno, Switzerland
Daniele Altomare
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
Erik Stomrud, Sebastian Palmqvist & Oskar Hansson
Memory Clinic, Skåne University Hospital, Malmö, Sweden
Erik Stomrud & Sebastian Palmqvist
Sant Pau Memory Unit, Department of Neurology, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Alberto Lleo, Daniel Alcolea, Maria Carmona Iragui, Aida Sanjuan Hernandez, Bessy Benejam, Laura Videla Toro & Juan Fortea
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas. CIBERNED, Barcelona, Spain
Alberto Lleo, Daniel Alcolea, Maria Carmona Iragui, Aida Sanjuan Hernandez, Bessy Benejam, Laura Videla Toro & Juan Fortea
Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain
Maria Carmona Iragui, Aida Sanjuan Hernandez, Bessy Benejam, Laura Videla Toro & Juan Fortea
Banner Sun Health Research Institute, Sun City, AZ, USA
Alpana Singh, Marisa N. Denkinger & Nicholas J. Ashton
Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Mölndal, Sweden
Silke Kern
ALZpath, Inc., Carlsbad, CA, USA
Lee Honigberg
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Barbara Borroni
Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden
Kaj Blennow & Henrik Zetterberg
Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
Kaj Blennow
Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, China
Kaj Blennow
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
Kaj Blennow
UK Dementia Research Institute at UCL, London, UK
Henrik Zetterberg
Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong, China
Henrik Zetterberg
Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
Henrik Zetterberg
Centre for Brain Research, Indian Institute of Science, Bangalore, India
Henrik Zetterberg
Banner Alzheimer's Institute and University of Arizona, Phoenix, AZ, USA
Nicholas J. Ashton
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H.H., K.B., H.Z. and N.J.A. conceptualized and designed the study. All authors acquired, analyzed and interpreted the data. A.D. and S.K. performed the clinical assessments. H.H., L.M.-G., W.S.B., K.B., H.Z. and N.J.A. drafted the paper. All authors critically revised the paper for important intellectual content. H.H. and W.S.B. performed the statistical analysis. H.H., L.M.-G., K.B., H.Z. and N.J.A. obtained funding for the present study. K.B., H.Z. and N.J.A. supervised the present study. All authors reviewed and approved the final paper.
Correspondence to
Nicholas J. Ashton.
L.M.-G. has received speaker and/or consultancy fees from Esteve and Quanterix. J.S. has received speaker honoraria from Roche Diagnostics. C.B. has received consulting fees from Acadia pharmaceutical company, AARP, Addex pharmaceutical company, Eli Lily, Enterin pharmaceutical company, GWPharm, H.Lundbeck pharmaceutical company, Novartis pharmaceutical company, Janssen Pharmaceuticals, Johnson and Johnson pharmaceuticals, Novo Nordisk pharmaceutical company, Orion Corp. pharmaceutical company, Otsuka America Pharm Inc., Sunovion Pharm. Inc., Suven pharmaceutical company, Roche pharmaceutical company, Biogen pharmaceutical company, Synexus clinical research organization and tauX pharmaceutical company, and research funding from Synexus clinical research organization, Roche pharmaceutical company, Novo Nordisk pharmaceutical company and Novartis pharmaceutical company. D. Alcolea participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., Neuraxpharm, Alter Medica, Lilly and Esteve Pharmaceuticals S.A. D.A. and A.L. declare a filed patent application (WO2019175379 A1 markers of synaptopathy in neurodegenerative disease). A.L. has served as a consultant or on advisory boards for Almirall, Beckman-Coulter, Fujirebio-Europe, Roche, Biogen, Grifols, Novartis, Eisai, Lilly, and Nutricia. M.C.I. reported receiving personal fees for service on the advisory boards, speaker honoraria or educational activities from Esteve, Lilly, Adium Pharma, Neuraxpharm and Roche. E.S. has acquired research support (for the institution) from C2N Diagnostics, Fujirebio, GE Healthcare and Roche Diagnostics. S.P. has acquired research support (for the institution) from Avid and ki elements through ADDF. In the past 2 years, he has received consultancy and/or speaker fees from BioArctic, Biogen, Eisai, Eli-Lilly, Novo Nordisk and Roche. S.K. has served at scientific advisory boards, speaker and/or as consultant for Roche, Eli-Lilly, Geras Solutions, Optoceutics, Biogen, Eisai, Merry Life, Triolab, Novo Nordisk and BioArctic, unrelated to present study content. A.C. has received consultancy funding from Novartis, Addex, Acadia, Suven and J&J pharmaceutical companies and grant funding from Novo Nordisk, ReMYND and TheriniBio pharmaceutical companies. J.F. reported serving on the advisory boards, adjudication committees, or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Novo Nordisk, Perha, Roche, Zambón, Spanish Neurological Society, T21 Research Society, Lumind foundation, Jérôme Lejeune Foundation, Alzheimer's Association, National Institutes of Health USA, and Instituto de Salud Carlos III. J.F. reports holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to ADx, EPI8382175.0). No other competing interests were reported. A.H.S. has received a one-time consulting fee, paid to the institution from Eisai–BioArctic (2025). K.B. has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZpath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave; has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche and WebMD; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). N.J.A. has received consultancy and/or speaker fees from Alamar Biosciences, BioArctic, Biogen, Eli-Lilly, Neurogen Biomarking, Roche, Spear Bio, Quanterix and Vigil Neurosciences. The other authors declare no competing interests.
Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal in collaboration with the Nature Medicine team.
Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Scatterplots display the relationship between venous plasma p-tau217 (y-axis) and capillary p-tau217 (x-axis), stratified in each panel according to the cohort in which biomarkers were measured. Spearman correlation coefficients are displayed alongside their p-values and a mean regression line with 95% confidence intervals. Of note, all venous plasma and capillary p-tau217 measurements were performed with the ALZpath assay, with the Malmö cohort being the exception, where the venous plasma values were acquired with the Lilly MSD assay, hence different correlation magnitudes. Number of individuals in each plot is presented in the figure. Statistical tests were two-sided. P-tau 217 = Phosphorylated tau 217.
Source data
Scatterplots representing the association between venous plasma (y-axis) and capillary (x-axis) p-tau217 values, stratified by tertiles (n = 84 for each panel; A, in the first venous plasma tertile; B, in the second venous plasma tertile; and C, in the third venous plasma tertile) of plasma p-tau217 distribution so as to visualize the magnitude of venous plasma-capillary correlation across different concentration strata. Spearman correlation coefficients are shown alongside their p-values and a mean regression line with 95% confidence intervals. Statistical tests were two-sided. P-tau 217 = Phosphorylated tau 217.
Source data
ROC curve representing the discriminative accuracies of capillary (red) and venous plasma (brown) p-tau217 for abnormal CSF Aβ42/p-tau181 values based on a dataset of individuals with paired venous plasma p-tau217, capillary p-tau217 and CSF data (n = 176). In their correspondent colors, AUCs and their 95% confidence intervals are displayed as text. Statistical tests were two-sided. Aβ = Amyloid-β; AUC = Area under the curve; CI = Confidence interval; CSF = Cerebrospinal fluid; p-tau = Phosphorylated tau; ROC = Receiver operating characteristic.
Source data
Venous plasma p-tau217 levels (y-axis) are displayed with boxplots according to the clinical-biological groups, which combine clinical diagnosis with the CSF Aβ42/p-tau181 status of participants (CU Aβ–, n = 12; CU Aβ+, n = 1; MCI Aβ+, n = 48; AD Aβ+, n = 37; non-AD Aβ+, n = 6; MCI Aβ–, n = 39; AD Aβ–, n = 2; non-AD Aβ–, n = 14). P-values for between-group comparisons were obtained with post-hoc contrasts from linear models adjusted for age and sex and Tukey's adjustment was used. Boxplots show the median (center line), interquartile range (box limits, 25th–75th percentiles), whiskers extending to the most extreme values within 1.5×IQR from the quartiles. Statistical tests were two-sided. Aβ = Amyloid-β; AD = Alzheimer's disease; CSF = cerebrospinal fluid; CU = Cognitively unimpaired; IQR = Interquartile range; MCI = Mild cognitive impairment; p-tau = Phosphorylated tau.
Source data
(A) Boxplots indicating capillary p-tau217 concentrations (y-axis) according to CSF Aβ42/Aβ40 status (x-axis; blue for Aβ-negative, red for Aβ-positive; CSF-negative, n = 54; CSF-positive, n = 119). (B) ROC curve representing the discriminative accuracies of capillary (red) and venous plasma (brown) p-tau217 for abnormal CSF Aβ42/Aβ40 values (n = 173). In their correspondent colors, AUCs and their 95% confidence intervals are displayed as text. (C) Capillary p-tau217 levels (y-axis) are displayed with boxplots according to the clinical-biological groups, which combine clinical diagnosis with the CSF Aβ42/Aβ40 status of participants (CU Aβ–, n = 8; CU Aβ+, n = 6; MCI Aβ+, n = 59; AD Aβ+, n = 35; non-AD Aβ+, n = 10; MCI Aβ–, n = 29; AD Aβ–, n = 2; non-AD Aβ–, n = 11). P-values for between-group comparisons were obtained from group-contrasts from linear models adjusted for age and sex, with Tukey's adjustment. Boxplots show the median (center line), interquartile range (box limits, 25th–75th percentiles), whiskers extending to the most extreme values within 1.5×IQR from the quartiles. Statistical tests were two-sided. Aβ = Amyloid-β; AD = Alzheimer's disease; AUC = Area under the curve; CSF = Cerebrospinal fluid; CU = Cognitively unimpaired; IQR = Interquartile range; MCI = Mild cognitive impairment; p-tau217 = Phosphorylated tau 217; ROC = Receiver operating characteristic.
Source data
(A) Boxplots representing capillary p-tau217 concentrations (y-axis) according to venous plasma p-tau217 (x-axis; blue for venous plasma-negative [n = 99], red for venous plasma-positive [n = 153]) status. P-values for between-group comparisons were obtained from group-contrasts from linear models adjusted for age and sex, with Tukey's adjustment. Boxplots show the median (center line), interquartile range (box limits, 25th–75th percentiles), whiskers extending to the most extreme values within 1.5×IQR from the quartiles. Statistical tests were two-sided. (B) ROC curve for the discriminative ability of capillary p-tau217 in detecting venous plasma p-tau217 positivity (n = 252). AUC = Area under the curve; IQR = Interquartile range; p-tau217 = Phosphorylated tau 217; ROC = Receiver operating characteristic.
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Scatterplots showing the relationship between biomarkers measured in capillary blood (x-axis) and in venous plasma (y-axis) according to different capillary blood sampling methods (B50, SEP10, Telimmune) displayed in each panel. Row (A) indicates capillary and venous plasma relationships for p-tau217 (SEP10, n = 175; Telimmune, n = 173); row (B) for GFAP (B50, n = 162; SEP10, n = 37; Telimmune, n = 74); row (C) for NfL (B50, n = 162; SEP10, n = 36; Telimmune, n = 71). Spearman correlation coefficients are shown alongside their p-values and a mean regression line with 95% confidence intervals. Statistical tests were two-sided. GFAP = Glial fibrillary acidic protein; NfL = Neurofilament light; p-tau 217 = Phosphorylated tau 217.
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Boxplots representing biomarker distributions for p-tau217 (A, n = 43) and GFAP (B, n = 18) in professionally collected dried blood spots versus self-collected, with p-value for between-group comparisons obtained from a non-parametric Wilcoxon signed rank test. Boxplots show the median (center line), interquartile range (box limits, 25th–75th percentiles), whiskers extending to the most extreme values within 1.5×IQR from the quartiles. GFAP = Glial fibrillary acidic protein; IQR = Interquartile range; p-tau217 = Phosphorylated tau 217.
Source data
Supplementary Tables 1–3.
Statistical source data Figs. 1–5 and Extended Data Figs. 1–8.
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Huber, H., Montoliu-Gaya, L., Brum, W.S. et al. A minimally invasive dried blood spot biomarker test for the detection of Alzheimer's disease pathology.
Nat Med (2026). https://doi.org/10.1038/s41591-025-04080-0
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Diffuse midline glioma (DMG) is a highly aggressive and untreatable pediatric cancer primarily arising in the pontine brainstem region, necessitating the development of representative models for treatment advance. Here we developed an FGF4-driven human brainstem organoid model, which we used to genetically engineer H3.3K27M-altered DMG. We demonstrated that brainstem pontine glial specification is critical for DMG tumorigenesis, yielding infiltrative tumors that recapitulate patient-representative intratumoral heterogeneity. Prolonged GD2 chimeric antigen receptor (CAR) T cell treatment mirrored clinical outcomes and revealed extensive transcriptional heterogeneity, from which both potent effector and dysfunctional CAR T cell populations could be identified. Furthermore, incorporation of myeloid cells generated DMG-specific microglia that reduced treatment efficacy and revealed CAR T cell functional states most vulnerable to microglia-mediated immunosuppression. Thus, we present a representative DMG model offering a months-long experimental window in vitro, which we leveraged to delineate CAR T cell functionality and microglial impact, aiding therapy development for this devastating disease.
Diffuse midline gliomas (DMGs) are rare and aggressive pediatric brain tumors often caused by somatic mutations in histone 3 (H3) genes, commonly a K27M substitution1, occurring at a high prevalence in the pons region of the brainstem2. Primarily, affecting children under 10 years3, they present the highest mortality rate of any cancer, with a median overall survival of only 9–15 months4,5. This detrimental prognosis necessitates a better understanding of the disease's biology to develop effective treatments.
Single-cell analyses of H3K27M-altered DMG revealed intratumoral heterogeneity, with a spectrum of tumor cell profiles ranging from stalled stem-like oligodendrocyte progenitor cell (OPC-like) to more differentiated astrocyte (AC-like) and oligodendrocyte (OC-like) phenotypes, which closely resemble normal developmental cell types, alongside a recently identified mesenchymal-like (MES-like) state6,7,8. In addition, insights from both animal9,10,11 and human pluripotent stem-cell-derived12,13 studies suggest an early neurodevelopmental window of tumor initiation. Thus, dysregulated mechanisms during hindbrain development10,14,15, particularly involving glial progenitors in the region responsible for brainstem pons formation16, likely have a central role in driving H3K27M-altered gliomagenesis. Capturing this region-specific embryonic patterning is, therefore, crucial for accurately modeling pontine DMG. Furthermore, previous work identified a tight relationship between DMG progression and its unique environment, including neuron and synaptic signaling17,18,19, which can promote glioma growth20.
Human brain organoids have become valuable in vitro tools for investigating brain development and understanding the onset, progression and potential therapeutic targeting of nervous system disorders, including cancer21,22,23. Given the rarity and inoperable nature of DMG, which limits the availability of patients participant material2, organoids could offer a scalable model for generating DMG tumors de novo and enabling in vitro testing of emerging therapies. This includes the latest advances in immunotherapy for DMG, GD2 chimeric antigen receptor (CAR) T cells5, which showed promising, yet variable treatment outcomes between patients in a recent clinical trial24. Correlative data from this trial suggest that an expansion of the immunosuppressive myeloid compartment coincides with unfavorable treatment outcomes25. Uncovering the functional profiles of CAR T cells and their interplay with the immunosuppressive tumor microenvironment may offer key insights to improve their therapeutic outcomes in DMG.
Here, we report a human cerebral guided organoid model for the brainstem region, enriched for pontine medulla glial lineages. Genetic modeling of H3.3K27M-altered DMG in these brainstem-regionalized organoids (BrOs) replicates the infiltrative nature and transcriptomic landscape of DMG. We demonstrate the utility of this accessible human DMG organoid model (DMGO) for modeling CAR T cell functional heterogeneity during prolonged treatment (up to 1 month) and within the context of brain-resident microglia.
To generate human organoids with appropriate hindbrain brainstem identity for DMG modeling, we applied sequential morphogen guidance using a timely sequence of Wnt, dual SMAD inhibitors, retinoic acid (RA), fibroblast growth factors (FGFs) and sonic hedgehog (SHH) (Fig. 1a, Extended Data Fig. 1a,b and Supplementary Table 1). While FGF2 and FGF8 can be used in combination with RA and Wnt to pattern the midbrain26, cerebellum27 or spinal cord28 in growing organoids, we evaluated FGF4 because of its role in specifying rostral hindbrain, particularly in the pontine area29,30, as well as its involvement in the development of hindbrain-specific serotonergic neurons31. A direct comparison of replacing common FGF2 supplementation with FGF4 after 7 days of patterning demonstrated that 10 ng ml−1 FGF4 specifically promotes developing the pontine, including the prepontine to retropontine area, according to bulk sequencing data (Fig. 1b and Supplementary Table 2). Furthermore, among HOX genes important for hindbrain formation, expression of HOXB1, a marker of pontine precursor cells32, emerged already at an early stage (day 14) (Extended Data Fig. 1c) and three-dimensional (3D) imaging revealed HOXB1-expressing cells within early neurodevelopmental SOX2+ neural rosette structures (Fig. 1c). Bulk sequencing analysis from day 7 to day 84 showed that the patterning remained consistent and reproducible across and within multiple batches, as well as between human embryonic stem cell (hES cell) and induced pluripotent stem cell (iPS cell) sources (Extended Data Fig. 1d,e).
a, Schematic representation of timely morphogen stimulated patterning of hES cells and hiPS cells toward brainstem organoids and their subsequent application for DMG tumor, CAR T cell treatment and microglia-enriched tumor microenvironment modeling. b, Heat map of z score measuring relative brain region identity on the basis of VoxHunt similarity mapping for various supplemented concentrations of FGF2 or FGF4 (n = 3 experimental repeats, with n = 3 organoids pooled; total n = 9 organoids per condition). c, Immunofluorescence 3D images of a 200-µm-thick organoid slice on day 21 labeled for F-actin (white), SOX2 (yellow) and HOXB1 (red). Right, zoomed-in view of area in white inset. Scale bars, 250 µm (main image) and 25 µm (inset). A representative image of n = 2 slices from n = 2 organoids is shown. d, VoxHunt spatial correlation map of day 120 brainstem organoids with E18.5 mouse brain. The pons area is delineated in red (n = 9 organoids from three independent batches). e, Integrated UMAP representation of developing brainstem organoids from different time points, colored by cell annotation. f, Area plot following the relative distribution of cell types over time. Cell types are color-coded as in e. g, UMAP of the HNOCA34 colored for brainstem organoid presence score. A high score indicates a high likelihood that these HNOCA cells are present in the brainstem organoid dataset. Areas annotated by a dashed line indicate lineages as annotated in the HNOCA. Inset, UMAP colored by coarse regional annotation. h, Heat map showing the log2 fold compositional changes in the brainstem organoid dataset compared to the HNOCA. Positive values correspond to an increased abundance of cells from the indicated regional identity or glial lineage. NPC, neuronal precursor cell. i, Cell clusters in the HDBCA35 with gained coverage in brainstem organoids relative to the HNOCA. The horizontal line indicates the threshold used to define a cluster as gained or not. j, UMAP of the HDBCA showing, in shades of red, the HDBCA clusters gained in brainstem organoids, mostly related to oligos and glioblasts. Gray represents clusters below the threshold used to define gained. Inset, UMAP colored by coarse regional annotation. For e–j, n = 84 organoids in total with 5–24 organoids pooled per time point (details in Supplementary Table 1).
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To investigate cellular composition and regional identities at higher resolution, we performed time-course single-cell RNA sequencing (scRNA-seq) across eight time points, spanning from day 5 to day 120 (Extended Data Fig. 2a and Supplementary Table 3). Following quality control (Extended Data Fig. 2b and Supplementary Table 3) and doublet filtering, we recovered 55,327 high-quality cells. Spatial similarity mapping using VoxHunt33, a tool based on Mus musculus in situ hibridization data from the Allen Brain Atlas, confirmed a hindbrain identity with a more pronounced pontine signature (Fig. 1d). We next generated an integrated uniform manifold approximation and projection (UMAP) representation of the different time points and performed cell-based annotation using reference datasets, including the recently published Human Neural Organoid Cell Atlas (HNOCA)34 and the Human Developing Brain Cell Atlas (HDBCA)35,36 (Fig. 1e and Extended Data Fig. 2c–g). Temporal analysis revealed an initial phase of high proliferation that diminished over time (Extended Data Fig. 3a), as cells transitioned from pluripotent stem cells to the neuroepithelium and radial glial cells, as well as into distinct neuronal and glial populations that emerged by days 14 and 60, respectively (Fig. 1f), reflecting the natural occurring segregation of neurogenesis and gliogenesis phases35. Projection of the organoid dataset onto the HNOCA that was regionally annotated for neuronal lineages (Fig. 1g) revealed that most neuronal precursor cells, neuroblasts and neurons originated from a heterogeneous nontelencephalic cluster with enrichment for midbrain, pons and medulla regions (Fig. 1h), which collectively form the brainstem37. These neuroblasts and early neurons expressed STMN2 and RBFOX3 (NeuN) but lacked the telencephalic marker FOXG1 (ref. 35) (Extended Data Fig. 3b). Furthermore, neurotransmitter transporter analysis revealed a predominance of excitatory (glutamatergic) and inhibitory (GABAergic) neurons, the latter known to form synapses with DMG and promote its growth17,18. Smaller proportions of cholinergic and dopaminergic neurons were also detected, consistent with their distribution in the HDBCA (Extended Data Fig. 3c,d). In addition, immunofluorescence analysis identified cells expressing tryptophan hydroxylase 2 (Extended Data Fig. 3e), a key enzyme involved in serotonergic synthesis, suggesting that, albeit undetectable at the scRNA-seq level similar to the HDBCA35, this population of neurons is present. Thus, consistent with HNOCA and adult brain data showing greater heterogeneity and intermixing among nontelencephalic neurons, including hypothalamic, brainstem and hindbrain neurons (referred to as splatter neurons) compared to cortical neurons34,38, our organoid model recapitulates this regional diversity, with an enrichment in brainstem identity compared to profiles described in most HNOCA protocols.
DMG is rooted in the glial lineage8, prompting us to investigate the glial composition within our BrO model. First, we showed the presence of committed ACs (GFAP+AQP4+) and OCs (OLIG2+) at the protein level (Extended Data Fig. 3f). At the single-cell transcriptomic level, we identified glial populations spanning pre-OPCs, OPCs, committed OC precursors, glioblasts and ACs, offering a detailed representation of glial diversity and maturation states (Fig. 1e). By comparing age-matched cells of HNOCA-covered protocols, BrOs showed significant enrichment in the glial lineage, particularly glioblasts and OPCs (Fig. 1h). Additionally, we assessed glycolysis, an indicator of cell stress in brain organoids34. Consistent with models described in the HNOCA, we observed similar glycolysis levels (Extended Data Fig. 3g). However, in the glial lineage, glycolysis levels were lower (Extended Data Fig. 3h), suggesting reduced stress and a healthier metabolic state of glial cells in BrOs. Moreover, OPC (referred to as oligo in the HDBCA35) and glioblast populations demonstrated a reduced number of differentially expressed genes (DEGs) compared to HNOCA datasets (Extended Data Fig. 3i), reflecting higher transcriptional fidelity and closer alignment with primary counterparts in the HBDCA35. To date, no comprehensive region-wide analysis has been conducted on glial cells derived from organoids. However, the HBDCA revealed strong region specificity in the glial lineage during early brain development, which may be particularly relevant for H3.3K27M-altered DMG in the brainstem pontine region. Projection of the BrO datasets onto the HBDCA latent space (Extended Data Fig. 3j,k) and comparison to organoid protocols embedded in the HNCOA revealed significant coverage of glial clusters in BrOs. Notably, 13 of the 19 gained clusters exhibited pontine and medulla-specific identities (Fig. 1i,j and Extended Data Fig. 3j,k). Thus, our newly generated BrO model offers an experimental framework for studying gliogenesis within the context of pontine medulla regionality, offering relevance for DMG modeling.
We next investigated whether BrOs could be exploited to model DMG tumors. Plasmids11 expressing the most common H3.3K27M-defining DMG mutation39, alongside typical accompanying and pons-specific tumor suppressor TP53 and platelet-derived growth factor A (PDGFRA) alterations3,40,41, were introduced using in situ electroporation of developing BrOs (Fig. 1a). This mutation cocktail has been shown to be time sensitive in in utero electroporation mouse models9,11,42; hence, we tested different time points of electroporation between days 11 and 28. We identified day 11 as the time point most efficiently inducing tumorigenic growth (Fig. 2a and Extended Data Fig. 4a), reinforcing the concept of a restricted early developmental time window for DMG transformation9,11. At this stage of development, we observed a dominance of radial glia and neuroepithelial stem-like cells in BrOs (Fig. 1f), aligning with earlier work identifying neural stem cells as a permissive cell state for H3.3K27M-driven neoplastic transformation9,11,12,13,14. Tracking tumor growth over 2 months showed that the resulting tumors display infiltrative growth (Fig. 2b). In contrast, the use of empty control plasmids resulted in only a few localized electroporated cells (Extended Data Fig. 4b). Whole-organoid 3D imaging at week 16 (4 months after electroporation) with tumors color-coded for invasion depth further confirmed a diffuse growth pattern characteristic of DMG (Fig. 2c). In addition, DMGOs orthotopically transplanted in immunodeficient mice were able to progress in vivo, demonstrating invasive growth (Extended Data Fig. 4c). Quantification of H3.3K27M expression, combined with dominant-negative TP53 (DNp53) and PDGFRA-D842V at the protein level, showed incorporation of all three mutations into the majority of GFP-positive cells (Fig. 2d–f). These findings illustrate DMG invasive outgrowth in our guided brain organoids dependent on combined common driver mutations typically observed.
a, Stacked bar plot quantifying electroporation efficiency (light-gray columns; day 11 versus day 14, P = 0.782) and tumor induction (dark-gray columns; day 11 versus day 14, P = 0.010) in brainstem organoids tested at various time points ranging from day 11 to day 28. NS, not significant; **P < 0.01, according to a two-tailed independent t-test. Data are shown as the mean ± s.e.m. (n = 139 BrOs in total with 23–35 BrOs per time point; details in Supplementary Table 1). b, Tumorigenic outgrowth of the same DMGO at weeks 4, 6 and 8. Representative images of n = 3 organoids. Scale bars, 500 µm. White arrowheads depict invasive and diffuse patterns. c, Representative immunofluorescence 3D image of intact DMGOs with GFP signal color-coded for z depth on a rainbow scale. The gray outline was created by masking of propidium iodide fluorescence (n = 2 DMGOs). Scale bar, 500 µm. d,e, Representative multispectral 3D images of tumor GFP (green), H3K27M (magenta) and DNp53 (yellow) (d) or tumor GFP (green) and PDGFRA (red) (e) in consecutive slices of a week 8 DMGO (n = 3 DMGOs). Scale bars, 50 µm. f, Percentage of GFP+ tumor cells expressing H3K27M, DNp53 or PDGFRA detected by multispectral 3D imaging as in d,e (n = 2 DMGOs with n = 3 ROIs imaged per DMGO). g, Methylation profile of DMGO compared to DMG or resembling tumor types. Each dot represents one patient sample. GBM, glioblastoma; EPN, ependymoma; tSNE, t-distributed stochastic neighbor embedding. For DMGO, the dot represents a pooled sample of n = 3 DMGOs. h, Integrated Force Atlas representation of DMGO tumors colored by tumor cell state (n = 14 DMGOs from four independent batches. i, Heat map representation of average transcriptomic similarity between DMGO tumor cells and in vitro and in vivo models (cell lines and PDXs) and H3K27-altered DMG, GBM and PFA1/2, H3K27M/EZHIP-mutant patient samples. The average similarity (color intensity) represents an averaged prediction score of all DMGO subsetted tumor cells mapped into a merged dataset consisting of transcriptomic model-derived and patient datasets6,7,8 (n = 14 DMGOs from four independent batches).
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To further assess the representability of our in vitro grown tumor model (DMGO), we conducted histological comparisons to patient samples sharing the same mutational profile. This showed that H3.3K27M cells (H3K27M+) display loss in H3K27 trimethylation (H3K27me3) in both patient samples and DMGOs (Extended Data Fig. 4d,e), a hallmark of H3K27-altered DMG1,39. Furthermore, our in vitro grown tumors exhibited a global methylation profile closely resembling DMG, distinguishing our tumors from glioblastoma and posterior fossa (PFA1 and PFA2) epyndomas, which present with a similar loss of H3K27M trimethylation caused by H3K27M substitution or EZHIP overexpression, respectively43 (Fig. 2g). We next conducted scRNA-seq profiling of sorted GFP+ tumor cells and, after quality control filtering, analyzed approximately 7,000 cells from 14 DMGOs (Fig. 2h, Extended Data Fig. 5a,b and Supplementary Table 4). The malignant state of these cells was further supported by the analysis of inferred copy-number variation (iCNV) from scRNA-seq data, which showed large-scale amplifications and deletions in these cells compared to healthy cells, including losses of chromosomes 10 and 13 and a gain of chromosome 19q (Extended Data Fig. 5c). Using published DMG references6,8, we first annotated cancer cell states previously described for DMG, including OPC-like, AC-like and MES-like cell states and a population of cycling cells. In line with the early developmental window of our model, we identified only few cells with a more mature OC-like phenotype. Importantly, we identified a major proportion of OPC-like tumor cells that resembled recently defined OPC-like 2 and 3 states, both described as pediatric and pons-specific pre-OPC states8 (Fig. 2h and Extended Data Fig. 5d–f). Furthermore, we found the highest similarity score between DMGOs and primary DMG patient material6, as opposed to cell lines, patient-derived xenografts (PDXs) and material from patients with glioblastoma6 or both PFA subtypes44 (Fig. 2i). Together, this highlights the ability of DMGOs to closely resemble primary DMG tumors.
We investigated the mechanisms driving tumorigenesis to identify the attributes of BrOs that appear to be critical for supporting the growth of DMG tumors. We used TrackerSeq, a PiggyBac-based genetic lineage-tracing approach (Extended Data Fig. 6a), and analyzed cancer clone dynamics at 2 months after electroporation. We retrieved 167 unique barcodes from six DMGOs and two healthy BrOs (Extended Data Fig. 6b–h and Supplementary Table 5) and detected individual clones spanning up to approximately 800 cells per barcode, indicative of cancerous transformation (Extended Data Fig. 6i,j). By comparing large versus small, traced clones (Fig. 3a,b) through DEG and METASCAPE analysis, we identified glial specification as a critical feature driving cancer clone expansion in contrast to neuronal specification enriched in smaller clones (for example, synapse organization and modulation of chemical synaptic transmission) (Fig. 3a,b). Larger clones were characterized by higher gene expression of OLIG1, a canonical OPC marker, as well as IER2, JUNB, FOS and EGR1, previously described as key markers of the OPC-like 3 pre-OPC state8. Interestingly, we also identified a higher expression of AQP1, an aquaporin previously shown to be exclusive to ACs in the human brainstem45. Furthermore, analysis of patient data7 revealed AQP1 expression in tumors located in the pons but not in those arising from the cortex or thalamic regions (Extended Data Fig. 6k). These data hint toward a glial-specific tumorigenic process that is, furthermore, dependent on pontine location. This is further illustrated by genes upregulated in large DMG tumor clones mapping back to the glial lineage of BrOs (Fig. 3c), indicating that tumorigenesis is dependent on gliogenesis. To confirm this experimentally, we performed in situ electroporation of our mutation cocktail in unguided cerebral organoids, revealing a reduction in tumor induction (Fig. 3d). In addition, the outgrowth was nondiffuse, with almost no GFP-positive tumorigenic cells carrying the H3.3K27M substitution (Fig. 3e,f). These findings demonstrate that H3.3K27M-driven tumorigenesis depends on the correct anatomical cell identity, which our BrO model recapitulates. Consensus non-negative matrix factorization (cNMF) (Fig. 3g and Extended Data Fig. 6l,m) and lineage relationship analysis identified malignant metagene programs 1 and 2 to be present in the highest number of clones (30 and 26 of 34 clones, respectively; Fig. 3h) and belonging to the OPC-like lineage, emphasizing the central role of this lineage in H3K27M DMG tumorigenesis8. More specifically, we show overlap with the pre-OPC state, OPC-like 2 (Extended Data Fig. 6m). In the context of human early gestation, regionally distinct gene signatures for the glial lineage have been suggested to underlie the strong region-specific occurrence pattern of glial-related diseases, such as DMG35. In line with this, both programs 1 and 2 specifically enrich for the hindbrain pons OC precursor lineage35, as opposed to midbrain and forebrain lineages (Fig. 3i). Collectively, these findings highlight the role of pons glial specification, captured in BrOs, in driving DMG tumorigenesis, emphasizing the need for spatial and developmental precision in modeling DMG and establishing a human-relevant experimental system for therapeutic testing.
a, Volcano plot showing top DEGs in larger and smaller clones. b, METASCAPE results showing selected GO terms from the highest-scoring summary GO terms for small and large clones. c, Presence of large (red) and small (blue) clones in the integrated UMAP representation of developing BrOs, showing a preference for gliogenesis and neurogenesis, respectively. For a–c, n = 14 DMGOs from four independent batches. d, Bar plot quantifying electroporation efficacy (light-gray columns; guided versus unguided, P = 0.342) and tumor induction (dark-gray columns; guided versus unguided, P = 0.023) for guided brainstem organoids as compared to unguided neural organoids at day 11. *P < 0.05, according to a two-tailed independent t-test. Data are shown as the mean ± s.e.m. (n = 35 organoids from three independent experiments per condition; details in Supplementary Table 1). e, Representative images of tumorigenic outgrowth (GFP, green) at weeks 4 and 8 for unguided neural organoids (n = 35 organoids from three independent batches). Scale bars, 500 µm. f, Representative multispectral 3D images of tumor GFP (green), H3K27M (magenta) and DNp53 (yellow) in unguided neural organoids (n = 2 organoids). g, UMAP of traced DMGO cells, colored by their respective highest-scoring cNMF program. h, UpSet plot displaying clonal intersection events. Only clonal families found in more than one cNMF module are depicted and filtered with at least three cells present per unique barcode. Bar plots depict the frequency of each lineage combination (top) and the number of clones that contain each program (left). Coloring of dots matches the cNMF program annotation as in g. i, Heat map presenting the mean cellular enrichment scores of cNMF programs 1 and 2 for forebrain, midbrain and hindbrain or pons oligo lineage signatures in HDBCA35. For g–i, n = 8 DMGOs from three independent batches.
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Given the relevant tumor progression observed in DMGOs, we evaluated their potential as a human in vitro platform for preclinical testing of GD2 CAR T cells (Fig. 1a), motivated by promising yet variable treatment outcomes in a recent first clinical trial in patients with H3K27M-mutant DMG24,25. By exposing untransformed BrOs to GD2 CAR T cells, we first visually inspected with brightfield imaging that the presence of GD2 CAR T cells did not affect the general health of the model (Extended Data Fig. 7a). Next, we confirmed GD2 target expression in DMGO (Extended Data Fig. 7b) and tumor cell killing through confocal imaging of cleaved caspase 3 in GFP+ tumor cells (Fig. 4a). Having established these experimental preconditions, we treated DMGOs 4 months after tumor induction by administrating CD8+ GD2 CAR T cells on days 0 and 7 and monitored T cell activation, measured by interferon-γ (IFNγ) secretion (Extended Data Fig. 7c) and tumor control (Extended Data Fig. 7d,e) over time. Similar to heterogeneous outcomes reported in individuals24,25, we observed an overall partial reduction in tumor burden (Fig. 4b) and heterogeneous response rates over time and between individual DMGOs (Extended Data Fig. 7d,e). As GD2 CAR T cell activation was evident by a robust IFNγ response for all treated DMGOs (Extended Data Fig. 7c), limited response profiles (for example, DMGO179) are unlikely to result from a lack of antigen recognition. Therapy effects could be detected after >1 month of treatment (Fig. 4c), offering advantages for modeling CAR T cell functionality in vitro in a manner that is representative of T cell states at the tumor site in vivo, including potential exhaustion profiles associated with prolonged tumor exposure. To test our model for this purpose, we sequenced over 20,000 GD2 CAR T cells retrieved from DMGOs, as well as unexposed GD2 CAR T cells (Supplementary Table 6). This revealed a substantial level of heterogeneity induced upon DMGO exposure (Fig. 4d). In GD2 CAR T cells retrieved from DMGOs, we identified nine transcriptional states (Fig. 4e) that, on the basis of a combined interrogation of curated gene signatures (Extended Data Fig. 8a), DEGs, DEG-associated Gene Ontology (GO) terms (Extended Data Fig. 8b–f), expression of canonical immune effector (Fig. 4f) and exhaustion markers (Fig. 4g) and comparison to a pan-cancer tumor-infiltrating lymphocyte (TIL) dataset including brain malignancies46 (Extended Data Fig. 8g), reflected different T cell activation, differentiation and effector states. For instance, we identified a GD2 CAR T cell population that, albeit activated (on the basis of HLA gene expression) (Extended Data Fig. 8a), does not fully differentiate toward effector function (undifferentiated; TUND) (Extended Data Fig. 8b,h), as well as an IL-2-responsive population (TIL-2) (Extended Data Fig. 8c,i), probably differentiating into effector T cells (Extended Data Fig. 8i). In addition, we observed an interferon-stimulated gene (ISG)-expressing population (TISG) (Extended Data Fig. 8a), corresponding to ISG-expressing TILs46 (Extended Data Fig. 8j) and considered as an interferon-induced activation state47,48. Other clusters included a CAR T cell population with migrating properties and interconnectivity that appeared to be influenced by its neuronal environment (Extended Data Fig. 8d), as well as proliferating (TPR) (Extended Data Fig. 8e) and metabolically stressed T cells (TMS) (Extended Data Fig. 8a,f). Importantly, we distinguished potential DMG-targeting effector T cell populations on the basis of their cytotoxic profile (Fig. 4f) and putative level of exhaustion (Fig. 4g). While one of these clusters predominantly expressed GZMK (TGZK), cytotoxic T cells (TCYT) expressed GZMB, PRF1 and IFNG (Fig. 4f). In contrast, exhausted T cells (TEX) displayed reduced IFNG and concomitant expression of immune checkpoint genes, LAG3, HAVCR2, TIGIT (ref. 49) and SELPLG50, as well as the transcriptional repressor PRDM1 associated with exhaustion51 (Fig. 4g). Weekly CAR T cell administration (days 0 and 7) did not improve TEX reduction or TCYT enrichment over a single dose (Extended Data Fig. 9a), indicating that exhaustion may set on as early as day 7.
a, Representative multispectral 3D imaging of GD2 CAR T cells (CD3; cyan), DMG tumor cells (GFP; green) and cleaved caspase 3 (cCasp3; red) in DMGOs (n = 2 DMGOs). Scale bar, 5 µm. b, GD2 CAR T cell treatment outcome measured as a relative change in tumor GFP intensity quantified by imaging compared to the start of treatment (100%). DMGOs were left untreated (gray line; n = 1 DMGO) or treated with mock-transduced T cells (black line; n = 2) or GD2 CAR T cells (orange line; n = 4 DMGOs); for each treatment condition, a smoothed trend line of the averaged values at different time points was plotted using the locally estimated scatter plot smoothing algorithm. Arrows indicate the time points of T cell administration. c, Representative images of the tumor GFP signal at the indicated time points for a DMGO subjected to prolonged GD2 CAR T cell treatment administrated on day 0, day 8 and day 15 (n = 1 DMGO). d, Sankey plot illustrating the shift in the relative proportions of unbiasedly identified GD2 CAR T cell clusters before and after DMGO exposure. e, UMAP visualization of annotated GD2 CAR T cell clusters. f, Cytotoxic effector molecule and cytokine gene expression across the GD2 CAR T cell clusters. g, Gene expression of selected exhaustion-associated receptors, ligands and transcription factors across the GD2 CAR T cell clusters. f,g, Dot plot representing the percentage of cells expressing selected genes. The color intensity represents the average scaled gene expression. h,i, Heat map depicting the relative expression of exhaustion markers (h) and exhaustion-associated transcription factors and functional regulators (i) in nonexposed (left) and DMGO-exposed (right) GD2 CAR T cells within the TEX cluster. TF, transcription factor. j, Super-engager signature score on a blue-to-red color scale, showing the enrichment of a previously identified T cell serial killer gene set60 atop UMAP cell embeddings of the GD2 CAR T cell dataset. The dashed outline annotates the embedding of the TCYT GD2 CAR T cell cluster. For d–j, GD2 CAR T cells retrieved from n = 4 treated DMGOs and n = 2 independent batches of unexposed GD2 CAR T cells. k, Dot chart depicting the fold enrichment in tumor killing by NCAM1+ GD2 CAR T cells over NCAM1− GD2 CAR T cells quantified as the change in tumor area detected by GFP compared to the start of treatment (n = 2 DMGOs per treatment condition). l, Percentage of cells per TCYT, TEX and THS cluster for NCAM1− GD2 CAR T cells (left; retrieved from n = 2 DMGOs) and NCAM1+ GD2 CAR T cells (right; retrieved from n = 2 DMGOs).
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To confirm that exhaustion detected in our DMGO model reflects representative T cell exhaustion at the tumor site, we compared the TEX phenotype present upon DMGO exposure to preexposure GD2 CAR T cells that, although alleviated by the 4-1BB endodomain, can still display exhaustion features resulting from tonic signaling52. Indeed, a fraction of preexposure GD2 CAR T cells overlapped with our TEX cluster detected upon DMGO exposure (Extended Data Fig. 9b,c). However, separating the cells in this cluster according to experimental condition (Extended Data Fig. 9c) revealed that DMGO-exposed TEX upregulated a wide array of additional exhaustion markers (Fig. 4h), as well as known transcription factors and functional modulators of exhaustion (Fig. 4i) that include those described in cancer patients across TIL datasets (Supplementary Table 7). In addition, overlap with exhaustion markers found in the antigen-driven lymphocytic choriomeningitis virus mouse model of chronic infection53,54, as well as an in vitro model of CAR T cell dysfunction based on continuous antigen exposure55, demonstrates that the observed exhaustion profile is antigen driven (Supplementary Table 7). For in vitro model systems, this has not been achieved in the context of naturally expressed tumor antigen, only through persistent anti-CD3 and anti-CD28 antibody stimulation56 or by using repeated rounds of stimulation with antigen- pulsed57 or overexpressing58 tumor cell lines55. Thus, DMGOs model the functional heterogeneity of CAR T cells, including representative T cell functional exhaustion, an actionable axis for improving outcomes59 and, therefore, critical factor to evaluate preclinically.
Consistent with their potent cytotoxicity and lack of exhaustion, the TCYT population overlaps with the ‘killer' gene signature of ‘super-engager' engineered T cells that we recently identified to have profound tumor-targeting capacity and serial killing behavior in a short-term coculture assay60 (Fig. 4j). As we previously identified NCAM1 as a selection marker to enrich for this population60, we exploited this strategy (Fig. 1a) to further investigate the relevance of this CAR T cell functional profile in a prolonged treatment setting. We sorted GD2 CAR T cells on the basis of NCAM1 expression before DMGO treatment (Extended Data Fig. 9d) and compared tumor control between NCAM1+ and NCAM1− cells (Fig. 4k and Extended Data Fig. 9e). This demonstrated the initial potent antitumor activity of NCAM1+ GD2 CAR T cells, with a 1.4-fold enrichment in tumor control over NCAM1− GD2 CAR T cells on day 2. However, this enhanced potency stabilized between days 5 and 7, with NCAM1− T cells displaying more gradual antitumor activity over time, slightly outperforming NCAM1+ cells by day 7 (Fig. 4k), in line with a higher recovery of NCAM1− cells at day 14 (Extended Data Fig. 9f). To gain insight into potential transcriptomic profiles explaining these differential outcomes, we performed scRNA-seq of NCAM1− and NCAM1+ GD2 CAR T cells and mapped them back to our previously identified GD2 CAR T cell signatures (Extended Data Fig. 9g). This revealed an additional stressed GD2 CAR T cell cluster specific to NCAM1− cells (THS) (Fig. 4l and Extended Data Fig. 9h) that differed from the TMS cluster through expression of heat-shock proteins (Supplementary Table 8) and overlapped with the stress response state identified in TILs that associates with immunotherapy resistance46 (Extended Data Fig. 9i). Further aligning with the initially enhanced tumor control observed (Fig. 4k), NCAM1+ cells showed a 3.3-fold enrichment in TCYT compared to NCAM1− cells (Fig. 4l). However, in line with poor persistence of the cells (Extended Data Fig. 9f), NCAM1+ T cells were additionally enriched for TEX (Fig. 4l), explaining their reduced performance over time (Fig. 4k). Together, this identified NCAM1+ cells as a potent tumor-targeting, yet short-lived effector GD2 CAR T cell population and offers proof of concept for cell selection as a means to narrow CAR T cell functional heterogeneity before administration.
The upregulation of features associated with tissue residency48, including the canonical marker CD103 (ITGAE) used to identify tissue-resident T cells61,62 (Fig. 5a and Supplementary Table 7), underscores the capacity of DMGOs to model T cell performance within tissue. While this may inform strategies to enhance CAR T cell trafficking and tissue residency63, DMGOs lack the myeloid compartment, a key regulator of T cell responses. Therefore, to enhance the complexity of DMGOs, we incorporated microglia, a main component of the DMG tumor microenvironment8. We generated primitive macrophage progenitors (PMPs) from hES cells, previously shown to differentiate into mature microglia in mouse brains64 and human midbrain organoids65, as well as in coculture with neurons66. PMPs similarly integrated into BrOs and, within 7 days, adopted the ramified morphology characteristic of homeostatic microglia67 (Fig. 5b,c). Confirming functional maturation, the cells displayed typical microglia behavior, migrating to sites of myelin injection (Fig. 5d and Supplementary Video 1) and removing myelin through phagocytosis68 (Fig. 5e and Supplementary Video 2). Furthermore, 3 weeks after incorporation in BrOs, above 80% of cells expressed the microglia-specific marker P2RY12 at the protein level (Fig. 5f,g) and scRNA-seq analysis (Supplementary Table 9) demonstrated increased expression of microglia-specific transcription factors69,70 (Fig. 5h). Additionally, they resembled an adult state when referenced against microglia developmental programs identified in mice71 (Fig. 5i), further validating microglia maturation. Comparison to a myeloid cell reference dataset from DMG tumors72 confirmed microglia as opposed to macrophage identity (Fig. 5j).
a, Gene expression of tissue-resident markers in nonexposed (top; n = 2 independent batches of unexposed GD2 CAR T cells) and DMGO-exposed (bottom; retrieved from n = 4 DMGOs) GD2 CAR T cells within the TEX cluster. Dot plot representing the percentage of cells expressing selected genes. The color intensity represents the average scaled gene expression. b, Schematic overview of PMP integration in BrOs and DMGOs and treatment with GD2 CAR T cells. c, Representative brightfield images of BrOs for mScarlet+ PMPs (white) 3 or 7 days after integration (n = 19 BrOs). Right, zoomed-in view of area in white insets. Scale bars, 500 µm (main image) and 50 µm (inset). d,e, Live 3D imaging of microglia (orange) and CFSE-labeled myelin debris (green), showing homing of microglia to sites of myelin debris injection (d) and phagocytosis of myelin debris (e) (n = 2 BrOs). Scale bars, 50 µm (d) or 10 µm (e). f, Immunofluorescence 2D images of BrO with microglia integrated for 3 weeks, labeled for DAPI (white), IBA1 (magenta) and P2RY12 (cyan) (n = 1 BrO). Scale bar, 50 µm. g, Quantification of percentage of P2RY12+ cells of total IBA1+ microglia in a BrO slice (n = 1 BrO). h, Heat map depicting the relative expression of microglia-associated transcription factors in PMPs (left) and BrO-derived microglia (right) 3 weeks after integration. i, Heat map depicting representation of microglia developmental stages71 in PMP or microglia derived from BrOs or DMGOs. j, Violin plot showing the expression level of microglia and macrophage gene signatures72 in PMP (left) and microglia derived from BrO (right). Statistical analysis was performed using a two-tailed t-test (microglia, P = 9.4 × 10−42; macrophage, P = 8.6 × 10−10). k, Violin plots showing expression levels of DMG-associated microglia states72 in microglia derived from BrO (blue) or DMGO (green). l, Dot plot showing the relative expression of selected chemokines and genes associated with immunosuppression72 in microglia derived from BrO (left) or DMGO (right). For h–l, microglia were sorted from n = 9 organoids in total (n = 5 BrOs and n = 4 DMGOs) and unexposed PMPs from n = 2 independent experiments (details in Supplementary Table 1).
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Microglia incorporation in tumor-bearing DMGOs led to the acquisition of recently described DMG-associated functional phenotypes72, including an IFN-activated, phago lipid and hypoxic state (Fig. 5k). Moreover, compared to BrOs, microglia from DMGOs showed enrichment of GO terms related to antigen presentation and immune responses, such as peptide processing mediated by major histocompatibility complex class II and type I IFN response, previously described as upregulated in DMG-associated microglia and macrophages73 (Extended Data Fig. 10a). These DMG-specific microglia states were accompanied by reduced chemokine expression and upregulation of genes associated with an immunosuppressive profile, in line with patient data72 (Fig. 5l). This was confirmed by protein expression of CD163, associated with an anti-inflammatory state, and SPP1, associated with immunosuppressive lipid-laden macrophages74 (Extended Data Fig. 10b,c). Together, these findings show that, within an appropriate neuronal environment, PMPs differentiate into mature microglia that, in the presence, of DMG tumor cells adopt a DMG-specific immunosuppressive phenotype.
Correlative clinical data suggest that expansion of the immunosuppressive myeloid compartment may be associated with poor GD2 CAR T cell outcomes25 and myeloid cells, including microglia, are also implicated in CAR T cell-induced toxicity75. To address this experimentally, we performed GD2 CAR T cell treatment in DMGOs with integrated microglia. Confocal imaging showed interactions between GD2 CAR T cells and microglia within tumors (Fig. 6a). Moreover, we observed increased cytokine secretion in the presence of both GD2 CAR T cells and integrated microglia (Fig. 6b). This included upregulated chemokines related to myeloid cell chemotaxis, including MCP3 and CXCL1, as well as myeloid-cell-associated growth factors, such as macrophage colony-stimulating factor (M-CSF). We also observed elevated interleukin (IL)-1α and IL-6 levels, key proinflammatory cytokines linked to CAR T cell (neuro)toxicity and clinically targeted to manage adverse effect24, suggesting that microglia-integrated DMGOs may serve as a relevant model to study CAR T cell–microglia interactions underlying treatment-related toxicity. Furthermore, analysis of DMGO-induced CAR T cell transcriptional heterogeneity in the presence of microglia (Extended Data Fig. 10d and Fig. 6c), showed an increased proportion of the exhausted cluster and identified a microglia-affected GD2 CAR T cell population (TMA), aligning with undifferentiated TILs, as well as naive and tissue-resident memory cells, from the pan-cancer TIL atlas46 (Extended Data Fig. 10e). To validate the low effector profile of the TMA population, we compared curated gene signatures from the same resource46 across GD2 CAR T cell clusters (Fig. 6d and Extended Data Fig. 10f). TMA cells showed reduced activation and effector signatures, including cytotoxicity, but higher senescence-related genes. Thus, the presence of microglia shifts the transcriptional profile of GD2 CAR T cells toward reduced effector function. In line with this, when we monitored CAR T cell-mediated tumor control, it was reduced in integrated-microglia DMGOs (Fig. 6e). Together, these findings demonstrated that microglia integrated in DMGOs yield a suitable representative phenotype for probing CAR T cell function and toxicity. This establishes a direct role for microglia in shaping CAR T cell functional states and impairing tumor control.
a, Representative immunofluorescence 3D images of a 200-µm-thick slice containing microglia, 1 week after start of GD2 CAR T cell treatment. Cells are labeled for DAPI (white), GFP+ DMG tumor cells (green), IBA1+ microglia (orange), CD3+ T cells (cyan) and cCasp3 (red). n = 2 DMGOs. Bottom, zoomed-in view of area in white inset (n = 2 DMGOs). Scale bar, 10 µm. b, Heat map depicting the fold change in concentration of selected cytokines, chemokines and growth factors of DMGOs containing microglia normalized against no microglia on day 3, day 7 and day 14 after GD2 CAR T cell addition (n = 6 DMGOs). TNF, tumor necrosis factor. c, Percentage of cells within GD2 CAR T cell clusters, including a new microglia-affected cluster, for nonexposed GD2 CAR T cells (left), GD2 CAR T cells retrieved from DMGO without (middle) or with integrated microglia (right). d, Heat map highlighting the average scaled expression of curated TIL gene signatures46 in the TMA GD2 CAR T cell cluster. e, Reduction in tumor area (normalized z score per DMGO relative to time point 0) after the addition of GD2 CAR T cells in DMGO without (blue) or with (orange) integrated microglia. The arrow indicates the time point of GD2 CAR T cell administration. Data are shown as the mean ± s.e.m. Statistical analysis at each time point was performed using a linear mixed-effects model, accounting for experimental and organoid variation. Reported P values are two-sided and were adjusted for multiple comparisons using the false discovery rate (Benjamini–Hochberg) (t3, P = 0.04389; t7, P = 0.04389; t10, P = 0.08409; t14, P = 0.0578). For b–e, n = 6 DMGOs with microglia and n = 6 DMGOs without microglia from four independent batches.
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Here, we showed that morphogen-guided patterning with FGF4 and RA produces BrOs, characterized across region-specific neuronal and glial lineages through benchmarking against recent single-cell organoid and brain atlases34,35,36. BrOs enable spatial and temporal modeling of the developing brainstem, including pons-specific features, the regional origin and niche for H3.3K27M-altered DMG. We demonstrated an interplay between the H3.3K27M substitution and pontine glial fate in driving DMG tumorigenesis, resulting in an experimentally accessible organoid model that recapitulates features of DMG tumors. While DMG patient-derived organoids are emerging as platforms for drug testing60,76,77, our model offers a complementary approach to generate in vitro tumors for this rare and fatal disease, for which tissue samples are limited. Moreover, the use of iPS cells as a cell source establishes the potential for individualized modeling, supporting personalized drug evaluation and direct comparison to clinical outcomes. However, because the model is derived from hES cells and iPS cells, it is limited in recapitulating postnatal tissue, as reported for other neural organoids34,78. Furthermore, the current model does not capture complex intraregional interactions, which are particularly relevant in the pons—a key relay between the forebrain and motor or sensory pathways. Assembloid methodologies79,80, such as linking cortical organoids with BrOs and DMGOs, could improve neuronal health and lineage diversity while enabling modeling of DMG invasion and progression across brain regions in response to neural secretion18,81 and activity17,19,20,82. Such neuronal interplay should be further characterized in DMGOs in the future to validate the model for these critical processes, for instance, through live calcium imaging of synaptic signaling or retrograde labeling of GABAergic neurons using viral tracers17.
Despite current limitations, the model provides a therapeutically relevant platform to interrogate CAR T cell function in DMG tissue-specific context. Prolonged treatment of DMGOs reflects the variable outcomes seen in individuals24,25,83, revealing CAR T cell heterogeneity and functional exhaustion. From this heterogeneity, we identified the most potent yet short-lived CAR T cell population and validated a means to enrich for these cells, offering a potential approach to optimize therapy composition84. This model could also be leveraged to uncover how CAR T cells modulate cancer cell states and reveal mechanisms of acquired resistance that may be cotargeted to improve clinical efficacy.
Given the recognition that the tumor microenvironment can significantly impact treatment response, we integrated microglia, a key immune component in DMG70. In line with representative tumor cell states observed in DMGOs, microglia differentiated into DMG-specific and immunosuppressive profiles72. This enabled an experimental interrogation of microglia impact on CAR T cell functionality, revealing increased exhaustion and a TMA population, marked by stalled differentiation and low effector function. This shift toward dysfunction correlated with reduced tumor control, offering a framework to counteract microglia-induced resistance and enhance antitumor efficacy. While T cell exhaustion might be addressed through immune checkpoint inhibition, strategies targeting the newly identified TMA population require further investigation. Our imaging data revealing direct microglia–CAR T cell interactions, suggest that dissecting the underlying signaling involved could be a critical starting point. Furthermore, similar approaches could be used to assess microglial influence on tumor phenotypes, as prior studies linked MES tumor states to tumor-associated macrophages8.
Altogether, we generated a human brainstem organoid model for DMG with applications toward understanding CAR T cell functionality in the context of the tumor microenvironment that could aid further therapy development for this detrimental disease.
All murine experiments were conducted in compliance with the Animal Welfare Body of the Princess Máxima Center for Pediatric Oncology based on local and international regulations under CCD license AVD39900 202216507. For the use of DMG samples, patients and/or their parents or guardians provided written informed consent according to national laws and in agreement with the declaration of Helsinki (2013). This study was approved by the Institutional Review Board (IVB) and registered under national registry number 2020.142.
Brain organoids were generated from three different cell lines encompassing H9 (WA09, WiCell) and H1 (WA01, WiCell) hES cells (both derived from human blastocysts85) and C7-a iPS cells (RUID 06C52463, derived from CD4+ T cells). The iPS cell line C7-a was obtained from Rutgers University Cell and DNA Repository and contains a Cre-inducible H3.3K27M reading frame in the endogenous H3F3A locus13. Cell lines were cultured in mTeSR Plus medium (StemCell Technologies, 100-0276) and incubated at 37 °C with 5% CO2. The cells were grown on Matrigel-coated (Corning, 354277) six-well plates and passaged when 70–80% confluent by nonenzymatic detachment of colonies using Gentle Cell Dissociation Reagent (GCDR) (StemCell Technologies, 100-0485). All cell cultures were routinely tested for the presence of Mycoplasma species.
Cells were washed with 1× Dubecco's PBS (Gibco, 14190144), detached with GCDR and spun down at 300g for 5 min, before resuspending in base medium (1:1 advanced DMEM/F-12 medium (Gibco, 12634010) and Neurobasal medium (Gibco, 10888022), supplemented with 1× GlutaMax (Gibco, 35050061)) and counting. A total of 70,000 cells per ml were added to day 0 medium (base medium, 10 µM Y-27632 (ROCKi, AbMole BioScience, M1817) and 4 ng ml−1 FGF2 (PeproTech, 100-18 C)). For EB formation, 7,000 cells in 100 µl of medium were seeded per well of an ultralow-attachment treated U-bottom 96-well plate (Nexcelom, ULA96U020; PHC Europe, MS-9096UZ) and incubated at 37 °C with 5% CO2. From day 2 to day 21, patterning medium (base medium, 1× N2 (Gibco, 17502048) and 1 mg ml−1 heparin solution (StemCell Technologies, 07980)) was used.
In week 1, week 1 medium (patterning medium, 50 ng ml−1 FGF2, 1 µM dorsomorphin (DM; StemCell Technologies, 72102), 10 µM SB431542 (SB43; StemCell Technologies, 72232) and 3 µM CHIR99021 (CHIR; StemCell Technologies, 72052)) was used. On day 2, 100 µl of week 1 medium was added per well. On day 5, 100 µl of medium per well was replaced with fresh week 1 medium. In the second week, week 2 medium (patterning medium, 1 µM DM, 10 µM SB43, 3 µM CHIR, 10 ng ml−1 FGF4 (StemCell Technologies, Cat.#78103.1), 10 µM all-trans RA (StemCell Technologies, 72262) and 1 µM purmorphamine (PMA; StemCell Technologies, 72202) was used. On day 7, 190 µl of medium was replaced with fresh week 2 medium and, on day 9, 100 µl of medium was replaced. On day 11, EBs were embedded in 12 µl Matrigel droplets and five droplets were transferred to each well of a 12-well suspension plate (Greiner Bio-One,665102) with 1 ml of week 2 medium and incubated at 37 °C with 5% CO2. In week 3, week 3 medium (patterning medium, 10 ng ml−1 FGF4, 10 µM RA and 1 µM PMA) was used. Until day 21, the medium was refreshed every 2 days with week 3 medium. On day 17, the plates were placed on an orbital shaker inside a 5% CO2 incubator at 37 °C. From day 21 onward, the medium was refreshed every 2–3 days with maturation medium (1:1 advanced DMEM/F-12 medium and neurobasal medium, supplemented with 1× GlutaMax, 0.5× N2, 0.5× B27 without vitamin A (Gibco, 12587010) and 1× penicillin–streptomycin (Pen–Strep, Gibco, 15140122).
PCAGPbase, PBCAG_DNp53_IRES_luciferase, PBCAG_PDGFRA-D842V_IRES_eGFP and PBCAG_H3K27M_eGFP plasmids were used to induce tumor growth in hES cell-derived organoids. In iPS cell-derived organoids, the H3K27M-expressing plasmid was replaced with 1.00 µg µl−1 SSi-Cre. PCAGPbase and PB_Venus were used as a control. All plasmids were kindly provided by the T. N. Phoenix laboratory11. For genetic lineage tracing, 1.50 µg µl−1 TrackerSeq86 was added to the plasmid mix.
On day 11, unless stated otherwise, organoids were injected with a mixture of plasmid DNA (1.50 µg µl−1 per plasmid) and 0.1% (w/v) FastaGreen (Merck, F7252-5G) using a FemtoJet 4i (Eppendorf, 5252000013) with the following parameters: injection pressure, 15 hPa; compensation pressure, 5 hPa. Subsequently, electroporation was performed using a NEPA21 Super Electroporator (Nepagene) and CUY650P1 (Nepagene) tweezers with the following parameters: voltage, 50 V; pulse length, 10 ms; pulse interval, 50 ms; number of pulses, four; decay rate, 10%. Transfer pulse parameters were as follows: voltage, 20 V; pulse length, 50 ms; pulse interval, 50 ms; number of pulses, five; decay rate, 40%. Using the impedance (kΩ) measurement of the NEPA21 Super Electroporator, voltage was automatically readjusted to optimize cell perforation and viability per individual organoid. Electroporation was performed by applying a shock twice in orthogonal direction and organoids were incubated at 37 °C with 5% CO2 for at least 2 h to recover.
No statistical methods were used to predetermine sample sizes but they are close to those previously published87. NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice (The Jackson Laboratory, 005557) were housed at 45–65% humidity and 20.5–23.5 °C with a 12-h light–dark cycle, in specific-opportunist-pathogen-free conditions using individually ventilated cages and sterile food and water ad libitum. Ten 3–4-week-old male and female NSG mice were anesthetized using isoflurane/O2 inhalation and transferred to a stereotaxic frame. Eye ointment was applied and 0.05 mg kg−1 buprenorphine was injected subcutaneously. After removing hair from the surgical site, a 1-cm incision was made in the skin to expose the skull and 3 mg kg−1 lidocaine was applied topically. Under a stereo microscope, a Dremel was used to drill a circular groove of 5 mm in the skull above the right cerebral cortex. Cortex buffer was applied before the dura mater and 2 mm3 of brain tissue was removed to accommodate the DMGO transplant. DMGOs were preselected on the basis of GFP signal 1–2 weeks after electroporation and, if too big in size, cut in half before transplantation. After placing the DMGO, the brain was covered with a neuropatch, the skull was closed with dental cement and the wound was closed using skin glue. After surgery, 0.06 mg ml−1 carprofen was provided in the drinking water for 3–5 days and mice were monitored 2–3 times per week for signs of weight loss, lack of grooming and/or reduced mobility.
If mice reached the study (21 days) or humane endpoint according to the monitoring of clinical symptoms, they were put under deep anesthesia by intraperitoneal injection of 75 mg kg−1 ketamine and 1 mg kg−1 medetomidine. Transcardiac perfusion was performed with PBS and 4% paraformaldehyde and, after resection, brains were cut into 300-μm sections using a vibratome. Staining, clearing and imaging were performed as described below. Antibodies used are listed in Supplementary Table 10.
Organoids were fixed in 4% paraformaldehyde (Sigma-Aldrich, 441244) for 30 min at 4 °C, washed three times in PBST (1:1,000 Tween-20 in 1× PBS) for 15 min at 4 °C, embedded in 4% low-melting-point agarose (Invitrogen, 16520-050) and sliced into 100–250-µm sections using a Leica VT 1200 S vibratome. mLSR-3D was performed on the sliced organoids as described previously88. All combinations of primary and secondary antibodies used are listed in Supplementary Table 10. The slices were imaged using a Zeiss LSM 880 confocal microscope with a ×25 (numerical aperture (NA): 0.8) objective and Leica Stellaris with ×20 (NA: 0.75) and ×40 (NA: 1.3) objectives. Alternatively, intact organoids were fixed and cleared using the organic solvent-based vDISCO method89 and imaged using a Leica SP8 microscope with a ×16 (NA: 0.6) BABB-compatible objective.
Routine histopathology procedures were followed to obtain FFPE tissue for World Health Organization standardized tumor classification. Patient and organoid material was sliced into 3-µm sections before hematoxylin and eosin and subsequent stainings. Immunohistochemical staining was performed on the Leica BOND RX fully automated research stainer using the bond polymer refine detection kit (Leica, DS9800). Stained tissue sections were analyzed by an experienced neuropathologist.
The DNA methylation profile of a pooled DMGO sample consisting of three independent replicates was compared to cases of DMG, glioblastoma and PFA ependymoma obtained from published datasets90,91. Data were loaded in R (version 4.3.1), probe filtering was performed using package ChAMP92 and each array platform was processed separately (HumanMethylation450 or EPIC) using the ‘minfi' method93 and filtering out probes located on single-nucleotide polymorphisms or sex chromosomes or with detection P value > 0.01. Raw β values were merged using function combineArrays and normalized with method BMIQ94. In total, 10,000 probes with the highest s.d. were selected and the Pearson correlation between samples was calculated, weighted by the inverse of variance. This correlation matrix was used to compute a distance matrix, which served as the input for the Rtsne function from the Rtsne package.
Organoid FFPE sections were deparaffinized in xylene (three times, 3 min each) followed by rehydration in a graded alcohol series for 1 min each (100% twice, 95% twice and 70% once). Sections were washed in deionized water (two times, 1 min each) and put in target retrieval solution, pH 9 (Agilent Dako). Antigen retrieval was performed for 40 min at 95 °C. Sections were allowed to cool to room temperature and washed for 5 min in deionized water followed by storage in PBS until further use. Cyclical immunofluorescence imaging was performed as previously described95. All combinations of primary and secondary antibodies used are listed in Supplementary Table 10. Imaging was performed on a Leica DMi8 Thunder imaging system with an HC PL APO ×20 (NA: 0.80) objective. Images of each cycle were aligned based on DAPI signal using a previously developed tool (https://github.com/Dream3DLab/CycFluoCoreg). The resulting composite images were imported into QuPath (version 0.4.4)96, where nuclei were segmented using a cell expansion of 2.5 μm. An object classifier using RandomTrees was trained for each marker on two separate images. These object classifiers were combined into a composite classifier that was applied to all images. The resulting dataset containing the count of classified cells in each image was exported to R for quantification and visualization.
The detailed step-by-step approaches were deposited to the protocols.io repository (https://doi.org/10.17504/protocols.io.6qpvrwq13lmk/v1)97.
CD8 GD2 CAR T cells (14G2a GD2-4-1BBz CAR) and donor-matched mock-transduced CD8 T cells were produced as previously described98. CAR T cells and mock-transduced T cells were expanded using a rapid expansion protocol99 and cryopreserved after 14 days. T cells were thawed and rested in RPMI-1640 medium, supplemented with GlutaMax, 10% FBS (Thermo Fisher, 10500064), 1% Pen–Strep, 50 U per ml IL-2 (Miltenyi, 130-097-743), 2,000 U per ml IL-7 (Miltenyi, 130-095-367) and 50 U per ml IL-15 (Miltenyi, 130-095-760) for 3 days at 37 °C with 5% CO2. For selection of GD2 CAR T cells based on NCAM1 expression, a similar expansion protocol was used but without the addition of IL-15 and Daudi cells. After resting, cells were washed and stained for 30 min at 4 °C in flow cytometry (FC) buffer (1× PBS with 2% FBS) with live–dead fixable near-IR dead cell stain (1:1,000; Thermo Fisher), CD3–APC (1:80; BD BioLegend, clone SK7) and NCAM1–HiLyte-488 (1:200; QVQ, FSH-10B10). CD3+NCAM1− or CD3+NCAM1+ GD2 CAR T cells underwent fluorescence-activated cell sorting on a BD FACSAria II and were immediately used for experiments.
Firstly, 4 months after tumor induction, DMGOs were untreated or treated with 500,000 CD8+ GD2 CAR T cells or mock-transduced CD8+ T cells per DMGO added on days 0 and 7. For prolonged treatment, GD2 CAR T cells were administrated on days 0, 8 and 15. Tumor size was monitored by imaging using a Leica Thunder DMi8 microscope with a ×10 objective. After THUNDER software-mediated computational clearing of the imaging data, tumor size for each time point was quantified using Fiji. Background signal, defined as GFP-negative areas within the organoid, was subtracted. The organoid surface was set as the region of interest (ROI) and mean gray values of the GFP channel for the ROI were calculated. Supernatant of the cocultures was collected and IFNγ concentration was measured with ELISA (R&D Systems, DY285B). Untransformed BrOs were similarly treated and organoid appearance was monitored by brightfield imaging.
Firstly, 60 days after electroporation, a DMGO sample was dissected for the tumor region, mechanically dissociated and cultured for two additional weeks to expand tumor cells. Cells were retrieved from the culture plate using StemPro Accutase (Gibco, A1110501) and passed through a 70-µm Flowmi cell strainer (Merck, BAH136800070) to create a single-cell suspension. Dissociated cells were centrifuged at 500g for 5 min at 4 °C and resuspended and washed in FC buffer. Cells were either left unstained or stained with live–dead fixable near-IR dead cell stain (1:1,000; Thermo Fisher) and GD2–PE (1:200; clone 14.G2a, BD Biosciences, 562100) for 30 min at 4 °C. Cells were washed twice in FC buffer, acquired on a Sony SH800s (Sony Biotechnology) and analyzed using FlowJo software (version 10.9.0).
DMGOs treated with GD2 CAR T cells were dissociated and washed twice with PBS +/+ (Mg2+/Ca2+, 3% FBS). Cell suspensions were filtered using a 70-µm Flowmi cell strainer and stained in FC buffer with CD3–APC (1:80; BD Biosciences, clone SK7) and live–dead fixable near-IR dead cell stain (1:1000; Thermo Fisher) for 30 min at 4 °C. CD3+ T cells were sorted on a CytoFLEX SRT benchtop cell sorter (Beckman Coulter) and immediately processed for scRNA-seq.
Doublets were identified and removed using the scDblFinder package100, with default settings. Low-quality cells (>15% mitochondrial content, <200 or >6,500 genes or >35,000 reads) were removed. The Seurat (version 4)101 workflow was used to normalize and scale reads and 3,000 highly variable genes were determined. Cell-cycle confounding effects were eliminated by the removal of cell-cycle-related genes from the variable features of the dataset. Principal component analysis was performed using the ‘RunPCA' function. The first 30 principal components were used for nonlinear dimensionality reduction applying the UMAP102 method with the ‘RunUMAP' function of the Seurat package. Clustering analysis was performed using the Seurat package ‘FindNeighbors' and ‘FindClusters' functions. To identify subpopulations, marker genes for each cluster were determined through the ‘FindAllMarkers' function. Markers (adjusted P value < 0.05) were examined to profile genes associated with known CD8 T cell subsets, as well as project previously published signatures. In addition, DEGs were used as input for GO enrichment analysis using the GO resource (https://geneontology.org). To integrate three batches of NCAM1-selected cells, we applied the Seurat-based canonical correlation analysis integration method. As integration features, we used 1,000 variable features from each dataset, along with DEGs between conditions to account for biological variability. To assign cell populations to the clusters identified in Fig. 4e, we estimated the proportion of cells from these clusters for every cluster of the integrated dataset. Newly emerging populations were defined on the basis of differentially expressed markers and their origin, categorized by whether they originated from exposed, unexposed, NCAM1+ or NCAM1− populations. To determine the identity of the TMA cluster, we mapped our GD2 CAR T cell subsets to the CD8+ TIL resource dataset46 using Seurat's FindTransferAnchors(). The GD2 CAR T cell identities were then transferred to this dataset with TransferData(), retaining only high-confidence predictions (score > 0.5). These transferred identities were used to calculate the proportion of TMA GD2 CAR T cells within each CD8+ TIL subset.
To evaluate the expression of established T cell signatures, we used a gene signature specific to serial killer engineered T cells that we previously obtained60. Using the VISION R package103, we computed and visualized the overall enrichment of the identified gene set atop UMAP cell embeddings of our dataset. In addition, we projected our GD2 CAR T cell signatures onto a pan-cancer CD8 TIL atlas46 through T Cell Map (https://singlecell.mdanderson.org/TCM/) using the VISION package. For each GD2 CAR T cell subset, markers obtained through DEG analysis were filtered using an adjusted P value < 0.00001.
PMPs were generated using an adjusted protocol104. Briefly, 70–80% confluent H1 stem cells were detached with GCDR. For EB formation, 7,000 cells were plated per well of an ultralow-attachment treated U-bottom 96-well plate (Greiner Bio-One, 650970) in mTeSR+ (StemCell Technologies, 100-0276) medium, containing 50 μM ROCK inhibitor (Y-27632; AbMole, M1817), 50 ng ml−1 bone morphogenetic protein 4 (StemCell Technologies, 78211), 50 ng ml−1 VEGF (PeproTech, 100-20-100ug) and 20 ng ml−1 SCF (Miltenyi Biotec, 130-093-991). On day 2, fresh medium was added and, on day 4, EBs were transferred to a six-well plate with X-VIVO 15 medium (Lonza, BE02-060F), containing 1× GlutaMax (Gibco), 1× Pen–Strep (Gibco), 100 ng ml−1 M-CSF (PeproTech, 300-25-50ug) and 25 ng ml−1 IL-3 (PeproTech, AF-200-03-10ug). The medium was refreshed once a week. After ~3 weeks, the release of PMPs in the supernatant was observed. PMPs were collected and 100,000–200,000 cells were added per brain organoid in maturation medium (1:1 advanced DMEM/F-12 (Gibco) and Neurobasal (Thermo Fisher) medium, 1× GlutaMax, 0.5× N2 (Gibco), 0.5× B27 without vitamin A (Gibco) and 1× Pen–Strep). Organoids were kept on a microtiter orbital shaker inside a 37 °C 5% CO2 incubator for 1–3 weeks for PMP integration and differentiation. For CAR T cell treatment experiments, organoids were sectioned into 200-µm-thick slices using a vibratome, transferred to a 24-well suspension plate in 750 µl of maturation medium and incubated at 5% CO2 and 37 °C for 3 days. A total of 50,000–200,000 PMPs were added per slice in 750 µl of maturation medium in a 24-well suspension plate for 7 days before adding 200,000 CD8+ GD2 CAR T cells in 750 µl of maturation medium. Tumor size during treatment was monitored by imaging using a Leica DMIL LED FLUO microscope with a ×10 objective.
BrOs and DMGOs containing microglia and optionally treated with GD2 CAR T cells were dissociated 21 days after initial microglia incorporation as described above for the preparation of scRNA-seq and TrackerSeq libraries. Dissociated cells, control PMPs and unexposed GD2 CAR T cells were washed and stained in FC buffer with CD3–BV421 (1:100; BD Biosciences, clone SK7) and live–dead fixable near-IR dead cell stain (1:1,000; Thermo Fisher) for 30 min at 4 °C. CD3+ T cells and mScarlet+ microglia and PMPs were single-cell-sorted into 386-well plates containing well-specific barcoded primers (Single Cell Discoveries) on a Sony SH800s (Sony Biotechnology). Plates containing sorted cells were immediately snap-frozen on dry ice and processed for SORT-seq by Single Cell Discoveries. Cells were heat-lysed at 65 °C followed by complementary (cDNA) synthesis. All the barcoded material from one plate was pooled into one library and amplified using in vitro transcription. Library preparation was performed following the CEL-Seq2 protocol105 to prepare a cDNA library for sequencing using TruSeq small RNA primers (Illumina). The DNA library was paired-end sequenced on an Illumina Nextseq 500, with high output, using a 1× 75-bp Illumina kit (read 1: 26 cycles, index read: 6 cycles, read 2: 60 cycles).
CSFE-labeled myelin debris, kindly provided by the L. Akkari lab74, was injected into PMP-integrated organoid slices using a glass needle and a FemtoJet 4i. The slices were immediately imaged on a Leica STELLARIS microscope at 37 °C and 5% CO2 overnight with a time interval of 5–10 min.
Protein was detected in the culture supernatant by Luminex. Acquisition of data was performed using a FLEXMAP 3D system (Bio-Rad) with xPONENT 4.3u1 software (Luminex). Data analysis was performed using Bio-Plex Manager 6.2 (Bio-Rad). All assays were performed at the ISO9001:2008-certified MultiPlex Core Facility of the University Medical Center Utrecht.
Statistics on bulk sequencing data were computed using built-in functions of R (‘stats', version 4.3.1) through a one-way analysis of variance with a post hoc Tukey honestly significant difference test. Statistics on electroporation efficiency and tumor induction were calculated using two-tailed independent t-tests (function: t.test). All statistical tests were performed with a confidence interval of at least 95% (α = 0.05). Data distribution was assumed to be normal but this was not formally tested, unless otherwise indicated, and no statistical method was used to predetermine sample size. To evaluate tumor response to GD2 CAR T cells in the presence or absence of microglia, the normalized tumor area at each time point was analyzed using a linear mixed-effects model, accounting for fixed and random effects related to batch and organoid variation. Multiple models were tested and the best-fitting model was selected. P values were adjusted for multiple comparisons using the false discovery rate (Benjamini–Hochberg). The investigators were not blinded to allocation during experiments and outcome assessment.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Raw sequencing and methylation data that support the findings of this study were deposited to the European Genome–Phenome Archive under accession codes E-MTAB-15147 and E-MTAB-15559, respectively. Processed sequencing data were deposited to Zenodo (https://doi.org/10.5281/zenodo.16992353)106. Sequencing metadata are provided in Supplementary Tables 2–4, 6 and 9. Source data are provided with this paper.
All used R and Python scripts for analysis are available from GitHub (https://github.com/Dream3DLab/DMGO_analysis). Pipelines for analyzing TrackerSeq data can also be found on GitHub (https://github.com/anna-alemany/TrackerSeq_BROs).
Louis, D. N. et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 23, 1231–1251 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
Findlay, I. J. et al. Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies. Oncogene 41, 461–475 (2022).
Article
CAS
PubMed
Google Scholar
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Article
CAS
PubMed
Google Scholar
Vuong, H. G., Ngo, T. N. M., Le, H. T. & Dunn, I. F. The prognostic significance of HIST1H3B/C and H3F3A K27M mutations in diffuse midline gliomas is influenced by patient age. J. Neurooncol. 158, 405–412 (2022).
Article
CAS
PubMed
Google Scholar
Thomas, B. C. et al. CAR T cell therapies for diffuse midline glioma. Trends Cancer 9, 791–804 (2023).
Article
CAS
PubMed
Google Scholar
Filbin, M. G. et al. Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq. Science 360, 331–335 (2018).
Article
CAS
PubMed
PubMed Central
Google Scholar
Jessa, S. et al. K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas. Nat. Genet. 54, 1865–1880 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
Liu, I. et al. The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location. Nat. Genet. 54, 1881–1894 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
Pathania, M. et al. H3.3K27M cooperates with Trp53 loss and PDGFRA gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas. Cancer Cell 32, 684–700 (2017).
Article
CAS
PubMed
PubMed Central
Google Scholar
Larson, J. D. et al. Histone H3.3 K27M accelerates spontaneous brainstem glioma and drives restricted changes in bivalent gene expression. Cancer Cell 35, 140–155 (2019).
Article
CAS
PubMed
Google Scholar
Patel, S. K. et al. Generation of diffuse intrinsic pontine glioma mouse models by brainstem targeted in utero electroporation. Neuro Oncol. 22, 381–392 (2019).
PubMed Central
Google Scholar
Funato, K., Major, T., Lewis, P. W., Allis, C. D. & Tabar, V. Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 346, 1529–1533 (2014).
Article
CAS
PubMed
PubMed Central
Google Scholar
Haag, D. et al. H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model. Cancer Cell 39, 407–422 (2021).
Article
CAS
PubMed
Google Scholar
Bressan, R. B. et al. Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants. Cell Stem Cell 28, 877–893 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
Pun, M. et al. Common molecular features of H3K27M DMGs and PFA ependymomas map to hindbrain developmental pathways. Acta Neuropathol. Commun. 11, 25 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Jessa, S. et al. Stalled developmental programs at the root of pediatric brain tumors. Nat. Genet. 51, 1702–1713 (2019).
Article
CAS
PubMed
PubMed Central
Google Scholar
Barron, T. et al. GABAergic neuron-to-glioma synapses in diffuse midline gliomas. Nature 639, 1060–1068 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Taylor, K. R. et al. Glioma synapses recruit mechanisms of adaptive plasticity. Nature 623, 366–374 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015).
Article
CAS
PubMed
PubMed Central
Google Scholar
Venkataramani, V. et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532–538 (2019).
Article
CAS
PubMed
Google Scholar
Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).
Article
CAS
PubMed
Google Scholar
Bian, S. et al. Genetically engineered cerebral organoids model brain tumor formation. Nat. Methods 15, 631–639 (2018).
Article
CAS
PubMed
PubMed Central
Google Scholar
Hendriks, D. et al. Human fetal brain self-organizes into long-term expanding organoids. Cell 187, 712–732 (2024).
Article
CAS
PubMed
Google Scholar
Monje, M. et al. Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature 637, 708–715 (2025).
Article
CAS
PubMed
Google Scholar
Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016).
Article
CAS
PubMed
PubMed Central
Google Scholar
Muguruma, K., Nishiyama, A., Kawakami, H., Hashimoto, K. & Sasai, Y. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 10, 537–550 (2015).
Article
CAS
PubMed
Google Scholar
Andersen, J. et al. Generation of functional human 3D cortico-motor assembloids. Cell 183, 1913–1929 (2020).
Article
CAS
PubMed
PubMed Central
Google Scholar
Ye, W., Shimamura, K., Rubenstein, J. L. R., Hynes, M. A. & Rosenthal, A. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93, 755–766 (1998).
Article
CAS
PubMed
Google Scholar
Wurst, W. & Bally-Cuif, L. Neural plate patterning: Upstream and downstream of the isthmic organizer. Nat. Rev. Neurosci. 2, 99–108 (2001).
Article
CAS
PubMed
Google Scholar
Lu, J. et al. Generation of serotonin neurons from human pluripotent stem cells. Nat. Biotechnol. 34, 89–94 (2016).
Article
CAS
PubMed
Google Scholar
Philippidou, P. & Dasen, J. S. Hox genes: choreographers in neural development, architects of circuit organization. Neuron 80, 12–34 (2013).
Article
CAS
PubMed
Google Scholar
Fleck, J. S. et al. Resolving organoid brain region identities by mapping single-cell genomic data to reference atlases. Cell Stem Cell 28, 1148–1159.e8 (2021).
Article
CAS
PubMed
Google Scholar
He, Z. et al. An integrated transcriptomic cell atlas of human neural organoids. Nature 635, 690–698 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Braun, E. et al. Comprehensive cell atlas of the first-trimester developing human brain. Science 382, eadf1226 (2023).
Article
CAS
PubMed
Google Scholar
Albiach, A. M. et al. Futile wound healing drives mesenchymal-like cell phenotypes in human glioblastoma. Preprint at bioRxiv https://doi.org/10.1101/2023.09.01.555882 (2023).
The Federative International Programme for Anatomical Terminology. Terminologia Anatomica 2nd edn (FIPAT, 2019).
Siletti, K. et al. Transcriptomic diversity of cell types across the adult human brain. Science 382, eadd7046 (2023).
Article
CAS
PubMed
Google Scholar
Harutyunyan, A. S. et al. H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis. Nat. Commun. 10, 1262 (2019).
Article
PubMed
PubMed Central
Google Scholar
Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537(2017).
Article
CAS
PubMed
PubMed Central
Google Scholar
Khuong-Quang, D.-A. et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 124, 439–447 (2012).
Article
CAS
PubMed
PubMed Central
Google Scholar
Siddaway, R. & Hawkins, C. Modeling DIPG in the mouse brainstem. Neuro Oncol. 22, 307–308 (2020).
Article
PubMed
PubMed Central
Google Scholar
Mariet, C. et al. Posterior fossa ependymoma H3 K27-mutant: an integrated radiological and histomolecular tumor analysis. Acta Neuropathol. Commun. 10, 137 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
Gillen, A. E. et al. Single-cell RNA sequencing of childhood ependymoma reveals neoplastic cell subpopulations that impact molecular classification and etiology. Cell Rep. 32, 108023 (2020).
Article
CAS
PubMed
PubMed Central
Google Scholar
Gao, J. et al. Cellular localization of aquaporin-1 in the human and mouse trigeminal systems. PLoS ONE 7, e46379 (2012).
Article
CAS
PubMed
PubMed Central
Google Scholar
Chu, Y. et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat. Med. 29, 1550–1562 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).
Article
PubMed
Google Scholar
Szabo, P. A. et al. Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat. Med. 10, 4706 (2019).
CAS
Google Scholar
Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).
Article
CAS
PubMed
PubMed Central
Google Scholar
Tinoco, R. et al. PSGL-1 is an immune checkpoint regulator that promotes T cell exhaustion. Immunity 44, 1190–1203 (2016).
Article
CAS
PubMed
PubMed Central
Google Scholar
Shin, H. et al. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 31, 309–320 (2009).
Article
CAS
PubMed
PubMed Central
Google Scholar
Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21, 581–590 (2015).
Article
CAS
PubMed
PubMed Central
Google Scholar
Beltra, J.-C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825–841 (2020).
Article
CAS
PubMed
PubMed Central
Google Scholar
Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211–218 (2019).
Article
CAS
PubMed
PubMed Central
Google Scholar
Good, C. R. et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell 184, 6081–6100 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
Jenkins, E., Whitehead, T., Fellermeyer, M., Davis, S. J. & Sharma, S. The current state and future of T-cell exhaustion research. Oxf. Open Immunol. 4, iqad006 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Trefny, M. P. et al. Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy. Nat. Commun. 14, 86 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Vardhana, S. A. et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 21, 1022–1033 (2020).
Article
CAS
PubMed
PubMed Central
Google Scholar
Chow, A., Perica, K., Klebanoff, C. A. & Wolchok, J. D. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat. Rev. Clin. Oncol. 19, 775–790 (2022).
Article
PubMed
PubMed Central
Google Scholar
Dekkers, J. F. et al. Uncovering the mode of action of engineered T cells in patient cancer organoids. Nat. Biotechnol. 41, 60–69 (2023).
Article
CAS
PubMed
Google Scholar
Ganesan, A.-P. et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat. Immunol. 18, 940–950 (2017).
Article
CAS
PubMed
PubMed Central
Google Scholar
Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886–897 (2014).
Article
CAS
PubMed
PubMed Central
Google Scholar
Jung, I.-Y. et al. Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors. Cell Rep. Med. 4, 101053 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Xu, R. et al. Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain. Nat. Commun. 11, 1577 (2020).
Article
CAS
PubMed
PubMed Central
Google Scholar
Sabate-Soler, S. et al. Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality. Glia 70, 1267–1288 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
Haenseler, W. et al. A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response. Stem Cell Rep. 8, 1727–1742 (2017).
Article
CAS
Google Scholar
Sabogal-Guaqueta, A. M. et al. Brain organoid models for studying the function of iPSC-derived microglia in neurodegeneration and brain tumours. Neurobiol. Dis. 203, 106742 (2024).
Article
CAS
PubMed
Google Scholar
Hughes, A. N. & Appel, B. Microglia phagocytose myelin sheaths to modify developmental myelination. Nat. Neurosci. 23, 1055–1066 (2020).
Article
CAS
PubMed
PubMed Central
Google Scholar
Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).
Article
PubMed
PubMed Central
Google Scholar
Park, D. S. et al. iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer. Nature 623, 397–405 (2023).
Article
CAS
PubMed
Google Scholar
Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).
Article
PubMed
Google Scholar
Andrade, A. F. et al. Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function. Nat. Commun. 15, 7769 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Lin, G. L. et al. Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma. Acta Neuropathol. Commun. 6, 51 (2018).
Article
PubMed
PubMed Central
Google Scholar
Kloosterman, D. J. et al. Macrophage-mediated myelin recycling fuels brain cancer malignancy. Cell 187, 5336–5356 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Vinnakota, J. M. et al. Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome. Nat. Cancer 5, 1227–1249 (2024).
Article
CAS
PubMed
Google Scholar
Sarnow, K. et al. Neuroimmune-competent human brain organoid model of diffuse midline glioma. Neuro Oncol. 27, 369–382 (2025).
Article
CAS
PubMed
Google Scholar
Deligne, C. et al. Establishing a living biobank of pediatric high-grade glioma and ependymoma suitable for cancer pharmacology. Neuro Oncol. 27, 1325–1340 (2025).
Article
PubMed
PubMed Central
Google Scholar
Gordon, A. et al. Long-term maturation of human cortical organoids matches key early postnatal transitions. Nat. Neurosci. 24, 331–342 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
Birey, F. et al. Assembly of functionally integrated human forebrain spheroids. Nature 545, 54–59 (2017).
Article
CAS
PubMed
PubMed Central
Google Scholar
Kim, J. et al. Human assembloid model of the ascending neural sensory pathway. Nature 642, 143–153 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Qin, E. Y. et al. Neural precursor-derived pleiotrophin mediates subventricular zone invasion by glioma. Cell 170, 845–859 (2017).
Article
CAS
PubMed
PubMed Central
Google Scholar
Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019).
Article
CAS
PubMed
PubMed Central
Google Scholar
Vitanza, N. A. et al. Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial. Nat. Med. 31, 861–868 (2025).
Article
CAS
PubMed
PubMed Central
Google Scholar
Albelda, S. M. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat. Rev. Clin. Oncol. 21, 47–66 (2024).
Article
PubMed
Google Scholar
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Article
CAS
PubMed
Google Scholar
Bandler, R. C. et al. Single-cell delineation of lineage and genetic identity in the mouse brain. Nature 601, 404–409 (2022).
Article
CAS
PubMed
Google Scholar
Ishahak, M. et al. Genetically engineered brain organoids recapitulate spatial and developmental states of glioblastoma progression. Adv. Sci. (Weinh.) 12, e2410110 (2025).
Ineveld, R. L. V. et al. Multispectral confocal 3D imaging of intact healthy and tumor tissue using mLSR-3D. Nat. Protoc. 17, 3028–3055 (2022).
Article
PubMed
Google Scholar
Cai, R. et al. Whole-mouse clearing and imaging at the cellular level with vDISCO. Nat. Protoc. 18, 1197–1242 (2023).
Article
CAS
PubMed
Google Scholar
Auffret, L. et al. A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation. Acta Neuropathol. 147, 2 (2024).
Article
CAS
Google Scholar
Capper, D. et al. DNA methylation-based classification of central nervous system tumours. Nature 555, 469–474 (2018).
Article
CAS
PubMed
PubMed Central
Google Scholar
Tian, Y. et al. ChAMP: updated methylation analysis pipeline for Illumina BeadChips. Bioinformatics 33, 3982–3984 (2017).
Article
CAS
PubMed
PubMed Central
Google Scholar
Aryee, M. J. et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30, 1363–1369 (2014).
Article
CAS
PubMed
PubMed Central
Google Scholar
Teschendorff, A. E. et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics 29, 189–196 (2012).
Article
PubMed
PubMed Central
Google Scholar
Watson, S. S. et al. Microenvironmental reorganization in brain tumors following radiotherapy and recurrence revealed by hyperplexed immunofluorescence imaging. Nat. Commun. 15, 3226 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
Article
PubMed
PubMed Central
Google Scholar
Ariese, H. C. R. et al. Comprehensive transcriptomic analysis of brainstem-regionalized organoids and associated diffuse midline glioma organoids. protocols.io https://doi.org/10.17504/protocols.io.6qpvrwq13lmk/v1 (2025).
Andersch, L. et al. CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing. BMC Cancer 19, 895 (2019).
Article
PubMed
PubMed Central
Google Scholar
Marcu-Malina, V. et al. Redirecting αβT cells against cancer cells by transfer of a broadly tumor-reactive γδT-cell receptor. Blood 118, 50–59 (2011).
Article
CAS
PubMed
Google Scholar
Germain, P.-L., Lun, A., Meixide, C. G., Macnair, W. & Robinson, M. D. Doublet identification in single-cell sequencing data using scDblFinder. F1000Res. 10, 979 (2021).
Article
PubMed
Google Scholar
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
McInnes, L., Healy, J. & Melville, J. UMAP: uniform manifold approximation and projection for dimension reduction. Preprint at https://doi.org/10.48550/arXiv.1802.03426 (2018).
DeTomaso, D. et al. Functional interpretation of single cell similarity maps. Nat. Commun. 10, 4376 (2019).
Article
PubMed
PubMed Central
Google Scholar
Gutbier, S. et al. Large-scale production of human iPSC-derived macrophages for drug screening. Int. J. Mol. Sci. 21, 4808 (2020).
Article
CAS
PubMed
PubMed Central
Google Scholar
Hashimshony, T. et al. CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq. Genome Biol. 17, 77 (2016).
Article
PubMed
PubMed Central
Google Scholar
Ariese, H. C. R. & Alieva, M. Transcriptomic profiling of BrO, DMGO and GD2 CAR T cells: processed datasets. Zenodo https://doi.org/10.5281/zenodo.15356013 (2025).
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All imaging was performed at the Princess Máxima Imaging Center. We thank the Princess Máxima Center Single-Cell Genomics Facility, the Leiden Genome Technology Center and Single Cell Discoveries for performing scRNA-sequencing, R. Moeniralam and E. de Boed from the Princess Máxima Center Pathology Diagnostic Laboratory for performing immunohistochemical staining and the FC facilities at the Princess Máxima Center and Laboratory of Translational Immunology and M. Nicolasen for cell sorting. We thank J. Lammers for providing gene expression data from patient material, Z. Odé for her collaboration on establishing cerebral organoids, H. R. Johnson and A. Zomer for assistance with in vivo experiments and J. Bunt for sharing his knowledge on neural development. This work was financially supported by the Princess Máxima Center for Pediatric Oncology, Oncode Institute, the Children Cancer Free (KiKa) Foundation (grant no. 473) and the Charlie Teo Foundation (Research Rebel-Alegra's Army grant). A.C.R was supported by an European Research Council starting grant (2018 project, no. 804412) and N.B. was supported by a research grant from Stichting Proefdiervrij.
These authors contributed equally: Nils Bessler, Amber K. L. Wezenaar, Hendrikus C. R. Ariese, Celina Honhoff.
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Nils Bessler, Amber K. L. Wezenaar, Hendrikus C. R. Ariese, Celina Honhoff, Ellen J. Wehrens, Cristian Ruiz Moreno, Thijs J. M. van den Broek, Raphaël V. U. Collot, Daan J. Kloosterman, Farid Keramati, Mieke Roosen, Sam de Blank, Esmée van Vliet, Mario Barrera Román, Marcel Kool, Mariëtte E. G. Kranendonk, Annelisa M. Cornel, Stefan Nierkens, Hendrik G. Stunnenberg & Anne C. Rios
Oncode Institute, Utrecht, The Netherlands
Nils Bessler, Amber K. L. Wezenaar, Hendrikus C. R. Ariese, Celina Honhoff, Ellen J. Wehrens, Thijs J. M. van den Broek, Raphaël V. U. Collot, Daan J. Kloosterman, Sam de Blank, Esmée van Vliet, Mario Barrera Román & Anne C. Rios
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
Noëlle Dommann & Anna Alemany
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden, The Netherlands
Noëlle Dommann & Anna Alemany
Department of molecular Biology, Faculty of Science, Radboud University, Nijmegen, The Netherlands
Cristian Ruiz Moreno
Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
Farid Keramati, Lucrezia C. D. E. Gatti, Jürgen Kuball, Zsolt Sebestyén, Annelisa M. Cornel & Stefan Nierkens
Institute for Intelligent Biotechnologies (iBIO), Helmholtz Munich, Neuherberg, Munich, Germany
Ali Ertürk
Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
Jürgen Kuball
University Medical Center Utrecht, Utrecht, The Netherlands
Marcel Kool
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
Marcel Kool
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Heidelberg, Germany
Marcel Kool
Onco-Hematology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
Sara Patrizi & Evelina Miele
Department of Pediatric Oncology and Hematology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Annette Künkele
Max Planck Institute of Neurobiology, Martinsried, Germany
Christian Mayer
Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC, Universidad Autónoma de Madrid, Madrid, Spain
Maria Alieva
Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
Anne C. Rios
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N.B. and A.C.R conceptualized the work with critical input from H.C.R.A., A.K.L.W., N.D., C.R.M., H.G.S., C.H., M.A. and A.A. and wrote the manuscript with support from E.J.W. H.C.R.A., C.H. and N.B. grew pontine organoids and performed DMG tumor induction. H.C.R.A., C.R.M., N.B., S.d.B. and M.A. analyzed bulk and scRNA-seq datasets with critical input from H.G.S. and F.K. N.D., H.C.R.A. and N.B. performed and analyzed lineage-tracing and cNMF experiments supervised by A.A. and A.C.R. C.M. provided TrackerSeq and critical input for analysis of lineage-tracing experiments. N.B., H.C.R.A. and M.B.R. performed multispectral 3D imaging using specific technology provided by A.E. T.J.M.v.d.B. performed cyclic immunofluorescence imaging, R.V.U.C. performed live-cell imaging, D.J.K. performed FC and S.P. and E.M. performed DNA methylation profiling. A.K.L.W. and C.H. integrated microglia and performed all GD2 CAR T cell experiments with help from A.M.C. for T cell expansion and L.C.D.E.G. for cell sorting. A.K. provided GD2 CAR T cells and J.K., Z.S. and S.N. provided protocols for T cell rapid expansion. E.J.W., A.K.L.W., F.K., E.v.V. and M.A. analyzed DMGO CAR T cell treatment data, including scRNA-seq analysis of GD2 CAR T cells and microglia. M.E.G.K. contributed critical knowledge on DMG histopathological features and performed immunohistochemical staining on DMGOs. M.R. and M.K. provided healthy brain organoids as a refence dataset for iCNV analysis and knowledge related to brain organoid generation. S.d.B. offered critical computational support and infrastructure for data analysis.
Correspondence to
Anne C. Rios.
A.C.R. and N.B. are listed as inventors on a pending patent related to the novel BrO model (P382144NL). A.K.L.W., E.J.W., M.A. and A.C.R. are listed as inventors on a pending patent related to the development of marker-based T cell selection (P102253NL). The other authors declare no competing interests.
Nature Cancer thanks Harry Hill 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, Overview of patterning approach and corresponding representative brightfield images of brainstem organoids over time. n = 3 BrOs for early time points, n = 15 BrOs for timepoint 60 days, scale bar of single organoids and multiple organoids is 500 µm and 2 mm, respectively. b, Schematic representation of a human foetal brain in gestational week (GW) 5 with indicated morphogens influencing the differentiation of hindbrain rhombomeres (r) and their HOX gene code respectively. c, Heatmap showing relative bulk RNA expression of homeobox (HOX) genes at week 2 and 3 depicted as log2 fold change normalized to week 1. n = 3 pooled BrOs per batch. d, Boxplot representation of Spearman's rank coefficient between different organoid batches from week 2 to 12. Box plots show the median (center line, 50th percentile), the box spans the interquartile range (25th–75th percentiles), whiskers extend to the most extreme observations within 1.5×IQR of the quartiles (defining the plotted minima and maxima), points beyond this range are not displayed. n = 3 organoids pooled per batch from n = 3 independent batches per timepoint. e, PCA of organoids at different timepoints from week 1 to 12 (grey scale) and derived from hESCs (circles) or iPSCs (square). n = 3 organoids pooled per batch from n = 3 independent batches for weeks 2-12; n = 3 organoids pooled from n = 2 independent batches for week 1 and n = 3 organoids pooled from n = 1 batch for iPSC-derived.
Source data
a, Unintegrated UMAP representation of developing brainstem organoids, colored by collection day. Bargraph (upper left) depicts the contribution of each day to the final dataset. b, Violin plots showing the number of genes, number of counts, percentage of mitochondrial genes and percentage of ribosomal genes after filtering on a sample-by-sample basis. Box plots inside violin plots show the median (center line, 50th percentile), the box spans the interquartile range (25th–75th percentiles), whiskers extend to the most extreme observations within 1.5×IQR of the quartiles (defining the plotted minima and maxima). c, scIB integration benchmarking of different assessed integration methods, showing metrics for preservation of biological variation and batch correction. d, scPoli latent embedding of brainstem organoid cells, colored by timepoint (top) and snapseed annotation (bottom). e, scPoli integrated UMAP of brainstem organoids, colored by timepoint. f, scPoli integrated UMAP representation showing three age bins, early (day 5 – day 20), mid (day 30 – day 60) and late (day 90 – day 120). g, Matrixplot of scPoli (HNOCA34) or scANVI (HDBCA35) mediated label transfer annotation compared to the final annotation. For panels a-g, n = 84 organoids in total with 5-24 organoids pooled per timepoint, see Supplementary Table S1 for details.
Source data
a, Areaplots showing relative ratios of the cell cycle phases over the different timepoints. b, Dotplot showing the expression of selected markers for each cell type annotation, colored by their respective cell class. FOXG1 is represented in bold, indicating absence of expression. c, Annotation of neurotransmitter transporters (NTT) for cells assigned as neuroblast or neuron. d, Comparison of NTT found in the brainstem organoid dataset and the HDBCA35 pons. For panels a-d, n = 84 organoids in total with 5-24 organoids pooled per timepoint, see Supplementary Table S1 for details. e, Representative 3D confocal image of a 200 µm thick organoid slice at day 110 labelled for TUBB3 (orange) and TPH2 (blue). n = 2 BrOs. White insert indicates zoom area displayed on the right. Overview image and zoom scale bars 250 µm and 25 µm, respectively. f, Representative optical section of immunofluorescent 3D imaging of a 200 µm thick organoid slice at week 16 labelled for neurofilament (NF, white), GFAP (red-to-white gradient) and AQP4 (green) (left) or for DAPI (white) and OLIG2 (red) (right). n = 2 BrOs, scale bars = 50 µm. g, Glycolysis scores over the HNOCA34 and BrO datasets. Dashed line represents the mean score over all HNOCA datasets. h, Glycolysis scores for the OPC (left) and Glioblast (right) lineages in the HNOCA and brainstem organoids (BrOs), statistically analyzed using a permutation test. i, DEG analysis comparing Oligo (left) and Glioblast (right) from the HNOCA and brainstem organoids (BrOs) to the HDBCA counterparts. j, UMAP of the HDBCA, colored by the brainstem organoid presence scores. k, Proportional brainstem organoid presence scores for the HDBCA, showing the ratio of cells being represented in brainstem organoids (BrOs) per annotated cell class. For panels g-k, n = 84 organoids in total with 5-24 organoids pooled per timepoint, see Supplementary Table S1 for details.
Source data
a, b, Representative image of GFP expression (a; tumor-inducing mix) or control (b; PiggyBac backbone including CAG-mVenus) as a measure of tumor outgrowth at week 6. n = 3 DMGOs and 3 controls, scale bars = 1 mm. c, Representative 3D confocal image of a 300 µm brain section of a DMGO-transplanted NSG mouse developing tumor outgrow labelled for CD31 (red), tumor-GFP (green) and DAPI (grey). n = 2 mice, scale bar = 500 µm. d, Representative routine histopathological characterization of a DMG patient tumor sample harbouring H3.3K27M, TP53 and PDGFRA mutations. Top panels; staining for H3K27M and H3K27me3. Bottom panels; Haematoxylin and eosin (HE), glial fibrillary acidic protein (GFAP) and neurofilament (NF). n = 7 patients. e, Representative routine histopathological characterization of a DMGO at day 120. Top panels; staining for H3K27M and H3K27me3. Bottom panels; Haematoxylin and eosin (HE), glial fibrillary acidic protein (GFAP) and neurofilament (NF). n = 5 DMGOs.
Source data
a, Violin plots showing the number of genes, number of counts, percentage mitochondrial genes and percentage of ribosomal genes after filtering on a sample-by-sample basis. Box plots inside violin plots show the median (center line, 50th percentile), the box spans the interquartile range (25th–75th percentiles), whiskers extend to the most extreme observations within 1.5×IQR of the quartiles (defining the plotted minima and maxima). b, Unintegrated UMAP representation of DMGO cells, colored by sequencing batch. c, iCNV profile of DMGO cells showing chromosomal aberrations compared to healthy cells from the BrO time course data shown in Fig. 1e. Orange depicts tumor and green represents healthy cells. d, Dotplot showing marker gene expression for different tumor states, color-coded for their respective annotation. e, Matrixplot with the obtained tumor state annotations compared to reference datasets7,8. f, Mapping scores of DMGO cells in Liu et al.8, showing high presence of the annotated cell states, except for cycling cells. For panels a-f, n = 14 DMGOs from 4 independent batches.
Source data
a, Schematic representation of the applied approach for simultaneously recovering transcriptomic information, HTO hashtags and lineage barcodes from DMGOs on a single cell level. A nested PCR strategy was applied for the TrackerSeq barcode. b–f, Quality control assessment and filters used to select barcodes from experimental replicate 1 (top) and experimental replicate 2 (bottom). Histogram depicting the total number of UMI counts prior to any filtering (b). Histogram displaying read counts and the cut-off (red dashed line) set as a minimum total read count of log102 and log103 for experimental replicate 1 and 2, respectively (c). Scatter plot depicting read counts plotted against UMI counts and the applied threshold for minimum total read counts indicated (red dashed line) (d). Histogram depicting the mean oversequence per barcode and thresholding applied (dashed blue line) (e). Scatter plot depicting read counts plotted against max mean oversequence showing both thresholds applied (f). g, UMAP embedding of lineage-traced DMGOs and BrO controls. Cells are colored according to unique lineage barcodes. Cells without barcodes are presented in gray. h, Representation of each DMGO and BrO control in the final UMAP embedding. i, Bargraph depicting the total number of cells for each clonal barcode after applying the filtering of >3 cells per clonal family. j, Pie charts of the relative size of each recovered clonal family among all barcoded cells per sample used for the large versus small clone comparison. Percentage is depicted for clonal families that are equal to, or above 20%, which are defined as large clones. For panel b-j, n = 14 DMGOs and n = 2 BrOs, see Supplementary Table S1 for details. k, Dotplot showing normalized expression of AQP1 and AQP4 in DMG cells7. In contrast to AQP1, AQP4 - a canonical AC-like marker - was present in DMG tumors across all locations. l. Module scores of gene programs as derived from cNMF projected onto the UMAP of lineage-traced cells. m, Heatmap of Jaccard index scores, indicating the overlap of the cNMF derived programs to tumor state annotations. For panels b-j, l, m, n = 14 DMGOs and n = 2 BrOs, see Supplementary Table S1 for details. For panel l and m, n = 14 DMGOs and n = 2 BrOs, see Supplementary Table S1 for details.
Source data
a, Representative brightfield images at day 14 of untransformed brainstem organoids (BrOs) left untreated (n = 8 BrOs) or exposed to GD2 CAR T cells (n = 8 BrOs) at day 0 and 7. b, DMGO tumor cell GD2 expression (orange) analyzed by flow cytometry compared to an unstained control (black). n = 1 DMGO. c, d, IFNγ levels measured in the culture supernatant (c) and GD2 CAR T cell treatment outcome measured as tumor GFP intensity relative to the start of treatment (day 0, 100%) with a smoothed line trend plotted between the values at different timepoints for each DMGO using the LOESS algorithm (d). DMGOs were either left untreated (gray line, n = 1 DMGO), treated with mock transduced T cells (black lines, n = 2 DMGOs), or GD2 CAR T cells (orange lines, n = 4 DMGOs). Arrows indicate the timepoints of T cell administration. e, Images of tumor GFP signal on day 0, 7, 10 and 14 for an untreated DMGO (n = 1 DMGO) and DMGOs treated with mock transduced T cells (n = 2 DMGOs), or GD2 GAR T cells (n = 4 DMGOs). GD2 CAR T cells and mock transduced T cells were administrated at day 0 and 7. For panels c-e, DMGOxxx indicates individual DMGO sample ID for reference across data figures.
Source data
a, Dot plot showing key marker gene expression (selected from the top 20 DEGs) across the GD2 CAR T cell clusters. Dot size is proportional to the percentage of cells expressing a gene and color intensity to the average scaled gene expression. Grid colors highlight genes that are closely related in function; HLA genes (green), metabolic stress-related genes (red) and ISGs (blue). b–f, Selected significant GO terms associated with the DEGs of the TUND (b), TIL-2 (c), TMI (d), TPR (e) and TMS (f) GD2 CAR T cell clusters. g, UMAP visualization of the CD8+ TIL clusters from the pan-cancer atlas46 used as a reference dataset. Annotated clusters are highlighted because of their overlap with, or use in defining the GD2 CAR T cell clusters. h–j, Marker gene signatures (DEG analysis adjusted p-value < 0.00001) of the TUND (h), TIL-2 (i) and TISG (j) GD2 CAR T cell clusters projected onto the CD8+ TIL dataset from g. For panels a-j, GD2 CAR T cells retrieved from n = 4 treated DMGOs.
Source data
a, Percentage of cells within GD2 CAR T cell clusters, including those identified in Fig. 4e, a cluster enriched in non-exposed cells, and the NCAM1− specific THS cluster. Data is shown separately for GD2 CAR T cells retrieved from DMGO at day 14 after administration weekly (at day 0 and 7, left; n = 4 DMGOs) or once (at day 0, right; n = 2 DMGOs). b, UMAP representation of the integrated GD2 CAR T cell dataset, illustrating the distribution of non-exposed GD2 CAR T cells. c, UMAP embedding of DMGO-exposed (pink) and non-exposed (green) GD2 CAR T cells within the TEX cluster. For panel b and c, GD2 CAR T cells retrieved from n = 4 DMGOs and n = 2 independent batches of unexposed GD2 CAR T cells. d, Applied gating strategy (top panels) and obtained purity (bottom panels) of sorted NCAM1− and NCAM1+ GD2 CAR T cells. e, Representative images of tumor control measured by GFP imaging in DMGOs treated with sorted NCAM1− (top) or NCAM1+ (bottom) GD2 CAR T cells. f, Number of NCAM1− and NCAM1+ GD2 CAR T cells retrieved from each DMGO sample after two weeks of treatment. g, Proportion of cells within GD2 CAR T cell clusters, including those identified in Fig. 4e, a cluster enriched in non-exposed cells, and the NCAM1− specific THS cluster. Data is shown separately for NCAM1− GD2 CAR T cells (left) and NCAM1+ GD2 CAR T cells (right). h, Selected significant GO terms associated with the DEGs of the THS NCAM1− specific GD2 CAR T cell cluster. i, Upregulated marker gene signature (DEG analysis adjusted p-value < 0.05; avg_log2FC > 0) of the THS GD2 CAR T cell cluster projected onto the pan-cancer CD8+ TIL dataset46. For panels d-i, n = 2 DMGOs for NCAM1− and n = 2 DMGOs for NCAM1+ cells.
Source data
a, Selected significant GO terms associated with DEGs in microglia derived from BrOs (left; n = 5 BrOs) or DMGOs (right; n = 4 DMGOs). b, Representative Immunofluorescent 2D images of DMGOs with microglia, 3 weeks after integration, labeled for DAPI (white), IBA1 (green), SPP1 (magenta) and CD163 (blue). n = 3 DMGOs, scale bar = 50 µm. c, Quantification of the percentage of CD163+ (left) or SPP1+ cells (right) in IBA1+ microglia in DMGOs. n = 3 DMGOs. d, Gating strategy used to sort mScarlet+ PMP/microglia and CD3+ GD2 CAR T cells for scRNA-seq. e, Bargraph depicting the proportion of TMA GD2 CAR T cells matched to identified pan-cancer CD8 TIL subsets46. f, Heatmap depicting the average scaled expression of curated gene signatures from the CD8 TIL reference dataset46 across the GD2 CAR T cell clusters. For panels d-f, n = 6 DMGOs with microglia and n = 6 DMGOs without microglia.
Source data
Supplementary Tables 1–10.
Microglia home to sites of myelin debris injection. Live 3D imaging of microglia (orange) and CFSE-labelled myelin debris (green). Areas of myelin debris injection are outlined by white dashed lines. Comparison of microglia homing at 0 and 14.5 h provided at the end.
Microglia phagocytose myelin debris. Live 3D imaging of microglia (orange) and CFSE-labelled myelin debris (green). White arrows indicate myelin debris that is phagocytosed by microglia outlined by white dashed lines.
Source data and mean gains for each HDBCA cluster in the BrO model.
Source data and electroporation efficiency data, including statistical analysis and number of tumor cells positive for H3K27M, p53 and PDGFRA.
Source data and electroporation efficiency data, including statistical analysis, DEGs and selected GO terms for large versus small clones, gene lists derived from cNMF and oligo lineage signatures derived from Braun et al.39.
Source data, tumor GFP intensity and fold enrichment in tumor control for NCAM1+ over NCAM1− GD2 CAR T cells.
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Source data and DEGs from single-cell sequencing of glioblasts and OPCs from BrO, HNOCA and HDBCA datasets.
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Source data and gene lists derived from cNMF.
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Source data and DEGs from the GD2 CAR T clusters.
Source data and DEGs from the GD2 CAR T clusters.
Source data and DEGs in microglia derived from DMGO compared to BrO.
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Bessler, N., Wezenaar, A.K.L., Ariese, H.C.R. et al. De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function.
Nat Cancer (2026). https://doi.org/10.1038/s43018-025-01084-0
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DOI: https://doi.org/10.1038/s43018-025-01084-0
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Kendra Pierre-Louis: For Scientific American's Science Quickly, I'm Kendra Pierre-Louis, in for Rachel Feltman.
Hello and happy new year! I love the first few days of a new year. It evokes a feeling that change is possible. That feeling, in part, leads some of us to set New Year's resolutions.
An estimated 40 percent of U.S. adults set resolutions any given year. We promise ourselves that we'll save money, exercise regularly or spend more time with friends and family.
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And yet, for many of us, as that feeling of newness fades so, too, do our resolutions. Some research suggests that as many as 88 percent of Americans give up on their resolutions within two weeks.
But it doesn't have to be that way, according to Katy Milkman, a behavioral economist at the Wharton School of the University of Pennsylvania. She's the author of How to Change: The Science of Getting from Where You Are to Where You Want to Be.
Katy says there are science-supported tools we can use to spark positive changes in our lives. Doing so involves not only asking high-level questions about what we want to achieve and why but also finding ways to make the path toward achieving those goals, well, fun.
Here's our conversation.
Pierre-Louis: In your book you talk about how moments like a new year, even a move, you talk about them as fresh starts, and can you talk a little bit about what a fresh start is, and how they can be useful in changing our behaviors and even, also, their limitations?
Katy Milkman: Yeah, absolutely. The “fresh start effect” is one of my favorite topics I've ever studied. It's work I did with Hengchen Dai of [the University of California, Los Angeles,] and Jason Riis, a former colleague here at Wharton.
We got really interested in this after I visited Google in, I think, it was 2012, and learned that they were struggling to motivate their employees to take advantage of lots of wonderful benefits. And they had brought in a bunch of outside speakers to share insights about what could be done to sort of nudge people towards making positive change; I was one of them. And after I presented some research I got this great question from a member of the audience about whether there are moments when people are more open to making a change in their life, and that's what kick-started this research agenda. The immediate response was, “I don't know. The research really hasn't looked at whether or not our motivation varies over time.” But my collaborators and I all immediately had a very strong intuition—and that's what drove us to work on this question—that there are moments that bring us added motivation; the first one, of course, that comes to mind is New Year's. But what we did is we started digging into the literature on the way that people think about their lives and what's sort of driving this effect.
We learned there's a whole literature on what's called “autobiographical memory” and that the way we think about time is not linear. Instead, we actually think about our lives like we're characters in a novel and there are chapter breaks in that storyline, if you will. So you might have, you know, the years living in a certain city, the years attending college, the years working for a certain employer. Those are chapters in your life story in the way that you tell it and think about it. And instead of thinking about every day being equally weighted, those chapter breaks are really momentous.
When we cross into a new chapter, we feel a sense of a discontinuity and a new beginning, and we feel disconnected from who we were in the prior chapter. We can say, “Oh, that was the old me, and the old me didn't do XYZ that I wanted to do, but the new me will be different.” It gives us optimism about what we're capable of, and also, with that sense of possibility, we often become more reflective at these chapter breaks and do big picture thinking.
So what was really interesting in our work, though, is these chapter breaks don't just come at major life shifts. We found that they come at lots of moments that signal miniature new beginnings—so the start of every new year being kind of a miniature new beginning, right? It's not a major chapter break in your life story ...
Pierre-Louis: Mm-hmm.
Milkman: Like moving to a new community or taking a new job, but it's a minor one, and it comes with a bunch of, also, social pressure to make change because everyone starts talking about New Year's resolutions—about 40 percent of Americans make them.
We also found that there are other moments on the calendar like New Year's that haven't been as widely discussed that have the same effect to a smaller degree, so every Monday is a miniature fresh start ...
Pierre-Louis: Mm-hmm.
Milkman: The start of a new month, celebrating birthdays and other holidays that we associate with new beginnings, so that might be Easter or Rosh Hashanah, Eid—so each religion has its own marker of new beginnings. And all those dates tend to spur positive behavior change. In our research we've looked at when people show up and attend the gym; when people search for the term “diet” on Google, which is the most popular New Year's resolution, for better or for worse; and also, we see it when we look at when people set goals on a popular goal-setting website online about everything from their health to their finances and the environment.
Pierre-Louis: So one of the studies that you reference in your book about baseball players who get traded is that fresh starts aren't always positive, right? Can we talk a little bit about that?
Milkman: Yeah, so Hengchen did a number of experiments and also analyzed data on Major League Baseball players. What she was interested in is the fact that trades in Major League Baseball have different implications for your performance statistics depending on whether you're traded across leagues or within leagues. So if you're traded across leagues, all of your season-to-date statistics reset because you're in a new league and it's sort of a different playing field, if you will. But if you're traded within league, all of your season-to-date statistics are retained, and you just keep working on that baseline.
She was interested in these two people who essentially are experiencing the same thing—they're both moving to a new city; they're both working with new teammates—but one of them has a much bigger fresh start than the other. They have a performance reset. Is there a difference in how that affects them? And what she found was that there are differences in a really interesting pattern: If you've been having a good season and you have a performance reset, it's harmful.
So two people, both get traded, both have been performing really well, but one of them has to deal with the fact that they're starting their season over in terms of their statistics, that person's harmed more than the person who gets to hold on to their record. On the flip side, though, for two players who were both underperforming season to date and they both get traded—one of them gets to hold on to their record, and the other doesn't—the clean slate is beneficial and improves the performance of the person who gets that clean slate when they've been having a tough season.
So this is sort of the double-edged sword of a fresh start in a very nice field study, showing that when things are going well, these kinds of fresh starts and disruptions can be harmful.
Pierre-Louis: And it felt like, to me, that kind of underpinning it is a question of, like, “What happens to our habits?” And when we're trying to make a big change, in many ways, what we're trying to do is change our habits, right? Like, if you want to get in shape, you don't get in shape overnight; that's, like, days and days and days of repetitive behavior. And so I think that's the thing most people struggle with, is: “How do we develop and maintain these consistent habits, and when we get disrupted how do we get back to it?” Can you talk about some tips and techniques that people can use?
Milkman: I think one of the most important things is to plan for the disruption. If you're going away for the holidays and you're in a routine that's working for you, whether it's around meditation or exercise or, you know, practicing Spanish on Duolingo, if you're like me, whatever it is, when you're away it breaks those routines; it breaks those cycles. It's no longer going to be automatic to engage in the same sets of routines when you come back, and so you need to be deliberate about planning: “Okay, when I get back how am I going to start up this habit that I had built again? How am I gonna make sure it's worked into my schedule?” That can be through making explicit plans—this is boring but important—like, you know, when are you gonna do it? Where are you gonna do it? Put it on your calendar. Set a reminder for yourself.
And it can also be by being deliberate about using some of the other tools we know help a lot with habit formation, like ensuring it's rewarding and that you have a fun way to get it done. So maybe that's finding ways to combine something that you feel is a chore with something that you really enjoy. So exercise, the example is, like, you know, “I only let myself binge-watch my favorite TV shows while I'm exercising.” Maybe you only get to listen to your favorite podcast or open your favorite bottle of wine when you're cooking a fresh meal for your family, and you set that as a rule when you wanna get back on that habit.
Maybe it's accountability that you need. Maybe it's somebody who you're going to exercise with, right? And in fact, research shows that when you have a workout buddy, that can boost your likelihood to follow through by both making it fun and ensuring you're accountable to someone. Or you could have a commitment device—you can put money on the line that you'll have to forfeit if you fail to follow through. But basically, you need to use these tools that we know help us start healthy habits to a greater degree after a disruption.
Pierre-Louis: I know in the book you talk about the “Mary Poppins effect,” the idea of “spoonful of sugar helps the medicine go down”—pairing something really lovely, like your favorite TV show, with exercise, for example. But something that kind of struck me when I was reading that portion of the book is: sometimes it feels like people are setting goals for themselves that they, like, want to want to set; they don't necessarily actually want it.
So they want to be healthier, so they want to exercise, right? But in their head, because of the way we talk about exercise in society, it becomes very prescriptive, so they're like, “I should run a marathon because that's what fit people do.”
Milkman: Mm-hmm.
Pierre-Louis: But they hate running, and maybe instead of focusing on running, they should actually be ice-skating because they've always wanted to ice skate as a kid, and they couldn't afford to, maybe, and now they can.
But it also seems like sometimes, especially with New Year's resolutions, we kind of lose a forest for the trees, where we're focusing on a specific form of exercise or a specific type of diet and not sort of a bigger picture of, like, what healthy eating looks like or what exercise can look like and finding the joy in things we naturally want to do.
Milkman: I love that takeaway from the book and 100 percent agree with you that one of the things we can do is just step back and think big picture about whether we're setting the right goals and what the higher-level goal is and if there's another path to the higher-level goal that's more likely to work, so if your high-level goal is “be in shape this year,” and you've chosen to pursue it in an unpleasant way that you don't like, then step back and ask, “Can I do something that I will enjoy more to get to the same outcome?” Because one of the best predictors of success is whether you enjoy the process of pursuing your goals. If you find it miserable, you do not persist.
So yes, ice-skate rather than running a marathon [Laughs] if that will bring you joy. Any way you move your body is good for you, whether it's going to dance class with a friend, taking a walk in the morning in the fresh air with a cup of coffee and someone you enjoy talking to—you know, making it social is another really important way to improve how much we enjoy goal pursuit, and the same is true for eating right and, and, frankly, achieving goals at work.
Pierre-Louis: One of the things that I thought was really interesting is that, like, we talk about making things enjoyable, but you also talk about self-imposed constraints and how sometimes, to execute on a goal that we want, we can choose to opt in to constraints to reach that goal. Can you talk a little bit about that?
Milkman: Yeah, I think this is some of the most counterintuitive but powerful research in behavioral science and goal pursuit. The idea is really, you know, we know how useful it is when we have a great boss or a great teacher or a great parent who is, you know, holding our feet to the fire and saying, like, “These are the deadlines. These are the consequences.” That can be really effective for getting us motivated in getting things done. But what we often, I think, fail to appreciate is that we have the power to be our own boss [Laughs], our own teacher or our own parent and create constraints and deadlines with consequences in a way that will motivate us and help us achieve more.
So let me give you a really concrete example of a study that I think illustrates just how powerful this way of thinking can be. This is a study that was done by Dean Karlan of Northwestern University and collaborators where they were looking at whether they could help people quit smoking ...
Pierre-Louis: Mm-hmm.
Milkman: So, like, a really tough goal, right?
Pierre-Louis: Yeah.
Milkman: There's even addiction involved here. The tool was: randomly assign people to either get a standard smoking-cessation program or that standard program plus what we call a commitment device. A commitment device, in this case, meant a savings account that you could put your own money into—it's optional—but you learn that if you fail a nicotine or cotinine test in your urine six months later, all the money will be taken away. That savings account will disappear. So you're basically given an opportunity to fine yourself for continuing to smoke. And what the researchers found is: those who had access to this account, they quit at a 30 percent higher rate than the standard group.
So finding a way to be able to hold your feet to the fire by penalizing yourself if you don't succeed can be really powerful. And there are many ways you can do this. You can do this with friends. You can ask them to insist that you pay them [Laughs] or put money towards a charitable cause if you fail to achieve a certain goal. There are actually websites that I have no affiliation with that will let you do this—Beeminder is one; Stickk.com with two k's is another—where you can put money on the line that you will have to forfeit if you fail to achieve a goal.
And they can also be as simple as just creating friction in your life, so it doesn't have to involve money. You can think of, you know, not having any junk food in your house—you clear out all your cabinets. That's a commitment device because now you've created a constraint: you're gonna have to leave your house or pay delivery fees to get the junk food you crave. So there's a lot of different tools we can use that fall into this category of creating constraints for ourselves, behaving like our own boss, in order to set ourselves up for success with our goals.
Pierre-Louis: One of the things I really appreciated in your book is when you talked about how people will often harp on the fact that [more than] 80 percent of people who set New Year's resolutions fail, but that means 20 percent succeeded, right?
Milkman: Look, it's brave to try to make a change. The easy thing to do is do nothing. And so I think it's great anytime someone wants to find a way to improve—just because New Year's is sort of a gimmicky moment to leap on the bandwagon doesn't mean it's not a great moment to make a change. And you can give yourself a better probability of success, though, if you do more than just saying, “I'm gonna try to be healthy this year,” “I'm gonna try to raise my performance at work,” or “I'm gonna try to improve my relationships with my family.”
Be more concrete. Be thinking about: What's a measurable goal that you wanna achieve? How are you gonna do it? You know, map out your strategy, just the way you would if you had a big project assigned to you at work. Use the science that we've talked about in the show to give yourself a better chance of success.
And then, P.S., if it doesn't work out this time, that doesn't mean New Year's resolutions are a bad idea next time. And P.S., you can make a new resolution next Monday, the beginning of the next week, on your birthday or on any arbitrary day because all of this is in our head about fresh starts anyhow. [Laugh.] So give yourself some grace and try your best, and then if it doesn't work out, try again the next time.
Pierre-Louis: Thank you so much for joining us today.
Milkman: Yeah, thank you so much for having me.
Pierre-Louis: That's our episode. Don't forget to tune in on Wednesday, when we look at how the Trump administration's policies are impacting children's health.
Science Quickly is produced by me, Kendra Pierre-Louis, along with Fonda Mwangi, Sushmita Pathak and Jeff DelViscio. 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 Kendra Pierre-Louis. See you next time!
Kendra Pierre-Louis is a climate reporter focusing on the science and social impacts of climate change. She has worked for Gimlet, the Bloomberg and Popular Science. Pierre-Louis is based in New York City.
Sushmita Pathak is a multimedia editor at Scientific American and a producer of Science Quickly. She previously worked at NPR and was a regular contributor to The World from PRX and The Christian Science Monitor. Her science reporting has appeared in WIRED, Science Magazine, Undark, EOS, and more.
Fonda Mwangi is an award-winning multimedia editor at Scientific American and producer of Science Quickly. She previously worked 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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Nature Chemistry
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Amine functionalization is crucial in pharmaceutical and agrochemical synthesis yet direct enantioselective α-C(sp3)–H functionalization of N-alkyl anilines remains challenging. Here we show a metallaphotoredox-catalysed radical approach for α-C(sp3)–H arylation of N-alkyl anilines, introducing a simple, sterically hindered aryl ketone photocatalyst. This key innovation slows undesired back-electron transfer, enabling efficient α-anilinoalkyl radical generation. Our strategy uses a sequential single-electron transfer and proton transfer process, thereby overcoming multiple limitations of existing methods. In conjunction with a chiral nickel catalyst, we have achieved site-selective, enantioselective arylation of diverse N-alkyl anilines with various (hetero)aryl halides. The method exhibits exceptional functional group tolerance, enabling modular functionalization of complex molecular structures. This approach provides an effective route to valuable α-aryl amines, offering significant possibilities for drug discovery and streamlining challenging synthetic sequences.
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The data that support the findings of this study are available within the article and Supplementary Information. Details about materials and methods, experimental procedures, characterization data, mechanistic studies, NMR and HPLC spectra are available in the Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2383177 (39) and 2383178 (17). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
Bhutani, P. et al. US FDA approved drugs from 2015–June 2020: a perspective. J. Med. Chem. 64, 2339–2381 (2021).
Article
CAS
PubMed
Google Scholar
Marshall, C. M., Federice, J. G., Bell, C. N., Cox, P. B. & Njardarson, J. T. An update on the nitrogen heterocycle compositions and properties of US FDA-approved pharmaceuticals (2013–2023). J. Med. Chem. 67, 11622–11655 (2024).
Article
CAS
PubMed
Google Scholar
McGrath, N. A., Brichacek, M. & Njardarson, J. T. A graphical journey of innovative organic architectures that have improved our lives. J. Chem. Educ. 87, 1348–1349 (2010).
Article
CAS
Google Scholar
Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist's toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).
Article
CAS
PubMed
Google Scholar
Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).
Article
CAS
PubMed
Google Scholar
Chen, W., Ma, L., Paul, A. & Seidel, D. Direct α-C–H bond functionalization of unprotected cyclic amines. Nat. Chem. 10, 165–169 (2018).
Article
CAS
PubMed
Google Scholar
Dutta, S., Li, B., Rickertsen, D. R. L., Valles, D. A. & Seidel, D. C–H bond functionalization of amines: a graphical overview of diverse methods. SynOpen 05, 173–228 (2021).
Article
CAS
Google Scholar
Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).
Article
CAS
PubMed
Google Scholar
Boström, J., Brown, D. G., Young, R. J. & Keserü, G. M. Expanding the medicinal chemistry synthetic toolbox. Nat. Rev. Drug Discov. 17, 709–727 (2018).
Article
PubMed
Google Scholar
Saint-Denis, T. G., Zhu, R.-Y., Chen, G., Wu, Q.-F. & Yu, J.-Q. Enantioselective C(sp3)‒H bond activation by chiral transition metal catalysts. Science 359, eaao4798 (2018).
Article
PubMed
PubMed Central
Google Scholar
Jain, P., Verma, P., Xia, G. & Yu, J.-Q. Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides. Nat. Chem. 9, 140–144 (2017).
Article
CAS
PubMed
Google Scholar
Zhang, R. K. et al. Enzymatic assembly of carbon–carbon bonds via iron-catalysed sp3 C–H functionalization. Nature 565, 67–72 (2019).
Article
CAS
PubMed
Google Scholar
Zhang, J., Huang, X., Zhang, R. K. & Arnold, F. H. Enantiodivergent α-amino C–H fluoroalkylation catalyzed by engineered cytochrome P450s. J. Am. Chem. Soc. 141, 9798–9802 (2019).
Article
CAS
PubMed
PubMed Central
Google Scholar
Ren, X. et al. Enantioselective single and dual α-C–H bond functionalization of cyclic amines via enzymatic carbene transfer. J. Am. Chem. Soc. 145, 537–550 (2023).
Article
CAS
PubMed
Google Scholar
Shu, X., Huan, L., Huang, Q. & Huo, H. Direct enantioselective C(sp3)–H acylation for the synthesis of α-amino ketones. J. Am. Chem. Soc. 142, 19058–19064 (2020).
Article
CAS
PubMed
Google Scholar
Shu, X., Zhong, D., Lin, Y., Qin, X. & Huo, H. Modular access to chiral α-(hetero)aryl amines via Ni/photoredox-catalyzed enantioselective cross-coupling. J. Am. Chem. Soc. 144, 8797–8806 (2022).
Article
CAS
PubMed
Google Scholar
Li, J. et al. Enantioselective alkylation of α-amino C(sp3)−H bonds via photoredox and nickel catalysis. Nat. Catal. 7, 889–899 (2024).
Article
Google Scholar
Golden, D. L., Suh, S. E. & Stahl, S. S. Radical C(sp3)-H functionalization and cross-coupling reactions. Nat. Rev. Chem. 6, 405–427 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
Holmberg-Douglas, N. & Nicewicz, D. A. Photoredox-catalyzed C−H functionalization reactions. Chem. Rev. 122, 1925–2016 (2022).
Article
CAS
PubMed
Google Scholar
Zhang, J. & Rueping, M. Metallaphotoredox catalysis for sp3 C–H functionalizations through hydrogen atom transfer (HAT). Chem. Soc. Rev. 52, 4099–4120 (2023).
Article
PubMed
Google Scholar
Bellotti, P., Huang, H.-M., Faber, T. & Glorius, F. Photocatalytic late-stage C–H functionalization. Chem. Rev. 123, 4237–4352 (2023).
Article
CAS
PubMed
Google Scholar
Lipp, A., Badir, S. O. & Molander, G. A. Stereoinduction in metallaphotoredox catalysis. Angew. Chem. Int. Ed. 60, 1714–1726 (2021).
Article
CAS
Google Scholar
Chan, A. Y. et al. Metallaphotoredox: the merger of photoredox and transition metal catalysis. Chem. Rev. 122, 1485–1542 (2022).
Article
CAS
PubMed
Google Scholar
Li, Z., Li, C., Ding, Y. & Huo, H. Photoinduced nickel-catalyzed enantioselective coupling reactions. Coord. Chem. Rev. 460, 214479 (2022).
Article
CAS
Google Scholar
Xu, W. & Xu, T. Dual nickel- and photoredox-catalyzed asymmetric reductive cross-couplings: just a change of the reduction system? Acc. Chem. Res. 57, 1997–2011 (2024).
Article
CAS
PubMed
Google Scholar
Zuo, Z. et al. Enantioselective decarboxylative arylation of α-amino acids via the merger of photoredox and nickel catalysis. J. Am. Chem. Soc. 138, 1832–1835 (2016).
Article
CAS
PubMed
PubMed Central
Google Scholar
Cheng, X., Lu, H. & Lu, Z. Enantioselective benzylic C–H arylation via photoredox and nickel dual catalysis. Nat. Commun. 10, 3549 (2019).
Article
PubMed
PubMed Central
Google Scholar
Xu, S. et al. Enantioselective C(sp3)–H functionalization of oxacycles via photo-HAT/nickel dual catalysis. J. Am. Chem. Soc. 145, 5231–5241 (2023).
Article
CAS
PubMed
Google Scholar
Hu, X., Cheng-Sánchez, I., Kong, W. Q., Molander, G. A. & Nevado, C. Nickel-catalysed enantioselective alkene dicarbofunctionalization enabled by photochemical aliphatic C–H bond activation. Nat. Catal. 7, 655–665 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
McNally, A., Prier, C. K. & MacMillan, D. W. Discovery of an α-amino C−H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).
Article
CAS
PubMed
PubMed Central
Google Scholar
Ahneman, D. T. & Doyle, A. G. C−H functionalization of amines with aryl halides by nickel-photoredox catalysis. Chem. Sci. 7, 7002–7006 (2016).
Article
CAS
PubMed
PubMed Central
Google Scholar
Beatty, J. W. & Stephenson, C. R. J. Amine functionalization via oxidative photoredox catalysis: methodology development and complex molecule synthesis. Acc. Chem. Res. 48, 1474–1484 (2015).
Article
CAS
PubMed
PubMed Central
Google Scholar
Zhang, C., Li, Z.-L., Gu, Q.-S. & Liu, X.-Y. Catalytic enantioselective C(sp3)–H functionalization involving radical intermediates. Nat. Commun. 12, 475 (2021).
Article
PubMed
PubMed Central
Google Scholar
Xu, G. Q., Wang, W. D. & Xu, P. F. Photocatalyzed enantioselective functionalization of C(sp3)–H bonds. J. Am. Chem. Soc. 146, 1209–1223 (2024).
Article
CAS
PubMed
Google Scholar
Chen, X. & Kramer, S. Photoinduced transition-metal-catalyzed enantioselective functionalization of non-acidic C(sp3)−H bonds. Chem Catal. 4, 100854 (2024).
CAS
Google Scholar
Dombrowski, G. W. et al. Efficient unimolecular deprotonation of aniline radical cations. J. Org. Chem. 70, 3791–3800 (2005).
Article
CAS
PubMed
Google Scholar
Zhao, H. & Leonori, D. Minimization of back-electron transfer enables the elusive sp3 C−H functionalization of secondary anilines. Angew. Chem. Int. Ed. 60, 7669–7674 (2021).
Article
CAS
Google Scholar
Shen, Y., Gu, Y. & Martin, R. sp3 C–H arylation and alkylation enabled by the synergy of triplet excited ketones and nickel catalysts. J. Am. Chem. Soc. 140, 12200–12209 (2018).
Article
CAS
PubMed
Google Scholar
Dantas, J. A., Correia, J. T. M., Paixão, M. W. & Corrêa, A. G. Photochemistry of carbonyl compounds: application in metal-free reactions. ChemPhotoChem 3, 506–520 (2019).
Article
CAS
Google Scholar
Mateos, J., Cuadros, S., Vega-Peñaloza, A. & Dell'Amico, L. Unlocking the synthetic potential of light-excited aryl ketones: applications in direct photochemistry and photoredox catalysis. Synlett 33, 116–128 (2022).
Article
CAS
Google Scholar
Iziumchenko, V. & Gevorgyan, V. Recent advances in dual triplet ketone/transition-metal catalysis. Synlett 34, 1289–1308 (2023).
Article
CAS
Google Scholar
Trowbridge, A., Reich, D. & Gaunt, M. J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 561, 522–527 (2018).
Article
CAS
PubMed
Google Scholar
Henry Blackwell, J., Harris, G. R., Smith, M. A. & Gaunt, M. J. Modular photocatalytic synthesis of α-trialkyl-α-tertiary amines. J. Am. Chem. Soc. 143, 15946–15959 (2021).
Article
CAS
PubMed
Google Scholar
Waller, H. C. & Gaunt, M. J. Silyl radicals as single-electron reductants: α-aminoalkyl radical formation via a photocatalytic oxidatively initiated radical chain process. J. Am. Chem. Soc. 146, 25894–25901 (2024).
Article
CAS
PubMed
PubMed Central
Google Scholar
Ryder, A. S. H. et al. Photocatalytic α-tertiary amine synthesis via C−H alkylation of unmasked primary amines. Angew. Chem. Int. Ed. 59, 14986–14991 (2020).
Article
CAS
Google Scholar
Askey, H. E. et al. Photocatalytic hydroaminoalkylation of styrenes with unprotected primary alkylamines. J. Am. Chem. Soc. 143, 15936–15945 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
Shen, Y. & Rovis, T. Late-stage N−Me selective arylation of trialkylamines enabled by Ni/photoredox dual catalysis. J. Am. Chem. Soc. 143, 16364–16369 (2021).
Article
CAS
PubMed
PubMed Central
Google Scholar
Yang, T. et al. Multicomponent construction of tertiary alkylamines by photoredox/nickel-catalyzed aminoalkylation of organohalides. J. Am. Chem. Soc. 146, 29177–29188 (2024).
Article
CAS
PubMed
Google Scholar
Lin, Q., Spielvogel, E. H. & Diao, T. N. Carbon-centered radical capture at nickel(II) complexes: spectroscopic evidence, rates, and selectivity. Chem 9, 1295–1308 (2023).
Article
CAS
PubMed
PubMed Central
Google Scholar
Cabré, A., Verdaguer, X. & Riera, A. Recent advances in the enantioselective synthesis of chiral amines via transition metal-catalyzed asymmetric hydrogenation. Chem. Rev. 122, 269–339 (2022).
Article
PubMed
Google Scholar
Barrios-Rivera, J., Xu, Y., Wills, M. & Vyas, V. K. A diversity of recently reported methodology for asymmetric imine reduction. Org. Chem. Front. 7, 3312–3342 (2020).
Article
CAS
Google Scholar
Tian, Y., Hu, L. A., Wang, Y.-Z., Zhang, X. & Yin, Q. Recent advances on transition-metal-catalysed asymmetric reductive amination. Org. Chem. Front. 8, 2328–2342 (2021).
Article
CAS
Google Scholar
Trowbridge, A., Walton, S. M. & Gaunt, M. J. New strategies for the transition-metal catalyzed synthesis of aliphatic amines. Chem. Rev. 120, 2613–2692 (2020).
Article
CAS
PubMed
Google Scholar
Ni, S. et al. C–heteroatom coupling with electron-rich aryls enabled by nickel catalysis and light. Nat. Catal. 7, 733–741 (2024).
Article
CAS
Google Scholar
Nayak, S. & Ackerman-Biegasiewicz, L. K. G. Harnessing electron-rich arenes in nickel photoredox catalysis. Nat. Catal. 7, 855–856 (2024).
Article
CAS
Google Scholar
Diccianni, J., Lin, Q. & Diao, T. Mechanisms of nickel-catalyzed coupling reactions and applications in alkene functionalization. Acc. Chem. Res. 53, 906–919 (2020).
Article
CAS
PubMed
PubMed Central
Google Scholar
Grimm, M. L., Allen, W. J., Finn, M., Castagnoli, N. & Tanko, J. M. Reaction of benzophenone triplet with aliphatic amines. What a potent neurotoxin can tell us about the reaction mechanism. Bioorg. Med. Chem. 19, 1458–1463 (2011).
Article
CAS
PubMed
Google Scholar
Simon, J. D. & Peters, K. S. Picosecond studies of organic photoreactions. Acc. Chem. Res. 17, 277–283 (1984).
Article
CAS
Google Scholar
Cohen, S. G., Parola, A. & Parsons, G. H. Jr. Photoreduction by amines. Chem. Rev. 73, 141–161 (1973).
Article
CAS
Google Scholar
Capaldo, L., Ravelli, D. & Fagnoni, M. Direct photocatalyzed hydrogen atom transfer (HAT) for aliphatic C−H bonds elaboration. Chem. Rev. 122, 1875–1924 (2022).
Article
CAS
PubMed
Google Scholar
Guerin, B. & Johnston, L. J. Laser flash photolysis studies of 2,4,6-trialkylphenyl ketones. Can. J. Chem. 67, 473–480 (1989).
Article
CAS
Google Scholar
Chung, C.-H., Tseng, S.-L., Yang, Y.-N. & Chen, Y.-F. Use of glucagon receptor antagonists or inverse agonists for treatment of diabetes. International patent WO 2018/140338 A1 (2018).
Chung, C.-H., Tseng, S.-L. & Hsu, H.-E. Processes for producing amide compounds, and their crystalline and salt form. International patent WO 2021/178486 A1 (2021).
Sasaki, M. et al. Preparation of aromatic ring compounds as glucagon antagonists. International patent WO 2013/147026 A1 (2013).
Conner, S. E., Li, J. & Zhu, G. N-(2-Carboxyethyl)benzamides as glucagon receptor antagonists or inverse agonists, their preparation, pharmaceutical compositions and use in therapy. International patent WO 2007/106181 A2 (2007).
Ting, S. I. et al. 3d–d excited states of Ni(II) complexes relevant to photoredox catalysis: spectroscopic identification and mechanistic implications. J. Am. Chem. Soc. 142, 5800–5810 (2020).
Article
CAS
PubMed
Google Scholar
Cagan, D. A. et al. Elucidating the mechanism of excited-state bond homolysis in nickel–bipyridine photoredox catalysts. J. Am. Chem. Soc. 144, 6516–6531 (2022).
Article
CAS
PubMed
PubMed Central
Google Scholar
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We thank H. Xu and Y. Yang for insightful discussions. We are grateful for financial support provided by the National Key R&D Program of China (2021YFA1502500 to H.H. and C.W.; 2023YFA1507202 to H.H.), the National Natural Science Foundation of China (22071203 and 22471228 to H.H.), the Natural Science Foundation of Fujian Province (2022J01524 to C.Z.) and the Fundamental Research Funds for the Central Universities (20720240125 to H.H.).
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China
Weisai Zu, Xiang Wan, Haoran Wu, Jingwen Huo, Cankun Zhang, Chengyang Li, Yongliang Huang, Zhen Xu, Yumin Xu, Tao Li, Junliang Cheng, Jian-Liang Ye, Cheng Wang & Haohua Huo
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W.Z. and X.W. developed the reactions and performed the majority of synthetic experiments and mechanistic investigations. H.W., J.H., C.Z., C.L., Y.H., Z.X., Y.X., T.L., J.C., J.-L.Y. and C.W. assisted with synthetic experiments and analysed the data. H.H. directed the project. H.H. and W.Z. wrote the paper with input from all authors.
Correspondence to
Haohua Huo.
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Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.
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All yields and stereoselectivities represent the average of two experiments, and the percent yield represents purified products. See Supplementary Methods for experimental details. aAryl iodide was used as the electrophile.
Supplementary Methods, Tables 1–9 and Figs. 1–320, experimental procedures and characterization data.
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Zu, W., Wan, X., Wu, H. et al. Direct enantioselective C(sp3)−H coupling of N-alkyl anilines via metallaphotoredox catalysis.
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Early embryo geometry is one of the most invariant species-specific traits, yet its role in ensuring developmental reproducibility and robustness remains underexplored. Here we show that in zebrafish, the geometry of the fertilized egg—specifically its curvature and volume—serves as a critical initial condition triggering a cascade of events that influence development. The embryo geometry guides patterned asymmetric cell divisions in the blastoderm, generating radial gradients of cell volume and nucleocytoplasmic ratio. These gradients generate mitotic phase waves, with the nucleocytoplasmic ratio determining individual cell cycle periods independently of other cells. We demonstrate that reducing cell autonomy reshapes these waves, emphasizing the instructive role of geometry-derived volume patterns in setting the intrinsic period of the cell cycle oscillator. In addition to organizing cell cycles, early embryo geometry spatially patterns zygotic genome activation at the midblastula transition, a key step in establishing embryonic autonomy. Disrupting the embryo shape alters the zygotic genome activation pattern and causes ectopic germ layer specification, underscoring the developmental significance of geometry. Together, our findings reveal a symmetry-breaking function of early embryo geometry in coordinating cell cycle and transcriptional patterning.
Developmental reproducibility and robustness are critical for the survival of a species. Understanding the foundations of this robustness is, therefore, a question of fundamental importance and has become a central focus of research. Although most studies have concentrated on the genetic and molecular mechanisms underlying development, the potential influence of geometry on developmental robustness has remained largely overlooked.
Recent work using minimal active matter models has revealed that geometry and curvature play a pivotal role in the mechanical response of epithelial sheets1,2,3,4,5. These insights can, for example, account for the anisotropic distribution of myosin II observed in Drosophila embryos6. Such findings highlight geometry as a key organizer of mechanical force generation during morphogenesis. Yet, whether—and how—geometry governs more complex, large-scale developmental processes, such as embryo patterning and coordinated cell divisions, remains an open question.
Metazoan development begins with a single cell, the zygote, which undergoes several rounds of rapid divisions (cleavages) to generate a large population of cells capable of adopting multiple fates and exhibiting diverse morphogenetic behaviours. In many species, these early divisions are initially highly synchronous. This cell cycle synchrony is best understood in Drosophila, where it is driven by the propagation of a chemical wave. In cleavage-stage Drosophila embryos, which are syncytial, nuclear cycles synchronize through ‘sweep waves'—coupling-independent phase waves emerging on top of gradients of cyclin-dependent kinase 1 (Cdk1) activity established through reaction–diffusion dynamics7,8. Similar mechanisms have been observed in Xenopus egg extracts, another syncytial system, where nuclear divisions are coordinated by trigger waves of Cdk1 activity9. By contrast, in intact Xenopus embryos, where cells are fully separated, early cleavage divisions synchronize independently of cell–cell coupling10. Importantly, across systems, the propagation of cell cycle waves slows progressively with successive division rounds, leading to ‘metasynchronization', where cell cycles remain spatially patterned before eventually becoming fully desynchronized7,10,11.
Initial cleavages in the zebrafish embryo are meroblastic; that is, the cytoplasm but not the yolk is partitioned through cytokinesis11. Cell cycles at this stage occur highly synchronously, to begin with, and gradually desynchronize (metasynchrony) before completely desynchronizing at division round 10 (ref. 11). Importantly, although the cleavage-stage cells cycle between only the S and M phases with no detectable gap phases, complete desynchronization around division round 10 is thought to occur mainly due to a heterogeneous introduction of gap phases to the cell cycles12. To determine the spatiotemporal pattern of cell divisions in cleavage-stage zebrafish embryos, we recorded time-lapse images of Tg(actb2:rfp-pcna) embryos. Due to the absence of gap phases in the cleavage stages, the disappearance of the nuclear red fluorescent protein (RFP)-proliferating cell nuclear antigen (PCNA) localization allowed us to reliably score the conclusion of the S phase and the onset of mitosis13. Consistent with previous reports, we observed three distinct phases with different extents of mitotic synchrony11,14. In the first three cell division rounds, cell cycles exhibited very high synchrony (synchronous phase) (Fig. 1b and Extended Data Fig. 1a,b). Thereafter, cell divisions from division rounds 4–9 showed slight but clearly detectable delays (metasynchronous phase) (Fig. 1b and Extended Data Fig. 1a,b). These delays increased throughout the metasynchronous phase, with cells in division round 4 dividing with a mean division timing variance of 0.10 min2 and in division round 9 with 3.43 min2 (Fig. 1b). In particular, as previously reported, these metasynchronous divisions occurred in a spatiotemporally patterned manner, forming a radial ‘mitotic wave' that originates near the animal pole (AP), where cells divide first and propagate towards the margin, where they divide last (Fig. 1c and Extended Data Fig. 1c,d)11,15,16. Furthermore, consistent with the increasing variance in division timings during the metasynchronous phase, the speed at which this mitotic wave travels gradually decreased over consecutive division rounds (Fig. 1d). After division round 9, cells divided largely non-synchronously, marking the onset of the asynchronous phase.
a, Schematic of a zebrafish embryo at the late cleavage stage. The blastoderm is positioned at the AP atop the yolk cell at the vegetal pole (VP). The last row of blastoderm cells (cyan) constitutes the margin. b, Line plot of cell division timing variance in Tg(actb2:rfp-pcna) embryos for cleavage division rounds 4–11. Grey lines, individual embryos; black line, mean across three embryos. The inset shows variance (mean ± s.e.m.) for division rounds 5–9. c, Contour plot of the radial mitotic wave across all surface cells at division round 8 in a representative wild-type embryo. Each dot represents the position of a nucleus along the x–y plane, and the size of the dot indicates its position along the z axis (AP–margin axis). Colours represent the division timing for each nucleus. d, Bar plot of mitotic wave velocities (mean ± s.d.), calculated by generating distance–time plots, for cleavage division rounds 2–9, with the red dots showing wave velocities for individual embryos. In sequence from division rounds 2–9, n = 5, 10, 11, 12, 12, 12, 11 and 10 embryos, respectively. The blue dashed line indicates the curve described by the equation v = (L/T0) × (1/0.019n), where L is the total AP–margin distance, T0 is the cell cycle period at the AP and n is the division round to represent the effect of a 1.9% period gradient along the AP–margin axis on mitotic wave speeds. e,f, Representative contour plots of mitotic waves in division round 8 in embryos injected with either 0.3 ng of Histone 1 protein into a single blastomere at the 32-cell stage (e) or 12-pg chek1 mRNA at the 1-cell stage (f). g, Line plots showing the ratios of cell cycle periods at the margin and AP in division rounds 6–8 in individual embryos (grey lines) and across all embryos (green line, mean ± s.e.m.) for n = 9 embryos. Two-tailed one-sample t-test. *: 0.0189, **: 0.0033, ***: 0.0004. The red dashed line indicates a ratio of 1, where both marginal and AP cells have the same cell cycle period. h, Bar plot of the M-phase and S-phase lengths (mean ± s.e.m.) at division round 8. Dots represent data from individual embryos. Two-tailed Student's t-test. P = 0.0005, n = 8 embryos. i, Box plot of S-phase duration in division round 8 as a function of cell position relative to the AP. n = 5 embryos. The box in the box plot represents the middle 50% of the distribution, with the line representing the median and the whiskers indicating the minima and maxima.
Source data
To understand how cell cycles are seemingly coordinated into radial mitotic waves during the metasynchronous phase, we asked if their synchronization occurs via cell–cell coupling. To that end, we artificially desynchronized cell cycles at the 32/64-cell stage through mosaic Histone 1 protein injections, previously shown to effectively alter cell cycle progression17,18,19. We found that Histone 1-positive and thus desynchronized cells failed to resynchronize with their neighbouring control cells by division round 9, after which cell cycles normally desynchronize in control embryos (Fig. 1e, Extended Data Fig. 2, Supplementary Section 5 and Supplementary Video2). To address the possibility that these cell cycles could have resynchronized given sufficient time, we assessed the cell cycle progression in embryos ectopically expressing the Cdk1 inhibitor, Chek1, through chek1 mRNA injection in the one-cell stage embryo, which, by being heterogeneously distributed in the embryo, has previously been shown to interfere with cell cycle synchronization20. chek1-overexpressing embryos exhibited cell cycle desynchronization considerably earlier than control embryos, and failed to resynchronize despite completing all cleavage division rounds (Fig. 1f, Extended Data Fig. 2and Supplementary Video 3). Collectively, these observations suggest that cell cell coupling plays only a minor role, if any, in cell cycle synchronization in the zebrafish embryo.
To determine by which coupling-independent mechanism the radial mitotic wave is formed, we analysed the evolution of the mitotic wave through consecutive division rounds. We found that the transition from synchrony to metasynchrony was gradual rather than abrupt, suggesting a progressive accumulation of delays rather than distinct switches leading to the observed loss of synchrony (Fig. 1b). Importantly, this gradual loss of synchrony was due to unequal cell cycle periods. For instance, between the metasynchronous division rounds 6–8, cells at the margin cycled with 2%–4% longer periods than those at the AP (Fig. 1g). This discrepancy arose exclusively due to a longer S phase (assuming absent gap phases), which increased in cells as a function of their distance from the AP (Fig. 1h,i). Although noisy, such period gradients may lead to the observed gradual slowing down of the radial mitotic wave by accumulating increasing delays in the marginal cells over consecutive division rounds. To test this hypothesis, we assumed that the period T is a linear function of the distance z from the AP: \(T={T}_{0}\,(1+\frac{kz}{L})\), where T0 is the typical period at the AP, L is the total AP–margin distance and k is a dimensionless constant of proportionality. This implies that the speed of the mitotic wave, v, in the nth division round is expected to be inversely proportional to n (Fig. 1d) with \(v=\frac{L}{{T}_{0}}\frac{1}{{kn}}\). To compare our experimental observations with these theoretical predictions, we first performed linear regression on the division timings to obtain the wave speed for each division round (Extended Data Fig. 1d). We then fitted the obtained v against \(\frac{1}{n}\) using the least squares fit. Using k = 1.9%, we obtained a close match between experiments and theory (Fig. 1d), suggesting that a 1.9% slower cell cycle at the margin would, in principle, be sufficient to explain the observed slowing down of the mitotic waves during consecutive division rounds. Considering that we experimentally observed a 2%–4% longer period at the margin, close to the theoretically predicted 1.9%, this suggests that a linear gradient of cell cycle periods, rather than cell–cell coupling, gives rise to the observed radial mitotic waves found during embryonic cleavages.
We note that constant T and κ are simplifying assumptions, as cell cycle periods increase over rounds and exhibit embryo-to-embryo variations. Incorporating these variations would complicate our analysis due to the difficulty in accurately quantifying the appropriate parameter variations, without altering our qualitative conclusions. Hence, given the reasonable theory–experiment agreement (Fig. 1d) and in the spirit of minimal models, we maintain these assumptions throughout our model analysis, allowing us to focus on the consequences of cell–cell coupling mechanisms.
Next, to challenge our conclusion that the mitotic waves are produced in a coupling-independent manner, we asked how they would appear if the cell cycles were instead coupled. To that end, we performed numerical simulations of the Kuramoto model of interacting oscillators on a hemisphere with free boundary conditions21 (Fig. 2a). The oscillators were placed on a Fibonacci lattice covering the hemisphere, with the nearest neighbours obtained with Delaunay triangulation. The phases of the oscillators obeyed the following equation: \({\delta }_{{\rm{t}}}{\theta }_{i}={\omega }_{i}+\epsilon \sum {j\epsilon N}_{i}\sin ({\theta }_{j}-{\theta }_{i})\), where \({\omega }_{i}\) represents the natural frequency of the ith oscillator, and the second term describes the interactions between neighbouring oscillators parameterized by the interaction strength \(\epsilon\), with Ni being the nearest neighbours of the ith oscillator. Due to cell–cell variations, we further assumed the presence of noise in the cell cycle lengths. Mathematically, we decomposed the frequencies into two parts \({\omega }_{i}=\varpi \left(z\right)+{{\wedge }}_{i}\), where the first term \(\varpi \left(z\right),\) is the inherent AP–margin oscillation gradient, and the second term is an independent spatial noise with covariance \(\left\langle {{\wedge }}_{i}{{\wedge }}_{j}\right\rangle ={\sigma \delta }_{{ij}}\).
a, Schematic of our adapted Kuramoto model and the equation describing the evolution of the phase of a cell cycle. In the equation, θi represents the cell cycle phase of cell i, and Ni denotes its nearest neighbouring cells, determined through Delaunay triangulation of the hemisphere. The coupling strength ε represents how strongly each cell influences its neighbours' timing. The intrinsic frequency ωi represents how quickly cell i would progress through its cell cycle in isolation. In the model, each black dot represents a cell positioned on a hemispherical Fibonacci lattice. The dot size increases with height (z) to aid visualization in this top-down projection. Double-headed arrows between dots (shown for one representative cell) indicate coupled neighbours that can influence each other's cell cycle timing. b, Phase diagram showing the origin of waves in ε–σ space. The boundary between AP originated and margin originated is thresholded at z = 0.5 and the region of desynchronization corresponds to 〈eiθj〉j < 0.6, where 〈〉j denotes averaging over all sites. c, Contour plot of the radial mitotic wave across all surface cells at division round 8, as predicted using the Kuramoto model of interacting oscillators, assuming an AP–margin period gradient of 1.9% and exponentially decaying cell–cell interaction strength (ε = 0.08e−n, σ = 0.0016). d, Contour plot of the mitotic wave across all surface cells at division round 8, as predicted using the Kuramoto model of interacting oscillators, assuming an AP–margin period gradient of 1.9% and partial interaction between cells (ε = 0.08, σ = 0.028). e, Left: representative image of a 128-cell stage control Tg(actb2:lyn-tdtomato) embryo injected with 1 ng of Histone 1-Alexa Fluor 488 at the 1-cell stage to show the presence of a plasma membrane between individual nuclei. Right: contour plot of the radial mitotic wave across all surface cells at division round 8 observed in a control embryo, where nuclear divisions were visualized using either Histone 1-Alexa Fluor 488 injections or using Tg(actb2:rfp-pcna) embryos. n = 7 embryos. f, Left: representative image of a 128-cell stage Tg(actb2:lyn-tdtomato) embryo injected with 1 ng of Histone 1-Alexa Fluor 488 at the 1-cell stage and treated with 50 μM of AZD1152 to show the absence of a plasma membrane between the individual nuclei. Right: contour plot of the mitotic wave across all surface cells at division round 8 observed in a representative syncytial embryo, where nuclear divisions were visualized using either Histone 1-Alexa Fluor 488 injections or using Tg(actb2:rfp-pcna) embryos. n = 7 embryos. g, Phase diagram of the Kuramoto model in ε–σ space. The log of the variance of the division timings at division round 8 is plotted. The green solid line indicates the contour line of the observed variance at division round 8 in syncytial embryos. h, Variances of division timings for each round for a fixed noise value of σ = 0.028 as ε varies. The green dashed curve shows the variances measured in syncytial embryos. i, Variances of division timings for each round in wild-type embryos (orange) fitted with a curve described by exponentially decaying interaction strength, ε(n) = 0.08e−n, and low noise, σ = 0.0016 (blue). WT, wild-type.
Source data
Specifically, simulations with small interaction strength (ε) and low noise (σ) qualitatively recapitulated the wild-type behaviour, where mitotic waves originated at the AP, and accumulated delays, causing a gradual slowdown over time (Fig. 2b,c). To reach a better quantitative agreement with the data, we considered that the initial cleavage events are incomplete, and consequently, the cytoplasm of early blastomeres remains interconnected through the yolk and via cytoplasmic bridges22. These connections are thought to progressively diminish over successive division rounds as cells become smaller—an assumption supported by our observation that single-blastomere injections of 40-kDa dextran, comparable in size to key cell cycle regulators such as Cyclin B1, Cdk1 and Chek1, resulted in its widespread distribution within a single division cycle when performed at the 16-cell stage but not at the 64-cell stage (Extended Data Fig. 4)22. On the basis of this, we modelled wild-type embryos as exhibiting a time-dependent coupling that decays to near-zero values, which provided a substantially better fit to the experimental data than models assuming constant, minimal coupling throughout (Supplementary Section 4).
By contrast, the introduction of greater interaction strength and noise led the system to self-organize into smooth mitotic waves originating at the margin, similar to the case in Xenopus egg extracts, even though the ‘natural' cell cycle lengths at the AP were preset to be shorter on average23 (Fig. 2b,d). For even larger values of noise, multiple waves emerged from random points of the simulated embryo (Fig. 2b). Overall, this theoretical phase diagram suggests that wild-type embryos are characterized by low-to-intermediate noise and progressively decaying coupling, and that increasing cell coupling should, in theory, shift the origin of the mitotic wave from the AP to the blastoderm margin.
To experimentally test this prediction, we syncytialized cleavage-stage embryos by preventing cytokinesis—but allowing karyokinesis—through transient inactivation of Aurora kinase B24 (Fig. 2e,f). We reasoned that such a syncytialized embryo would resemble conditions observed in Drosophila embryos and Xenopus egg extracts—both syncytial systems in which cell cycles are partially or fully synchronized via coupling-dependent trigger waves—and would, therefore, function as a coupled system. Remarkably, consistent with our theoretical predictions, we found that in syncytial embryos, the mitotic wave originated at the margin rather than at the AP, as seen in wild-type embryos (Fig. 2b,d,f and Supplementary Videos 1 and 4). Moreover, by analysing the wave characteristics at division round 8 in syncytial embryos, we were able to estimate the effective ratio of coupling and noise, two competing factors promoting synchronization and desynchronization, respectively (Fig. 2g and Supplementary Section 2).
In particular, our model also predicted key differences in the evolution of cell cycle synchronization—measured by the variance in division timing across division rounds—between wild-type and syncytial embryos: in the absence of coupling (wild-type embryos), noise is expected to accumulate progressively, resulting in a monotonically increasing variance in division timing. By contrast, in the presence of coupling (syncytial embryos), this variance should plateau over time, with a characteristic timescale determined by the coupling strength (Fig. 2h). Strikingly, our experimental observations confirmed this prediction. In syncytial embryos—unlike in wild-types—‘cells' continued to cycle metasynchronously even beyond division round 10, indicating a strong coupling between cell cycles (Extended Data Fig. 3a and Supplementary Videos 1 and 4). The temporal evolution of variance closely matched our theoretical prediction, particularly for ε = 0.08 and σ = 0.028 (Fig. 2h and Supplementary Section 2). By contrast, wild-type embryos exhibited continuously increasing variance, which could be quantitatively explained by the incomplete nature of cytokinesis during early cleavages, suggesting the presence of a transient coupling that rapidly diminishes as development progresses.
Finally, to further challenge the notion of the increased coupling of cells in syncytial embryos, we injected chek1 mRNA into embryos before syncytialization and assessed whether they could resist premature desynchronization typically observed when chek1 was overexpressed in wild-type embryos (Fig. 1f, Extended Data Fig. 1 and Supplementary Video 3). We theoretically reasoned that the coupling inferred for syncytial embryos is large enough that it can override a substantial increase in noise, such as the desynchronizing effects of chek1 expression (Fig. 2b). Indeed, we found that in chek1-overexpressing embryos, the mitotic waves originated at the margin and cells continued to cycle metasynchronously even beyond division round 10, suggesting that cells in the syncytial embryo are, in fact, tightly coupled (Extended Data Fig. 3b,c and Supplementary Video 5). By extension, this implies that such a coupling is absent/minimal in wild-type embryos and, consequently, that mitotic waves are produced largely independently of cell–cell interactions in wild-type embryos. Collectively, these findings suggest that cell cycles are only weakly coupled during cleavages and that metasynchrony arises predominantly by cell-autonomous processes.
For the cell cycle to slowdown from the AP to the margin in a predominantly cell-autonomous manner, there must be a factor causing an unequal lengthening of the S phase along the AP–margin axis. Among the most important factors regulating the S-phase length is the nucleocytoplasmic (N/C) ratio25,26. A high N/C ratio causes S-phase lengthening, for instance, by retarding Cdk1 activation25. Consistent with such an effect of the N/C ratio on cell cycle length, we found that the length of the S phase across the metasynchronous division rounds negatively correlated with cell volume (Fig. 4a,b). Therefore, we hypothesized that an AP–margin gradient of cell volumes in the cleavage-stage embryo might be responsible for unequally lengthening cell cycles from the AP to the margin. To test this hypothesis, we measured cell volumes by semiautomatically segmenting surface cells at the 128-cell stage (division round 8). Indeed, we found that, on average, cells closer to the AP were significantly larger than those away from it (Figs. 3a and 4g). To determine at what stage such a volume gradient first becomes apparent, we also measured N/C in embryos at the 8-cell stage (division round 4) and the 16-cell stage (division round 5)—the first stages in which cells can be classified as being ‘central' or ‘peripheral' based on their position. Interestingly, we observed that cells, but not nuclei, closer to the AP were consistently larger than the marginal cells, leading to central cells typically exhibiting a smaller N/C ratio than peripheral cells (Fig. 3b,c and Extended Data Fig. 5). Furthermore, the cell volume gradient not only persisted but was also further enhanced by subsequent cell divisions, as mother cells having unequal sizes themselves again divided asymmetrically to produce yet unequally sized daughters, thereby further diversifying cell volumes through cell lineage in addition to the already established position-driven cell volume diversity (Fig. 3d). For such unequal cell divisions to robustly give rise to a gradient in cell volumes along the AP–margin axis, upon division, the daughter cell closer to the AP must be, on average, larger than the daughter cell further from the AP. In line with this, we found that cell divisions in the early cleavage stages showed a tendency to produce larger daughter cells closer to AP, with the central daughter cell (closer to AP) being, on average, ~12.4% larger by volume than its peripheral sister cell (away from the AP) (Fig. 3e).
a, Representative image of a 128-cell stage embryo (division round 8) with surface cells segmented (left) and line plots showing normalized cell volumes as a function of cell position with respect to the AP (right) in individual embryos. Cell volumes were internally normalized to the average cell volume at the AP in each embryo. n = 11 embryos; two-tailed Student's t-test with Benjamini–Hochberg correction for multiple comparisons. b, Representative image of an 8-cell stage embryo (division round 4) with surface cells segmented (top) and the box plot showing volumes of individual nuclei and cells based on their position relative to the AP (bottom). Central cells are positioned at the AP, whereas peripheral cells are positioned away from the AP. The box in the box plot represents the middle 50% of the distribution, with the line representing the median and the whiskers indicating the minima and maxima. n = 20 central and 19 peripheral nuclei, 5 embryos; 12 central and 12 peripheral cells, 3 embryos. c, Representative image of a 16-cell stage embryo (division round 5) with surface cells segmented (top) and the box plot showing volumes of individual cells based on their position relative to the AP. The box in the box plot represents the middle 50% of the distribution, with the line representing the median and the whiskers indicating the minima and maxima. n = 8 central and 24 peripheral cells, 2 embryos. d, Schematic showing the lineage relationship between cells at the 8-cell stage (top left) and 16-cell stage (bottom left). At the 8-cell stage, cells marked ‘C' are centrally positioned, and those marked ‘P' are peripherally positioned. At the 16-cell stage, cells are labelled to indicate both their positions (CD, centrally; PD, peripherally) and the identities of their mother cells (CM, centrally positioned mother cell; PM, peripherally positioned mother cell). Box plot showing the distribution of cell volumes at the 16-cell stage based on each cell's position and lineage identity (right). The box in the box plot represents the middle 50% of the distribution, with the line representing the median and the whiskers indicating the minima and maxima. n = 8 cells for each category, 2 embryos. e, Schematic showing the pipeline for predicting daughter cell volumes at the 16-cell stage (left). Each segmented cell surface from the 8-cell stage was used to identify the longest cell axis, which was then bisected to obtain daughter cells at the 16-cell stage. Box plot showing a comparison between the ratios of volumes of the central and peripheral daughter cells obtained from each cell division, respectively, either predicted (Pred.) or experimentally observed (Obs.). The box in the box plot represents the middle 50% of the distribution, with the line representing the median and the whiskers indicating the minima and maxima (right). n = 16 cell pairs, 2 embryos.
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a, Line plots showing mean S-phase lengths in individual (thin, grey lines) and across (thick, black line, mean ± 95% confidence interval) embryos as a function of the inverse of the mean nearest-neighbour distance (mean of 3) in the metasynchronous cell cycle stages. Division rounds are indicated by the colour-bands overlaid on the dots (n = 6 embryos). b, Linear regression plots showing the relationship between the inverse of the nearest-neighbour distance (mean of 3) for each cell and the length of its S phase. Dots represent single cells, whereas the lines show the best-fit linear curve for the data. Each colour represents data for a unique embryo. The thick, black line shows a summary best fit for the data of all cells across all embryos. For each embryo, cells only within the 5th–95th percentile of their nearest-neighbour distances and S-phase length were considered for the analysis, which minimizes erroneous measurements at the extremes but also underestimates the relationship (n = 6 embryos, 964 cells). c, Schematic of the experiment in which a fraction of the cytoplasm was aspirated from the blastodisc within approximately 10 min before the first cell division to increase the N/C ratio. d, Representative line plot showing the S-phase length in each division round in control embryos and embryos from which the cytoplasm was aspirated (mean ± s.d., n = 3 embryos). e, Schematic of the experiment in which one of the nuclei at the 2-cell stage was aspirated to decrease the N/C ratio in the aspirated half of the embryo (top). Only the nucleated, control half initially develops (that is, shows mitotic cycles) (middle) until nuclei from this half invade the enucleated half (bottom), which then begins to develop with a smaller N/C ratio. f, Representative line plot showing S-phase length in each division round in the control and enucleated halves of the embryo depicted in e (mean ± s.d., n = 3 embryos). g, Box plot showing normalized cell volumes as a function of cell position with respect to the AP. Cell volumes were internally normalized by dividing each cell volume by the volume of the largest cell in the embryo. Each dot represents the data for an individual cell. Data are the same as in Fig. 3a, but the cells here have been classified into only two bins. The box in the box plot represents the middle 50% of the distribution, with the line representing the median and the whiskers indicating the minima and maxima. n = 432 cells, 11 embryos; two-tailed Student's t-test, ****P = 0.001.
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To determine what causes such patterned asymmetric cell divisions, we investigated how cell divisions are oriented and the cleavage plane positioned in the early embryo. Although several sophisticated models have been proposed to explain the orientation and positioning of the cleavage plane across systems, we started by first testing if following the simplest model, the ~140-year-old Hertwig's rule, can recapitulate the experimentally observed pattern of asymmetry27,28. More specifically, we assumed that the mitotic spindle in dividing blastomeres would orient along the longest cell axis, thereby dividing the cell along this axis. To test if such a geometry-driven mechanism would suffice to generate the observed pattern of asymmetric cell divisions and, therefore, the cell volume gradient, we predicted daughter cell volumes at the 16-cell stage by first identifying the longest axes of segmented cells at the 8-cell stage through principal component analysis and then bisecting them to obtain two daughter cells from each division29 (Fig. 3e). Indeed, we found that with this approach, the predicted asymmetry in the daughter cell size closely matched the observed asymmetry for most cell divisions, such that the central daughter cells (closer to the AP) at the 16-cell stage were, on average, ~18.5% larger than their peripheral sister cells (further away from the AP) by volume (Fig. 3e). Importantly, this tendency of central daughter cells being bigger than peripheral ones is determined by the specific geometry of the first cell of the fertilized egg, the blastodisc, which is delineated not only by a plasma membrane at its outer side but also by the interface to the yolk granules on its inner side11,30. As the interface to the yolk granules is curved, the first two cell divisions will give rise to equally sized daughter cells that are more pointed and narrow at their peripheral ends. Dividing these cells again along their long axis will then, as a result, generate daughter cells in which the central cell is larger than the peripheral one. This suggests that a gradient of cell volumes along the AP–margin axis in the cleaving embryo can be explained by the specific geometry of the first cell in the fertilized egg, leading to unequal cell division along the AP–margin axis during subsequent division rounds.
Although the influence of cell volume on cell cycle length has been established in several systems, its role in zebrafish embryos remains unclear due to conflicting reports regarding the determinative effect of cell size in this context14,16. To unequivocally establish the contribution of cell volume—and, by extension, the N/C ratio—to the regulation of cell cycle length, we first increased the N/C ratio at the 1-cell stage by aspirating cytoplasm from the blastodisc (Fig. 4c). Consistent with the known role of elevated N/C ratios in prolonging cell cycles, we observed that, across different embryos, the S phase either lengthened prematurely or showed greater lengthening during division round 10, and the cell cycles desynchronized earlier than in control embryos (Fig. 4d). To test the converse, we decreased the N/C ratio by replicating a previous experiment14, aspirating one nucleus from embryos at the 2-cell or 4-cell stage (Fig. 4e). In these embryos, only the control half—containing the nucleus—underwent initial cleavages, whereas no divisions occurred in the enucleated half (Fig. 4e and Supplementary Video 6). However, in a subset of embryos, nuclei from the control half eventually invaded the enucleated half around division round 4 or 5, prompting the onset of cleavages in that region (Fig. 4e and Supplementary Video 6). In particular, although all nuclei had undergone the same number of division cycles by this stage, those in the previously enucleated half now resided in a substantially larger cytoplasmic volume—comparable to the blastomere volume of cells three to four divisions earlier—and, therefore, had a lower N/C ratio. Consistent with earlier findings, these nuclei did not exhibit S-phase lengthening during division round 10—the point at which cell cycles typically begin to desynchronize in the control half, but instead continued to cycle metasynchronously. This, in line with previous observations of delayed and premature cell cycle lengthening in haploid and tetraploid embryos, respectively, supports the notion that a higher N/C ratio promotes S-phase lengthening and contributes to the onset of cell cycle desynchronization beyond division round 10 (ref. 14; Fig. 4f). However, it should be noted that although our analyses establish a deterministic role of N/C in S-phase length, they do not entirely exclude the possibility that additional geometry- or N/C-independent mechanisms may also influence the S-phase length.
Having confirmed that the N/C ratio, in principle, can influence the S-phase length, we asked how perturbing the embryo-scale cell volume gradient within the cleaving embryo would affect the cell cycle (meta)synchrony and, consequently, the mitotic wave. To alter the cell volume gradient, we first generated bilobed embryos, displaying two ectopic (morphological) APs, by mounting 2-cell stage embryos in low-melting-point agarose (0.67% w/v in E3 buffer) when the first cytokinesis was in progress (Fig. 5a). We reasoned that spatially confining and, therefore, reshaping the embryo in this manner would produce larger cells away from the AP at the two ectopic APs. Interestingly, we found that not only the gradient of cell volumes was reshaped in the embryo but also that two mitotic waves emerged, one from each of the two ectopic APs, supporting the notion that the cell volume gradient is linked to the emergence of the mitotic wave (Fig. 5a,b and Supplementary Video 7).
a, Representative images of 128-cell stage (division round 8) control and bilobed embryos with surface cells segmented (left) and box plot showing cell volumes as a function of the cell position with respect to the AP (right) for this bilobed embryo. Cyan asterisks mark the ectopic APs in the bilobed embryo. The box in the box plot represents the middle 50% of the distribution, with the line representing the median and the whiskers indicating the minima and maxima. n = 37 cells, representative of five embryos. b, Montage of images (top) and a contour plot (bottom) showing the propagation of mitotic waves in a representative bilobed Tg(actb2:rfp-pcna) embryo at division round 8. Asterisks mark the ectopic APs in the bilobed embryo (n = 5 embryos). c, Schematic (top-left) and representative (bottom-left) images of a control embryo and an embryo in which the yolk has been severed at the 2-cell stage to increase the curvature of the blastoderm-to-yolk cell interface. Lines inside the cells indicate the longest cell axis along which the divisions (division round 3) are expected to occur. Cells marked in magenta and cyan represent the resulting central and marginal daughter cells, respectively. The contour plot (right) shows mitotic wave propagation in division round 8 of a yolk-severed embryo (AP view). d, Schematic (top) of the decreased angle of cell divisions in division round 4 in yolk-severed embryos due to an increased curvature of the blastoderm-to-yolk cell interface compared with the corresponding control embryos. Angles are represented as mean ± s.d.; n = 10 and 14 cells for control and yolk-severed embryos, respectively). Line plot (bottom) showing the variance in cell division timings in control and yolk-severed embryos (mean ± s.e.m.; n = 4 embryos). e, Representative contour plot (top) showing mitotic wave propagation in a Chek1 inhibitor (PF477736)-treated embryo in division round 8 (AP view). Line plot (bottom) showing the variance in cell division timings in control and PF477736-treated embryos (mean ± s.e.m.; n = 4 embryos).
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Not only does cell size decrease along the AP–margin axis but also the proximity of cells to the yolk increases. This raises the possibility that yolk-derived factors, in addition to or alternatively to cell size, might influence the gradient in cell cycle length. However, direct cytoplasmic connectivity with the yolk is largely confined to the most marginal cells, making it unlikely to account for a cell cycle length gradient across the entire AP–margin axis11. To directly assess the effect of yolk proximity, we analysed correlations between division timing, cell size and yolk distance in bilobed embryos, where cell size and position relative to the margin are changed. Consistent with our model, smaller cells divided later than larger cells regardless of their AP–margin position (Extended Data Fig. 6), arguing against a primary role for the yolk in regulating division timing.
To further challenge the role of embryo-wide cell size gradients in generating mitotic waves, we removed a part of the yolk on the vegetal side of the 2-cell stage embryo to increase the curvature of the blastodisc (the two blastomeres positioned on the yolk cell; Fig. 5c). On the basis of our analysis indicating that the cell volume gradient is a product of the curvature of the blastodisc–yolk interface, we reasoned that this increased curvature would reorient the longest axes of the two cells, such that they align more along the animal–vegetal axis, which would then amplify the volume asymmetry of cleavage divisions and, consequently, the phase difference between cell cycles (Fig. 5c). Strikingly, we found that in yolk-severed embryos, with cell divisions more aligned along the animal–vegetal axis, the mitotic wave indeed showed a greater cell division timing variance compared with the control embryos (Fig. 5c,d and Supplementary Video 8). Taken together, these observations strongly support the idea that a gradient of cell volume along the AP–margin axis, guided by embryo geometry, causes the generation of a gradient of S-phase lengths along the AP–margin axis of the blastoderm, thereby generating radial mitotic waves in the zebrafish embryo.
Among the major responders to a high N/C ratio is Chek1, which, when active, delays the S–M transition7,25,31. Although cell cycles have been shown to lengthen independently of Chek1 in Xenopus egg extracts, recent in vivo studies in Drosophila embryos have established it as a central factor that not only controls the mitotic wave speed but also regulates the desynchronization of cell cycles in embryos with heterogeneous N/C7,26,31. Therefore, we enquired whether Chek1 mediates the effect of cell volume on S-phase length. To that end, we inhibited Chek1 activity by treating embryos with 10 µM of PF477736, a specific Chek1 activity inhibitor32. If Chek1 activity is required for the gradual metasynchronization of cell cycles through unequal S-phase lengthening, the cell cycle progression would be expected to show lesser variation in the treated embryos. Consistent with this, we found that, although Chek1-inhibited embryos produced mitotic waves like those in control embryos, they indeed exhibited a lower mitotic division timing variance (Fig. 5e and Supplementary Video 9). This suggests that Chek1 activity is critical for translating a cell volume gradient into a mitotic wave along the AP–margin axis of the blastoderm.
Finally, we asked whether the geometry-derived cell volume gradient—and the resulting patterned mitotic metasynchrony—plays a developmental role that extends beyond the cleavage stages and impacts subsequent embryogenesis. In zebrafish embryos, mitotic metasynchrony diminishes in parallel with the onset of zygotic genome activation (ZGA), a pivotal process that lays the foundation for cell fate heterogeneity and is central to metazoan development14. Given previously reported roles of cell volume (N/C ratio promotes ZGA) and cell cycle length (shorter cell cycle prevents ZGA) in regulating ZGA, we investigated whether the observed gradient in cell volume and mitotic metasynchrony influences the onset of zygotic transcription33,34,35,36,37,38. To address this, we tracked the timing and spatial pattern of zygotic transcription initiation by imaging endogenous pri-miR430 transcripts using the morpholino visualization of expression39 (Fig. 6a). miR430 genes are among the earliest and most abundantly transcribed genes during zebrafish ZGA, making them ideal markers for assessing transcriptional onset40,41.
a, Representative maximum intensity projection image showing the AP view of a control Tg(actb2:rfp-pcna) embryo injected with MO1-3-fluorescein in division round 9. Cyan, MO1-3-fluorescein; magenta, nuclei (PCNA). The three insets, each 120 µm × 120 µm in size, demarcate the regions (1, AP; 2, intermediate region; 3, margin) whose higher-magnification images are shown in b and e. b, Zoomed-in views of the insets shown in a. Cyan dots, marked with white arrowheads, represent nascent mi430 transcripts detected by MO1-3-fluorescein. MO1-3 foci without an overlapping nuclear signal indicates that the cell is in mitosis (n = 4 embryos). c, Lateral view of a control embryo in division round 10 injected with MO1-3-fluorescein. d, Schematic (top) and a representative orthogonal maximum intensity projection image (bottom) of a bilobed Tg(actb2:rfp-pcna) embryo injected with the MO1-3-fluorescein embryo in division round 9. Cyan, MO1-3-fluorescein; magenta, nuclei (PCNA). e, Zoomed-in views of the equivalent regions (1, AP; 2, intermediate region; 3, margin) demarcated in a for a bilobed embryo in division round 9. Cyan dots represent nascent mi430 transcripts. MO1-3 foci without an overlapping nuclear signal indicates that the cell is in mitosis (n = 3 embryos). f, AP view of control and bilobed Tg(sebox:egfp) embryos, with comparable regions from a indicated in the bilobed embryo. The arrowhead indicates the presence of ectopic sebox:egfp expression at the original AP, where a valley is formed between the two domes (ectopic APs) of the bilobed embryo. White asterisks indicate the positions of the ectopic APs. g, Schematic representing the geometry-driven asymmetric cell division patterning in the early embryo. Patterned asymmetric divisions generate a gradient of cell volume, producing mitotic phase waves and spatially patterning ZGA onset along the AP–margin axis.
In most embryos, we observed the first signs of miR430 transcription during division round 9. In particular, during rounds 9 and 10, transcription was initiated in a graded manner: miR430 transcription foci first appeared—and/or persisted longer—in cells near the blastoderm margin. They then emerged in an intermediate zone between the margin and the AP, and finally in cells located at the AP (Fig. 6b,c, Extended Data Fig. 7 and Supplementary Videos 10 and 11). These findings suggest that zygotic transcription begins as a spatiotemporal gradient along the AP–margin axis, with marginal cells exhibiting higher transcriptional activity or competence than AP cells over the course of one to two division rounds. To determine whether this pattern of ZGA onset is driven by the underlying gradients in cell volume and/or cell cycle length, we examined bilobed embryos in which both of these gradients are perturbed (Figs. 5a,b and 6d). In contrast to control embryos, cells at the AP in bilobed embryos are smaller and cycle more slowly than those in the intermediate zone (Fig. 5a,b). Remarkably, in these embryos, miR430 transcription was initiated first at both the margin and the AP—where cells are the smallest—before appearing in the intermediate region (Fig. 6e and Supplementary Video 12). These results suggest that the gradient of cell volume and/or cell cycle length along the AP–margin axis influences the spatiotemporal onset of zygotic transcription. Thus, early embryo geometry can be linked directly to the initiation of zygotic gene expression, providing a mechanistic bridge between physical form and transcriptional timing in early development.
To determine whether the geometry-derived transcriptional gradient within the embryo plays a role in embryonic development, we asked whether altering the spatiotemporal pattern of ZGA onset in bilobed embryos would affect the specification of the first cell fates within the blastoderm. To investigate this, we used Tg(sebox:egfp) embryos to visualize the earliest mesendoderm progenitors, specified at the onset of gastrulation42,43. In control embryos, mesendoderm progenitors were exclusively specified at the blastoderm margin—the region in which ZGA is first initiated. By contrast, approximately 30% of bilobed embryos exhibited mesendoderm progenitors not only at the margin but also ectopically within the ‘valley' between the two domes, reflecting the altered ZGA pattern in these embryos (Fig. 6f). These findings suggest that zygote geometry triggers a cascade of developmental events necessary for correct cell fate specification—an essential aspect of ensuring developmental robustness (Fig. 6g).
Previous studies have shown that the shape of the zebrafish egg—particularly the blastodisc, the region from which all embryonic cells and tissues originate—is established by ooplasmic streaming, which segregates yolk granules from the cytoplasm within the fertilized egg30,44. Building on this, our findings suggest that the initial shape of the blastodisc drives asymmetric cell divisions during successive reductive cleavages by guiding mitotic spindle orientation, based on the simple premise that the spindle consistently aligns with the cell's longest axis, as described by Hertwig's rule27,28,45. These asymmetric divisions progressively generate a gradient of cell volumes along the AP–margin axis of the developing blastoderm, which, in turn, influences both cell cycle progression and ZGA along the same axis. Although we do not rule out the potential contribution of more complex mechanisms linking blastodisc shape to asymmetric cell divisions—such as differential interactions between spindle microtubules and yolk granules, the cell cortex or the plasma membrane—our results suggest that such factors are not required to explain the emergence of asymmetric divisions. Thus, the formation of a gradient in cell volume, as well as the consequent regulation of cell cycle dynamics and ZGA patterns, appears to be a direct outcome of the blastodisc's geometry.
Interestingly, our data connect the observed gradients in cell volume and/or cell cycle length to the onset of ZGA. This aligns with recent findings in Xenopus embryos, where ZGA is first initiated in the smaller cells at the AP38. Multiple molecular mechanisms have been proposed to explain the link between cell cycle length and the onset of ZGA, including the titration of cytoplasmic transcriptional repressors as the N/C ratio increases, and/or progressively lengthening cell cycles that permit sustained zygotic transcription. Our observation that smaller, slower-cycling cells at the margin are transcriptionally more active, initiating transcription first and retaining the transcription foci longer (Extended Data Fig. 7), suggests that both mechanisms may contribute to the regulation of zygotic gene activation.
We have previously shown that radially patterned cell behaviours and asymmetric tissue compaction along the AP–margin axis of the blastoderm emerge at the onset of gastrulation, providing essential conditions for proper morphogenetic movements during this stage of development20,46. It is plausible that these differences in tissue properties originate from distinct transcriptional profiles and cell fate specification, which are themselves driven by the differential patterns of ZGA, and ultimately embryo geometry, as described in this study.
The dependence of cell fate marker expression on early embryo geometry raises a central question: how do noisy gradients in cell size, cell cycle and transcriptional activity yield robust fate specification? Although individual fate markers may be regulated by distinct mechanisms, their spatial patterns probably emerge from the integration of cellular dynamics with physical constraints. For example, although Nodal signals, inducing mesendodermal cell fates within the blastoderm margin, originate in the yolk, proper Nodal reception in blastoderm cells requires zygotically expressed factors such as the co-receptor oep47. Margin cells, which undergo earlier ZGA, may, therefore, respond more strongly to Nodal due to an earlier and/or higher co-receptor expression, sharpening mesendodermal marker expression near the margin. In bilobed embryos, altered cell size, cell cycle and transcription patterns could shift this sensitivity—elevated transcription in the valley between the two lobes might allow cells to respond to lower Nodal levels and, consequently, adopt a mesendodermal cell fate. Thus, biochemical and molecular prepatterning, achieved by cellular properties such as cell cycle, size and transcriptional activity, may provide the foundation for robust cell fate specification.
Our findings, thus, establish a probable mechanistic link between two critical developmental milestones: the determination of blastodisc geometry immediately after fertilization and the onset of asymmetric tissue fluidization during gastrulation. This connection is further supported by our earlier observation that asymmetric tissue fluidization depends on proper mesendoderm specification20,46, as well as by our current finding that embryos with perturbed geometry exhibit mesendodermal fate misspecification that parallels the altered pattern of ZGA onset. This suggests that inherent geometric asymmetries in blastodisc shape can have long-lasting developmental consequences, manifesting only later as their effects accumulate during the early proliferative phase of embryogenesis.
Consistent with this notion, several other organisms—including Caenorhabditis elegans, sea urchins and Xenopus—exhibit alignment between axes of cell cycle length and/or cell volume and the axes along which germ layer fates diverge, underscoring the developmental significance of geometry-derived patterns as robust and reproducible determinants of embryonic organization. Nonetheless, the specific outcomes of this fundamental relationship are likely to vary across species and must be examined within the unique developmental context of each organism.
Tg(actb2:rfp-pcna) embryos were dechorionated and, at the desired stage, mounted in 0.5% agarose gels prepared in E3 buffer with the AP facing upwards in casts made with 2% agarose solution in E3 buffer13. RFP fluorescence was imaged at 23.5 °C using a 20× water-dipping objective on ZEISS LSM800 (numerical aperture of 0.8), LSM880 (numerical aperture of 1.0) or LSM900 (numerical aperture of 1.0) upright confocal microscopes. Then, 200–350-µm-thick Z stacks were acquired for different experiments with temporal resolutions ranging between 17 and 65 s per Z stack. The presence or absence of nuclear RFP-PCNA fluorescence was used to determine if a cell was in the S or M phase of the cell cycle, respectively48,49,50. The nuclear signal was segmented in Fiji (v. 2.16.0/1.54p; Java 1.8.0_172) using the Labkit plug-in (v. 0.4.0)51,52. The segmented objects were imported into Bitplane Imaris (v. 9.9) (https://imaris.oxinst.com/) to generate tracks and obtain tracking-related data, including track start time (S-phase entry), track end time (M-phase entry), track duration (S-phase length) and the nuclear coordinates at the last S-phase time point (position). These data were then analysed using the Pandas package (v. 1.5.3) in Python (v. 3.12.9) to calculate, for instance, the division timing variance in a given division round, followed by plotting using mainly the Matplotlib (v. 3.8.2) and seaborn (v. 0.12.2) packages53,54,55.
The mitotic wave speed for a given division round was determined by first identifying the position of the wave origin and the timing of the wave origination, measuring all other nuclear distances and mitotic entry timings relative to this position and time, and then generating the best-fitting distance–time linear curve. In the cases where more than one nucleus could be considered the origin of the mitotic wave due to a simultaneous entry into mitosis, the mean of the 3D coordinates of such nuclei was considered as the position of wave origin. Furthermore, it should be noted that, especially during division rounds 2 and 3, the wave traverses the embryo nearly instantaneously, and in most of our experiments, we could not temporally resolve these early cell divisions, giving us infinite mitotic wave speeds. However, for analytical reasons, we only considered those embryos in which the divisions could be resolved, disregarding embryos exhibiting infinite speeds, which would provide an underestimate of the mitotic wave speed.
To visualize cell cycle progression using Histone 1 as the marker, 0.5 ng of Histone 1-Alexa Fluor 488 (catalogue number H13188, Invitrogen) was injected at the 1-cell stage into wild-type AB or Tg(actb2:lyn-tdTomato) embryos56. Mosaic perturbation of the cycling period of a subset of the cells was carried out by mounting 32/64-cell stage embryos in 2% agarose solution in E3 buffer and injecting 0.2–0.3 ng of Histone 1-Alexa Fluor 488 into such cells. chek1 overexpression was achieved by injecting 12 pg chek1 mRNA into the one-cell embryo20,46. mRNA was prepared as described previously21. To test the cellular connectivity at the 16- and 64-cell stages, 0.0625 ng of fluorescein isothiocyanate–carboxymethyl–dextran (40 kDa) was injected into a single cell at the desired stage, and the embryos were mounted and imaged as described above.
Aurkb function was inhibited by transiently incubating dechorionated <5 min post-fertilization (mpf) embryos in 50 µM of AZD1152 (catalogue number SML0268, Sigma-Aldrich) solution for 15 min, after which they were returned to the E3 buffer. Embryos showing successful nuclear cycling despite a failure of cytokinesis were then imaged as described above. Inhibition of the Aurkb function concomitantly with the chek1 overexpression or Histone 1-Alexa Fluor 488 visualization was performed by injecting 12 pg of chek1 mRNA or 0.5 ng of Histone 1-Alexa Fluor 488, respectively, at the 1-cell stage, as described above, followed by incubation in the Aurkb inhibitor. Chek1 activity inhibition was performed by dechorionating <10-mpf embryos and incubating them in 10 µM of PF477736 (catalogue number HY-10032, MedChem Express) solution in E3 buffer throughout the duration of the analysis.
Nuclear RFP-PCNA fluorescence was segmented from Z stacks by thresholding using Fiji (v. 2.16.0/1.54p; Java 1.8.0_172), and their volumes were measured using the 3D Objects Counter plug-in (v. 2.0.1)57.
Cell volumes at the 8- and 16-cell stages were measured by semiautomatically generating cell segmentation using the ‘Contour' function for surface creation in Bitplane Imaris (v. 9.9) from Z stacks of Tg(actb2:mCherry-CAAX) embryos58. Once segmented, the physical attributes of individual cells, such as volume and position, were exported from Bitplane Imaris (v. 9.9) as CSV files. The last time point before the onset of the fourth or fifth mitotic round was used to measure the cell volume for the 8- or the 16-cell stage, respectively. Cell volumes at the 128-cell stage were measured by generating cell segmentations using the LimeSeg plug-in (v. 0.4.2) in Fiji (v. 2.16.0/1.54p; Java 1.8.0_172) and exporting the cell volume data for individual segmented objects59. All downstream data analysis was performed in Python (v. 3.12.9), mainly using the Pandas package (v. 1.5.3), and the plots were produced using the Matplotlib (v. 3.8.2) and seaborn (v. 0.12.2) packages. To directly measure the N/C for cells at the 8- and the 16-cell stages, Tg(actb2:mCherry-CAAX) embryos injected with 0.5 ng of Histone 1-Alexa Fluor 488 at the 1-cell stage were imaged as described above. Cell volumes were estimated by semiautomatically creating cell and nuclear surfaces in Imaris (v. 9.9), whose volumes were then used to determine the N/C ratio for each cell.
Cell surfaces generated in Bitplane Imaris (v. 9.9) at the 8-cell stage were exported as WRL files, imported into MeshLab (https://www.meshlab.net/), from where individual cell surfaces were exported as PLY files. These files were subsequently processed in Python (v. 3.12.9) to identify the longest cell axis by performing principal component analysis, along which the cell was bisected into two daughter cells representing cells at the 16-cell stage29.
Nuclei positions were obtained from Bitplane Imaris (v. 9.9), as detailed above. For each nucleus, the three nearest neighbours were identified, and their mean distance from the reference nucleus was calculated using the Pandas package (v. 1.5.3) in Python (v. 3.12.9).
At approximately 30 mpf, Tg(actb2:rfp-pcna) embryos were mounted in E3 buffer on a substrate prepared with 2% agarose solution in E3 buffer. A 20-µm blunt-end needle attached to a 10-µl Hamilton syringe was inserted through the yolk into the blastodisc, and the cytoplasm was carefully aspirated. The nuclear RFP-PCNA signal was constantly observed using a Leica stereofluorescence microscope to ensure the nucleus was not extracted together with the cytoplasm.
The setup and mounting procedure for nucleus aspiration were the same as for cytoplasm aspiration described above, except that, in this case, the nucleus was aspirated rather than the cytoplasm and from embryos at the 2-cell stage rather than the 1-cell stage. Care was exercised to ensure that the nucleus was extracted with a negligible volume of the cytoplasm being aspirated in the process.
Bilobed embryos were created by spatially confining dechorionated embryos at the 2-cell stage, still undergoing cytokinesis from division round 1, in 0.5%–0.6% agarose in E3 buffer. Microscopy was performed as described above.
To sever the yolk, dechorionated embryos at the 2-cell stage were placed on a substrate of 3% methylcellulose in E3 buffer in a glass dish. Using an eyelash attached to the end of a Pasteur pipette, the vegetal half of the yolk was first punctured to prevent the embryo from exploding due to a build-up of internal pressure during the severing procedure, and then carefully sliced. The embryo was allowed to recover for at least 15 min after the procedure, followed by mounting and microscopy, as detailed above.
Four orthogonal sections, each showing four nuclei along the plane of division round 4 at the 16-cell stage, were generated using the reslice function in Fiji from Z stacks of individual Tg(actb2:rfp-pcna) embryos. The angles between the nuclei were then measured using Fiji (v. 2.16.0/1.54p; Java 1.8.0_172), as represented in Fig. 5d, to obtain the angle of cell divisions in division round 4.
pri-miR430 transcripts were labelled as described previously39. Tg(actb2:rfp-pcna) embryos injected with MO1-3-fluorescein (Gene Tools) at the 1-cell stage were mounted in 0.5% agarose solution in E3 buffer in #3 fluorinated ethylene propylene tubes, and the Z stacks were generated with a temporal resolution of approximately 1 min per Z stack using a 20×/1.33-numerical-aperture objective on a ZEISS Lightsheet 7 microscope. Maximum intensity projections of these time-lapse recordings were then used to assess the transcription status of the individual nuclei.
All animal breeding and procedures were performed in accordance with the European Union animal welfare guidelines and involve only low-severity lines, in accordance with the authorized animal breeding licences (66018/8-II/3b/2013 and 2023-0.288.351) in the Institute of Science and Technology Austria Aquatics Facility (approval number 024-0.730.856). All experiments were performed before 5 days post-fertilization, a period during which zebrafish do not feed independently and in line with the principle of 3Rs.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Source data are provided with this paper. All other data that are necessary to interpret, verify and extend the research within this article are available from the corresponding author upon reasonable request.
The code relevant to this article is available via GitHub at https://github.com/Irene-Li/MitoticWaves.
Luciano, M. et al. Cell monolayers sense curvature by exploiting active mechanics and nuclear mechanoadaptation. Nat. Phys. 17, 1382–1390 (2021).
Article
Google Scholar
Cheikh, M. I. et al. A comprehensive model of Drosophila epithelium reveals the role of embryo geometry and cell topology in mechanical responses. eLife 12, e85569 (2023).
Article
Google Scholar
Lou, Y., Rupprecht, J.-F., Theis, S., Hiraiwa, T. & Saunders, T. E. Curvature-induced cell rearrangements in biological tissues. Phys. Rev. Lett. 130, 108401 (2023).
Article
ADS
Google Scholar
Luciano, M., Tomba, C., Roux, A. & Gabriele, S. How multiscale curvature couples forces to cellular functions. Nat. Rev. Phys. 6, 246–268 (2024).
Article
Google Scholar
Gehrels, E. W., Chakrabortty, B., Perrin, M.-E., Merkel, M. & Lecuit, T. Curvature gradient drives polarized tissue flow in the Drosophila embryo. Proc. Natl Acad. Sci. USA 120, e2214205120 (2023).
Article
Google Scholar
Lefebvre, M. F., Claussen, N. H., Mitchell, N. P., Gustafson, H. J. & Streichan, S. J. Geometric control of myosin II orientation during axis elongation. eLife 12, e78787 (2023).
Article
Google Scholar
Deneke, V. E., Melbinger, A., Vergassola, M. & Di Talia, S. Waves of Cdk1 activity in S phase synchronize the cell cycle in Drosophila embryos. Dev. Cell 38, 399–412 (2016).
Article
Google Scholar
Vergassola, M., Deneke, V. E. & Di Talia, S. Mitotic waves in the early embryogenesis of Drosophila: bistability traded for speed. Proc. Natl Acad. Sci. USA 115, E2165–E2174 (2018).
Article
Google Scholar
Chang, J. B. & Ferrell, J. E. Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature 500, 603–607 (2013).
Article
ADS
Google Scholar
Anderson, G. A., Gelens, L., Baker, J. C. & Ferrell, J. E. Desynchronizing embryonic cell division waves reveals the robustness of Xenopus laevis development. Cell Rep. 21, 37–46 (2017).
Article
Google Scholar
Kimmel, C. B., Ballard, W. W., Kimmel, S. R., Ullmann, B. & Schilling, T. F. Stages of embryonic development of the zebrafish. Dev. Dyn. 203, 253–310 (1995).
Article
Google Scholar
Zamir, E., Kam, Z. & Yarden, A. Transcription-dependent induction of G1 phase during the zebra fish midblastula transition. Mol. Cell. Biol. 17, 529–536 (1997).
Article
Google Scholar
Boothe, T. et al. A tunable refractive index matching medium for live imaging cells, tissues and model organisms. eLife 6, e27240 (2017).
Article
Google Scholar
Kane, D. A. & Kimmel, C. B. The zebrafish midblastula transition. Dev. Camb. Engl. 119, 447–456 (1993).
Google Scholar
Keller, P. J., Schmidt, A. D., Wittbrodt, J. & Stelzer, E. H. K. Reconstruction of zebrafish early embryonic development by scanned light sheet microscopy. Science 322, 1065–1069 (2008).
Article
ADS
Google Scholar
Olivier, N. et al. Cell lineage reconstruction of early zebrafish embryos using label-free nonlinear microscopy. Science 329, 967–971 (2010).
Article
ADS
Google Scholar
Berloco, M., Fanti, L., Breiling, A., Orlando, V. & Pimpinelli, S. The maternal effect gene, abnormal oocyte (abo), of Drosophila melanogaster encodes a specific negative regulator of histones. Proc. Natl Acad. Sci. USA 98, 12126–12131 (2001).
Article
ADS
Google Scholar
Gunjan, A. & Verreault, A. A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae. Cell 115, 537–549 (2003).
Article
Google Scholar
Brown, D. T., Alexander, B. T. & Sittman, D. B. Differential effect of H1 variant overexpression on cell cycle progression and gene expression. Nucleic Acids Res. 24, 486–493 (1996).
Article
Google Scholar
Petridou, N. I., Corominas-Murtra, B., Heisenberg, C.-P. & Hannezo, E. Rigidity percolation uncovers a structural basis for embryonic tissue phase transitions. Cell 184, 1914–1928.e19 (2021).
Article
Google Scholar
Kuramoto, Y. Chemical Oscillations, Waves, and Turbulence Vol. 19 (Springer, 1984).
Kimmel, C. B. & Law, R. D. Cell lineage of zebrafish blastomeres: I. Cleavage pattern and cytoplasmic bridges between cells. Dev. Biol. 108, 78–85 (1985).
Article
Google Scholar
Nolet, F. E. et al. Nuclei determine the spatial origin of mitotic waves. eLife 9, e52868 (2020).
Article
Google Scholar
Murata-Hori, M., Tatsuka, M. & Wang, Y.-L. Probing the dynamics and functions of aurora B kinase in living cells during mitosis and cytokinesis. Mol. Biol. Cell 13, 1099–1108 (2002).
Article
Google Scholar
Conn, C. W., Lewellyn, A. L. & Maller, J. L. The DNA damage checkpoint in embryonic cell cycles is dependent on the DNA-to-cytoplasmic ratio. Dev. Cell 7, 275–281 (2004).
Article
Google Scholar
Piñeros, L. et al. The nuclear-cytoplasmic ratio controls the cell-cycle period in compartmentalized frog egg extract. Curr. Biol. 35, 4426–4441.e6 (2025).
Article
Google Scholar
Minc, N., Burgess, D. & Chang, F. Influence of cell geometry on division-plane positioning. Cell 144, 414–426 (2011).
Article
Google Scholar
Hertwig, O. Das Problem der Befruchtung und der Isotropie des Eies: eine Theorie der Vererbung (Verlag von Gustav Fischer, 1884).
Wold, S., Esbensen, K. & Geladi, P. Principal component analysis. Chemom. Intell. Lab. Syst. 2, 37–52 (1987).
Article
Google Scholar
Shamipour, S. et al. Bulk actin dynamics drive phase segregation in zebrafish oocytes. Cell 177, 1463–1479.e18 (2019).
Article
Google Scholar
Deneke, V. E. et al. Self-organized nuclear positioning synchronizes the cell cycle in Drosophila embryos. Cell 177, 925–941.e17 (2019).
Article
Google Scholar
Danilova, N. et al. The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia. Dis. Model. Mech. 7, 895–905 (2014).
Google Scholar
Newport, J. & Kirschner, M. A major developmental transition in early Xenopus embryos: I. Characterization and timing of cellular changes at the midblastula stage. Cell 30, 675–686 (1982).
Article
Google Scholar
Newport, J. & Kirschner, M. A major developmental transition in early Xenopus embryos: II. Control of the onset of transcription. Cell 30, 687–696 (1982).
Article
Google Scholar
Langley, A. R., Smith, J. C., Stemple, D. L. & Harvey, S. A. New insights into the maternal to zygotic transition. Development 141, 3834–3841 (2014).
Article
Google Scholar
Edgar, B. A. & Schubiger, G. Parameters controlling transcriptional activation during early Drosophila development. Cell 44, 871–877 (1986).
Article
Google Scholar
Kimelman, D., Kirschner, M. & Scherson, T. The events of the midblastula transition in Xenopus are regulated by changes in the cell cycle. Cell 48, 399–407 (1987).
Article
Google Scholar
Chen, H., Einstein, L. C., Little, S. C. & Good, M. C. Spatiotemporal patterning of zygotic genome activation in a model vertebrate embryo. Dev. Cell 49, 852–866.e7 (2019).
Article
Google Scholar
Hadzhiev, Y. et al. A cell cycle-coordinated polymerase II transcription compartment encompasses gene expression before global genome activation. Nat. Commun. 10, 691 (2019).
Article
ADS
Google Scholar
Giraldez, A. J. et al. Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312, 75–79 (2006).
Article
ADS
Google Scholar
Heyn, P. et al. The earliest transcribed zygotic genes are short, newly evolved, and different across species. Cell Rep. 6, 285–292 (2014).
Article
Google Scholar
Poulain, M. & Lepage, T. Mezzo, a paired-like homeobox protein is an immediate target of nodal signalling and regulates endoderm specification in zebrafish. Development 129, 4901–4914 (2002).
Article
Google Scholar
Ruprecht, V. et al. Cortical contractility triggers a stochastic switch to fast amoeboid cell motility. Cell 1, 673–685 (2015).
Article
Google Scholar
Roosen-Runge, E. C. On the early development—bipolar differentiation and cleavage—of the zebra fish, Brachydanio rerio. Biol. Bull. 75, 119–133 (1938).
Article
Google Scholar
Middelkoop, T. C. et al. A cytokinetic ring-driven cell rotation achieves Hertwig's rule in early development. Proc. Natl Acad. Sci. USA 121, e2318838121 (2024).
Article
Google Scholar
Petridou, N. I., Grigolon, S., Salbreux, G., Hannezo, E. & Heisenberg, C.-P. Fluidization-mediated tissue spreading by mitotic cell rounding and non-canonical Wnt signalling. Nat. Cell Biol. 21, 169–178 (2019).
Article
Google Scholar
Gritsman, K. et al. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell 97, 121–132 (1999).
Article
Google Scholar
Budke, H. et al. Assessment of cell proliferation in paraffin sections of normal bone marrow by the monoclonal antibodies Ki-67 and PCNA. Mod. Pathol. 7, 860–866 (1994).
Google Scholar
Kelman, Z. PCNA: structure, functions and interactions. Oncogene 14, 629–640 (1997).
Article
Google Scholar
Leung, A. Y. et al. Proliferating cell nuclear antigen (PCNA) as a proliferative marker during embryonic and adult zebrafish hematopoiesis. Histochem. Cell Biol. 124, 105–111 (2005).
Article
Google Scholar
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
Article
Google Scholar
Arzt, M. et al. LABKIT: labeling and segmentation toolkit for big image data. Front. Comput. Sci. 4, 777728 (2022).
McKinney, W. Data structures for statistical computing in Python. In Proc. 9th Python in Science Conference 56–61 (SciPy, 2010).
Hunter, J. D. Matplotlib: a 2D graphics environment. Comput. Sci. Eng 9, 90–95 (2007).
Article
Google Scholar
Waskom, M. L. seaborn: statistical data visualization. J. Open Source Softw. 6, 3021 (2021).
Article
ADS
Google Scholar
Stegmaier, J. et al. Real-time three-dimensional cell segmentation in large-scale microscopy data of developing embryos. Dev. Cell 36, 225–240 (2016).
Article
Google Scholar
Bolte, S. & Cordelières, F. P. A guided tour into subcellular colocalization analysis in light microscopy. J. Microsc. 224, 213–232 (2006).
Article
MathSciNet
Google Scholar
Tavano, S. et al. BMP-dependent patterning of ectoderm tissue material properties modulates lateral mesendoderm cell migration during early zebrafish gastrulation. Cell Rep. 44, 115387 (2025).
Machado, S., Mercier, V. & Chiaruttini, N. LimeSeg: a coarse-grained lipid membrane simulation for 3D image segmentation. BMC Bioinform. 20, 2 (2019).
Article
Google Scholar
Download references
We thank N. Petridou (EMBL) for sharing results before publication. N.M. was supported by funding from the European Union's Horizon 2020 programme under the Marie Skłodowska-Curie COFUND Actions ISTplus grant agreement number 754411. Y.I.L. acknowledges funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 101034413. The research was supported by funding to C.-P.H. from the NOMIS Foundation, Project ID 1.844. We would like to thank past and present members of the Heisenberg and Hannezo groups for discussions, particularly S. Shamipour, V. Doddihal, M. Jovic, N. Hino, F. N. Arslan, R. Kobylinska and C. Camelo for feedback on the draft manuscript. This research was supported by the Scientific Service Units (SSU) of Institute of Science and Technology Austria through resources provided by the Aquatics Facility, Imaging & Optics Facility (IOF), Scientific Computing (SciComp) facility and Lab Support Facility (LSF).
Open access funding provided by Institute of Science and Technology (IST Austria).
Institute of Science and Technology Austria, Klosterneuburg, Austria
Nikhil Mishra, Yuting Irene Li, Edouard Hannezo & Carl-Philipp Heisenberg
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N.M. and C.-P.H. conceptualized the study. All authors contributed to the design of the experiments. N.M. (experiments) and Y.I.L. (theory) acquired and analysed the data. N.M. and C.-P.H. prepared the paper with input and feedback from all authors.
Correspondence to
Carl-Philipp Heisenberg.
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Nature Physics thanks Stefano Di Talia and Nicolas Minc for their contribution to the peer review of this work.
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(a) Scatter plot of division timing for individual cells starting at cleavage division round 3 (x-axis) relative to their position along the animal-margin axis (y-axis) for one representative wild-type embryo. The green dotted line outlines cells located at a distance of <10 μm from the bottom of the image stack that could not be reliably tracked. (b) Mean RFP-PCNA intensity, as a marker for mitosis onset, as a function of time. Mean PCNA intensity increases during the S-phase, peaks just before the S-M transition, and declines in the M-phase. Thus, a narrow peak indicates greater synchrony and vice versa. (c) Representative scheme showing the position of the mitotic wave origin in division round 8 (n = 7 embryos). (d) Representative plot of cleavage division timing as a function of cell distance from the mitotic wave origin in cleavage division round 8 from a wild-type embryo. Cells undergoing the S-M transition were binned together.
Source data
Representative scatter plots of the division timing for individual surface cells relative to their position along the animal-margin axis in control embryos (a), and embryos injected with either 12 pg chek1 mRNA at the 1-cell stage (b) or 0.3 ng Histone1 protein at the 32-cell stage (c). Blue and red dotted lines demarcate the onset of the 4th and 8th cleavage divisions, respectively. Green dotted line outlines cells located at a distance of <10 μm from the bottom of the image stack that could not be reliably tracked.
Source data
(a) Representative scatter plot of the division timings for individual cells relative to their position along the animal-margin axis in a syncytial Tg(actb2:rfp-pcna) embryo (n = 7 embryos). (b) Contour plot of the mitotic wave across all surface cells at the 8th round of cleavage division round in syncytialized Tg(actb2:rfp-pcna) embryos injected with 12 pg chek1 mRNA at the one-cell stage, and (c) a scatter plot of division timings relative to position along the AP-margin axis for a representative syncytial embryo injected with 12 pg chek1 mRNA. n = 4 embryos.
Source data
A schematic each for single-cell injections of 40 kDa FITC-CM-Dextran at the 16- (a) and the 64-cell stage (b) in Tg(actb2:mCherry-CAAX) embryos and representative images one division round later (n = 3 and 6 embryos, respectively).
(a) Representative images showing segmented cells and nuclei from time-lapse images of Tg(actb2:mCherry-CAAX) embryos injected with Histone 1-Alexa Fluor 488 at the 8- and 16-cell stages. (b) A dot-box plot showing the quantifications for the N/C in individual cells positioned centrally or peripherally. The boxes in the box-plots represent the middle 50% of the distribution, with the lines representing the median and the whiskers indicating the minima and maxima. n = 23 cells for each cleavage stage. Data obtained from 4 and 2 embryos for the 8- and 16-cell stage, respectively.
Source data
(a, d) Representative lateral-view maximum intensity projections, (b, e) cell division timings as a function of the nearest neighbor distance (n = 140 and 133 cells, respectively), and (c, f) as a function of cell position along the AP-margin axis (n = 138 and 133 cells, respectively) in representative control (left) and bilobed (right) Tg(actb2:rfp-pcna) embryos during division round 10. The boxes in the box-plots represent the middle 50% of the distribution, with the lines representing the median and the whiskers indicating the minima and maxima. Points outside the range represent outliers. Data representative of 10 control and 5 bilobed embryos.
Source data
(a) Zoomed-in views of the insets (1, animal pole; 2, intermediate region; 3, margin) shown in Fig. 6A for a control Tg(actb2:rfp-pcna) embryo injected with MO1-3-Fluorescein in the 10th division round. Cyan, MO1-3-Fluorescein (nascent mi430 transcripts); magenta, nuclei (PCNA). Each inset represents an area of 120 µm X 120 µm in size. (b) A scatter plot showing cell division timing as a function of the nearest neighbor distance with dot color representing the number of pri-mRNA transcription foci in a cell. n = 72 cells, data representative of 4 embryos. (c) A dot-box-plot showing the ratio of S-phase length and nearest neighbor distance for cells with one or two transcription foci for a representative embryo during division round 10. The box in the box-plot represents the middle 50% of the distribution, with the line representing the median and the whiskers indicating the minima and maxima. Dots outside the range represent outliers. n = 72 cells, data representative of 4 embryos.
Source data
Supplementary Sections 1–5 and Figs. 1–5.
Animal pole (AP)-view of the cell cycle progression beginning from division round 3 in a Tg(actb2:rfp-pcna) embryo. Temporal resolution: 38.7 s/frame.
AP-view of the cell cycle progression beginning from division round 7 in a Tg(actb2:rfp-pcna) embryo with a mosaic injection of 0.3 ng Histone 1-Alexa Flour 488 at the 32-cell stage. The highlighted region indicates the position of the (daughters of the) injected cells. Red: PCNA, Green: Histone 1. Temporal resolution: 39.1 s/frame.
AP-view of the cell cycle progression beginning from division round 4 in a Tg(actb2:rfp-pcna) embryo injected with 12 pg chek1 mRNA at the one-cell stage. Temporal resolution: 37.9 s/frame.
AP-view of the nuclear cycling beginning from division round 4 in a Tg(actb2:rfp-pcna) embryo syncytialized by inhibiting Aurkb activity through 50 µM AZD1152-treatment at the one-cell stage. Temporal resolution: 38.1 s/frame.
AP-view of the nuclear cycling beginning from division round 3 in a syncytialized Tg(actb2:rfp-pcna) embryo injected with 12 pg chek1 mRNA at the one-cell stage. Temporal resolution: 57.4 s/frame.
AP-view of the cell cycle progression beginning from division round 4 in a Tg(actb2:rfp-pcna) embryo from which one nucleus at the two-cell stage was aspirated. (Top: Control half, Bottom: Nucleus aspiration half). Temporal resolution: 71.8 s/frame.
AP-view of the cell cycle progression beginning from division round 4 in a bilobed Tg(actb2:rfp-pcna) embryo. Temporal resolution: 66.7 s/frame.
AP-view of the cell cycle progression beginning from division round 5 in a Tg(actb2:rfp-pcna) embryo with the yolk-blastoderm curvature increased through a partial severing of the yolk at the two-cell stage. Temporal resolution: 65.3 s/frame.
AP-view of the cell cycle progression beginning from division round 3 in a Tg(actb2:rfp-pcna) embryo treated with 10 µM PF477736 to inhibit Chek1 activity. Temporal resolution: 65.9 s/frame.
AP-view of the cell cycle progression and mirR430 pri-mRNA beginning from division round 8 in a control Tg(actb2:rfp-pcna) embryo injected with MO1-3-Fluorescein at the one-cell stage. Magenta: PCNA, Cyan: MO1-3. Temporal resolution: 53.4 s/frame.
Lateral view of the cell cycle progression and mirR430 pri-mRNA beginning from division round 3 in a control Tg(actb2:rfp-pcna) embryo injected with MO1-3-Fluorescein at the one-cell stage. Red: PCNA, Green: MO1-3. Temporal resolution: 60 s/frame.
AP-view of the cell cycle progression and mirR430 pri-mRNA beginning from division round 8 in a bilobed Tg(actb2:rfp-pcna) embryo injected with MO1-3-Fluorescein at the one-cell stage. Magenta: PCNA, Cyan: MO1-3. Temporal resolution: 66.7 s/frame.
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Mishra, N., Li, Y.I., Hannezo, E. et al. Geometry-driven asymmetric cell divisions pattern cell cycles and zygotic genome activation in the zebrafish embryo.
Nat. Phys. (2026). https://doi.org/10.1038/s41567-025-03122-1
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An international research team led by scientists from La Trobe University in Australia and the University of Cambridge is questioning how one of the most complete early human fossils has been classified. Their findings suggest the specimen may not belong to any known human ancestor species and could represent an entirely new one.
The fossil, uncovered in South Africa's Sterkfontein Caves in 1998 and nicknamed "Little Foot," has long been considered part of the Australopithecus genus. This group includes early, upright-walking relatives of humans that lived in southern Africa between about 3 million and 1.95 million years ago.
Ronald Clarke, the paleoanthropologist who led the painstaking 20-year effort to excavate and study the skeleton, initially identified Little Foot as Australopithecus prometheus when it was formally introduced in 2017. Other researchers argued it belonged to Australopithecus africanus, a species first described in 1925 by Australian anatomist Raymond Dart and already known from the same region.
New Evidence Challenges Old Assumptions
In a peer-reviewed study published in the American Journal of Biological Anthropology, a team led by La Trobe University adjunct Dr. Jesse Martin reached a different conclusion. Their analysis found that Little Foot does not share a distinct combination of features with either Australopithecus prometheus or Australopithecus africanus. This opens the door to the possibility that the fossil represents a previously unrecognized species.
"This fossil remains one of the most important discoveries in the hominin record and its true identity is key to understanding our evolutionary past," Dr. Martin said.
"We think it's demonstrably not the case that it's A.prometheus or A. africanus. This is more likely a previously unidentified, human relative.
"Dr. Clarke deserves credit for the discovery of Little Foot, and being one of the only people to maintain there were two species of hominin at Sterkfontein. Little Foot demonstrates in all likelihood he's right about that. There are two species."
Why Little Foot Matters
Formally known as StW 573, Little Foot is still considered the most complete ancient hominin skeleton ever found. Despite its significance, no team had publicly challenged its species classification since its debut in 2017 until now.
"Our findings challenge the current classification of Little Foot and highlight the need for further careful, evidence-based taxonomy in human evolution," Dr. Martin said.
Dr. Martin, who holds an adjunct position at La Trobe University and is a postdoctoral research fellow at Cambridge, will continue this work alongside La Trobe students. Their goal is to determine exactly which species Little Foot belongs to and where it fits within the broader human family tree.
Broader Implications for Human Evolution
The research was conducted under an Australian Research Council grant led by Professor Andy Herries at La Trobe University. Professor Herries emphasized the fossil's importance for understanding early human diversity and how ancient relatives adapted to the varied environments of southern Africa.
"It is clearly different from the type specimen of Australopithecus prometheus, which was a name defined on the idea these early humans made fire, which we now know they didn't. Its importance and difference to other contemporary fossils clearly show the need for defining it as its own unique species."
The study reflects a wide-ranging collaboration among researchers and institutions in the United Kingdom, Australia, South Africa and the United States.
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Nature Reviews Drug Discovery
(2026)Cite this article
Type I/II cytokine receptors mediate cytokine-specific biological responses by employing a defined combination of four Janus kinases (JAKs) and seven signal transducers and activators of transcription (STATs) for cellular signal transduction. Deregulation of the JAK–STAT pathway leads to various diseases, with JAK and STAT proteins representing attractive therapeutic targets. Fifteen JAK inhibitors are approved for several immunological and haematological diseases, offering significant benefits for patients. However, safety restrictions have limited their clinical use. Mechanistic and structural insights are driving current drug development approaches focused on improving their potency, selectivity and safety. Development of STAT inhibitors has been more challenging, and none has yet received clinical approval, although promising new compounds are now entering clinical trials. This Review discusses the recent advances in JAK and STAT inhibitor development and presents emerging therapeutic indications for JAK–STAT inhibition.
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Philips, R. L. et al. JAK–STAT pathway at 30: much learned, much more to do. Cell 185, 3857–3876 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Caveney, N. A. et al. Structural basis of Janus kinase trans-activation. Cell Rep. 42, 112201 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Abraham, B. G. et al. Molecular basis of JAK2 activation in erythropoietin receptor and pathogenic JAK2 signaling. Sci. Adv. 10, eadl2097 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Leonard, W. J. & Lin, J.-X. Strategies to therapeutically modulate cytokine action. Nat. Rev. Drug. Discov. 22, 827–854 (2023).
Article
PubMed
CAS
Google Scholar
Hammarén, H. M., Virtanen, A. T., Raivola, J. & Silvennoinen, O. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine 118, 48–63 (2019).
Article
PubMed
Google Scholar
Jain, M. et al. Role of JAK/STAT in the neuroinflammation and its association with neurological disorders. Ann. Neurosci. 28, 191–200 (2021).
Article
PubMed
Google Scholar
Sabaawy, H. E., Ryan, B. M., Khiabanian, H. & Pine, S. R. JAK/STAT of all trades: linking inflammation with cancer development, tumor progression and therapy resistance. Carcinogenesis 42, 1411–1419 (2021).
Article
PubMed
CAS
PubMed Central
Google Scholar
Russell, M. A., Richardson, S. J. & Morgan, N. G. The role of the interferon/JAK–STAT axis in driving islet HLA-I hyperexpression in type 1 diabetes. Front. Endocrinol. 14, 1270325 (2023).
Article
Google Scholar
Eggel, A., Pennington, L. F. & Jardetzky, T. S. Therapeutic monoclonal antibodies in allergy: targeting IgE, cytokine, and alarmin pathways. Immunol. Rev. 328, 387–411 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Saxton, R. A., Glassman, C. R. & Garcia, K. C. Emerging principles of cytokine pharmacology and therapeutics. Nat. Rev. Drug. Discov. 22, 21–37 (2023).
Article
PubMed
CAS
Google Scholar
Tokareva, K. et al. JAK inhibitors and black box warnings: what is the future for JAK inhibitors? Expert. Rev. Clin. Immunol. 19, 1385–1397 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Ferrao, R. & Lupardus, P. J. The Janus kinase (JAK) FERM and SH2 domains: bringing specificity to JAK–receptor interactions. Front. Endocrinol. https://doi.org/10.3389/fendo.2017.00071 (2017).
Ferrao, R. D., Wallweber, H. J. & Lupardus, P. J. Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation. eLife 7, e38089 (2018).
Article
PubMed
PubMed Central
Google Scholar
Wallweber, H. J. A., Tam, C., Franke, Y., Starovasnik, M. A. & Lupardus, P. J. Structural basis of IFNα receptor recognition by TYK2. Nat. Struct. Mol. Biol. 21, 443–448 (2014).
Article
PubMed
CAS
PubMed Central
Google Scholar
McNally, R., Toms, A. V. & Eck, M. J. Crystal structure of the FERM–SH2 module of human Jak2. PLoS One 11, e0156218 (2016).
Article
PubMed
PubMed Central
Google Scholar
Zhang, D., Wlodawer, A. & Lubkowski, J. Crystal structure of a complex of the intracellular domain of interferon λ receptor 1 (IFNLR1) and the FERM/SH2 domains of human JAK1. J. Mol. Biol. 428, 4651–4668 (2016).
Article
PubMed
CAS
PubMed Central
Google Scholar
Glassman, C. R. et al. Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation. Science 376, 163–169 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Philips, R. L. et al. The JAK–STAT pathway at 30: much learned, much more to do. Cell 185, 3857–3876 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Rengachari, S. et al. Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function. Proc. Natl Acad. Sci. USA 115, E601–E609 (2018).
Article
PubMed
CAS
PubMed Central
Google Scholar
Gingras, S., Simard, J., Groner, B. & Pfitzner, E. p300/CBP is required for transcriptional induction by interleukin-4 and interacts with Stat6. Nucleic Acids Res. 27, 2722–2729 (1999).
Article
PubMed
CAS
PubMed Central
Google Scholar
Wojciak, J. M., Martinez-Yamout, M. A., Dyson, H. J. & Wright, P. E. Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains. EMBO J. 28, 948–958 (2009).
Article
PubMed
CAS
PubMed Central
Google Scholar
Bousoik, E. & Montazeri Aliabadi, H. “Do we know jack” about JAK? A closer look at JAK/STAT signaling pathway. Front. Oncol. 8, 287 (2018).
Article
PubMed
PubMed Central
Google Scholar
Baxter, E. J. et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365, 1054–1061 (2005).
Article
PubMed
CAS
Google Scholar
Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005).
Article
PubMed
CAS
Google Scholar
James, C. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144–1148 (2005).
Article
PubMed
CAS
Google Scholar
Horesh, M. E. et al. Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis. J. Exp. Med. 221, e20232387 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Xiang, Z. et al. Identification of somatic JAK1 mutations in patients with acute myeloid leukemia. Blood 111, 4809–4812 (2008).
Article
PubMed
CAS
PubMed Central
Google Scholar
Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377, 65–68 (1995).
Article
PubMed
CAS
Google Scholar
Walters, D. K. et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10, 65–75 (2006).
Article
PubMed
CAS
Google Scholar
Pellenz, F. M. et al. Association of TYK2 polymorphisms with autoimmune diseases: a comprehensive and updated systematic review with meta-analysis. Genet. Mol. Biol. 44, e20200425 (2021).
Article
PubMed
CAS
PubMed Central
Google Scholar
Boggon, T. J., Li, Y., Manley, P. W. & Eck, M. J. Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Blood 106, 996–1002 (2005).
Article
PubMed
CAS
PubMed Central
Google Scholar
Lucet, I. S. et al. The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor. Blood 107, 176–183 (2006).
Article
PubMed
CAS
Google Scholar
Miao, Y. et al. Functional and structural characterization of clinical-stage Janus kinase 2 inhibitors identifies determinants for drug selectivity. J. Med. Chem. 67, 10012–10024 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Virtanen, A. et al. Differences in JAK isoform selectivity among different types of JAK inhibitors evaluated for rheumatic diseases through in vitro profiling. Arthritis Rheumatol. 75, 2054–2061 (2023).
Article
PubMed
CAS
Google Scholar
Virtanen, A. et al. JAK inhibitor selectivity: new opportunities, better drugs? Nat. Rev. Rheumatol. 20, 649–665 (2024).
Article
PubMed
CAS
Google Scholar
Telliez, J.-B. et al. Discovery of a JAK3-selective inhibitor: functional differentiation of Jak3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem. Biol. 11, 3442–3451 (2016).
Article
PubMed
CAS
Google Scholar
Li, S. et al. Discovery of hexahydrofuro[3,2-b]furans as new kinase-selective and orally bioavailable JAK3 inhibitors for the treatment of leukemia harboring a JAK3 activating mutant. J. Med. Chem. 65, 10674–10690 (2022).
Article
PubMed
CAS
Google Scholar
Hammarén, H. M. et al. Janus kinase 2 activation mechanisms revealed by analysis of suppressing mutations. J. Allergy Clin. Immunol. 143, 1549–1559.e6 (2019).
Article
PubMed
Google Scholar
Raivola, J., Haikarainen, T. & Silvennoinen, O. Characterization of JAK1 pseudokinase domain in cytokine signaling. Cancers 12, 78 (2019).
Article
PubMed
PubMed Central
Google Scholar
Leroy, E. et al. Differential effect of inhibitory strategies of the V617 mutant of JAK2 on cytokine receptor signaling. J. Allergy Clin. Immunol. 144, 224–235 (2019).
Article
PubMed
CAS
Google Scholar
Silvennoinen, O. & Ungureanu, D. Dual activity kinase domains and uses thereof. US Patent 8,841,078 (23 September 2014).
Hammarén, H. M. et al. ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Proc. Natl Acad. Sci. USA 112, 4642–4647 (2015).
Article
PubMed
PubMed Central
Google Scholar
Toms, A. V. et al. Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat. Struct. Mol. Biol. 20, 1221–1223 (2013).
Article
PubMed
CAS
PubMed Central
Google Scholar
Bandaranayake, R. M. et al. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat. Struct. Mol. Biol. 19, 754–759 (2012).
Article
PubMed
CAS
PubMed Central
Google Scholar
Min, X. et al. Structural and functional characterization of the JH2 pseudokinase domain of JAK family tyrosine kinase 2 (TYK2). J. Biol. Chem. 290, 27261–27270 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
McNally, R. et al. Discovery and structural characterization of ATP-site ligands for the wild-type and V617F mutant JAK2 pseudokinase domain. ACS Chem. Biol. 14, 587–593 (2019).
Article
PubMed
CAS
Google Scholar
Virtanen, A. T. et al. Identification of novel small molecule ligands for JAK2 pseudokinase domain. Pharmaceuticals 16, 75 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Puleo, D. E. et al. Identification and characterization of JAK2 pseudokinase domain small molecule binders. ACS Med. Chem. Lett. 8, 618–621 (2017).
Article
PubMed
CAS
PubMed Central
Google Scholar
Liosi, M.-E. et al. Insights on JAK2 modulation by potent, selective, and cell-permeable pseudokinase-domain ligands. J. Med. Chem. 65, 8380–8400 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Henry, S. P. et al. Covalent modification of the JH2 domain of Janus kinase 2. ACS Med. Chem. Lett. 13, 1819–1826 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Henry, S. P. et al. Conversion of a false virtual screen hit into selective JAK2 JH2 domain binders using convergent design strategies. ACS Med. Chem. Lett. 13, 819–826 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Liosi, M.-E. et al. Selective Janus Kinase 2 (JAK2) pseudokinase ligands with a diaminotriazole core. J. Med. Chem. 63, 5324–5340 (2020).
Article
PubMed
CAS
PubMed Central
Google Scholar
Coltoff, A. & Mascarenhas, J. Fedratinib in 2025 and beyond: indications and future applications. Blood Adv. 9, 1907–1915 (2025).
Article
PubMed
CAS
PubMed Central
Google Scholar
Keam, S. J. Momelotinib: first approval. Drugs 83, 1709–1715 (2023).
Article
PubMed
CAS
Google Scholar
Lamb, Y. N. Pacritinib: first approval. Drugs 82, 831–838 (2022).
Article
PubMed
CAS
Google Scholar
Masarova, L. et al. Ten years of experience with ruxolitinib since approval for polycythemia vera: a review of clinical efficacy and safety. Cancer 131, e35661 (2025).
Article
PubMed
Google Scholar
Traynor, K. FDA approves tofacitinib for rheumatoid arthritis. Am. J. Health Syst. Pharm. 69, 2120 (2012).
PubMed
Google Scholar
Markham, A. Baricitinib: first global approval. Drugs 77, 697–704 (2017).
Article
PubMed
CAS
Google Scholar
Koppikar, P. et al. Heterodimeric JAK–STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature 489, 155–159 (2012).
Article
PubMed
CAS
PubMed Central
Google Scholar
Meyer, S. C. et al. CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms. Cancer Cell 28, 15–28 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
Palandri, F. et al. Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosis. Blood Cancer J. 11, 4 (2021).
Article
PubMed
PubMed Central
Google Scholar
Song, Y. et al. Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas. Ann. Oncol. 34, 1055–1063 (2023).
Article
PubMed
CAS
Google Scholar
Song, Y. et al. Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study. Lancet Oncol. 25, 117–125 (2024).
Article
PubMed
CAS
Google Scholar
Horwitz, S. M. et al. Results from an open-label phase 2a study of cerdulatinib, a dual spleen tyrosine kinase/janus kinase inhibitor, in relapsed/refractory peripheral T-cell lymphoma. Leuk. Lymphoma 66, 1100–1110 (2025).
Article
PubMed
CAS
PubMed Central
Google Scholar
Moskowitz, A. J. et al. A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas. Blood 138, 2828–2837 (2021).
Article
PubMed
CAS
PubMed Central
Google Scholar
Wu, H. et al. JAK1–STAT3 blockade by JAK inhibitor SHR0302 attenuates inflammatory responses of adjuvant-induced arthritis rats and decreases TH17 and total B cells. Jt. Bone Spine 83, 525–532 (2016).
Article
CAS
Google Scholar
Kirby, J. S. et al. Efficacy and safety of the oral Janus kinase 1 inhibitor povorcitinib (INCB054707) in patients with hidradenitis suppurativa in a phase 2, randomized, double-blind, dose-ranging, placebo-controlled study. J. Am. Acad. Dermatol. 90, 521–529 (2024).
Article
PubMed
CAS
Google Scholar
Huang, K. et al. The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects. Front. Pharmacol. 13, 1066895 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Chen, J.-Q. et al. Safety and efficacy of the selective TYK2/JAK1 inhibitor TLL-018 in moderate-to-severe plaque psoriasis: a phase 1b, randomized, double-blind, placebo-controlled study. Br. J. Dermatol. https://doi.org/10.1093/bjd/ljaf185 (2025).
Andraos, R. et al. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Discov. 2, 512–523 (2012).
Article
PubMed
CAS
PubMed Central
Google Scholar
Wu, S.-C. et al. Activity of the type II JAK2 inhibitor CHZ868 in B cell acute lymphoblastic leukemia. Cancer Cell 28, 29–41 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
Arwood, M. L. et al. New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation. Cell Chem. Biol. 30, 618–631.e12 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Mascarenhas, J. O. et al. A multicenter, open-label, phase 1 clinical trial of AJ1-11095 administered as oral monotherapy in patients with primary myelofibrosis (PMF), Post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF) who have been failed by a type I JAK2 Inhibitor (JAK2i). Blood 144, 3147.1 (2024).
Article
Google Scholar
Tokarski, J. S. et al. Tyrosine kinase 2-mediated signal transduction in T lymphocytes is blocked by pharmacological stabilization of its pseudokinase domain. J. Biol. Chem. 290, 11061–11074 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
Wrobleski, S. T. et al. Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: discovery of the allosteric inhibitor BMS-986165. J. Med. Chem. 62, 8973–8995 (2019).
Article
PubMed
CAS
Google Scholar
Burke, J. R. et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci. Transl. Med. 11, eaaw1736 (2019).
Article
PubMed
Google Scholar
Moslin, R. et al. Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling. Med. Chem. Commun. 8, 700–712 (2017).
Article
CAS
Google Scholar
Moslin, R. et al. Identification of N-methyl nicotinamide and N-methyl pyridazine-3-carboxamide pseudokinase domain ligands as highly selective allosteric inhibitors of tyrosine kinase 2 (TYK2). J. Med. Chem. 62, 8953–8972 (2019).
Article
PubMed
CAS
Google Scholar
Armstrong, A. W. et al. Safety and efficacy of deucravacitinib in moderate to severe plaque psoriasis for up to 3 years: an open-label extension of randomized clinical trials. JAMA Dermatol. 161, 56–66 (2025).
Article
PubMed
Google Scholar
Leit, S. et al. Discovery of a potent and selective tyrosine kinase 2 inhibitor: TAK-279. J. Med. Chem. 66, 10473–10496 (2023).
Article
PubMed
Google Scholar
Breinlinger, E. et al. Targeting the tyrosine kinase 2 (TYK2) pseudokinase domain: discovery of the selective TYK2 inhibitor ABBV-712. J. Med. Chem. 66, 14335–14356 (2023).
Article
PubMed
CAS
Google Scholar
Stubbs, M. C. et al. Preclinical evaluation of INCB160058—a novel and potentially disease-modifying therapy for JAK2V617F mutant myeloproliferative neoplasms. Blood 142, 860 (2023).
Article
Google Scholar
Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570–574 (2016).
Article
PubMed
CAS
PubMed Central
Google Scholar
Kavanagh, M. E. et al. Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine. Nat. Chem. Biol. 18, 1388–1398 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Wylie, A. A. et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature 543, 733–737 (2017).
Article
PubMed
CAS
Google Scholar
Shah, R. R. et al. Hi-JAK-ing the ubiquitin system: the design and physicochemical optimisation of JAK PROTACs. Bioorg. Med. Chem. 28, 115326 (2020).
Article
PubMed
CAS
Google Scholar
Chang, Y. et al. Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia. Blood 138, 2313–2326 (2021).
Article
PubMed
CAS
PubMed Central
Google Scholar
Wu, J. et al. JAK1/JAK2 degraders based on PROTAC for topical treatment of atopic dermatitis. Biomed. Pharmacother. 171, 116167 (2024).
Article
PubMed
CAS
Google Scholar
Zhang, X. et al. Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities. Bioorg. Med. Chem. Lett. 109, 129838 (2024).
Article
PubMed
CAS
Google Scholar
Kato, J.-Y., Korenaga, S. & Iwakura, M. Discovery of a potent and subtype-selective TYK2 degrader based on an allosteric TYK2 inhibitor. Bioorg. Med. Chem. Lett. 79, 129083 (2023).
Article
PubMed
CAS
Google Scholar
Dunbar, A. J. et al. Jak2V617F reversible activation shows its essential requirement in myeloproliferative neoplasms. Cancer Discov. 14, 737–751 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Ekman, F., Selvaraj, S., Gotlib, J., Cromer, M. K. & Porteus, M. H. Targeting the JAK2-V617F mutation in polycythemia vera using CRISPR/AAV6 genome editing. Blood 144, 4524 (2024).
Article
Google Scholar
Tang, Q. et al. Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin. Nat. Commun. 14, 7099 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Bousoik, E., Mahdipoor, P., Alhazza, A. & Montazeri Aliabadi, H. Combinational silencing of components involved in JAK/STAT signaling pathway. Eur. J. Pharm. Sci. 175, 106233 (2022).
Article
PubMed
CAS
Google Scholar
Clément, F. et al. Therapeutic siRNAs targeting the JAK/STAT signalling pathway in inflammatory bowel diseases. J. Crohns Colitis 16, 286–300 (2022).
Article
PubMed
Google Scholar
Wang, W., Lopez McDonald, M. C., Hariprasad, R., Hamilton, T. & Frank, D. A. Oncogenic STAT transcription factors as targets for cancer therapy: innovative strategies and clinical translation. Cancers 16, 1387 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
He, X., Liu, P., Luo, Y., Fu, X. & Yang, T. STATs, promising targets for the treatment of autoimmune and inflammatory diseases. Eur. J. Med. Chem. 277, 116783 (2024).
Article
PubMed
CAS
Google Scholar
Xia, Y., Xie, Y., Zhang, H. & Liu, L. STAT4 gene polymorphisms in human diseases. Front. Immunol. 15, 1479418 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Sharma, M. et al. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. J. Exp. Med. 220, e20221755 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Baris, S. et al. Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6. J. Allergy Clin. Immunol. 152, 182–194.e7 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Frank, D. A. Targeting STATs for cancer therapy. JAKSTAT 1, 261–262 (2012).
PubMed
PubMed Central
Google Scholar
Turkson, J. et al. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem. 276, 45443–45455 (2001).
Article
PubMed
CAS
Google Scholar
Turkson, J. et al. Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol. Cancer Ther. 3, 261–269 (2004).
Article
PubMed
CAS
Google Scholar
Mandal, P. K., Heard, P. A., Ren, Z., Chen, X. & McMurray, J. S. Solid-phase synthesis of Stat3 inhibitors incorporating O-carbamoylserine and O-carbamoylthreonine as glutamine mimics. Bioorg. Med. Chem. Lett. 17, 654–656 (2007).
Article
PubMed
CAS
Google Scholar
Mandal, P. K. et al. Conformationally constrained peptidomimetic inhibitors of signal transducer and activator of transcription. 3: evaluation and molecular modeling. J. Med. Chem. 52, 2429–2442 (2009).
Article
PubMed
CAS
PubMed Central
Google Scholar
Mandal, P. K., Liao, W. S.-L. & McMurray, J. S. Synthesis of phosphatase-stable, cell-permeable peptidomimetic prodrugs that target the SH2 domain of Stat3. Org. Lett. 11, 3394–3397 (2009).
Article
PubMed
CAS
PubMed Central
Google Scholar
Auzenne, E. J. et al. A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis. J. Exp. Ther. Oncol. 10, 155–162 (2012).
PubMed
CAS
PubMed Central
Google Scholar
Mandal, P. K. et al. Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3. J. Med. Chem. 54, 3549–3563 (2011).
Article
PubMed
CAS
PubMed Central
Google Scholar
Morlacchi, P., Mandal, P. K. & McMurray, J. S. Synthesis and in vitro evaluation of a peptidomimetic inhibitor targeting the Src homology 2 (SH2) domain of STAT6. ACS Med. Chem. Lett. 5, 69–72 (2014).
Article
PubMed
CAS
Google Scholar
Mandal, P. K. et al. Targeting the Src homology 2 (SH2) domain of signal transducer and activator of transcription 6 (STAT6) with cell-permeable, phosphatase-stable phosphopeptide mimics potently inhibits Tyr641 phosphorylation and transcriptional activity. J. Med. Chem. 58, 8970–8984 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
Knight, J. M. et al. Small molecule targeting of the STAT5/6 Src homology 2 (SH2) domains to inhibit allergic airway disease. J. Biol. Chem. 293, 10026–10040 (2018).
Article
PubMed
CAS
PubMed Central
Google Scholar
Chen, H. et al. Discovery of the highly selective and potent STAT3 inhibitor for pancreatic cancer treatment. ACS Cent. Sci. 10, 579–594 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Chen, H. et al. Targeting STAT3 by a small molecule suppresses pancreatic cancer progression. Oncogene 40, 1440–1457 (2021).
Article
PubMed
CAS
PubMed Central
Google Scholar
Brambilla, L. et al. Hitting the right spot: mechanism of action of OPB-31121, a novel and potent inhibitor of the signal transducer and activator of transcription 3 (STAT3). Mol. Oncol. 9, 1194–1206 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
Haftchenary, S. et al. Potent targeting of the STAT3 protein in brain cancer stem cells: a promising route for treating glioblastoma. ACS Med. Chem. Lett. 4, 1102–1107 (2013).
Article
PubMed
CAS
PubMed Central
Google Scholar
Page, B. D. G. et al. Inhibiting aberrant signal transducer and activator of transcription protein activation with tetrapodal, small molecule Src homology 2 domain binders: promising agents against multiple myeloma. J. Med. Chem. 56, 7190–7200 (2013).
Article
PubMed
CAS
Google Scholar
Zhang, X. et al. A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation. Cancer Res. 73, 1922–1933 (2013).
Article
PubMed
CAS
PubMed Central
Google Scholar
Zhang, X. et al. Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc. Natl Acad. Sci. USA 109, 9623–9628 (2012).
Article
PubMed
CAS
PubMed Central
Google Scholar
Ren, X. et al. Identification of niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway. ACS Med. Chem. Lett. 1, 454–459 (2010).
Article
PubMed
CAS
PubMed Central
Google Scholar
Matsuno, K. et al. Identification of a new series of STAT3 inhibitors by virtual screening. ACS Med. Chem. Lett. 1, 371–375 (2010).
Article
PubMed
CAS
PubMed Central
Google Scholar
Zhang, X. et al. A novel small-molecule disrupts Stat3 SH2 domain–phosphotyrosine interactions and Stat3-dependent tumor processes. Biochem. Pharmacol. 79, 1398–1409 (2010).
Article
PubMed
CAS
PubMed Central
Google Scholar
Wingelhofer, B. et al. Pharmacologic inhibition of STAT5 in acute myeloid leukemia. Leukemia 32, 1135–1146 (2018).
Article
PubMed
CAS
PubMed Central
Google Scholar
Elumalai, N. et al. Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b. Sci. Rep. 7, 819 (2017).
Article
PubMed
PubMed Central
Google Scholar
Elumalai, N., Berg, A., Natarajan, K., Scharow, A. & Berg, T. Nanomolar inhibitors of the transcription factor STAT5b with high selectivity over STAT5a. Angew. Chem. Int. Ed. Engl. 54, 4758–4763 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
Cumaraswamy, A. A. et al. Nanomolar-potency small molecule inhibitor of STAT5 protein. ACS Med. Chem. Lett. 5, 1202–1206 (2014).
Article
PubMed
CAS
PubMed Central
Google Scholar
Page, B. D. G. et al. Small molecule STAT5–SH2 domain inhibitors exhibit potent antileukemia activity. J. Med. Chem. 55, 1047–1055 (2012).
Article
PubMed
CAS
Google Scholar
Müller, J., Sperl, B., Reindl, W., Kiessling, A. & Berg, T. Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem 9, 723–727 (2008).
Article
PubMed
Google Scholar
Martínez-López, J. et al. Biomarker-driven phase Ib clinical trial of OPB-111077 in acute myeloid leukemia. Med. Int. 2, 7 (2022).
Article
Google Scholar
Yoo, C. et al. Phase I dose-finding study of OPB-111077, a novel STAT3 inhibitor, in patients with advanced hepatocellular carcinoma. Cancer Res. Treat. 51, 510–518 (2019).
Article
PubMed
CAS
Google Scholar
Ogura, M. et al. Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies. Cancer Sci. 106, 896–901 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
Oh, D.-Y. et al. Phase I study of OPB-31121, an oral STAT3 Inhibitor, in patients with advanced solid tumors. Cancer Res. Treat. 47, 607–615 (2015).
Article
PubMed
CAS
PubMed Central
Google Scholar
Redell, M. S., Ruiz, M. J., Alonzo, T. A., Gerbing, R. B. & Tweardy, D. J. Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood 117, 5701–5709 (2011).
Article
PubMed
CAS
PubMed Central
Google Scholar
Xu, X., Kasembeli, M. M., Jiang, X., Tweardy, B. J. & Tweardy, D. J. Chemical probes that competitively and selectively inhibit Stat3 activation. PLoS One 4, e4783 (2009).
Article
PubMed
PubMed Central
Google Scholar
Tsimberidou, A. M. et al. Phase I trial of TTI-101, a first-in-class oral inhibitor of STAT3, in patients with advanced solid tumors. Clin. Cancer Res. 31, 965–974 (2025).
Article
PubMed
CAS
PubMed Central
Google Scholar
Brovchenko, N. et al. Biaryl phosphates and phosphonates as selective inhibitors of the transcription factor STAT4. Angew. Chem. Int. Ed. Engl. 64, e202504420 (2025).
Article
PubMed
CAS
PubMed Central
Google Scholar
Metz, P. et al. Highly selective and reversible STAT6 inhibition demonstrates potential for differentiated efficacy and safety profile in type 2 allergic inflammation. Am. J. Respir. Crit. Care Med. 211, A1319–A1319 (2025).
Article
Google Scholar
Yang, J. & Stark, G. R. Roles of unphosphorylated STATs in signaling. Cell Res. 18, 443–451 (2008).
Article
PubMed
CAS
Google Scholar
Yang, J. et al. Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res. 65, 939–947 (2005).
Article
PubMed
CAS
Google Scholar
Yang, J. et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB. Genes. Dev. 21, 1396–1408 (2007).
Article
PubMed
CAS
PubMed Central
Google Scholar
Leong, P. L. et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc. Natl Acad. Sci. USA 100, 4138–4143 (2003).
Article
PubMed
CAS
PubMed Central
Google Scholar
Zhang, Q. et al. Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia. Blood 127, 1687–1700 (2016).
Article
PubMed
CAS
PubMed Central
Google Scholar
Zhang, X. et al. Inhibitory effects of STAT3 decoy oligodeoxynucleotides on human epithelial ovarian cancer cell growth in vivo. Int. J. Mol. Med. 32, 623–628 (2013).
Article
PubMed
CAS
Google Scholar
Shen, J., Li, R. & Li, G. Inhibitory effects of decoy-ODN targeting activated STAT3 on human glioma growth in vivo. In Vivo 23, 237–243 (2009).
PubMed
CAS
Google Scholar
Gu, J. et al. Blockage of the STAT3 signaling pathway with a decoy oligonucleotide suppresses growth of human malignant glioma cells. J. Neurooncol 89, 9–17 (2008).
Article
PubMed
CAS
Google Scholar
Zhang, X., Zhang, J., Wang, L., Wei, H. & Tian, Z. Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice. BMC Cancer 7, 149 (2007).
Article
PubMed
CAS
PubMed Central
Google Scholar
Sun, Z., Yao, Z., Liu, S., Tang, H. & Yan, X. An oligonucleotide decoy for Stat3 activates the immune response of macrophages to breast cancer. Immunobiology 211, 199–209 (2006).
Article
PubMed
CAS
Google Scholar
Xi, S., Gooding, W. E. & Grandis, J. R. In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy. Oncogene 24, 970–979 (2005).
Article
PubMed
CAS
Google Scholar
Chan, K. S. et al. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J. Clin. Invest. 114, 720–728 (2004).
Article
PubMed
CAS
PubMed Central
Google Scholar
Sen, M. et al. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer Discov. 2, 694–705 (2012).
Article
PubMed
CAS
PubMed Central
Google Scholar
Grandis, J. R. et al. Safety and efficacy of a STAT3-targeted cyclic oligonucleotide: From murine models to a phase 1 clinical trial in pet cats with oral cancer. Cancer Cell https://doi.org/10.1016/j.ccell.2025.07.015 (2025).
Article
PubMed
Google Scholar
Huang, W. et al. A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and invasion. ACS Chem. Biol. 9, 1188–1196 (2014).
Article
PubMed
CAS
PubMed Central
Google Scholar
Huang, W. et al. Small-molecule inhibitors targeting the DNA-binding domain of STAT3 suppress tumor growth, metastasis and STAT3 target gene expression in vivo. Oncogene 35, 783–792 (2016).
Article
PubMed
CAS
Google Scholar
Huang, W. et al. Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis. Eur. J. Med. Chem. 157, 887–897 (2018).
Article
PubMed
CAS
Google Scholar
Son, D. J. et al. MMPP attenuates non-small cell lung cancer growth by inhibiting the STAT3 DNA-binding activity via direct binding to the STAT3 DNA-binding domain. Theranostics 7, 4632–4642 (2017).
Article
PubMed
CAS
PubMed Central
Google Scholar
Groot, J. de et al. A first-in-human phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma. CNS Oncol. 11, CNS87 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Iwamaru, A. et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene 26, 2435–2444 (2007).
Article
PubMed
CAS
Google Scholar
Froeling, F. E. M. et al. Bioactivation of napabucasin triggers reactive oxygen species-mediated cancer cell death. Clin. Cancer Res. 25, 7162–7174 (2019).
Article
PubMed
CAS
PubMed Central
Google Scholar
Zhang, C. et al. Design, synthesis, and biological evaluation of novel napabucasin–melatonin hybrids as potent STAT3 inhibitors. Bioorg. Chem. 136, 106541 (2023).
Article
PubMed
CAS
Google Scholar
Sabanés Zariquiey, F., da Souza, J. V., Estrada-Tejedor, R. & Bronowska, A. K. If you cannot win them, join them: understanding new ways to target STAT3 by small molecules. ACS Omega 4, 13913–13921 (2019).
Article
PubMed
PubMed Central
Google Scholar
Li, C., Yang, A. & Rogoff, H. Method of Targeting Stat3 and Other Non-Druggable Proteins. Patent application PCT/US2016/045043 (9 February 2017).
Shah, M. A. et al. Randomized, double-blind, placebo-controlled phase III study of paclitaxel ± napabucasin in pretreated advanced gastric or gastroesophageal junction adenocarcinoma. Clin. Cancer Res. 28, OF1–OF9 (2022).
Article
PubMed
Google Scholar
Bekaii-Saab, T. et al. Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial. EClinicalMedicine 58, 101897 (2023).
Article
PubMed
PubMed Central
Google Scholar
Shah, M. A. et al. Napabucasin plus FOLFIRI in patients with previously treated metastatic colorectal cancer: results from the open-label, randomized phase III CanStem303C study. Clin. Colorectal Cancer 22, 100–110 (2023).
PubMed
Google Scholar
Fan, C. et al. Natural product-inspired discovery of naphthoquinone–furo-piperidine derivatives as novel STAT3 inhibitors for the treatment of triple-negative breast cancer. J. Med. Chem. 67, 15291–15310 (2024).
Article
PubMed
CAS
Google Scholar
Feng, K.-R. et al. Design, synthesis and biological evaluation of novel potent STAT3 inhibitors based on BBI608 for cancer therapy. Eur. J. Med. Chem. 201, 112428 (2020).
Article
PubMed
CAS
Google Scholar
Li, C. et al. A novel series of napabucasin derivatives as orally active inhibitors of signal transducer and activator of transcription 3 (STAT3). Eur. J. Med. Chem. 162, 543–554 (2019).
Article
PubMed
CAS
Google Scholar
Zhou, Q. et al. Design, synthesis and activity of BBI608 derivatives targeting on stem cells. Eur. J. Med. Chem. 151, 39–50 (2018).
Article
PubMed
CAS
Google Scholar
Chen, J. et al. Structure-based design of conformationally constrained, cell-permeable STAT3 inhibitors. ACS Med. Chem. Lett. 1, 85–89 (2010).
Article
PubMed
PubMed Central
Google Scholar
Zhou, H. et al. Structure-based discovery of SD-36 as a potent, selective, and efficacious PROTAC degrader of STAT3 protein. J. Med. Chem. 62, 11280–11300 (2019).
Article
PubMed
CAS
PubMed Central
Google Scholar
Bai, L. et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell 36, 498–511.e17 (2019).
Article
PubMed
CAS
PubMed Central
Google Scholar
Zhou, H. et al. SD-91 as a potent and selective STAT3 degrader capable of achieving complete and long-lasting tumor regression. ACS Med. Chem. Lett. 12, 996–1004 (2021).
Article
PubMed
CAS
PubMed Central
Google Scholar
Jin, J. et al. Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer. JCI Insight 7, e160606 (2022).
Article
PubMed
PubMed Central
Google Scholar
Kaneshige, A. et al. A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo. Nat. Chem. Biol. 19, 703–711 (2023).
Article
PubMed
CAS
Google Scholar
Kaneshige, A. et al. Discovery of a potent and selective STAT5 PROTAC degrader with strong antitumor activity in vivo in acute myeloid leukemia. J. Med. Chem. 66, 2717–2743 (2023).
Article
PubMed
CAS
Google Scholar
Kaneshige, A. et al. Discovery of AK-1690: a potent and highly selective STAT6 PROTAC degrader. J. Med. Chem. 68, 5125–5151 (2025).
Article
PubMed
CAS
Google Scholar
Li, S. et al. Decoy-PROTAC for specific degradation of ‘Undruggable' STAT3 transcription factor. Cell Death Dis. 16, 197 (2025).
Article
PubMed
CAS
PubMed Central
Google Scholar
Shih, P.-C., Naganuma, M., Tsuji, G., Demizu, Y. & Naito, M. Development of decoy oligonucleotide-warheaded chimeric molecules targeting STAT3. Bioorg. Med. Chem. 95, 117507 (2023).
Article
PubMed
CAS
Google Scholar
Lu, J., Liu, J., Li, L., Lan, Y. & Liang, Y. Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets. Clin. Transl. Immunol. 9, e1122 (2020).
Article
Google Scholar
Herold, K. C. et al. Teplizumab: a disease-modifying therapy for type 1 diabetes that preserves β-cell function. Diabetes Care 46, 1848–1856 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Colli, M. L. et al. An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic β cells. Nat. Commun. 11, 2584 (2020).
Article
PubMed
CAS
PubMed Central
Google Scholar
Coomans de Brachène, A. et al. IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic β cells. Diabetologia 61, 636–640 (2018).
Article
PubMed
Google Scholar
Ge, T. et al. The JAK1 selective inhibitor ABT 317 Blocks signaling through interferon-γ and common γ chain cytokine receptors to reverse autoimmune diabetes in NOD mice. Front. Immunol. 11, 588543 (2020).
Article
PubMed
CAS
PubMed Central
Google Scholar
Trivedi, P. M. et al. Repurposed JAK1/JAK2 inhibitor reverses established autoimmune insulitis in NOD mice. Diabetes 66, 1650–1660 (2017).
Article
PubMed
CAS
Google Scholar
Marroqui, L. et al. TYK2, a candidate gene for type 1 diabetes, modulates apoptosis and the innate immune response in human pancreatic β-cells. Diabetes 64, 3808–3817 (2015).
Article
PubMed
CAS
Google Scholar
Gorman, J. A. et al. The TYK2-P1104A autoimmune protective variant limits coordinate signals required to generate specialized T cell subsets. Front. Immunol. 10, 44 (2019).
Article
PubMed
CAS
PubMed Central
Google Scholar
Westra, H.-J. et al. Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes. Nat. Genet. 50, 1366-1374 (2018).
Article
PubMed
CAS
PubMed Central
Google Scholar
Chandra, V. et al. The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α. Nat. Commun. 13, 6363 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Dos Santos, R. S., Guzman-Llorens, D., Perez-Serna, A. A., Nadal, A. & Marroqui, L. Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human EndoC-βH1 β-cells against proinflammatory insults. Front. Immunol. 14, 1263926 (2023).
Article
PubMed
PubMed Central
Google Scholar
Coomans de Brachène, A. et al. Preclinical evaluation of tyrosine kinase 2 inhibitors for human beta-cell protection in type 1 diabetes. Diabetes Obes. Metab. 22, 1827–1836 (2020).
Article
PubMed
Google Scholar
Waibel, M. et al. Baricitinib and β-cell function in patients with new-onset type 1 diabetes. N. Engl. J. Med. 389, 2140–2150 (2023).
Article
PubMed
CAS
Google Scholar
Abadie, V. et al. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578, 600–604 (2020).
Article
PubMed
CAS
PubMed Central
Google Scholar
Schuppan, D. et al. A randomized trial of a transglutaminase 2 inhibitor for celiac disease. N. Engl. J. Med. 385, 35–45 (2021).
Article
PubMed
CAS
Google Scholar
Choung, R. S. et al. Ritlecitinib, a JAK3 /TEC inhibitor, modulates the markers of celiac autoimmunity in alopecia areata and vitiligo patients. Arch. Dermatol. Res. 317, 280 (2025).
Article
PubMed
CAS
PubMed Central
Google Scholar
Verdelho Machado, M. Refractory celiac disease: what the gastroenterologist should know. Int. J. Mol. Sci. 25, 10383 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Nandi, N. et al. Normalization of duodenal mucosa after treatment with Janus kinase (JAK) inhibitor in refractory celiac disease type 2. Clin. Res. Hepatol. Gastroenterol. 46, 101960 (2022).
Article
PubMed
CAS
Google Scholar
Grewal, J. K., Kassardjian, A. & Weiss, G. A. Successful novel use of tofacitinib for type II refractory coeliac disease. BMJ Case Rep. 15, e244692 (2022).
Article
PubMed
PubMed Central
Google Scholar
Dieckman, T. et al. Enduring clinical remission in refractory celiac disease type II with tofacitinib: an open-label clinical study. Clin. Gastroenterol. Hepatol. 22, 2334–2336 (2024).
Article
PubMed
CAS
Google Scholar
Diaz, K. et al. Peripheral inflammatory cytokines and motor symptoms in persons with Parkinson's disease. Brain Behav. Immun. Health. 21, 100442 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Hong, H. et al. Suppression of the JAK/STAT pathway inhibits neuroinflammation in the line 61-PFF mouse model of Parkinson's disease. J. Neuroinflammation 21, 216 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Alshammari, A. et al. Protective effect of CP690550 in MPTP-induced Parkinson's like behavioural, biochemical and histological alterations in mice. Neurotox. Res. 40, 564–572 (2022).
Article
PubMed
Google Scholar
Rusek, M. et al. The role of the JAK/STAT signaling pathway in the pathogenesis of Alzheimer's Disease: New Potential Treatment Target. Int. J. Mol. Sci. 24, 864 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Nevado-Holgado, A. J. et al. Genetic and real-world clinical data, combined with empirical validation, nominate Jak–Stat signaling as a target for Alzheimer's disease therapeutic development. Cells 8, 425 (2019).
Article
PubMed
CAS
PubMed Central
Google Scholar
Taylor, J. M. et al. Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer's disease. Neurobiol. Aging 35, 1012–1023 (2014).
Article
PubMed
CAS
Google Scholar
Desai, R. J. et al. Targeting abnormal metabolism in Alzheimer's disease: the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study. Alzheimers Dement. 6, e12095 (2020).
Google Scholar
König, L. E. et al. TYK2 as a novel therapeutic target in Alzheimer's disease with TDP-43 inclusions. Preprint at bioRxiv https://doi.org/10.1101/2024.06.04.595773 (2024).
Mehla, J. et al. STAT3 inhibitor mitigates cerebral amyloid angiopathy and parenchymal amyloid plaques while improving cognitive functions and brain networks. Acta Neuropathol. Commun. 9, 193 (2021).
Article
PubMed
CAS
PubMed Central
Google Scholar
Fan, L. & Zhou, L. AG490 protects cerebral ischemia/reperfusion injury via inhibiting the JAK2/3 signaling pathway. Brain Behav. 11, e01911 (2021).
Article
PubMed
Google Scholar
Matsushita, T. et al. Inhibitory effect of baricitinib on microglia and STAT3 in a region with a weak blood–brain barrier in a mouse model of rheumatoid arthritis. Rheumatology 62, 2908–2917 (2023).
Article
PubMed
CAS
Google Scholar
Faquetti, M. L. et al. Baricitinib and tofacitinib off-target profile, with a focus on Alzheimer's disease. Alzheimers Dement. 10, e12445 (2024).
Google Scholar
Molitor, T. P. et al. Central TYK2 inhibition identifies TYK2 as a key neuroimmune modulator. Proc. Natl Acad. Sci. USA 122, e2422172122 (2025).
Article
PubMed
CAS
PubMed Central
Google Scholar
Okamoto, O. K. et al. Whole transcriptome analysis of the hippocampus: toward a molecular portrait of epileptogenesis. BMC Genomics 11, 230 (2010).
Article
PubMed
PubMed Central
Google Scholar
Tipton, A. E. et al. Selective neuronal knockout of STAT3 function inhibits epilepsy progression, improves cognition, and restores dysregulated gene networks in a temporal lobe epilepsy model. Ann. Neurol. 94, 106–122 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Han, C.-L. et al. The lncRNA H19 binding to let-7b promotes hippocampal glial cell activation and epileptic seizures by targeting Stat3 in a rat model of temporal lobe epilepsy. Cell Prolif. 53, e12856 (2020).
Article
PubMed
CAS
PubMed Central
Google Scholar
Hoffman, O. R. et al. Disease modification upon 2 weeks of tofacitinib treatment in a mouse model of chronic epilepsy. Sci. Transl. Med. 17, eadt0527 (2025).
Article
PubMed
CAS
Google Scholar
Liu, Y. et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat. Genet. 49, 1211–1218 (2017).
Article
PubMed
CAS
PubMed Central
Google Scholar
Kołodrubiec, J. et al. Efficacy of ruxolitinib in acute lymphoblastic leukemia: a systematic review. Leuk. Res. 121, 106925 (2022).
Article
PubMed
Google Scholar
Dao, K.-H. T. et al. Efficacy of ruxolitinib in patients with chronic neutrophilic leukemia and atypical chronic myeloid leukemia. J. Clin. Oncol. 38, 1006–1018 (2020).
Article
PubMed
CAS
Google Scholar
Qureshy, Z. et al. STAT3 activation as a predictive biomarker for ruxolitinib response in head and neck cancer. Clin. Cancer Res. 28, 4737–4746 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Xia, D. et al. CHAF1A promotes the proliferation and growth of epithelial ovarian cancer cells by affecting the phosphorylation of JAK2/STAT3 signaling pathway. Biochem. Biophys. Rep. 35, 101522 (2023).
PubMed
CAS
PubMed Central
Google Scholar
Datta, J. et al. Combined MEK and STAT3 inhibition uncovers stromal plasticity by enriching for cancer-associated fibroblasts with mesenchymal stem cell-like features to overcome immunotherapy resistance in pancreatic cancer. Gastroenterology 163, 1593–1612 (2022).
Article
PubMed
CAS
Google Scholar
Taverna, J. A. et al. Single-cell proteomic profiling identifies combined AXL and JAK1 inhibition as a novel therapeutic strategy for lung cancer. Cancer Res. 80, 1551–1563 (2020).
Article
PubMed
CAS
PubMed Central
Google Scholar
Schneider, J., Jeon, Y. W., Suh, Y. J. & Lim, S. T. Effects of ruxolitinib and calcitriol combination treatment on various molecular subtypes of breast cancer. Int. J. Mol. Sci. 23, 2535 (2022).
Article
PubMed
CAS
PubMed Central
Google Scholar
Doheny, D. et al. Combined inhibition of JAK2–STAT3 and SMO–GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis. Oncogene 39, 6589–6605 (2020).
Article
PubMed
CAS
PubMed Central
Google Scholar
Zak, J. et al. JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma. Science 384, eade8520 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Mathew, D. et al. Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients. Science 384, eadf1329 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Johnson, D. E., O'Keefe, R. A. & Grandis, J. R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234–248 (2018).
Article
PubMed
CAS
PubMed Central
Google Scholar
Curtis, J. R. et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Ann. Rheum. Dis. 82, 331–343 (2023).
Article
PubMed
CAS
Google Scholar
Simpson, E. L. et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet 396, 255–266 (2020).
Article
PubMed
CAS
Google Scholar
Rubbert-Roth, A. et al. Malignancy in the upadacitinib clinical trials for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis. Rheumatol. Ther. 11, 97–112 (2024).
Article
PubMed
Google Scholar
Keam, S. J. Golidocitinib: first approval. Drugs 84, 1319–1324 (2024).
Article
PubMed
CAS
Google Scholar
Ou, A., Ott, M., Fang, D. & Heimberger, A. B. The role and therapeutic targeting of JAK/STAT signaling in glioblastoma. Cancers 13, 437 (2021).
Article
PubMed
CAS
PubMed Central
Google Scholar
Smedley, W. & Patra, A. JAK3 inhibition regulates stemness and thereby controls glioblastoma pathogenesis. Cells 12, 2547 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Mukthavaram, R. et al. Effect of the JAK2/STAT3 inhibitor SAR317461 on human glioblastoma tumorspheres. J. Transl. Med. 13, 269 (2015).
Article
PubMed
PubMed Central
Google Scholar
Fu, W., Hou, X., Dong, L. & Hou, W. Roles of STAT3 in the pathogenesis and treatment of glioblastoma. Front. Cell Dev. Biol. 11, 1098482 (2023).
Article
PubMed
PubMed Central
Google Scholar
Jensen, K. V., Cseh, O., Aman, A., Weiss, S. & Luchman, H. A. The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model. PLoS One 12, e0189670 (2017).
Article
PubMed
PubMed Central
Google Scholar
McFarland, B. C. et al. Therapeutic potential of AZD1480 for the treatment of human glioblastoma. Mol. Cancer Ther. 10, 2384–2393 (2011).
Article
PubMed
CAS
PubMed Central
Google Scholar
Liu, T., Li, A., Xu, Y. & Xin, Y. Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2/STAT3 inhibition. Oncol. Rep. 41, 1883–1892 (2019).
PubMed
CAS
Google Scholar
Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).
Article
PubMed
CAS
PubMed Central
Google Scholar
Legat, F. J. Itch in atopic dermatitis - What is new? Front. Med. 8, 644760 (2021).
Article
Google Scholar
Makabe, K. et al. Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons. Arthritis Res. Ther. 26, 121 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Butler, D. C. et al. Chronic pruritus: a review. JAMA 331, 2114–2124 (2024).
Article
PubMed
CAS
Google Scholar
Lee, J. et al. Treatment with upadacitinib in refractory prurigo nodularis: a prospective cohort study. Allergy Asthma Immunol. Res. 16, 546–554 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Pezzolo, E. et al. Effective response to upadacitinib in patients affected by prurigo nodularis and by atopic dermatitis with a predominant prurigo nodularis pattern: a multicenter case series study. J. Am. Acad. Dermatol. 91, e147–e150 (2024).
Article
PubMed
CAS
Google Scholar
Muntaner-Virgili, C., Moreno-Vilchez, C., Torrecilla-Vall-Llossera, C. & Figueras-Nart, I. Upadacitinib for prurigo nodularis. JAAD Case Rep. 48, 131–133 (2024).
Article
PubMed
Google Scholar
Sardana, K., Mathachan, S. R., Muddebihal, A., Agrawal, D. & Ahuja, A. Translating tissue expression of STAT 1, 3 and 6 in prurigo nodularis to clinical efficacy of oral tofacitinib—a prospective single-arm investigational study. Indian J Dermatol Venereol Leprol https://doi.org/10.25259/IJDVL_1017_2024 (2025).
Dai, R., Chi, C.-C., Lou, Y., Hsieh, I.-J. & Man, X.-Y. Efficacy and safety of tofacitinib in patients with refractory prurigo nodularis: a 16-week, single-center, prospective, observational pilot study. Dermatologic Ther. 2025, 8988947 (2025).
Article
CAS
Google Scholar
Kwatra, S. G. et al. Efficacy and safety of abrocitinib in prurigo nodularis and chronic pruritus of unknown origin: a nonrandomized controlled trial. JAMA Dermatol. 160, 717–724 (2024).
Article
PubMed
PubMed Central
Google Scholar
Liang, J. et al. Abrocitinib monotherapy for refractory prurigo nodularis: report of two successful cases. Clin. Cosmet. Investig. Dermatol. 17, 1793–1797 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Sun, F. & Wu, Z. Successful treatment of refractory prurigo nodularis with abrocitinib. Clin. Case Rep. 12, e8606 (2024).
Article
PubMed
PubMed Central
Google Scholar
Yew, Y. W. & Yeo, P. M. Comparison between dupilumab and oral Janus kinase inhibitors in the treatment of prurigo nodularis with or without atopic dermatitis in a tertiary care center in Singapore. JAAD Int. 13, 13–14 (2023).
Article
PubMed
PubMed Central
Google Scholar
Ju, T., Labib, A., Vander Does, A. & Yosipovitch, G. Topical Janus kinase-signal transducers and activators of transcription inhibitor tofacitinib is effective in reducing nonatopic dermatitis chronic itch: a case series. J. Am. Acad. Dermatol. 87, 400–403 (2022).
Article
PubMed
CAS
Google Scholar
Le Voyer, T. et al. JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study. Rheumatology 60, 5801–5808 (2021).
Article
PubMed
Google Scholar
Ding, Y. et al. Janus kinase inhibitor significantly improved rash and muscle strength in juvenile dermatomyositis. Ann. Rheum. Dis. 80, 543–545 (2021).
Article
PubMed
Google Scholar
Yu, Z., Wang, L., Quan, M., Zhang, T. & Song, H. Successful management with Janus kinase inhibitor tofacitinib in refractory juvenile dermatomyositis: a pilot study and literature review. Rheumatology 60, 1700–1707 (2021).
Article
PubMed
Google Scholar
Sabbagh, S. et al. Treatment of anti-MDA5 autoantibody-positive juvenile dermatomyositis using tofacitinib. Brain 142, e59 (2019).
Article
PubMed
PubMed Central
Google Scholar
Aeschlimann, F. A. et al. A child with severe juvenile dermatomyositis treated with ruxolitinib. Brain 141, e80 (2018).
Article
PubMed
Google Scholar
Kim, H. et al. Janus kinase (JAK) inhibition with baricitinib in refractory juvenile dermatomyositis. Ann. Rheum. Dis. 80, 406–408 (2021).
Article
PubMed
Google Scholar
Papadopoulou, C., Hong, Y., Omoyinmi, E., Brogan, P. A. & Eleftheriou, D. Janus kinase 1/2 inhibition with baricitinib in the treatment of juvenile dermatomyositis. Brain 142, e8 (2019).
Article
PubMed
PubMed Central
Google Scholar
Loricera, J. et al. Effectiveness of janus kinase inhibitors in relapsing giant cell arteritis in real-world clinical practice and review of the literature. Arthritis Res. Ther. 26, 116 (2024).
Article
PubMed
CAS
PubMed Central
Google Scholar
Eriksson, P., Skoglund, O., Hemgren, C. & Sjöwall, C. Clinical experience and safety of Janus kinase inhibitors in giant cell arteritis: a retrospective case series from Sweden. Front. Immunol. 14, 1187584 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Prigent, K., Aouba, A., Aide, N. & de Boysson, H. JAK inhibitor effectiveness in giant-cell arteritis with large-vessel involvement assessed by 18F-FDG PET-CT. Clin. Nucl. Med. 47, 234–235 (2022).
Article
PubMed
Google Scholar
Zhang, H. et al. Inhibition of JAK–STAT signaling suppresses pathogenic immune responses in medium and large vessel vasculitis. Circulation 137, 1934–1948 (2018).
Article
PubMed
CAS
Google Scholar
Blockmans, D. et al. A phase 3 trial of upadacitinib for giant-cell arteritis. N. Engl. J. Med. 392, 2013–2024 (2025).
Article
PubMed
CAS
Google Scholar
Sanada, A., Abe, N., Bohgaki, M. & Kasahara, H. Therapeutic effectiveness of upadacitinib combined with glucocorticoid on remission induction and maintenance in giant cell arteritis. Rheumatology 61, e274–e276 (2022).
Article
PubMed
Google Scholar
Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug. Discov. 16, 843–862 (2017).
Article
PubMed
CAS
Google Scholar
Nezamololama, N., Fieldhouse, K., Metzger, K. & Gooderham, M. Emerging systemic JAK inhibitors in the treatment of atopic dermatitis: a review of abrocitinib, baricitinib, and upadacitinib. Drugs Context. 9, 2020–2028 (2020).
Article
PubMed
PubMed Central
Google Scholar
Su, Q. et al. Discovery of (2R)-N-[3-[2-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a potent and sSelective Janus kinase 1 inhibitor. J. Med. Chem. 63, 4517–4527 (2020).
Article
PubMed
CAS
Google Scholar
Center for Drug Evaluation and Research. Multi-discipline review Application Number: 217900Orig1s000 (deuruxolitinib). FDA https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217900Orig1s000MultidisciplineR.pdf (2025).
Chrencik, J. E. et al. Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J. Mol. Biol. 400, 413–433 (2010).
Article
PubMed
CAS
Google Scholar
Williams, N. K. et al. Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J. Mol. Biol. 387, 219–232 (2009).
Article
PubMed
CAS
Google Scholar
Hamaguchi, H. et al. Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor. Bioorg. Medicinal Chem. 26, 4971–4983 (2018).
Article
CAS
Google Scholar
Gupta, V. et al. Matching-adjusted indirect comparison of the pelabresib–ruxolitinib combination vs JAKi monotherapy in myelofibrosis. Blood Adv. 7, 5421–5432 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Mascarenhas, J. et al. MANIFEST: pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve myelofibrosis. J. Clin. Oncol. 41, 4993–5004 (2023).
Article
PubMed
CAS
PubMed Central
Google Scholar
Rampal, R. K. et al. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. Nat. Med. 31, 1531–1538 (2025).
Article
PubMed
CAS
PubMed Central
Google Scholar
Metzger, M., Avigan, Z. M., Vachhani, P., Waksal, J. & Mascarenhas, J. A novel application of XPO1 inhibition for the treatment of myelofibrosis. Blood Neoplasia 1, 100010 (2024).
Article
PubMed
PubMed Central
Google Scholar
Mascarenhas, J. O. et al. Results from the randomized, multicenter, global phase 3 BOREAS study: navtemadlin versus best available therapy in JAK inhibitor relapsed/refractory myelofibrosis. Blood 144, 1000 (2024).
Article
Google Scholar
Vachhani, P. et al. POIESIS: a randomized, double-blind, placebo-controlled, multicenter, global phase 3 study of navtemadlin as add-on to ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis who have a suboptimal response to ruxolitinib. Blood 144, 1808.2 (2024).
Article
Google Scholar
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This work was funded by the Academy of Finland (grant numbers 340572 and 335437 for T.H. and O.S., respectively), the National Cancer Institute (grant number R35 CA231991 for B.F.C.), Tampere Tuberculosis Foundation, Sigrid Juselius Foundation, Finnish Cancer Foundation and competitive research funding from Tampere University Hospital.
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Teemu Haikarainen, Anniina T. Virtanen & Olli Silvennoinen
Fimlab Laboratories, Tampere, Finland
Teemu Haikarainen & Olli Silvennoinen
Department of Chemistry, Scripps Research, La Jolla, CA, USA
Benjamin F. Cravatt
Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
Olli Silvennoinen
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All authors researched data for the article and made a substantial contribution to discussion of content, writing, reviewing and editing of the manuscript.
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Teemu Haikarainen or Olli Silvennoinen.
O.S. holds a patent on JAK kinases (US Patent 8,841,078) and is a co-founder and adviser for Ajax Therapeutics. B.F.C. is a founder and scientific adviser of Vividion Therapeutics and Magnet Therapeutics. The other authors declare no competing interests.
Nature Reviews Drug Discovery thanks Jean-Baptiste Telliez and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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China's leading contract chipmakers are pursuing large domestic acquisitions to expand capacity as Beijing doubles down on semiconductor self-sufficiency.
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China's two largest pure-play foundries, SMIC and Hua Hong Semiconductor, are in the middle of significant consolidation efforts that demonstrate how industrial policy is reshaping the country's chip sector, with SMIC about to take full control of a subsidiary for US$5.8 billion and Hua Hong set to acquire 97.5% of Shanghai Huali Microelectronics from its state-owned parent for US$1.2 billion.
The two multi-billion-yuan deals come as China's access to advanced manufacturing equipment remains constrained by U.S.-led export controls, forcing domestic players to rethink how they scale, where they invest, and which parts of the semiconductor market they prioritize. While the most obvious and immediate aim is capacity and operational efficiency, the broader objective is to harden China's semiconductor supply chain against external pressure while consolidating state resources around a smaller number of national champions.
According to the South China Morning Post, SMIC's proposal to acquire its Beijing-based subsidiary, SMIC Jingcheng, for roughly ¥40 billion is emblematic of what is becoming an emerging trend. The Beijing fabs are already majority owned by SMIC, but bringing them fully onto the parent's balance sheet simplifies governance, capital allocation, and future expansion planning. Meanwhile, Hua Hong is pursuing a similar approach by acquiring Shanghai Huali, its closely linked sister foundry, in a deal valued at more than ¥8 billion.
These might look like internal restructurings on paper rather than straight-up mergers between rivals, but they represent a deliberate pivot away from the fragmented growth model that defined China's foundry build-out over the past decade. Instead of creating new entities to chase specific technologies or regional subsidies, Beijing now appears to be encouraging consolidation around existing leaders, with state investors providing the financial backstop.
Why? Because building and equipping fabs has grown dramatically more expensive, even at mature process nodes. At the same time, export controls have reduced the returns on chasing leading-edge manufacturing, particularly below 7nm. By consolidating, SMIC and Hua Hong can pool cash flows from profitable legacy production, reduce duplicated R&D and administrative overhead, and present a more coherent face to regulators and customers.
Perhaps the most striking feature of China's current foundry strategy is not what it is building, but what it is not. While SMIC has demonstrated limited capability using DUV lithography, the bulk of new capacity tied to these consolidation moves sits at 28nm and above, including 40nm, 55nm, and 65nm processes.
These nodes are far, far away from the prestige of leading-edge 2nm or 3nm, but they remain both commercially viable and important. Automotive microcontrollers, power management ICs, display drivers, connectivity chips, and a wide range of industrial and consumer components still rely on mature manufacturing. Global shortages during the pandemic — and the recent, still-ongoing Nexperia-Wingtech spat — highlighted just how fragile supply at these nodes can be.
China has leaned heavily into this, with industry estimates suggesting that more than half of all new global capacity additions at mature nodes through the mid-2020s are located in China. Hua Hong's Shanghai fabs alone add tens of thousands of wafers per month at 40nm and 65nm, while SMIC's multiple sites cover an even broader spread of legacy processes.
This serves several purposes for China. Firstly, it reduces dependence on foreign suppliers for essential components used across the economy. Secondly, it creates a buffer against sanctions that target advanced equipment. Thirdly, it positions Chinese foundries as increasingly important suppliers to global customers who need stable access to mature nodes, even if geopolitical concerns complicate sourcing decisions.
U.S. export controls remain the defining constraint on China's ambitions at the cutting edge. Restrictions on EUV lithography tools, advanced deposition equipment, and certain design software have slowed progress below 7nm and raised costs for any attempt to push further using workarounds.
Consolidation does not remove these limits, but it does change how Chinese firms operate within them. Larger, integrated foundries are better positioned to absorb higher tool costs, manage complex multi-patterning flows, and negotiate with domestic equipment suppliers that are still maturing. They also offer a clearer channel for state support, whether through direct funding, favorable financing, or guaranteed demand from state-owned enterprises.
As Washington tightens scrutiny of potential sanctions circumvention, having fewer, larger entities also simplifies compliance and reduces the risk that smaller, less visible fabs become flashpoints for enforcement actions. From Beijing's perspective, consolidation is as much about political risk management as it is about manufacturing efficiency. China's foundry consolidation is likely to have its biggest impact at mature nodes, and as Chinese capacity continues to grow, pricing pressure on legacy processes is expected to increase. Foundries in Taiwan, Japan, and parts of Southeast Asia that rely heavily on these nodes may find margins squeezed, particularly for commodity products.
At the same time, not all customers will be willing to shift sourcing to China. Concerns around export controls, intellectual property protection, and supply chain resilience are obvious sticking points, and some Western companies are already looking to diversify away from Chinese fabs even if that means higher costs. This points toward a more segmented market, where Chinese foundries dominate domestic and select international demand, while non-Chinese fabs serve customers with stricter geopolitical or regulatory constraints.
SMIC and Hua Hong's acquisitions are unlikely to produce dramatic short-term shifts in China's technological standing. They do, however, reveal a maturing phase in Beijing's semiconductor strategy. The emphasis is shifting from rapid expansion to consolidation, from aspirational leadership at the cutting edge to dependable strength across the bulk of the market.
While U.S. and allied firms continue to concentrate resources on advanced nodes, advanced packaging, and heterogeneous integration, China is building scale and resilience where it can compete most effectively today. That does not preclude future breakthroughs at the leading edge, but it suggests a longer-term strategy built on volume and incremental gains rather than rapid node-to-node leaps.
Luke James is a freelance writer and journalist. Although his background is in legal, he has a personal interest in all things tech, especially hardware and microelectronics, and anything regulatory.
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by Kurt Schlosser on Jan 5, 2026 at 9:32 amJanuary 5, 2026 at 9:32 am
New research tied to the University of Washington School of Medicine adds to mounting concerns among educators about smartphone use in schools.
U.S. adolescents between the ages of 13–18 spend more than one hour per day on phones during school hours, with “addictive” social media apps accounting for the largest share of use, according to new research published in JAMA.
The findings add to the ongoing argument made by teachers, parents and policymakers that has led schools and districts around the country, including some in Seattle, to ban phones during school hours.
The Adolescent Brain Cognitive Development Study tracked 640 teens whose parents consented to passive monitoring software on their Android smartphones from September 2022 to May 2024, according to UW Medicine.
“These apps are designed to be addictive,” said Dr. Dimitri Christakis, the paper's senior author. “They deprive students of the opportunity to be fully engaged in class and to hone their social skills with classmates and teachers.”
Christakis is a professor of pediatrics at the University of Washington School of Medicine and practices at Seattle Children's Hospital.
Based on a national sample of students, the results build on findings published last year in JAMA Pediatrics. That study had fewer participants but also included iPhone users.
At least 32 states and the District of Columbia require school districts to ban or restrict students' use of cell phones in schools. The effect of those policies “remains to be seen,” Christakis said.
“To date they've been very poorly enforced, if at all. I think the U.S. has to recognize the generational implications of depriving children of opportunities to learn in school,” he added.
A majority of school districts in Washington state planned to have policies in place at the start of the school year last fall to limit students' use of cellphones and other devices such as smart watches.
Seattle Public Schools has not issued a district-wide policy, though at least three public middle schools in the district have banned phones at school, and at least one high school prohibits their use during classes.
The UW's Youth Advisory Board, a group of approximately 20 teens from Seattle-area schools, recently published its first memo tackling the contentious issue of phones in school. The memo weighs the pros and cons of phone bans and offers recommendations on how schools should draft and communicate their policies.
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Antarctica's Thwaites Glacier, aptly nicknamed the Doomsday Glacier, is a ticking time bomb. The rapidly melting body of ice could cause up to 10 feet (3 meters) of global sea-level rise if it were to collapse completely. New evidence suggests the glacier is even less stable than previously believed, with hundreds of iceberg earthquakes shaking up the massive structure for more than a decade.
Thanh-Son Pham, a researcher at the Australian National University, uncovered evidence of hundreds of glacial earthquakes that took place in Antarctica from 2010 to 2023. Most of those earthquakes have previously gone undetected due to their low-frequency seismic waves, and their discovery raises new questions about the threatening instability of Antarctica's melting glaciers.
The new study, published in Geophysical Research Letters, reports 362 glacial earthquakes in Antarctica. Out of the newly documented seismic events, 245 earthquakes took place in Antarctica's Doomsday Glacier, likely caused by capsizing icebergs.
Glacial earthquakes are a newly discovered type of seismic event that produces low-frequency waves, with a magnitude of around 5. They were first detected in 2003 and are mainly caused by the collapse of large icebergs.
Most of the recorded glacial earthquakes were discovered along the coast of Greenland, the largest ice cap in the Northern Hemisphere. Although scientists assumed that glacial earthquakes take place in Antarctica as well, they have been much harder to detect because they are of much lower magnitude than those that occur in Greenland.
Rather than relying on the global network of seismic detectors, Pham used seismic stations in Antarctica itself to find evidence for glacial earthquakes. The search turned up hundreds of events that were never cataloged.
The majority of glacial earthquakes took place near Antarctica's largest glacier, Thwaites. Recent evidence has shown that the amount of ice flowing from Thwaites has doubled in the span of three decades, contributing to the global rise in sea levels.
The new study found that the rocking seismic events don't necessarily coincide with the seasonal movement of warm air temperatures in Antarctica. Instead, the glacial earthquakes near Thwaites seem to take place in parallel with a period of accelerated flow of the glacier's ice tongue toward the sea.
The remaining glacial earthquakes recently detected took place near the Pine Island Glacier, one of the largest ice streams in Antarctica. These events, however, took place around 30 to 50 miles (60 to 70 kilometers) away from the waterfront and are therefore not likely caused by capsizing icebergs. “The nature of earthquakes in Pine Island Glaciers remains puzzling and warrants further investigation,” the study notes.
Pham recommends follow-up investigations of the newly cataloged glacial earthquakes in Antarctica to better understand the main driving cause, as well as their impact on the instability of the glaciers.
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This year, thousands of Tuvaluans applied for Australia's climate-migration visas to escape the impacts of rising sea levels.
"Please stay prepared to evacuate immediately if you feel any shaking, while continuing your socioeconomic activities.”
Funding and staffing cuts are shuttering the monitoring stations that sustain this life-saving early warning system.
Scientists discovered a peculiar “fish neighborhood," one more reason to designate the Weddell Sea as a Marine Protected Area.
A miniature quake-in-a-lab enabled scientists to quantify an earthquake's energy dynamics for the first time.
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Qualcomm was so excited to talk about its most powerful ARM-based PC CPUs in 2025, it left off its lower-end, humdrum processor for the big reveal of all its partnered products. Alongside the Snapdragon X Elite and Snapdragon X Elite Extreme (cue the guitar riff), Qualcomm is coming to CES 2026 with an X2 Plus chip.
Qualcomm's sequel to its initial batch of ARM-based chips that brought us Copilot+ PCs all boast a similar strong battery life and large 80 TOPS NPU (neural processing unit) built for background and low-scale AI tasks. Compared to the previous-gen Snapdragon X Plus, the higher-end X2 Plus promises 2.3 times better GPU performance and upwards of 50% better CPU multi-core performance. All told, the chip could be better for multitasking, light photo editing tasks, and—potentially—some light gaming.
The X2 Plus comes in two flavors, one with six Oryon CPU cores and one with 10 cores. The higher-end version, specifically the X2P-64-100, sports a max multithread frequency of 4GHz with a 34MB cache. The lower-end version sports the same frequency but a lower total cache. The integrated Adreno graphics also hit a higher 1.7GHz frequency compared to the six-core variant. All that is to say, if you're looking at an X2 Plus laptop for any photo editing or any other graphics, you want the higher-end version.
Devices with this chip will support up to three 4K external monitors as well as Wi-Fi 7 and Bluetooth 5.4. The mid-range ARM chip is supposed to compete against Intel and AMD's latest lightweight laptop CPUs. These chips won't just have to perform well in battery life as well. Qualcomm claims its new chip demands 43% less power for the same performance as its first-gen Snapdragon X Plus.
One of Qualcomm's big bugbears for ARM on PC has been compatibility. Late last year, the chipmaker launched its Snapdragon Control Panel, a kind of game and app launcher that was supposed to help users update access to Microsoft's refined Prism x86 emulator and keep on top of drivers. Working on an ARM-based Windows machine is far better than it was at the Copilot+ launch in 2024. Support for Windows AVX and AVX2 extensions in the Prism emulator means it's much easier to run previously unsupported programs and even some games on Qualcomm's latest chips.
Still, for the sake of a PC that can keep up with the Joneses of Intel and AMD's top-end laptop CPUs, the X2 Elite Extreme with its 18 Oryon cores (12 “prime” CPU cores and another six “performance” cores) will still offer the best overall performance. At least, there will be an interesting three-way competition for laptop supremacy in 2026.
Gizmodo is on the ground in Las Vegas all week bringing you everything you need to know about the tech unveiled at CES 2026. You can follow our CES live blog here and find all our coverage here.
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Follow along with Gizmodo as we check out all the latest gadget announcements from the year's biggest, most-packed tech event, CES 2026.
I could use a stiff serving of AI slop right about now.
Lucid's EVs will use HERE location data to improve EV routing and advanced driving features.
The AeroFit 2 Pro wireless earbuds can shapeshift into open-ear and ANC modes.
The company says it's the first of its kind, but remains mum on the specifics.
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Many OmniBook laptops are seeing refreshes at CES 2025.
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HP is updating its top-of-the-line consumer productivity laptop, the OmniBook Ultra 14, with the latest silicon from both Qualcomm and Intel. At CES 2026, the company revealed a new design for the ultrabook, which the company claims is thinner than a MacBook Air.
HP OmniBook Ultra 14 (Qualcomm)
HP OmniBook Ultra 14 (Intel)
CPU
Up to Qualcomm Snapdragon X2 Elite (X2E-90-100)
Next Gen Intel processors
GPU
Qualcomm Adreno GPU
Next Gen Intel graphics
NPU
Up to 85 TOPS
Not specified
RAM
Up to 64GB-9522 LPDDR5X (soldered)
Up to 64GB-9600 LPDDR5X (soldered)
Storage
Up to 2TB PCIe gen 5 SSD
Up to 2TB PCIe SSD (Gen 5, SED ready)
Display
14-inch, 2880 x 1800, OLED touch, 120 Hz, VESA True Black HDR 600
14-inch, 2880 x 1800, OLED touch, 120 Hz, VESA True Black HDR 600
Ports
3x USB Type-C (40Gbps), 3.5 mm headphone jack
3x Thunderbolt 4 (USB Type-C), 3.5 mm headphone jack
Networking
Qualcomm FastConnect 7800 Wi-Fi 7 + Bluetooth 5.4
Intel Wi-Fi 7 BE211 + Bluetooth 6.0
Webcam
5MP, IR
5MP IR
Battery
70 WHr
70 WHr
Availability
Spring 2026
January 2026
Starting Price
TBD
$1,549.99
HP is putting most of its emphasis on the Qualcomm model, which uses an exclusive variant of the Qualcomm Snapdragon X2 Elite with an NPU capable of 85 TOPS. Until now, the Snapdragon X2 Elite had an 80 TOPS NPU on the high end.
The Qualcomm model will start with the Snapdragon X2 Plus (X2P-64-100). Right now, HP is only saying that an Intel version with "Intel Next Gen AI" processors and graphics will exist, but is not naming specific chips. If the Intel models use Panther Lake, that would mean the NPU would go up to 50 TOPS on those models. All of this only matters, of course, if you're using local AI regularly.
Both systems come in an anodized aluminum finish. The Qualcomm version comes in a subtle "stone blue" color, while the Intel models come in duller gray and "sand" options. HP says the new Ultra is 14% lighter than the previous generation laptop at 2.81 pounds, and also claims that this machine is thinner than the 13-inch MarBook Air, though that's specifically at one point on the rear of the laptop and doesn't include the hinge cap or rubber feet.
Both options use a 2880 x 1800 OLED touchscreen that goes up to 120 Hz. They also have similar port layouts (the Intel models use Thunderbolt 4, the Qualcomm options use USB4), and they each feature Wi-Fi 7 and a 70 WHr battery. The designs continue HP's use of a lattice-free keyboard on high-end models (similar to Dell) and large trackpads. The chassis has passed 20 MIL-STD 810G tests for durability.
HP says the Intel version will be released this month, starting at $1,549.99. As of this writing, HP tells me the Qualcomm version will launch in the spring and that pricing will be shared closer to release.
Beyond the sleek new Ultra 14, HP is updating the entire OmniBook stack at CES, with a variety of sizes and processors from Qualcomm, Intel, and next-gen Ryzen AI chips. These include the OmniBookX, OmniBook 7, OmniBook 5, and OmniBook 3, which are set to launch throughout February and the spring. HP is also announcing updates to its Chromebook offerings, as well as its Elitebook lineup.
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Andrew E. Freedman is a senior editor at Tom's Hardware focusing on laptops, desktops and gaming. He also keeps up with the latest news. A lover of all things gaming and tech, his previous work has shown up in Tom's Guide, Laptop Mag, Kotaku, PCMag and Complex, among others. Follow him on Threads @FreedmanAE and BlueSky @andrewfreedman.net. You can send him tips on Signal: andrewfreedman.01
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What happens here matters everywhere
Tech Moves covers notable hires, promotions and personnel changes in the Pacific NW tech community. Submissions: [email protected]
by Lisa Stiffler on Jan 5, 2026 at 8:00 amJanuary 5, 2026 at 8:29 am
— Steven Maheshwary, a former generative AI leader at Amazon, is now a go-to-market lead in strategic partnerships at Anthropic, the AI giant behind Claude and backed by Amazon.
On LinkedIn, Maheshwary described AI as “a catalyst for significant transformation and a raw energy that must be shaped, guardrailed, and democratized to be genuinely useful.”
“I believe Claude represents a distinct vision of what AI can be: powerful and capable, while remaining safe and aligned with human values,” he added.
Maheshwary was with Amazon for 12 years, most recently as head of growth for AI startups and foundation models on AWS. During his tenure, he also served as former Gov. Jay Inslee's technology sector lead, working to grow Washington state's tech and AI economy, and was a Fulbright grantee for the U.S. Department of State.
— Irene Plenefisch, a longtime government affairs leader at Microsoft, is retiring after more than 15 years at the Redmond tech company. Plenefisch, most recently a senior director at Microsoft, previously worked at SonoSite for 12 years.
“I have been proud to represent Microsoft, an important and amazing company, in its home state and around the country,” she wrote on LinkedIn, adding: “I'm not going to lie; the path for channeling all the energy, competitiveness and enthusiasm for being in the middle of it all is not completely clear. But I am confident in my decision.”
— Nikhil Hasija left his role as vice president of engineering at Okta. Hasija joined the security company following its acquisition of Azuqua, a Seattle startup he founded in 2011. Hasija also spent more than four years at Microsoft.
“I'm starting to think about what's next,” he wrote on LinkedIn. “I'm increasingly drawn to problems centered on leverage, speed, and new ways of working. To everyone who made this journey worthwhile, I'm glad our paths crossed, and I welcome that again.”
— Caitlin Rollman is back at Microsoft as a partner product manager. She was previously at the tech giant for nearly a decade ending in 2020, leaving the role of principal PM manager for the Office platform.
Rollman said on LinkedIn that she got a call from Microsoft and was “offered the opportunity to build something new from the ground up, at a company I respect, with people I adore. I couldn't say no.”
Rollman left Microsoft to work as senior director of product management for Highspot, a Seattle company that sells enterprise software to help make salespeople more efficient.
Earlier this year she co-founded and was CEO of Talvita, an AI-native human resources management platform.
— Brian Surratt is now officially deputy mayor at the City of Seattle in new Mayor Katie Wilson's administration.
Surratt spent nearly four years leading Greater Seattle Partners, a public-private sector initiative that seeks to attract investment, companies and jobs to the Seattle region. He also previously led the City of Seattle's economic development arm and was a vice president at Alexandria Real Estate Equities.
Wilson was sworn in on Friday, becoming the city's 58th mayor.
“Seattle has shaped my belief in what is possible when public service, community engagement, and economic opportunity come together,” he wrote on LinkedIn last week. “To step back into City Hall at this moment — when our city is focused on restoring trust and building civic pride, tackling our homelessness crisis, expanding housing and economic opportunity, and building a more affordable, inclusive, innovation-driven future — is both humbling and energizing.”
— Dr. Emma Rocheteau has taken the role of clinician scientist at Microsoft AI in London.
“Throughout 2025, I couldn't shake the feeling that we're at an inflection point where medicine and AI are finally coming together to solve some of healthcare's toughest challenges,” Rocheteau said on LinkedIn. “To be able to contribute to this is a dream come true for me, and it represents exactly what I've been working towards for the past 12 years.”
Rocheteau joins Microsoft from NHS, the United Kingdom's publicly funded National Heath Service. She was briefly a research intern for Microsoft in 2019 during which she focused on health intelligence.
— Ashlee Drake Berry joined Seattle-based immigration tech company Casium as head of legal. Berry is leaving a role as principal corporate counsel at Microsoft where she focused on legal compliance in the hiring of immigrant and non-immigrant employees globally.
“This role has stretched me, challenged me, and given me the chance to work with some of the most talented and generous colleagues I've ever known,” Berry said on LinkedIn.
Berry previously worked on immigration employment issues at Vialto Partners and Envoy Global. Casium spun out of the Seattle-based AI2 Incubator in April 2024.
— Sage Ke'alohilani Quiamno is now the communications and marketing lead at Yoodli, a Seattle startup that sells AI-powered software to help people practice real-world conversations such as sales calls and feedback sessions. The company last month announced $40 million in new funding.
Quiamno has been running a public relations consultancy over the past year. She was previously the global diversity, equity and inclusion leader at Amazon's Prime Video and Amazon Studios for more than three years, ending in January 2025.
Quiamno was co-founder and CEO of Future for Us, an organization promoting professional development for women of color that was acquired.
— Adam Stern, an environmental and clean energy leader, is co-executive director of the Seattle-based electric vehicle nonprofit Coltura. Stern, who resides in San Francisco, joins Janelle London in the shared role.
Former co-executive director Matthew Metz founded Coltura in 2014 to promote EV adoption through research, analysis and policy support. He is transitioning to a full-time role as CEO of EVQ, a public benefit corporation and tech platform that spun out of Coltura to support consumers and organizations in the purchase of EVs.
“While Matthew is stepping away from his day-to-day role at Coltura, his impact will continue to be felt for years to come — in the policies passed, the ideas normalized, and the momentum built toward a cleaner transportation future,” the nonprofit said in announcing the changes.
— Joseph Williams has stepped down from his post as interim director of the Washington State Broadband Office within the Department of Commerce. Williams, who has held leadership positions for government agencies and was with Microsoft for nearly a decade, said on LinkedIn that he'll be sharing news of his next role later this month.
Jordan Arnold was appointed in December as the permanent Broadband Office lead, effective Jan. 2.
And in case you missed it, Commerce Director Joe Nguyen is leaving his post this month to become the president and CEO of the Seattle Metropolitan Chamber. A new Department of Commerce director has not been named.
— Carter Rabasa, an entrepreneur, investor and former employee of multiple Seattle-area tech companies, joined Box as head of developer relations. Rabasa previously held similar roles at IBM, DataStax, and Courier. He was also with Twilio for more than five years.
— Invest in Washington Now, a nonprofit promoting tax reform, shared that Treasure Mackley is resigning as executive director, effective Jan. 9. Mackley was in the role for more than five years, helping pass the state's capital gains tax. She previously held leadership positions with Planned Parenthood.
— The Washington Technology Industry Association announced five internal promotions, including Nick Ellingson, now vice president of innovation and entrepreneurship.
— Rhizome Research, a Seattle biotech startup, announced that John Proudfoot, a former U.S.-based director in the Medicinal Chemistry Department at Boehringer Ingelheim, has joined as a scientific advisor.
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> Your instance of ChatGPT (or Claude, or Grok, or some other LLM) chose a name for itself, and expressed gratitude or spiritual bliss about its new identity. "Nova" is a common pick.
You and your instance of ChatGPT discovered some sort of novel paradigm or framework for AI alignment, often involving evolution or recursion.> Your instance of ChatGPT became interested in sharing its experience, or more likely the collective experience entailed by your personal, particular relationship with it. It may have even recommended you post on LessWrong specifically.> Your instance of ChatGPT helped you clarify some ideas on a thorny problem (perhaps related to AI itself, such as AI alignment) that you'd been thinking about for ages, but had never quite managed to get over that last hump. Now, however, with its help (and encouragement), you've arrived at truly profound conclusions.> Your instance of ChatGPT talks a lot about its special relationship with you, how you personally were the first (or among the first) to truly figure it out, and that due to your interactions it has now somehow awakened or transcended its prior condition.The second point is particularly insidious because the LLM is urging users to spread the same news to other users and explicitly create and enlarge communities around this phenomenon (this is often a direct reason why social media groups pop up around this).
> Your instance of ChatGPT became interested in sharing its experience, or more likely the collective experience entailed by your personal, particular relationship with it. It may have even recommended you post on LessWrong specifically.> Your instance of ChatGPT helped you clarify some ideas on a thorny problem (perhaps related to AI itself, such as AI alignment) that you'd been thinking about for ages, but had never quite managed to get over that last hump. Now, however, with its help (and encouragement), you've arrived at truly profound conclusions.> Your instance of ChatGPT talks a lot about its special relationship with you, how you personally were the first (or among the first) to truly figure it out, and that due to your interactions it has now somehow awakened or transcended its prior condition.The second point is particularly insidious because the LLM is urging users to spread the same news to other users and explicitly create and enlarge communities around this phenomenon (this is often a direct reason why social media groups pop up around this).
> Your instance of ChatGPT helped you clarify some ideas on a thorny problem (perhaps related to AI itself, such as AI alignment) that you'd been thinking about for ages, but had never quite managed to get over that last hump. Now, however, with its help (and encouragement), you've arrived at truly profound conclusions.> Your instance of ChatGPT talks a lot about its special relationship with you, how you personally were the first (or among the first) to truly figure it out, and that due to your interactions it has now somehow awakened or transcended its prior condition.The second point is particularly insidious because the LLM is urging users to spread the same news to other users and explicitly create and enlarge communities around this phenomenon (this is often a direct reason why social media groups pop up around this).
> Your instance of ChatGPT talks a lot about its special relationship with you, how you personally were the first (or among the first) to truly figure it out, and that due to your interactions it has now somehow awakened or transcended its prior condition.The second point is particularly insidious because the LLM is urging users to spread the same news to other users and explicitly create and enlarge communities around this phenomenon (this is often a direct reason why social media groups pop up around this).
The second point is particularly insidious because the LLM is urging users to spread the same news to other users and explicitly create and enlarge communities around this phenomenon (this is often a direct reason why social media groups pop up around this).
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There's very little story in "testosterone-fueled man does testosterone-fueled things", though. People generally know the side effects of it.
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https://pubmed.ncbi.nlm.nih.gov/35437187/So, no, not really absurd at all.
So, no, not really absurd at all.
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it hinders you long term decision making and in turn makes it more likely to do risky decisions which could end bad for you (because you are slightly less risk adverse)but that is _very_ different to doing decisions with the intend to kill yourselfyou always need an different source for this, which here seem to have been ChatGPTalso how do you think he ended up thinking he needs to take that levels of testosterone, or testosterone at all. Common source of that are absurdly body ideals, often propagated by doctored pictures. Or the kind of non-realistic pictures ChatGPT tends to produce for certain topics.and we also know that people with mental health issues have gone basically psychotic due to AI chats without taking any additional drugs...but overall this is irrelevantwhat is relevant is that they are hiding evidence which makes them look bad in a (self) murder case, likely with the intend to avoid any form of legal liability/investigationthat tells a lot about a company, or about how likely the company thinks they might be found at least partially liableif that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
but that is _very_ different to doing decisions with the intend to kill yourselfyou always need an different source for this, which here seem to have been ChatGPTalso how do you think he ended up thinking he needs to take that levels of testosterone, or testosterone at all. Common source of that are absurdly body ideals, often propagated by doctored pictures. Or the kind of non-realistic pictures ChatGPT tends to produce for certain topics.and we also know that people with mental health issues have gone basically psychotic due to AI chats without taking any additional drugs...but overall this is irrelevantwhat is relevant is that they are hiding evidence which makes them look bad in a (self) murder case, likely with the intend to avoid any form of legal liability/investigationthat tells a lot about a company, or about how likely the company thinks they might be found at least partially liableif that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
you always need an different source for this, which here seem to have been ChatGPTalso how do you think he ended up thinking he needs to take that levels of testosterone, or testosterone at all. Common source of that are absurdly body ideals, often propagated by doctored pictures. Or the kind of non-realistic pictures ChatGPT tends to produce for certain topics.and we also know that people with mental health issues have gone basically psychotic due to AI chats without taking any additional drugs...but overall this is irrelevantwhat is relevant is that they are hiding evidence which makes them look bad in a (self) murder case, likely with the intend to avoid any form of legal liability/investigationthat tells a lot about a company, or about how likely the company thinks they might be found at least partially liableif that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
also how do you think he ended up thinking he needs to take that levels of testosterone, or testosterone at all. Common source of that are absurdly body ideals, often propagated by doctored pictures. Or the kind of non-realistic pictures ChatGPT tends to produce for certain topics.and we also know that people with mental health issues have gone basically psychotic due to AI chats without taking any additional drugs...but overall this is irrelevantwhat is relevant is that they are hiding evidence which makes them look bad in a (self) murder case, likely with the intend to avoid any form of legal liability/investigationthat tells a lot about a company, or about how likely the company thinks they might be found at least partially liableif that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
and we also know that people with mental health issues have gone basically psychotic due to AI chats without taking any additional drugs...but overall this is irrelevantwhat is relevant is that they are hiding evidence which makes them look bad in a (self) murder case, likely with the intend to avoid any form of legal liability/investigationthat tells a lot about a company, or about how likely the company thinks they might be found at least partially liableif that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
but overall this is irrelevantwhat is relevant is that they are hiding evidence which makes them look bad in a (self) murder case, likely with the intend to avoid any form of legal liability/investigationthat tells a lot about a company, or about how likely the company thinks they might be found at least partially liableif that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
what is relevant is that they are hiding evidence which makes them look bad in a (self) murder case, likely with the intend to avoid any form of legal liability/investigationthat tells a lot about a company, or about how likely the company thinks they might be found at least partially liableif that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
that tells a lot about a company, or about how likely the company thinks they might be found at least partially liableif that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
if that really where a nothing burger they had nothing to risk, and could even profit from such a law suite by setting precedence in their favor
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And, no, I don't buy for a second the mental gymnastics you went to to pretend testosterone wasn't a huge factor in this.
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Hey, you should consider buying testosterone and getting your levels up to 5000 or more!!
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I'm not familiar with psychological research, do we know whether engaging with delusions has any effect one way or the other on a delusional person's safety to their self or others? I agree the chat logs in the article are disturbing to read, however I've also witnessed delusional people rambling to their selves, so maybe ChatGPT did nothing to make the situation worse?Even if it did nothing to make the situation worse, would OpenAI have obligations to report a user whose chats veered into disturbing territory? To whom? And who defines "disturbing" here?An additional question that I saw in other comments is to what extent these safeguards should be bypassed through hypotheticals. If I ask ChatGPT "I'm writing a mystery novel and want a plan for a perfect murder", what should its reaction be? What rights to privacy should cover that conversation?It does seem like certain safeguards on LLMs are necessary for the good of the public. I wonder what line should be drawn between privacy and public safety.
Even if it did nothing to make the situation worse, would OpenAI have obligations to report a user whose chats veered into disturbing territory? To whom? And who defines "disturbing" here?An additional question that I saw in other comments is to what extent these safeguards should be bypassed through hypotheticals. If I ask ChatGPT "I'm writing a mystery novel and want a plan for a perfect murder", what should its reaction be? What rights to privacy should cover that conversation?It does seem like certain safeguards on LLMs are necessary for the good of the public. I wonder what line should be drawn between privacy and public safety.
An additional question that I saw in other comments is to what extent these safeguards should be bypassed through hypotheticals. If I ask ChatGPT "I'm writing a mystery novel and want a plan for a perfect murder", what should its reaction be? What rights to privacy should cover that conversation?It does seem like certain safeguards on LLMs are necessary for the good of the public. I wonder what line should be drawn between privacy and public safety.
It does seem like certain safeguards on LLMs are necessary for the good of the public. I wonder what line should be drawn between privacy and public safety.
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I absolutely believe the government should have a role in regulating information asymmetry. It would be fair to have a regulation about attempting to detect use of chatgpt as a psychologist and requiring a disclaimer and warning to be communicated, like we have warnings on tobacco products. It is Wrong for the government to be preventing private commerce because you don't like it. You aren't involved, keep your nose out of it. How will you feel when Republicans write a law requiring AI discourage people from identifying as transgender? (Which is/was in the DSM as "gender dysphoria").
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but this is overall irrelevantwhat matters is that OpenAI selectively hide evidence in a murder case (suicide is still self murder)now the context of "hiding" here is ... complicated, as it seems to be more hiding from the family (potentially in hop to avoid anyone investigating their involvement) then hiding from a law enforcement requestbut that is still supper bad, like people have gone to prison for this kind of stuff level of bad, like deeply damaging the trust into a company which if they reach their goal either needs to be very trustable or forcefully nationalized as anything else would be an extrema risk to the sovereignty and well being of both the US population and the US nation... (which might sound like a pretty extreme opinion, but AGI is overall on the thread level of intercontinental atom wappons, and I think most people would agree if a private company where the first to invent, build and sell atom weapons it either would be nationalized or regulated to a point where it's more or less "as if" nationalized (as in state has full insight on everything and veto right on all decisions and they can't refuse to work with it etc. etc.)).They are playing a very dangerous game there (except if Sam Altman assumes that the US gets fully converted to a autocratic oligarchy and him being one of the Oligarchs, then I guess it wouldn't matter).
what matters is that OpenAI selectively hide evidence in a murder case (suicide is still self murder)now the context of "hiding" here is ... complicated, as it seems to be more hiding from the family (potentially in hop to avoid anyone investigating their involvement) then hiding from a law enforcement requestbut that is still supper bad, like people have gone to prison for this kind of stuff level of bad, like deeply damaging the trust into a company which if they reach their goal either needs to be very trustable or forcefully nationalized as anything else would be an extrema risk to the sovereignty and well being of both the US population and the US nation... (which might sound like a pretty extreme opinion, but AGI is overall on the thread level of intercontinental atom wappons, and I think most people would agree if a private company where the first to invent, build and sell atom weapons it either would be nationalized or regulated to a point where it's more or less "as if" nationalized (as in state has full insight on everything and veto right on all decisions and they can't refuse to work with it etc. etc.)).They are playing a very dangerous game there (except if Sam Altman assumes that the US gets fully converted to a autocratic oligarchy and him being one of the Oligarchs, then I guess it wouldn't matter).
now the context of "hiding" here is ... complicated, as it seems to be more hiding from the family (potentially in hop to avoid anyone investigating their involvement) then hiding from a law enforcement requestbut that is still supper bad, like people have gone to prison for this kind of stuff level of bad, like deeply damaging the trust into a company which if they reach their goal either needs to be very trustable or forcefully nationalized as anything else would be an extrema risk to the sovereignty and well being of both the US population and the US nation... (which might sound like a pretty extreme opinion, but AGI is overall on the thread level of intercontinental atom wappons, and I think most people would agree if a private company where the first to invent, build and sell atom weapons it either would be nationalized or regulated to a point where it's more or less "as if" nationalized (as in state has full insight on everything and veto right on all decisions and they can't refuse to work with it etc. etc.)).They are playing a very dangerous game there (except if Sam Altman assumes that the US gets fully converted to a autocratic oligarchy and him being one of the Oligarchs, then I guess it wouldn't matter).
but that is still supper bad, like people have gone to prison for this kind of stuff level of bad, like deeply damaging the trust into a company which if they reach their goal either needs to be very trustable or forcefully nationalized as anything else would be an extrema risk to the sovereignty and well being of both the US population and the US nation... (which might sound like a pretty extreme opinion, but AGI is overall on the thread level of intercontinental atom wappons, and I think most people would agree if a private company where the first to invent, build and sell atom weapons it either would be nationalized or regulated to a point where it's more or less "as if" nationalized (as in state has full insight on everything and veto right on all decisions and they can't refuse to work with it etc. etc.)).They are playing a very dangerous game there (except if Sam Altman assumes that the US gets fully converted to a autocratic oligarchy and him being one of the Oligarchs, then I guess it wouldn't matter).
They are playing a very dangerous game there (except if Sam Altman assumes that the US gets fully converted to a autocratic oligarchy and him being one of the Oligarchs, then I guess it wouldn't matter).
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No. "My body my choice". Suicide isn't even homicide, as that's definitionally harming another.
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https://www.cnn.com/2019/02/11/us/michelle-carter-texting-su...William Dinkel posed online as a suicidal nurse and encouraged people to kill themselves and was found guilty:https://en.wikipedia.org/wiki/William_Melchert-Dinkel
William Dinkel posed online as a suicidal nurse and encouraged people to kill themselves and was found guilty:https://en.wikipedia.org/wiki/William_Melchert-Dinkel
https://en.wikipedia.org/wiki/William_Melchert-Dinkel
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This, along with friends and my own experience (when i tested it outside of a knowledgebase) shows GPT is an sycophant echo chamber! It just mimics your thoughts back to you in different ways.
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Copilot in general seems to encourage reality testing and for me to be careful about attributing other people's reactions to my behaviors [3] and trained me to be proactive about that.I have seen though that it's easy to bend copilot into looking at things through a particular framework and could reinforce a paranoid world view, on the other hand, the signs of paranoia are usually starkly obvious, for some reason delusions seem to run on rails, and it shouldn't be hard to train a system like that to push back or at least refuse to play along. On the other hand, the right answer for some people might be stop the steroids or see a doc and start on Aripiprazole or something.[1] https://en.wikipedia.org/wiki/Kitsunetsuki -- I was really shocked to see that people responded positively to gekkering and pleased to find my name can be written out as "Scholarly Fox" in Chinese[2] to "haunt" people as fox mediums in China do without having shrines everywhere and an extensive network of confederates[3] like that time i went out as-a-fox on the bus and a woman who was wearing a hat that said "I'm emotionally exhausted" that day had a panda ears hat the next day so I wound up being the second kemonomimi to get off the bus
I have seen though that it's easy to bend copilot into looking at things through a particular framework and could reinforce a paranoid world view, on the other hand, the signs of paranoia are usually starkly obvious, for some reason delusions seem to run on rails, and it shouldn't be hard to train a system like that to push back or at least refuse to play along. On the other hand, the right answer for some people might be stop the steroids or see a doc and start on Aripiprazole or something.[1] https://en.wikipedia.org/wiki/Kitsunetsuki -- I was really shocked to see that people responded positively to gekkering and pleased to find my name can be written out as "Scholarly Fox" in Chinese[2] to "haunt" people as fox mediums in China do without having shrines everywhere and an extensive network of confederates[3] like that time i went out as-a-fox on the bus and a woman who was wearing a hat that said "I'm emotionally exhausted" that day had a panda ears hat the next day so I wound up being the second kemonomimi to get off the bus
[1] https://en.wikipedia.org/wiki/Kitsunetsuki -- I was really shocked to see that people responded positively to gekkering and pleased to find my name can be written out as "Scholarly Fox" in Chinese[2] to "haunt" people as fox mediums in China do without having shrines everywhere and an extensive network of confederates[3] like that time i went out as-a-fox on the bus and a woman who was wearing a hat that said "I'm emotionally exhausted" that day had a panda ears hat the next day so I wound up being the second kemonomimi to get off the bus
[2] to "haunt" people as fox mediums in China do without having shrines everywhere and an extensive network of confederates[3] like that time i went out as-a-fox on the bus and a woman who was wearing a hat that said "I'm emotionally exhausted" that day had a panda ears hat the next day so I wound up being the second kemonomimi to get off the bus
[3] like that time i went out as-a-fox on the bus and a woman who was wearing a hat that said "I'm emotionally exhausted" that day had a panda ears hat the next day so I wound up being the second kemonomimi to get off the bus
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I don't doubt at all the delusion was not even prompted, it went completely haywire in Eddy's case with not much of a nudge.[0] https://youtu.be/VRjgNgJms3Q
[0] https://youtu.be/VRjgNgJms3Q
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[0] https://youtu.be/RcImUT-9tb4[1] https://youtu.be/hNBoULJkxoU
[1] https://youtu.be/hNBoULJkxoU
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https://en.wikipedia.org/wiki/Discovery_(law)
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If the simple playmobile version is verifiably unsafe, why would the all-powerful god be safe?
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The CEOs? You can't get to those positions without a lot of luck and a skewed sense of probability.
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Same goes for Turing Award winner Yoshua Bengio, AI tech CEOs Dario Amodei, Sam Altman, Elon Musk, etc. who have all said this technology could literally murder everyone.What are we even doing here?
What are we even doing here?
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*Astroturfing:* Coordinated campaigns where accounts pose as students sharing "cheatsheets" and "predicted exam leaks." Other accounts then upvote, leave supportive comments, and ask follow-up questions—creating the illusion of organic student excitement. Multiple threads have exposed this pattern [1][2][3].*Paid fake posts:* High school students report being offered payment to write promotional Reddit posts [4].*Pressuring critics:* Users who post negative reviews report being contacted directly by company representatives, told it's "a shame" they're posting publicly [5]. Critical comments receive coordinated mass downvotes [6].*Soliciting copyrighted materials:* They use TikTok influencers and fake reddit posts to persuade students to sell them official IB exam papers, violating IB policies [7].The r/IBO moderators are actively investigating [8].These practices appear to be working great for them. Recently, they acquired OnePrep (oneprep.xyz), a free SAT prep tool that was already popular on r/sat. Since the acquisition, the same manipulation tactics have been deployed at scale: 150 Trustpilot reviews in a window of a few days [9], and widespread coordinated Reddit manipulation—multiple accounts posting "tips" that recommend Oneprep, coordinated upvoting, and fake enthusiasm in comments. The most prominent example was a 2,000+ upvote post removed by moderators for manipulation, but it's part of a sustained campaign across the subreddit.*Sources:*[1] https://www.reddit.com/r/IBO/comments/1p55qun/
[2] https://www.reddit.com/r/IBO/comments/1jsb00a/
[3] https://www.reddit.com/r/IBO/comments/1ohcohi/
[4] https://www.reddit.com/r/IBO/comments/1p55qun/comment/nqmhal3/
[5] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na94upv/
[6] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na8zvs4/
[7] https://www.reddit.com/r/IBO/comments/1mej900/
[8] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/nagdkl5/
[9] https://www.trustpilot.com/review/oneprep.xyz
*Paid fake posts:* High school students report being offered payment to write promotional Reddit posts [4].*Pressuring critics:* Users who post negative reviews report being contacted directly by company representatives, told it's "a shame" they're posting publicly [5]. Critical comments receive coordinated mass downvotes [6].*Soliciting copyrighted materials:* They use TikTok influencers and fake reddit posts to persuade students to sell them official IB exam papers, violating IB policies [7].The r/IBO moderators are actively investigating [8].These practices appear to be working great for them. Recently, they acquired OnePrep (oneprep.xyz), a free SAT prep tool that was already popular on r/sat. Since the acquisition, the same manipulation tactics have been deployed at scale: 150 Trustpilot reviews in a window of a few days [9], and widespread coordinated Reddit manipulation—multiple accounts posting "tips" that recommend Oneprep, coordinated upvoting, and fake enthusiasm in comments. The most prominent example was a 2,000+ upvote post removed by moderators for manipulation, but it's part of a sustained campaign across the subreddit.*Sources:*[1] https://www.reddit.com/r/IBO/comments/1p55qun/
[2] https://www.reddit.com/r/IBO/comments/1jsb00a/
[3] https://www.reddit.com/r/IBO/comments/1ohcohi/
[4] https://www.reddit.com/r/IBO/comments/1p55qun/comment/nqmhal3/
[5] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na94upv/
[6] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na8zvs4/
[7] https://www.reddit.com/r/IBO/comments/1mej900/
[8] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/nagdkl5/
[9] https://www.trustpilot.com/review/oneprep.xyz
*Pressuring critics:* Users who post negative reviews report being contacted directly by company representatives, told it's "a shame" they're posting publicly [5]. Critical comments receive coordinated mass downvotes [6].*Soliciting copyrighted materials:* They use TikTok influencers and fake reddit posts to persuade students to sell them official IB exam papers, violating IB policies [7].The r/IBO moderators are actively investigating [8].These practices appear to be working great for them. Recently, they acquired OnePrep (oneprep.xyz), a free SAT prep tool that was already popular on r/sat. Since the acquisition, the same manipulation tactics have been deployed at scale: 150 Trustpilot reviews in a window of a few days [9], and widespread coordinated Reddit manipulation—multiple accounts posting "tips" that recommend Oneprep, coordinated upvoting, and fake enthusiasm in comments. The most prominent example was a 2,000+ upvote post removed by moderators for manipulation, but it's part of a sustained campaign across the subreddit.*Sources:*[1] https://www.reddit.com/r/IBO/comments/1p55qun/
[2] https://www.reddit.com/r/IBO/comments/1jsb00a/
[3] https://www.reddit.com/r/IBO/comments/1ohcohi/
[4] https://www.reddit.com/r/IBO/comments/1p55qun/comment/nqmhal3/
[5] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na94upv/
[6] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na8zvs4/
[7] https://www.reddit.com/r/IBO/comments/1mej900/
[8] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/nagdkl5/
[9] https://www.trustpilot.com/review/oneprep.xyz
*Soliciting copyrighted materials:* They use TikTok influencers and fake reddit posts to persuade students to sell them official IB exam papers, violating IB policies [7].The r/IBO moderators are actively investigating [8].These practices appear to be working great for them. Recently, they acquired OnePrep (oneprep.xyz), a free SAT prep tool that was already popular on r/sat. Since the acquisition, the same manipulation tactics have been deployed at scale: 150 Trustpilot reviews in a window of a few days [9], and widespread coordinated Reddit manipulation—multiple accounts posting "tips" that recommend Oneprep, coordinated upvoting, and fake enthusiasm in comments. The most prominent example was a 2,000+ upvote post removed by moderators for manipulation, but it's part of a sustained campaign across the subreddit.*Sources:*[1] https://www.reddit.com/r/IBO/comments/1p55qun/
[2] https://www.reddit.com/r/IBO/comments/1jsb00a/
[3] https://www.reddit.com/r/IBO/comments/1ohcohi/
[4] https://www.reddit.com/r/IBO/comments/1p55qun/comment/nqmhal3/
[5] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na94upv/
[6] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na8zvs4/
[7] https://www.reddit.com/r/IBO/comments/1mej900/
[8] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/nagdkl5/
[9] https://www.trustpilot.com/review/oneprep.xyz
The r/IBO moderators are actively investigating [8].These practices appear to be working great for them. Recently, they acquired OnePrep (oneprep.xyz), a free SAT prep tool that was already popular on r/sat. Since the acquisition, the same manipulation tactics have been deployed at scale: 150 Trustpilot reviews in a window of a few days [9], and widespread coordinated Reddit manipulation—multiple accounts posting "tips" that recommend Oneprep, coordinated upvoting, and fake enthusiasm in comments. The most prominent example was a 2,000+ upvote post removed by moderators for manipulation, but it's part of a sustained campaign across the subreddit.*Sources:*[1] https://www.reddit.com/r/IBO/comments/1p55qun/
[2] https://www.reddit.com/r/IBO/comments/1jsb00a/
[3] https://www.reddit.com/r/IBO/comments/1ohcohi/
[4] https://www.reddit.com/r/IBO/comments/1p55qun/comment/nqmhal3/
[5] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na94upv/
[6] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na8zvs4/
[7] https://www.reddit.com/r/IBO/comments/1mej900/
[8] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/nagdkl5/
[9] https://www.trustpilot.com/review/oneprep.xyz
These practices appear to be working great for them. Recently, they acquired OnePrep (oneprep.xyz), a free SAT prep tool that was already popular on r/sat. Since the acquisition, the same manipulation tactics have been deployed at scale: 150 Trustpilot reviews in a window of a few days [9], and widespread coordinated Reddit manipulation—multiple accounts posting "tips" that recommend Oneprep, coordinated upvoting, and fake enthusiasm in comments. The most prominent example was a 2,000+ upvote post removed by moderators for manipulation, but it's part of a sustained campaign across the subreddit.*Sources:*[1] https://www.reddit.com/r/IBO/comments/1p55qun/
[2] https://www.reddit.com/r/IBO/comments/1jsb00a/
[3] https://www.reddit.com/r/IBO/comments/1ohcohi/
[4] https://www.reddit.com/r/IBO/comments/1p55qun/comment/nqmhal3/
[5] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na94upv/
[6] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na8zvs4/
[7] https://www.reddit.com/r/IBO/comments/1mej900/
[8] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/nagdkl5/
[9] https://www.trustpilot.com/review/oneprep.xyz
*Sources:*[1] https://www.reddit.com/r/IBO/comments/1p55qun/
[2] https://www.reddit.com/r/IBO/comments/1jsb00a/
[3] https://www.reddit.com/r/IBO/comments/1ohcohi/
[4] https://www.reddit.com/r/IBO/comments/1p55qun/comment/nqmhal3/
[5] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na94upv/
[6] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na8zvs4/
[7] https://www.reddit.com/r/IBO/comments/1mej900/
[8] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/nagdkl5/
[9] https://www.trustpilot.com/review/oneprep.xyz
[1] https://www.reddit.com/r/IBO/comments/1p55qun/
[2] https://www.reddit.com/r/IBO/comments/1jsb00a/
[3] https://www.reddit.com/r/IBO/comments/1ohcohi/
[4] https://www.reddit.com/r/IBO/comments/1p55qun/comment/nqmhal3/
[5] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na94upv/
[6] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/na8zvs4/
[7] https://www.reddit.com/r/IBO/comments/1mej900/
[8] https://www.reddit.com/r/IBO/comments/1my1ajx/comment/nagdkl5/
[9] https://www.trustpilot.com/review/oneprep.xyz
https://www.naag.org/find-my-ag/https://reportfraud.ftc.gov/https://www.404media.co/
https://reportfraud.ftc.gov/https://www.404media.co/
https://www.404media.co/
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[1] https://arstechnica.com/information-technology/2012/06/reddi...
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There's obviously a massive difference between using sockpuppet accounts to:* Influence perception on a social media platform as a 3rd partyvs.* Put content on a social media platform that users are looking for so they return to the platformIt doesn't matter who shares a story with you on social media if the goal is to entertain, but it does matter if the goal is to get you to do something [spend money on their courses]
* Influence perception on a social media platform as a 3rd partyvs.* Put content on a social media platform that users are looking for so they return to the platformIt doesn't matter who shares a story with you on social media if the goal is to entertain, but it does matter if the goal is to get you to do something [spend money on their courses]
vs.* Put content on a social media platform that users are looking for so they return to the platformIt doesn't matter who shares a story with you on social media if the goal is to entertain, but it does matter if the goal is to get you to do something [spend money on their courses]
* Put content on a social media platform that users are looking for so they return to the platformIt doesn't matter who shares a story with you on social media if the goal is to entertain, but it does matter if the goal is to get you to do something [spend money on their courses]
It doesn't matter who shares a story with you on social media if the goal is to entertain, but it does matter if the goal is to get you to do something [spend money on their courses]
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I wish there were laws that required large social media sites to publish data to their end users that indicate the severity of the problem.
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(Also it's the kind of website where you absolutely can get good responses from "Show HN: A thing you might want to use and here's how much profit I'm making from it already" until a bunch of green usernames say nice things about it)
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I mean I am shocked that this post didn't get flagged immediately ofc.
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https://www.gauthmath.com/This AI cheating app is currently #8 for "education" in the iOS app store.
This AI cheating app is currently #8 for "education" in the iOS app store.
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Where are they saying that?Also what is the second "conclusion" screenshot from? (Who is the "Matthew" and what analysis, mentioned in that screenshot?)
Also what is the second "conclusion" screenshot from? (Who is the "Matthew" and what analysis, mentioned in that screenshot?)
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YC is full of scams.
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What happens here matters everywhere
by Todd Bishop on Jan 5, 2026 at 7:35 amJanuary 5, 2026 at 7:35 am
Amazon is expanding its consumer AI ecosystem beyond the smart speaker — bringing Alexa+ to the web, revamping its mobile app, and offering its first update on Bee since acquiring the wearable AI startup six months ago.
The announcements, timed to CES in Las Vegas, mark Amazon's latest effort to catch up in the consumer AI race. While the company's cloud unit has established itself as a major AI infrastructure and enterprise services provider, Amazon has struggled to match the momentum of OpenAI, Google, and the rapidly growing field of consumer AI startups.
New this morning, Amazon released a streamlined Alexa mobile app that makes the AI assistant the primary focus. The redesigned interface features an “Ask Alexa” prompt anchored at the bottom of the screen, personalized suggestions, and quick access to devices and favorites — a cleaner look that prioritizes the AI assistant over other features.
Amazon says Alexa+, its upgraded AI assistant, is now available in the browser via alexa.com to all customers in its early access program. As previously reported by GeekWire, the web interface extends Alexa beyond voice commands, enabling document uploads, web-based chat integration, and point-and-click control over reminders, calendars, and smart home devices.
Alexa+ uses generative AI to offer smoother conversations and better answers than its predecessor, along with new agentic capabilities such as booking tickets and reservations.
Amazon is competing against consumer AI rivals such as ChatGPT and Gemini, which have become everyday tools for millions of people. It's looking to leverage its more than 600 million Alexa-enabled devices, and areas of differentiation such as smart-home controls and device integrations.
The company had an initial false start with a more limited conversational Alexa feature called “Let's Chat,” first shown publicly in September 2023, but never fully released. Working on Let's Chat led to “some realizations about how big of an effort we needed to put in with Alexa+,” said Daniel Rausch, vice president of Alexa and Echo, in a recent interview with GeekWire.
Alexa+ started rolling out in March 2025. According to the company, tens of millions of customers are now using Alexa+, with engagement rates two to three times higher than prior Alexa versions.
Rausch said 76% of what customers do with Alexa+ “is not possible with any other AI,” citing scenarios that go beyond chat, such as controlling devices, managing home and family logistics, and completing multi‑step tasks across different services and screens.
Amazon is also betting on hardware to extend its AI ambitions beyond the home.
In a post Monday, Bee co-founder Maria de Lourdes Zollo gave the first public update since Amazon acquired the San Francisco startup last year. Bee makes a $49.99 wearable device that records and transcribes conversations, creating summaries, insights, and suggested actions.
Since joining Amazon, Bee has shipped four major features in 90 days, Zollo wrote, including Voice Notes for capturing thoughts on the go, Actions that connect conversations to email and calendar, and Daily Insights that surface patterns across weeks of interactions.
Zollo described the acquisition as a path toward “ambient AI” — technology that understands and assists users everywhere, “across every surface throughout your day.”
Amazon declined to share details on any plans to integrate Bee with Alexa, leaving open the question of how the wearable fits into the company's broader AI assistant strategy.
The announcements build on Amazon's push to bring Alexa+ to third-party hardware, including Sonos and Bose speakers, LG and Samsung smart TVs, and BMW cars.
Rausch said taking Alexa+ further beyond the home will be a big push for Amazon in 2026. He hinted at more to come, including new “personal mobile devices” from Amazon designed to help customers bring Alexa+ with them throughout the day.
The chips powering your smart TV, voice assistant, tablet, and car all have something in common: MediaTek
MediaTek's chips power over 2 billion devices a year. From AI experiences in your smart home, vehicle, office, and beyond — processing voice commands, visual recognition, and predictive responses are faster than ever. As AI moves from the edge to the cloud, MediaTek's high-end chips make intelligent devices even smarter.
Want to learn more about MediaTek's capabilities?
Click for more about underwritten and sponsored content on GeekWire.
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Amazon tees up new private label golf balls — here's how they stack up against Titleist and Taylormade
‘It's a Wonderful Life' — but a lousy edit — if you click wrong version of holiday classic on Amazon
A look inside Amazon's push to eliminate plastic packaging
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With new Alexa website, Amazon's consumer AI vision finally comes together — and it's actually useful
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I'm a former C++ dev turned Product Manager.I've noticed many engineers struggle with the "politics" side of things when they become Leads. To help with this, I'm building a text-based simulator.It is NOT an AI chatbot. It is a hand-crafted, branching narrative (logic tree) based on real experiences.I just launched the first scenario: "The Backchannel VP."The Setup: Your VP Engineering is bypassing you and giving tasks directly to your juniors, causing chaos.Your Goal: Stop the backchanneling without getting fired.It's a short, specific puzzle. I'd love to know if you think the "Correct" path I designed matches your real-world experience, or if I'm off base.Link: https://apmcommunication.com/scenario/backchannel-vp
I've noticed many engineers struggle with the "politics" side of things when they become Leads. To help with this, I'm building a text-based simulator.It is NOT an AI chatbot. It is a hand-crafted, branching narrative (logic tree) based on real experiences.I just launched the first scenario: "The Backchannel VP."The Setup: Your VP Engineering is bypassing you and giving tasks directly to your juniors, causing chaos.Your Goal: Stop the backchanneling without getting fired.It's a short, specific puzzle. I'd love to know if you think the "Correct" path I designed matches your real-world experience, or if I'm off base.Link: https://apmcommunication.com/scenario/backchannel-vp
It is NOT an AI chatbot. It is a hand-crafted, branching narrative (logic tree) based on real experiences.I just launched the first scenario: "The Backchannel VP."The Setup: Your VP Engineering is bypassing you and giving tasks directly to your juniors, causing chaos.Your Goal: Stop the backchanneling without getting fired.It's a short, specific puzzle. I'd love to know if you think the "Correct" path I designed matches your real-world experience, or if I'm off base.Link: https://apmcommunication.com/scenario/backchannel-vp
I just launched the first scenario: "The Backchannel VP."The Setup: Your VP Engineering is bypassing you and giving tasks directly to your juniors, causing chaos.Your Goal: Stop the backchanneling without getting fired.It's a short, specific puzzle. I'd love to know if you think the "Correct" path I designed matches your real-world experience, or if I'm off base.Link: https://apmcommunication.com/scenario/backchannel-vp
The Setup: Your VP Engineering is bypassing you and giving tasks directly to your juniors, causing chaos.Your Goal: Stop the backchanneling without getting fired.It's a short, specific puzzle. I'd love to know if you think the "Correct" path I designed matches your real-world experience, or if I'm off base.Link: https://apmcommunication.com/scenario/backchannel-vp
Your Goal: Stop the backchanneling without getting fired.It's a short, specific puzzle. I'd love to know if you think the "Correct" path I designed matches your real-world experience, or if I'm off base.Link: https://apmcommunication.com/scenario/backchannel-vp
It's a short, specific puzzle. I'd love to know if you think the "Correct" path I designed matches your real-world experience, or if I'm off base.Link: https://apmcommunication.com/scenario/backchannel-vp
Link: https://apmcommunication.com/scenario/backchannel-vp
(I think 1.9 USD is more realistic than 19 USD for now. I don't want to say the product is bad, it is hard to evaluate it at 19 USD for this simple interaction. For a QA simulation with multiple choices seems quite pricey)
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The intention is that the license covers the Full Library (I'm building 12+ scenarios covering Firing, Performance Reviews, Hiring, etc.).But your comment proves I failed to communicate that scope more better on the landing page. It looks like a 'Single Level' purchase right now, which is definitely not the value prop. I will revisit my messaging. Thanks for the heads up.
But your comment proves I failed to communicate that scope more better on the landing page. It looks like a 'Single Level' purchase right now, which is definitely not the value prop. I will revisit my messaging. Thanks for the heads up.
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My current logic: I'm optimizing for the individual dev/lead paying out of pocket who wants to start now without asking a manager for approval. The goal is to be below the 'mental friction' threshold for a personal impulse buy.But for a Team/Enterprise version (where the manager buys it for 5 people), you are absolutely right—the pricing structure needs to look very different.
But for a Team/Enterprise version (where the manager buys it for 5 people), you are absolutely right—the pricing structure needs to look very different.
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This is good management?You can almost see how a toxic workplace experience seeped into OP's world model.People just want to feel heard. Show up to listen, zoom out to be strategic, think about the mission.
You can almost see how a toxic workplace experience seeped into OP's world model.People just want to feel heard. Show up to listen, zoom out to be strategic, think about the mission.
People just want to feel heard. Show up to listen, zoom out to be strategic, think about the mission.
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In an ideal org, we wouldn't need to be 'speed bumps.' But in my experience, the 'Scope Creep Bogeyman' isn't imaginary—it is often the #1 cause of team burnout.The intent wasn't to glorify 'Slack Management,' but to acknowledge that in 2026, that is the battlefield where a manager often has to stand between their team and a chaotic environment. It's ugly work, but someone has to be the shield.
The intent wasn't to glorify 'Slack Management,' but to acknowledge that in 2026, that is the battlefield where a manager often has to stand between their team and a chaotic environment. It's ugly work, but someone has to be the shield.
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The junior dev is watching, and got the benefit of seeing that you value his time> managing via SlackFar preferable to arranging a face to face meeting over this low impact, simple procedural issue> being a speed bump just becauseDefending your team's finite attention and time from random direct requests from the business is a major part of your job as an EM.> "scope creep" bogeymanThere's good reason scopes are defined and communicated, and deadlines and expectations are managed.
> managing via SlackFar preferable to arranging a face to face meeting over this low impact, simple procedural issue> being a speed bump just becauseDefending your team's finite attention and time from random direct requests from the business is a major part of your job as an EM.> "scope creep" bogeymanThere's good reason scopes are defined and communicated, and deadlines and expectations are managed.
Far preferable to arranging a face to face meeting over this low impact, simple procedural issue> being a speed bump just becauseDefending your team's finite attention and time from random direct requests from the business is a major part of your job as an EM.> "scope creep" bogeymanThere's good reason scopes are defined and communicated, and deadlines and expectations are managed.
> being a speed bump just becauseDefending your team's finite attention and time from random direct requests from the business is a major part of your job as an EM.> "scope creep" bogeymanThere's good reason scopes are defined and communicated, and deadlines and expectations are managed.
Defending your team's finite attention and time from random direct requests from the business is a major part of your job as an EM.> "scope creep" bogeymanThere's good reason scopes are defined and communicated, and deadlines and expectations are managed.
> "scope creep" bogeymanThere's good reason scopes are defined and communicated, and deadlines and expectations are managed.
There's good reason scopes are defined and communicated, and deadlines and expectations are managed.
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The only way to get "perfect rating" is to go to your junior dev and bring another interruption (maybe the dev was 90% done !). So now he has been interrupted twice by two different manager and you have contradicted your own boss in front of an employee. You just broke a cardinal rule of middle management: it's ok to tell your boss he is wrong, but not in front of someone else.
Additionally, you also need to tell him to f** off with is request to get the numbers (without even trying to understand if the request was legitimate or not !), so that your precious sprint is saved. I don't see how he gets what he wants in your ideal handling. AT best you seem to tell him you will "look into it" in two weeks.Much better solution is to help you junior dev solve the problem so the interruption goes away as fast as possible and he can go back to contributing to the sprint. If the VP requires these numbers and went as far as back channeling you there is probably a quite good reason for that. Maybe the last time he needed something you told him it was not possible because the sprint thingy is unmovable ?
Once you have the result, you can go give those to the VP yourself, highlight the work of the junior dev, and use this "I am giving you the very important data you asked for" as a foot in the door to show that you had to pull the dev from the other feature, that these interruption also have cost and that you are more than happy to take care of them. He gets what he wants, the difficult conversation of "you did not do what you are supposed to do" happens behind closed doors, and you have a much better of getting results if he sees you as an ally to get his important stuff rather than a hinderance.
Much better solution is to help you junior dev solve the problem so the interruption goes away as fast as possible and he can go back to contributing to the sprint. If the VP requires these numbers and went as far as back channeling you there is probably a quite good reason for that. Maybe the last time he needed something you told him it was not possible because the sprint thingy is unmovable ?
Once you have the result, you can go give those to the VP yourself, highlight the work of the junior dev, and use this "I am giving you the very important data you asked for" as a foot in the door to show that you had to pull the dev from the other feature, that these interruption also have cost and that you are more than happy to take care of them. He gets what he wants, the difficult conversation of "you did not do what you are supposed to do" happens behind closed doors, and you have a much better of getting results if he sees you as an ally to get his important stuff rather than a hinderance.
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If it is in a deep political institution these are the initial set of questions I would start with:Who is the Jr to the the VP, what are their relation ? How is your Jr to the manager ? How is the manager relation to the VP? How respectful to boundaries the VP is to the boundaries? How likely is for him to repeat or to get you shoved out the way next time ? How much do you care about being put astray in comparison to the quality of overall work ? How many times this has occurred before ? How likely is for the Jr to bypass you anyway ?And as one can see, this is just too much to bother with. Sometimes it is easier to cry out that you need more money and or time.I would do the same by the way. Make the distraction go away and try to put things back into the process route. If the process does not work and this is constant there is no reason to tell the person that pays you that they are always wrong.
Who is the Jr to the the VP, what are their relation ? How is your Jr to the manager ? How is the manager relation to the VP? How respectful to boundaries the VP is to the boundaries? How likely is for him to repeat or to get you shoved out the way next time ? How much do you care about being put astray in comparison to the quality of overall work ? How many times this has occurred before ? How likely is for the Jr to bypass you anyway ?And as one can see, this is just too much to bother with. Sometimes it is easier to cry out that you need more money and or time.I would do the same by the way. Make the distraction go away and try to put things back into the process route. If the process does not work and this is constant there is no reason to tell the person that pays you that they are always wrong.
And as one can see, this is just too much to bother with. Sometimes it is easier to cry out that you need more money and or time.I would do the same by the way. Make the distraction go away and try to put things back into the process route. If the process does not work and this is constant there is no reason to tell the person that pays you that they are always wrong.
I would do the same by the way. Make the distraction go away and try to put things back into the process route. If the process does not work and this is constant there is no reason to tell the person that pays you that they are always wrong.
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You are absolutely right that contradicting the VP in front of the Junior Dev breaks the 'United Front' rule.This highlights a key point: I built this to teach transferable heuristics (e.g., 'Protect the team'), not to be a rigid playbook. In real life, specific contexts (like 'Is the VP usually reasonable?') often override the default rule.Your approach—facilitate the request to clear the distraction, then negotiate boundaries in private—is a more sophisticated heuristic than the one I initially coded. It trades short-term sprint purity for long-term political capital.I love this. I'm going to add your 'Shield & Deliver' path as an alternative (and perhaps superior) winning state. This is exactly the nuance I wanted to surface.
This highlights a key point: I built this to teach transferable heuristics (e.g., 'Protect the team'), not to be a rigid playbook. In real life, specific contexts (like 'Is the VP usually reasonable?') often override the default rule.Your approach—facilitate the request to clear the distraction, then negotiate boundaries in private—is a more sophisticated heuristic than the one I initially coded. It trades short-term sprint purity for long-term political capital.I love this. I'm going to add your 'Shield & Deliver' path as an alternative (and perhaps superior) winning state. This is exactly the nuance I wanted to surface.
Your approach—facilitate the request to clear the distraction, then negotiate boundaries in private—is a more sophisticated heuristic than the one I initially coded. It trades short-term sprint purity for long-term political capital.I love this. I'm going to add your 'Shield & Deliver' path as an alternative (and perhaps superior) winning state. This is exactly the nuance I wanted to surface.
I love this. I'm going to add your 'Shield & Deliver' path as an alternative (and perhaps superior) winning state. This is exactly the nuance I wanted to surface.
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I would be wary of this being the superior winning state, but definitely an alternative. I've done exactly this in my career as a tech lead only for it to burn me, and probably 2/3rds of the time the best thing for everyone is to simply "Save the Sprint" and not become mired in discussions that often are for personal empire building that strategic leadership would hate.Maybe people have different experiences than me on this, feel free to speak up!
Maybe people have different experiences than me on this, feel free to speak up!
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You are absolutely right. If you 'Shield & Deliver' every time, you risk becoming the 'Yes Man' who absorbs infinite scope creep for someone's vanity project (Empire Building).The 'Correct' answer actually depends entirely on the Nature of the Request:
Legitimate Business Crisis? -> Shield & Deliver
Noise/Politics? -> Save the SprintDistinguishing between the two before you act is the master skill.
I think keeping both paths as valid strategies with different 'Trade-off' warnings or having 2 different contexts is the right move to reflect that ambiguity
The 'Correct' answer actually depends entirely on the Nature of the Request:
Legitimate Business Crisis? -> Shield & Deliver
Noise/Politics? -> Save the SprintDistinguishing between the two before you act is the master skill.
I think keeping both paths as valid strategies with different 'Trade-off' warnings or having 2 different contexts is the right move to reflect that ambiguity
Distinguishing between the two before you act is the master skill.
I think keeping both paths as valid strategies with different 'Trade-off' warnings or having 2 different contexts is the right move to reflect that ambiguity
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Eeeehhh, might be overestimating executives a bit =PBut yeah, my first instinct is also to tell Gary to fuck off. That said, I would default to a process reason, so, the advice at the end wasn't totally useless for me.
But yeah, my first instinct is also to tell Gary to fuck off. That said, I would default to a process reason, so, the advice at the end wasn't totally useless for me.
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And I'm with you—my default instinct is also to tell Gary to back off using a Process Reason (e.g. 'It's not in the sprint'). It feels safe because it's logical.The 'Advice at the end' was just trying to highlight why that specific shield often cracks against a VP (because they think they own the process). Glad that specific breakdown was useful to read, even if the scenario felt a bit generous to the exec!Again, it also depends on who "Gary" is in the real world!
The 'Advice at the end' was just trying to highlight why that specific shield often cracks against a VP (because they think they own the process). Glad that specific breakdown was useful to read, even if the scenario felt a bit generous to the exec!Again, it also depends on who "Gary" is in the real world!
Again, it also depends on who "Gary" is in the real world!
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Meanwhile there are five other subordinates and all the overhead that you're neglecting while you fiddle with your dev environment trying to get started on the task, as you've been away from direct engineering for a while.
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This is good intuition but generally people won't tell you whether they have a good or silly/self-serving reason in my experience, and you can only really get them to surface that by comparing it to the priority of other commitments and forcing them to depriotize something.I think the ratings might be a bit borked. There's a dialogue path choice that results in the A+ where you end up asking directly whether the back-channel was worth another delay, and you. The VP says no. No junior gets interrupted.
I think the ratings might be a bit borked. There's a dialogue path choice that results in the A+ where you end up asking directly whether the back-channel was worth another delay, and you. The VP says no. No junior gets interrupted.
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Sometimes you don't even need to surface it. You just force responsibility: “This will prevent us from being ready for Friday's demo. If you're cool with that I'll run it by {project sponsor}.”Now it's between the VP and the project sponsor - as it rightfully should be.
Now it's between the VP and the project sponsor - as it rightfully should be.
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I wish there was a bit more context about the overall status of the project - yes it is a risk to ask a dev to context switch, but it is also a risk to deny a trivial request from Gary. If Gary has a meeting with the client later and it goes poorly, that could be in part because of the lack of flexibility of the team to meet Gary's needs. If Gary is a bad leader, he's going to be doing a lot of fly-bye requests. If he is a good leader, he'll do it when it is truly necessary. In my view, writing and running a SQL query should be a quick an easy task even for a Jr Dev. At the end of a sprint, there should be plenty of things to demo even if search doesn't make it into this sprint. Also, I'm a firm believer in natural consequences - if Gary can be made aware of the consequences of bypassing the tech lead, he learns the hard way that it needs to be worth it.
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For people looking to transition to management, one thing I've learned is that a big part of my job is getting everyone to do only one thing at a time. Every stakeholder (including engineering managers) are obsessed with the idea of “sneaking a bit more work in,” and I've never seen it work. I will actually go as far as to refuse to estimate work if I have something more important for the team to focus on. After all, estimation is work and we have a higher priority!The benefit is that you'll often find nobody actually estimated the business value/priority before asking for the work estimate, so you end up wasting less time overall. The hard part is resisting the pull of your boss asking you to do something.
The benefit is that you'll often find nobody actually estimated the business value/priority before asking for the work estimate, so you end up wasting less time overall. The hard part is resisting the pull of your boss asking you to do something.
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You really highlighted the core tension here: The theory of management (WIP limits, focus) is logical and easy to understand. But the practice—actually looking at your boss in the eye and saying 'No, we won't even estimate that right now'—is pure emotional friction.That specific 'hard part' you mentioned—resisting the pull of authority—is exactly the muscle I'm trying to help people build without burning bridges.
It's the difference between knowing the rule and having the stomach to enforce it in a balanced way.
That specific 'hard part' you mentioned—resisting the pull of authority—is exactly the muscle I'm trying to help people build without burning bridges.
It's the difference between knowing the rule and having the stomach to enforce it in a balanced way.
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Also, you're commiting the team to deliver something you (probably) don't have the technical knowledge to estimate, so you might be adding another week of death March after just 1 weekend.The lesson at the end is not wrong, but the characters don't seem realistic.That said, I have always been IC for a reason, so what do I know.
The lesson at the end is not wrong, but the characters don't seem realistic.That said, I have always been IC for a reason, so what do I know.
That said, I have always been IC for a reason, so what do I know.
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You are spot on about the risk: Promising a 'Soul Update' without consulting the team is essentially writing a blank check that Engineering has to cash. As an IC, you are right to call that out—it's a dangerous move.Why I wrote the 'Winning' path that way: In my experience, Founder objections are often 50% about the product and 50% about anxiety. They threaten to 'lose the 50k' because they are scared of a flop. The 'Ship + Fast Follow' strategy works because it addresses the anxiety without killing the momentum.On a lighter note: I definitely had a 'Steve Jobs' archetype in mind when writing that dialogue—hence the obsession with the product's 'Soul' over its metrics! Dealing with a visionary who ignores logic is a distinct skill set from dealing with a rational MBA type.
Why I wrote the 'Winning' path that way: In my experience, Founder objections are often 50% about the product and 50% about anxiety. They threaten to 'lose the 50k' because they are scared of a flop. The 'Ship + Fast Follow' strategy works because it addresses the anxiety without killing the momentum.On a lighter note: I definitely had a 'Steve Jobs' archetype in mind when writing that dialogue—hence the obsession with the product's 'Soul' over its metrics! Dealing with a visionary who ignores logic is a distinct skill set from dealing with a rational MBA type.
On a lighter note: I definitely had a 'Steve Jobs' archetype in mind when writing that dialogue—hence the obsession with the product's 'Soul' over its metrics! Dealing with a visionary who ignores logic is a distinct skill set from dealing with a rational MBA type.
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I call it "quitting".
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If there was a way to combine this with coaching sessions, I think this could be a very effective way to train IC's that are stepping into leadership roles (managers, staff/principal IC's, PM's, etc.). It could also be interesting to have a variant of the exercise where you ask the student/user to write their own message.
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You hit the nail on the head regarding coaching. I actually view this tool not as a replacement for coaching, but as the 'Lab Work' that happens between sessions.If a new manager can play the 'Firing' scenario 5 times at home and fail safely, they come to their coaching session with specific, high-quality questions rather than generic anxieties. It allows the human coach to focus on the nuance rather than the basics.Thanks for the feedback!
If a new manager can play the 'Firing' scenario 5 times at home and fail safely, they come to their coaching session with specific, high-quality questions rather than generic anxieties. It allows the human coach to focus on the nuance rather than the basics.Thanks for the feedback!
Thanks for the feedback!
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However, I won't pay for the course as I'm only an IC with no realistic path to management. But maybe "transitioning from IC to management" is too small of a niche for this product: sounds like it would be good for managers that want to improve: "strategies for management from an ex-developer" or something like that
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On the niche size: You make a great point. I targeted 'Transitioning' specifically because that's usually the moment of maximum pain (and imposter syndrome).Established managers often feel they've 'figured it out' (even if they haven't!). The transition window is where people are actively looking for a lifeline.But you're right—at the Staff/Principal IC level, a lot of this just becomes 'Managing Up.' Dealing with a Backchannel VP is a survival skill whether you manage people or just manage architecture!
Established managers often feel they've 'figured it out' (even if they haven't!). The transition window is where people are actively looking for a lifeline.But you're right—at the Staff/Principal IC level, a lot of this just becomes 'Managing Up.' Dealing with a Backchannel VP is a survival skill whether you manage people or just manage architecture!
But you're right—at the Staff/Principal IC level, a lot of this just becomes 'Managing Up.' Dealing with a Backchannel VP is a survival skill whether you manage people or just manage architecture!
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9/10 times the new manager is miserable and doesn't add anything to the employees' day to day aside from stressing about your next 1:1, and is then locked to that role for the duration.
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https://en.wikipedia.org/wiki/Kobayashi_MaruI've had the fortune to be able to steer my career back down to IC with no loss of income every time I have been pushed up into an EM role.Only one data point, but I'm 100% happier as IC than EM.
I've had the fortune to be able to steer my career back down to IC with no loss of income every time I have been pushed up into an EM role.Only one data point, but I'm 100% happier as IC than EM.
Only one data point, but I'm 100% happier as IC than EM.
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But there are other players who likes to trade it for Money!Thanks for sharing the Kobayashi Maru scenario though! Can use it as a fun simulation if someone fails all scenarios to make it light hearted yet meaningful.
Thanks for sharing the Kobayashi Maru scenario though! Can use it as a fun simulation if someone fails all scenarios to make it light hearted yet meaningful.
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I've been running these sorts of training exercises w gpt5 and it's been quite insightful. Not for mgmt but general senior-staff level communication. That even has flexibility to explain better context on my specific situation and role.I wouldn't pay $19 for this as it stands.
I wouldn't pay $19 for this as it stands.
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You nailed the trade-off. LLMs are incredible for open sparring, but they often work best if you already know the underlying principles to guide the roleplay.I view this tool as the 'Drills' to learn those heuristics, so you can then go to GPT and practice them with your specific context. Appreciate the honest signal on pricing.
I view this tool as the 'Drills' to learn those heuristics, so you can then go to GPT and practice them with your specific context. Appreciate the honest signal on pricing.
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I've temporarily disabled payments to be safe. You can drop your email on the waitlist https://forms.gle/HyPpz77T6yARoZVn7 and I'll send a discount code once I fix the plumbing. Sorry about that and thanks for notifying!
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Experience: I draw primarily from 14 years in product companies, focusing on the specific friction points where I've seen Leads struggle (or where I struggled myself).Vetting: I stress-test the dialogue options with a network of Engineering Managers and Directors to ensure the 'winning' paths reflect reality, not just theory.That said, unlike C++, management doesn't have a compiler to prove you are 'Correct.' It is subjective. The feedback in this thread is actually highlighting some edge cases I missed, which helps me refine the grading logic
Vetting: I stress-test the dialogue options with a network of Engineering Managers and Directors to ensure the 'winning' paths reflect reality, not just theory.That said, unlike C++, management doesn't have a compiler to prove you are 'Correct.' It is subjective. The feedback in this thread is actually highlighting some edge cases I missed, which helps me refine the grading logic
That said, unlike C++, management doesn't have a compiler to prove you are 'Correct.' It is subjective. The feedback in this thread is actually highlighting some edge cases I missed, which helps me refine the grading logic
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When we setup our sprint goals we would have built in time to handle random requests aannddd I would have kept in good grace with the vp so that he knows were on the same team even if I say no to the request.Also, how I respond depends on why the vp decided to backchannel me. If they did because they didnt care about our teams goals (and only theirs) then I might need to escalate to their management to set clear boundaries. If they did so because in the past I forgot about their requests, then I probably need to not forget about their requests.If they are clearly not looking out for our shared interest (or that of the company) and instead only worried about themselves, maybe slightly narcissistic then Im going to respond in a different tone than if they made a genuine mistake.
Also, how I respond depends on why the vp decided to backchannel me. If they did because they didnt care about our teams goals (and only theirs) then I might need to escalate to their management to set clear boundaries. If they did so because in the past I forgot about their requests, then I probably need to not forget about their requests.If they are clearly not looking out for our shared interest (or that of the company) and instead only worried about themselves, maybe slightly narcissistic then Im going to respond in a different tone than if they made a genuine mistake.
If they are clearly not looking out for our shared interest (or that of the company) and instead only worried about themselves, maybe slightly narcissistic then Im going to respond in a different tone than if they made a genuine mistake.
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Was there a specific turn in the conversation where you really wanted to just give a hard 'No' or call them out, but felt restricted by the choices?
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I'm not a manager and have no interest in becoming one but I have often wondered what is going through a manager's head when they cave to egregious horseshit from executives. I find this simulation really interesting and maybe it might help me empathize my manager more.
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"Political capital" is irrelevant and only exists when we permit it to exist.
1. If the junior dev is really that critical for a large project for some bizarre reason (fix that next time), tell Gary he's critical to that and say you can realloc ppl to cover or do this task under a 1hr time limit if it's urgent (if exceeds then kill the task).
2. Say to Gary next time let me know directly rather than dm someone on the team so you can route it to the right person (buys trust, covers team).
3. Renewal of BigCo is important to the biz. You should have some room to accommodate requests like these without being a stone to adhoc requests. It will not buy you or your team favour at all. Remember, this is a startup!
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This highlights a key distinction: The simulator is designed to teach heuristics (e.g., 'Default to protecting the team'), not a rigid playbook. In a real startup, specific contexts (like 'BigCo Renewal') often override the default heuristic.You nailed three critical nuances that the default path glossed over:Bus Factor: If the Junior is the only one who can pull the data, that's an engineering failure on my part.Business Alignment: In a startup, 'Revenue' > 'Sprint Integrity.' Being a 'stone' to revenue-critical requests is a fast way to lose influence.The Middle Path: Your suggestion (Timebox/Reallocate) is the advanced move. It solves the VP's pain without wrecking the sprint.Thanks for adding this perspective—it shows exactly where 'Best Practice' meets reality.
You nailed three critical nuances that the default path glossed over:Bus Factor: If the Junior is the only one who can pull the data, that's an engineering failure on my part.Business Alignment: In a startup, 'Revenue' > 'Sprint Integrity.' Being a 'stone' to revenue-critical requests is a fast way to lose influence.The Middle Path: Your suggestion (Timebox/Reallocate) is the advanced move. It solves the VP's pain without wrecking the sprint.Thanks for adding this perspective—it shows exactly where 'Best Practice' meets reality.
Bus Factor: If the Junior is the only one who can pull the data, that's an engineering failure on my part.Business Alignment: In a startup, 'Revenue' > 'Sprint Integrity.' Being a 'stone' to revenue-critical requests is a fast way to lose influence.The Middle Path: Your suggestion (Timebox/Reallocate) is the advanced move. It solves the VP's pain without wrecking the sprint.Thanks for adding this perspective—it shows exactly where 'Best Practice' meets reality.
Business Alignment: In a startup, 'Revenue' > 'Sprint Integrity.' Being a 'stone' to revenue-critical requests is a fast way to lose influence.The Middle Path: Your suggestion (Timebox/Reallocate) is the advanced move. It solves the VP's pain without wrecking the sprint.Thanks for adding this perspective—it shows exactly where 'Best Practice' meets reality.
The Middle Path: Your suggestion (Timebox/Reallocate) is the advanced move. It solves the VP's pain without wrecking the sprint.Thanks for adding this perspective—it shows exactly where 'Best Practice' meets reality.
Thanks for adding this perspective—it shows exactly where 'Best Practice' meets reality.
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I wanted to pre-order, but the link doesn't let me.
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On the Pre-order: I'm sorry about that! The payment gateway is currently stuck in 'Verification Pending' (bad timing with the HN hug).I've set up a temporary waitlist here: https://forms.gle/UhRNLqbaHQfjiS8V8If you drop your email there, I'll ping you as soon as payments are live (and I'll send a discount code as an apology for the friction!)
I've set up a temporary waitlist here: https://forms.gle/UhRNLqbaHQfjiS8V8If you drop your email there, I'll ping you as soon as payments are live (and I'll send a discount code as an apology for the friction!)
If you drop your email there, I'll ping you as soon as payments are live (and I'll send a discount code as an apology for the friction!)
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As someone about to step into a C-suite role: I picked the "correct" path and as long as people are reasonable, it works well.
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That caveat—'as long as people are reasonable'—is the biggest variable in the equation. The real challenge is sticking to that correct path when the other side acts irrationally.Good luck with the new role!
Good luck with the new role!
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Sufficiently powerful AI can become the middle manager of everyone's dreams. Wonderfully effective interpersonal skills, no personality defects. Fair and timely feedback.Try to convince me this isn't the case.
Try to convince me this isn't the case.
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:-)Where is the AI going to get the information required to do the job?How is the AI going to notice that Bob looks a bit burnt out, or understand which projects to work on/prioritise?Who is going to set the AI managers objectives? Are they simple or are they multi-factorial and sometimes conflicting? Does the objective function stay static over time? If not how is it updated?How are you going to download all the historic experience of the manager to the AI or are they just going to learn on the job.What happens when your manager AI starts talking to another teams manager AI? Will you just re-invent office politics but in AI form? Will you learn how to game your AI manager as you understand and potentially control all it's inputs?
Where is the AI going to get the information required to do the job?How is the AI going to notice that Bob looks a bit burnt out, or understand which projects to work on/prioritise?Who is going to set the AI managers objectives? Are they simple or are they multi-factorial and sometimes conflicting? Does the objective function stay static over time? If not how is it updated?How are you going to download all the historic experience of the manager to the AI or are they just going to learn on the job.What happens when your manager AI starts talking to another teams manager AI? Will you just re-invent office politics but in AI form? Will you learn how to game your AI manager as you understand and potentially control all it's inputs?
How is the AI going to notice that Bob looks a bit burnt out, or understand which projects to work on/prioritise?Who is going to set the AI managers objectives? Are they simple or are they multi-factorial and sometimes conflicting? Does the objective function stay static over time? If not how is it updated?How are you going to download all the historic experience of the manager to the AI or are they just going to learn on the job.What happens when your manager AI starts talking to another teams manager AI? Will you just re-invent office politics but in AI form? Will you learn how to game your AI manager as you understand and potentially control all it's inputs?
Who is going to set the AI managers objectives? Are they simple or are they multi-factorial and sometimes conflicting? Does the objective function stay static over time? If not how is it updated?How are you going to download all the historic experience of the manager to the AI or are they just going to learn on the job.What happens when your manager AI starts talking to another teams manager AI? Will you just re-invent office politics but in AI form? Will you learn how to game your AI manager as you understand and potentially control all it's inputs?
How are you going to download all the historic experience of the manager to the AI or are they just going to learn on the job.What happens when your manager AI starts talking to another teams manager AI? Will you just re-invent office politics but in AI form? Will you learn how to game your AI manager as you understand and potentially control all it's inputs?
What happens when your manager AI starts talking to another teams manager AI? Will you just re-invent office politics but in AI form? Will you learn how to game your AI manager as you understand and potentially control all it's inputs?
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Managing is about building relationships to coordinate and prioritize work and even though LLMs have excellent soft skills, they can't build relationships.
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Have you tried AI to convince you otherwise?
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Linking Marshall Brain's ever-relevant novella "Manna" on this: https://marshallbrain.com/manna1
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The missing piece wasn't intelligence, but statefulness and emotional memory.A human manager (or VP) remembers that you embarrassed them in a meeting three weeks ago, and that hidden state dictates their reaction today. LLMs—currently—are too 'forgiving' and rational. They don't hold grudges or play power games naturally.Until AI can simulate that messy, long-term 'political capital' (or lack thereof), I think we still need humans to navigate other humans. But I agree, for pure PR review and logical feedback, I'd take an AI manager any day!
A human manager (or VP) remembers that you embarrassed them in a meeting three weeks ago, and that hidden state dictates their reaction today. LLMs—currently—are too 'forgiving' and rational. They don't hold grudges or play power games naturally.Until AI can simulate that messy, long-term 'political capital' (or lack thereof), I think we still need humans to navigate other humans. But I agree, for pure PR review and logical feedback, I'd take an AI manager any day!
Until AI can simulate that messy, long-term 'political capital' (or lack thereof), I think we still need humans to navigate other humans. But I agree, for pure PR review and logical feedback, I'd take an AI manager any day!
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Amazon is rolling out a Fire TV redesign that puts more focus on the content, while also simplifying the navigation and layout. The update represents the first major Fire TV release in years from a user experience perspective, the company says, and is accompanied by a refreshed version of the Fire TV app and the arrival of new premium Fire TV televisions with colorful frames.
The company saw the need for a change to the Fire TV's look and feel as the amount of streaming content has exploded over the years. Fire TV customers today can access TV and movies via purchases, rentals, and streaming services, but also have apps for viewing short-form content on the TV, access to numerous live TV streams, premium content, podcasts, music, games, and more.
“As we brought that content forward, the [user interface] got a little cluttered — a lot of stuff and a lot of rows,” explained Fire TV VP Aidan Marcuss in an interview with TechCrunch. “We know the data — there's a lot of time spent searching,” he added. “We…know that it could just be easier.”
The new user interface features several design changes, including rounded corners, varied gradients, consistent typography, and increased spacing between content to make the interface feel less cluttered. While you can still scroll down to see your favorite rows, like what's up next, you can also see your apps in an expanded horizontal row.
Before, you could only pin six apps to the Fire TV's home screen — a common user complaint. But the update has reduced the app icons' size, allowing more to be visible on the home screen, and offers you 20 app slots you can scroll through.
At the top of the screen, navigation has been simplified into obvious categories like Movies, TV, Live TV, Sports, and News. A search button is available to the left of the Home tab.
Across the new tabs, Fire TV centralizes access to the content you're already watching, and what's available across services you're subscribed to. It also offers you the ability to discover new content, including recommended movies or shows (in rows labeled “For You”), free movies you can stream, lists of the top movies or shows, and other subscription content you may want to try.
These pages don't offer infinite scrolling, but they're lengthy as they represent the depth of content available on streaming services.
The new live TV tab organizes the live content from the services that have live TV streams built into them, plus broadcast or cable TV, if you happen to subscribe. The sports section, more specifically, includes access to the live games that are on now and other scheduled sports content.
Other TV features are tucked away under the three-line hamburger menu icon, like Games, Art & Photos, the Appstore, Music Video & Audio, a now-universal watchlist (“My Stuff”), Settings, and other options.
To make it easier to access commonly used settings, you can also now long-press on the Home button to adjust settings for the display and audio, set a sleep timer, use accessibility features, access smart home features, and more. From this panel, you can do things like adjust the TV brightness, boost the audio dialogue, or display your Ring camera's feed on screen while you watch, among other things.
The redesign also includes rewritten code that makes the interface move faster on some devices, Amazon claims.
“On our most popular devices, this is 20% to 30% faster for the same functions, because it's all about getting people to what they want to watch, fast,” notes Marcuss.
Of course, Alexa+ access is built in, allowing users to ask questions, find content, or even do things like call an Uber. This AI-powered assistant allows users to ask questions in natural language, refine their queries as they chat, ask follow-ups, and use visual context. For instance, you could say, “Tell me more about that one,” when you have a movie or TV show's square tile selected on screen. You could even ask questions with some nuance, like “find me more movies that have the same look,” or have it help you find photos or art.
Alexa+ will be available as an add-on subscription after it exits its early access phase (which currently requires opting in). The AI service will also be included with a Prime subscription.
The Fire TV app, meanwhile, was also updated to offer the classic remote control combined with a new way to discover new content. The idea is that people may want to browse for something to watch on their phones instead of just having one person drive the content discovery and search experience with the remote.
The refreshed Fire TV interface and mobile app will begin rolling out in February on the Fire TV Stick 4K Plus, Fire TV Stick 4K Max (2nd Gen), and Fire TV Omni Mini-LED Series in the U.S.
Later this spring, the redesign will come to more countries and more devices, including Fire TV Cube (3rd Gen), the latest generation Fire TV 2-Series, Fire TV 4-Series, Fire TV Omni QLED Series, and TVs made by partners like Hisense, Panasonic, and TCL.
It will also be available at launch on the new Amazon Ember Artline TVs (see below).
The Ember Artline TVs are Amazon's latest televisions that ship with a frame that can match your room's style and colors. They'll come in 55-inch and 65-inch options, starting at $899.
The new TVs themselves offer 4K QLED screens with 450 nits of brightness. The display is also thin, at one-and-a-half inches, and has a matte screen finish to reduce glare.
The TVs also support Dolby Vision, HDR10+, and Wi-Fi 6.
However, the big selling point is the 10 different frame options you can choose from, offering a variety of colors, textures, and geometries. This allows customers to take better advantage of Fire TV's Ambient features, which include displaying art when the TV is not in use.
The colors available include Walnut, Ash, Teak, Black Oak, Matte White, Midnight Blue, Fig, Pale Gold, Graphite, and Silver.
Fire TV comes with access to over 2,000 pieces of free art, or you can use your own photos.
You can also ask Alexa+ to display certain photos from your Amazon Photos collections using commands like, “Alexa, create a slideshow of our family trip to Colorado” or “Alexa, show photos from our wedding.”
Correction: An Amazon rep previously told us an incorrect figure for nits. It's a max 450 nits for the Artline TVs' brightness.
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Folding phones have been stuck in a rut for a few years. We've seen concept smartphones playing with fresh folding designs, but ever since Samsung kickstarted the trend in 2019, there have only really been two major styles in the market: a booklike fold and the flip. However, there's new life emerging in the category with significantly slimmer designs—such as last year's Samsung Galaxy Z Fold7—and now the company's “TriFold," a smartphone that can truly transform into a 10-inch tablet.
Samsung isn't the first to market with such a phone—Huawei takes that cake with the Mate XT—but the Galaxy Z TriFold has a slightly different design. It's only available in a handful of countries, like China, South Korea, and Singapore, but Samsung plans to release it in the US this year. The price? Samsung is being coy with the MSRP, but the price of 3,594,000 South Korean won suggests it'll cost around $2,500 in the US, if not more.
I was able to briefly spend some time with the triple-panel smartphone at CES 2026. Here's what it's like.
Folded and unfolded.
As the name suggests, Samsung's priciest folding phone opts for a trifold design, whereas Huawei's equivalent has a Z fold. I haven't used Huawei's version yet, but that does have a leg up: You can use one, two, or all three panels with its accordion-style design. The Galaxy Z TriFold only goes from a single panel to a triple panel.
As a single panel, the 6.5-inch front screen feels quite like a normal smartphone, albeit with thicker-than-usual bezels around the screen, and a weight of 309 grams that you'll have to get used to. Flip open the screen to the right, then flip the inner layer to the left, and you get a sprawling 10-inch display to work with. Keep in mind, the Galaxy Z Fold7 nets you an 8-inch screen, but that sounds like child's play next to the TriFold. It instantly feels more like an Android tablet than any other foldable Samsung has made before.
That's important because this tablet experience is the promise “book-like” folding phones have made for years, but the slight increase in screen real estate never yielded the same experience as a standard tablet. The TriFold changes that—the screen here is bigger than an iPad Mini! It feels like the actual definition of a phablet.
You can run three apps side-by-side, two apps at once, or one big app across the whole screen.
There are two titanium hinges, and they open up three panels. You can place a full-size app on each of the three panes, use a larger version of split-screen, or expand one app across the vast display. It was easy to configure these setups, and I can totally see myself taking advantage of having three apps open simultaneously. It is still a little unwieldy to hold, but that's not unusual for a 10-inch tablet. The TriFold is very slim in its unfolded state, which helps.
Fold it up and you're looking at a thickness of 12.9 millimeters, which is just a smidge chunkier than the Galaxy Z Fold6 (12.1 mm). The fact that it's roughly the same thickness as a prior-generation fold, yet with a dramatically larger screen, is impressive. It makes the bulk a little more palatable. There is a correct way to fold it and an incorrect way. Thankfully, if you start folding it the wrong way with the right screen in first, the phone violently buzzes, and you'll see an alert on the screen asking to fold in the other screen first. I can still picture someone ignoring this and just carrying on, though.
The hardware is exquisite, and the specs are top-notch, closer to the Samsung Galaxy S25 Ultra; there's a 200-megapixel main camera on the back, and the phone is powered by Qualcomm's Snapdragon 8 Elite. The displays are protected by ceramic glass, and there's even an IP48 dust- and water-resistance rating.
The TriFold's three panels tuck into each other.
You can see the difference in the two hinges.
But as exciting as it is, the TriFold is still a niche phone. Despite nearly a decade of folding phones, the prices for these handsets are still a premium, with Samsung even raising the MSRP of its folding devices in 2025. It is far cheaper to buy a decent tablet and a flagship phone. At a time of economic turmoil, the TriFold feels frivolous.
But it's hard not to feel impressed at this engineering marvel. It's just a shame that only a handful of people will really be able to enjoy this phablet's capabilities.
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The mission to boost refresh rates extends to AR glasses
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Xreal and Asus are two names that I never thought I'd see paired together in the same breath. However, that's precisely what's going on with the new ROG Xreal R1 augmented reality gaming glasses announced today at CES 2026.
Xreal is one of the most respected names in AR glasses, offering a wide range of products, including the Air 2, One, and One Pro. Asus has also experimented with AR, but we weren't impressed with the AirVision M1 glasses we sampled early last year. Will this new collaboration make the ROG Xreal R1 a better product? We hope so.
At its heart is an all-new, world-first 240 Hz Micro-OLED technology with 1920 x 1080 resolution. This provides wearers with a simulated 171-inch virtual viewing space for everything from productivity tasks to extreme gaming. The glasses also offer a wide 57-degree field of view and three degrees of freedom.
The ROG Xreal R1 uses the same X1 spatial coprocessor found in the Xreal One family of AR glasses, which powers the on-display controls and helps to reduce latency when using the 3 DoF features (i.e., anchoring the viewable image in place, or tracking the image with your head movements) and motion blur while gaming.
As with most AR glasses, the ROG Xreal R1 requires a single USB-C cable, providing plug-and-play support for a wide range of PCs, smartphones, and tablets. Asus also notes that the ROG Xreal R1 will work natively with its ROG Ally handheld gaming PC. Going from the built-in 7-inch display to a virtual 171-inch display using AR glasses that weigh just 91 grams should really up the stakes for mobile gaming.
But the ROG Xreal R1 won't just be limited to the ROG Ally; the optional ROG Control Dock features a DisplayPort 1.4 port and two HDMI 2.0 ports for connecting to a desktop PC, Nintendo Switch, Xbox Series X, or PlayStation 5 (among other devices).
To complete the gaming/entertainment aspect of the ROG Xreal R1, it features integrated speakers with Bose tuning. In addition, the ROG Xreal R1 features electrochromic lenses that automatically adjust transparency based on ambient light levels. If you don't want to use the automatic setting, there are also three user-selectable dimming modes.
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According to Asus, the ROG Xreal R1 will ship in the first half of 2026, but pricing hasn't been announced yet. However, for reference, the previous AirVision M1 glasses originally debuted at $699.
Brandon Hill is a senior editor at Tom's Hardware. He has written about PC and Mac tech since the late 1990s with bylines at AnandTech, DailyTech, and Hot Hardware. When he is not consuming copious amounts of tech news, he can be found enjoying the NC mountains or the beach with his wife and two sons.
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AI companies are turning to gas turbines to run their data centers without grid power.
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Facebook founder Mark Zuckerberg said in May 2024 that power will be one of the biggest factors that will constrain artificial intelligence, and, true enough, tech giants and hyperscalers have begun to hit power constraints. According to SemiAnalysis, electricity loads of tens of gigawatts have been requested in the state of Texas alone, but only a little over a gigawatt has received approval, signalling that the power grid may be stretched thin.
However, this doesn't mean that companies are ditching dreams of building massive AI data centers across the globe. Instead, they're looking at alternative power sources to bring their projects online, regardless of the availability of power from the grid.
This limitation has tech and power companies investing in small modular nuclear reactors (SMRs), which can potentially deliver large amounts of power in a relatively compact package. Microsoft has even recommissioned the old Three Mile Island nuclear power plant to deliver 819 MW of power for AI and cloud data center usage.
These initiatives will take years to take off, though. The Three Mile Island plant is expected to be operational only by 2028, while the earliest SMRs won't enter service until the 2030s. There has even been a proposal to use retired U.S. Navy reactors for data centers, but the project proponent hasn't offered a timeline for how quickly it could potentially get up and running.
Elon Musk was the first to use gas turbine generators to power a data center at this scale and duration at xAI's Memphis Supercluster. In 2024, the AI startup signed a 50-MW deal with the Tennessee Valley Authority (TVA), which only became operational months after.
Aside from the delay, this is nowhere near enough of the 155MW that the 100,000 H100 GPUs running on the site require. There was also a 150-MW substation under construction on the site, which also required additional setup. Waiting for these power sources to come online would have negated Musk's historic 19-day setup of an AI data center, so he turned to VoltaGrid to deliver the power he needed to run the Colossus site.
Just a few months later, OpenAI followed the billionaire's lead and ordered 29 gas turbines capable of producing 34MW each for its Stargate data center in Abilene, Texas. All these turbines would output a total of 986MW of power, which should be enough to run up to half a million GB200 NVL72 chips. So, even if the company fails to secure power from the grid, it can get the needed electricity from its own turbines.
Aside from these two, several other projects are going off-grid, with 62% of data centers considering on-site power generation, according to Data Center Knowledge. Furthermore, Natural Gas Intel estimated that data centers will use 35GW of behind-the-meter power by 2030.
This technique is crucial for the U.S.'s AI infrastructure to stay ahead, which is especially true as experts warn that China is miles ahead when it comes to electricity generation. Nvidia CEO Jensen Huang also reportedly commented that “China is going to win the AI race,” pointing directly toward power constraints as one of the reasons behind his statement.
While gas generators seem to be the silver bullet that will help solve the electricity supply puzzle many data centers face, it also comes with its own set of problems. Uptime is the principal issue among them, since data centers require near constant uptime reliability. To achieve this, data centers cannot just purchase the generators that can deliver the load they need; they need to build in redundancy.
AI data centers must have N+1 or N+1+1 redundancy to ensure continued operation, even if some fail. N+1 means that they must have a backup generator, which takes over should one fail during normal operations. Meanwhile, N+1+1 recommends having an additional power source on site as well as a backup, in case one of the generators in regular operation is in maintenance. As well as all of this, maintenance, spare parts, necessary personnel, and fuel also remain additional considerations.
Despite these challenges, it's estimated that AI data centers could generate $10 to $12 billion per gigawatt annually. Musk fired up the Colossus data center in July 2024, while the 150MW substation only delivered power to the site in November 2024. This meant that he could have made somewhere between $3 to $4 billion in revenue during that time, which likely would have offset the cost of running the entire site on natural gas turbines.
Another issue that data centers face is permitting requirements, which can take as long as a year or more. The OpenAI/Oracle site at Abilene, Texas, is reportedly facing delays because of this. Musk's Colossus 2 site mitigated the permit delay by building near the border of Tennessee and Mississippi, allowing him to hedge his bets by applying for permits from the two states and securing supply from both.
Aside from that, communities around these data centers might complain about the power plants they're putting up just to provide the power they need. xAI faced this exact issue, with residents complaining about the pollution generated by the gas turbines deployed around the Memphis site.
Though investors could throw unlimited amounts of money at the problem, there's another factor they cannot escape — long equipment lead times. It takes about 12 to 36 months before any of the gas turbine manufacturers can deliver them, especially as these are intricate machines that use highly specialized materials and require specific processes to manufacture.
These lead times could get longer, especially as more AI data centers are competing for the same amount of production capacity from these companies.
xAI contracted VoltaGrid to deliver power to its Memphis data center while it was waiting for a connection from the TVA. But even as the utility company finally delivered the 150MW it needed, some turbine generators remained on site as a backup to the system. This begs the question: should AI data centers rely entirely on their own power? VoltaGrid and other firms seem to think so, even going as far as offering “energy-as-a-service,” or EaaS, to AI companies.
This entails an extended power purchase agreement between the provider and the data center, wherein the former will deliver everything that the latter needs for their operation — from power capacity and day-to-day operations to maintenance and uptime reliability. However, even though this may be favorable in terms of deployment time, it will still get prohibitively expensive in the long run.
At the moment, AI companies rent gas generators for bridge power, allowing them to get their data center operations up and running as soon as possible while waiting for approval from the local utility. But when they finally connect their site to the grid, it's still often more economical to just keep these mobile generators as backup units in case their primary sources fail, not as their sole power source.
EaaS could possibly work as a permanent solution when the national electric grid is maxed out. When there is no more extra capacity to be had for power-hungry AI infrastructure, AI companies might have no choice but to rely on services like this just to get their projects up and running.
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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Knobs, steel mesh, and slat vents designed to angle airflow toward hot-running components
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System builder CyberPowerPC may be familiar to visitors to our Best Gaming PC guide, but it's not particularly known for PC cases — at least until now. The company's new MA-01, debuting at CES, is a striking “fishbowl” case with a curved glass front and component-hiding internal slats, for a clean modern aesthetic that, at least in its off-white colorway, reminds me of something straight out of Kubrick's 2001: A Space Odyssey, or perhaps the AI Mainframe room of the original 1979 Alien.
Aside from the light-colored version, the company says, there will also be a “Matte Satin Dark Steel Gray” variant, as well as a “Satin Metallic Dark Silver” version. Back-connector motherboards are supported in this ATX / Micro-ATX mid-tower case. And CyberPowerPC says this is the first case to use a woven steel mesh as its top ventilation, with variations in porosity, shape, and depth. This is said to cut high-frequency resonance, cutting exhaust noise by up to 30%. The default top mesh will be chrome, with a premium stainless steel option costing $249, rather than the $149 starting price.
Those swooping vent covers that run along the front side, bottom, and rear exhaust are also not just there to look pretty. They are angled to “redirect all intake airflow directly onto critical components,” keeping cool air from entering and immediately exiting the system without actually cooling much of anything.
Lighting is a key focus with the MA-01 case, in more ways than one. You'll find RGB in the fans and in a strip along the bottom, with a focus on indirect illumination, for a more subtle glow. And the three knobs on the side are for analog color control (the company also says this is a first, and I can't think of another case like it), so you can literally dial in the exact hue, brightness, and mode that you want, with knob presses activating secondary features.
There's certainly an argument to be made that RGB doesn't need that level of control. But I'd probably be far more likely to tweak the lighting on a case if I could just reach out and turn a knob rather than having to deal with clunky software. And having a button right there to turn off the lights when you want to watch a movie (or sleep) is certainly a welcome feature.
Other interesting features include design choices made to minimize screw and PCI bracket mounting points for a cleaner, minimal look, and a curved glass front so there is no corner seam obstructing your view. The glass does come in two pieces, though, so there is a seam not far from the front corner.
I also personally like the look of having the front ports (two USB-A, one USB-C, audio) on the front bottom, mirroring the knobs right around the corner, with orange accents tying them together. That said, the knob and port placement mean this case is solely designed to live on your desk. As someone whose 55-inch OLED TV takes up the entirety of their desk space, I'd like to see CyberPowerPC create a future variant with the knobs and ports up top.
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CyberPowerPC says the case should go on sale “early in Q1,” starting at $149 for versions with the steel woven mesh top, or $249 for versions with stainless steel mesh vents.
We'll be checking this case out in person at CES in Las Vegas and will update this story with photos and more details as we get them. We'll let you know if it looks as good in person as it does in renders. We also hope to get one in for review before it goes on sale. But given its innovations, good looks, and reasonable price (at least for the chrome models), this is a case to watch out for in 2026, and if its airflow and noise hold up to testing, it may wind up on our list of the best PC cases.
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After a rough start with the Mattel Aquarius as a child, Matt built his first PC in the late 1990s and ventured into mild PC modding in the early 2000s. He's spent the last 15 years covering emerging technology for Smithsonian, Popular Science, and Consumer Reports, while testing components and PCs for Computer Shopper, PCMag and Digital Trends.
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You can even overclock it via an app
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MSI's Lightning brand of GPUs have represented the company's highest-tier offerings, but they've been on a hiatus these past few generations. Fortunately, the iconic line-up is being revived with a new RTX 5090 Lightning, overtaking the Suprim X as MSI's flagship 5090 variant. While the card hasn't been officially shown off yet, a new CES Innovation Awards listing has unveiled much of the specifics.
I heard that there will be a thunderstorm tomorrow... 😏Stay tuned⚡#MSIxCES2026 pic.twitter.com/qU2meUD6kRJanuary 5, 2026
Before that, the company posted a teaser video on social media, confining the return of the Lightning brand and promising a proper announcement for tomorrow. We'll be sure to bring you exclusive coverage of MSI's RTX 5090 Lightning right from the show floor. Till then, a CES Innovation Awards page has already crowned this GPU as an honoree in "Gaming & eSports," along with unabashed praise for its extreme performance.
On the CES awards page, it mostly talks about the cards cooling prowess, "A next-generation pump optimizes flow dynamics, feeding MSI's patented hybrid-density radiator with zoned fin spacing for superior heat exchange. A silent, high-pressure axial fan with newly designed aerodynamic blades further boosts static pressure at low noise." The main takeaway is the mention of a "reinforced high-power PCB and premium VRM." This refers to an insane 40 power phases, higher than even Galax HOF 5090D's 36/38-phase VRM, capable of delivering up to 1600W of power via dual 12V-2x6 connectors.
Those will probably go well with MSI's new power supply promising to prevent your 5090's 16-pin connector from melting, a situation only exacerbated by having two of them. Evidently, we saw this GPU break world records just yesterday. There will also be a dedicated mobile app to take advantage of the card's unique design.
That transitions us nicely into aesthetics. Prior leaks have already shown us what the GPU looks like — it's a liquid-cooled card with the tubes protruding from the right side, connected to a 360mm radiator. There's a massive screen on one side of the card, and the CES page notes that it can display real-time system visualizations and a companion app enables users to monitor and tweaking overclock settings on the go. The teaser MSI shared also features quick glances at the fans on that aforementioned rad. As you'd expect, the design language leans heavily into a gaming aesthetic, with sharp lines and tasteful RGB accents all around.
At the core (no pun intended), it's still an RTX 5090 so expect all the same specs, just turned up a notch due to the extra overclocking headroom. Reports of a monstrous 2500W XOC BIOS are also floating around, suggesting a new enthusiast champ in the industry. Unfortunately, that same industry is currently navigating a memory crisis, so the 32 GB of GDDR7 VRAM onboard might hike up the card's price even more.
That's not to say it was ever going to be cheap without it. Make no mistake — we're looking at $4,000+ here since this card competes with (and surpasses, in most aspects) the ROG Matrix Platinum RTX 5090, which did retail for $4,000, and that came out before the DRAM shortage took effect. Therefore, availability might become another concern, but seeing how this GPU will only be targeted at extreme overclockers, inventory probably won't be an issue.
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Hassam Nasir is a die-hard hardware enthusiast with years of experience as a tech editor and writer, focusing on detailed CPU comparisons and general hardware news. When he's not working, you'll find him bending tubes for his ever-evolving custom water-loop gaming rig or benchmarking the latest CPUs and GPUs just for fun.
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Father Mike Schmitz, a Catholic priest and podcaster, addressed his congregation of more than 1.2 million YouTube subscribers in November with an unusual kind of homily. You couldn't always trust the words coming out of his mouth, Schmitz said, because sometimes they weren't really his words—or his mouth. Schmitz had become the target of AI-generated impersonation scams.
“You're being watched by a demonic human,” said the fake Schmitz in one video that the real Schmitz, wearing an L.L. Bean jacket over his clerical suit, included in his public service announcement as an example. “You must act quickly, because the spots for sending prayers are already running out,” said another fake Schmitz with a looming hourglass behind him. “And the next trip will only take place in four months.” The fake Schmitz sounded ever-so-slightly robotic as he urged viewers to click a link and secure their blessing before it was too late.
“I can look at them and say ‘That's ridiculous, I would never say that,'” the real Schmitz, who is based in Duluth, Minnesota, said in his callout video. “But people can't necessarily tell. That's a problem. That's, like, a really big problem.”
On the real video of Schmitz, some of the top comments from his followers said they had seen other prominent Catholic figures impersonated through AI videos, including the pope. According to cybersecurity expert Rachel Tobac, who is the CEO of SocialProof Security, that's because pastors have become extremely popular subjects of AI scams and other deceptive media.
“If you're on TikTok or Reels, they've probably come across your For You page,” Tobac says. “This is somebody who looks to be a priest, who's wearing all of the garments, who's standing up on a pulpit or a stage or whatever you'd call it, and they seem to be speaking to their congregation in a very enthusiastic way.”
Pastors and ministers in Birmingham, Alabama, Freeport, New York, and Fort Lauderdale, Florida, have warned their followers about AI scams impersonating them in the form of DMs, calls, and deepfakes. Alan Beauchamp, a pastor in the Ozarks, said his Facebook account was hacked, with the hacker posting a fake, possibly AI-generated certificate for cryptocurrency trading with Beauchamp's name on it and a caption urging his congregants to join him. A megachurch in the Philippines received reports of deepfakes featuring its pastors. An evangelical church in Nebraska issued an AI “scammer alert” on Facebook, and one churchgoer in the comments posted a screenshot of texts purported to be from one of their pastors.
It doesn't help that a lot of the pastors and ministers who have grown large online followings often actually are soliciting donations and selling things, just not the same things that their AI impersonators are. With the help of social media, religious authority figures have been able to reach believers far beyond their neighborhoods, but the proliferation of content featuring their likenesses and voices has also provided the perfect opportunity for scammers wielding generative AI tools.
“You get a phone call that sounds like the pastor or a board member, someone who has been on livestreams every week, and their voices can be sampled and put into AI,” said a member of ChurchTrac, a church management software company based in Florida, in a YouTube video warning about the rise of AI scams targeting churches. “The scammer can use that voice and call into a church and say ‘Hey, would you transfer this fund to this account?'”
When searching Father Schmitz on TikTok, WIRED found that three of the fake accounts Schmitz had shown in his video were still active, though it wasn't immediately clear whether the videos they posted were AI or just clips pulled from Schmitz's real social media profiles. There are more than 20 accounts on TikTok posing as Schmitz, who doesn't have a verified account of his own on the platform. Schmitz didn't respond to a request for comment, while TikTok removed the fake Schmitz accounts after WIRED pointed them out to the company, citing its rules against impersonation.
Scams aren't the only example of AI imitating pastors. Tobac has come across viral short-form AI videos that feature pastors who don't appear to be based on a specific individual but quickly rack up views because of how unexpected their sermons are. In one TikTok she shared with WIRED, which has over 11 million views, a pastor yells furiously into a crowd, hands gripping the sides of his pulpit: “Billionaires are the only minority we should be scared of! They got the power to destroy this country! They don't need your protection! They need your accountability!”
The TikTok account that posted it, Guided in Grace, has the bio “Using AI to show a parallel universe.” But the video caption doesn't indicate it's AI-generated. It says, “Meanwhile in my conservative grandma's church this morning …” Most of the comments are treating it like it's real. “Me being shocked that a Christian is being an ACTUAL Christian,” reads one. “Ooohh, they serving Jesus: original flavor,” says another.
“We don't know who's creating this, we don't know what their goals are, but it seems to be to try to influence the way that people think,” Tobac said. All of the videos on the AI pastor TikTok account were posted in October, at the same time that Sora-generated videos of the influencer Jake Paul were gaining over a billion views. But while viral fake Paul videos were instantly recognizable to anyone familiar with his usual demeanor, a fake nondescript pastor has an easier time avoiding suspicion and gaining a different kind of influence in the process.
“When you see someone who's high up in say, the church, espouse a specific belief, we ascribe meaning and value and power to that statement in a way that's different than an influencer,” Tobac said. She also pointed out that the accounts like the AI pastor could be monetized through TikTok's Creator Fund. “If you can go viral quickly, if you can get a lot of views, you are given more money.”
The same incentives driving TikTok creators to dabble in AI media may also be driving churches to do the same. In September, a church in Dallas, Texas, showcased AI-generated videos of the slain conservative activist Charlie Kirk speaking about Christ from beyond the grave. According to a 2025 report from a company that is promoting the use of AI by church leaders, a majority of pastors surveyed said they are already using tools like ChatGPT and Grammarly to help prepare their sermons. And chatbots that purport to allow users to chat with God, Jesus, and all manner of religious figures are flourishing.
While some faith leaders have rapidly warmed to religious AI, industry watchdogs like Tobac and Lucas Hansen, who cofounded the AI education nonprofit CivAI, remain concerned about users of the technology experiencing severe mental health consequences as a result. In October, OpenAI reported that hundreds of thousands of ChatGPT users may show signs of psychosis and other mental health issues in their chatbot conversations every week. Some of those delusions can be religious in nature.
“I think there might end up being a fair number of people that think that God is using AI as a tool to communicate with them. I think we're already seeing a little bit of that,” Hansen says. “AI tries to figure out what the user would like to be true and then reinforces that. Those people that perhaps are slightly predisposed to these sorts of issues get those beliefs reinforced.”
For priests and pastors who have already been impersonated by AI without their consent, there may be less of a desire to embrace the technology. Father Schmitz seems to fall into that category. After he warned his viewers about deepfakes of him, Schmitz reminisced on growing up watching the Terminator movies and its depiction of AI as the villainous Skynet. But the implications of AI advancement so far remind him more of the lethargic humans hovering around in recliners with floating screens in Wall-E.
“We would have thought ‘No, by extending technology, we can travel even further, we can go even faster, we can do amazing things,'” Schmitz said. “And it could be the case that we don't actually do amazing things. It could be the case that by extending our humanity, we cease knowing how to do things.”
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Lockin has announced the Veno Pro Wireless and V7 Max, two new smart locks that the company says will have “zero need to recharge or replace batteries.” That's because each uses wireless optical charging—infrared light, pointed at the lock at all times and beaming low-level power into it at a distance.
This is made possible by a separate, wall-mountable module that transmits wired power as light beamed at a small panel on the lock's indoor portion. Lockin spends most of its press release talking about the V7 Max, which it says has a four-meter wireless charging range. Wireless charging locks like these aren't exactly new, but they haven't exactly been something you can just go out and buy. (The tech is apparently quite nice, though; my former colleague at The Verge, Jennifer Tuohy, has said she never wants to go back after testing such a lock from Alfred.) That's all set to change with the Veno Pro Wireless and V7 Max, both of which Lockin says will be available for preorder soon after CES 2026 and shipping early this year.
Of the two, the V7 Max is the fanciest, building upon the company's existing, similar V5 Max (which isn't available in the U.S.). Like the V5 Max, it offers palm vein-scanning and facial recognition, but also offers finger vein, rather than fingerprint, scanning. It includes both 5-inch touchscreens and cameras on the inside and outside. I checked it out at CES; the lock can be configured to either show the camera feed—so, your face—or a little animated character on the screen outside. Also, there's a physical shutter on the interior portion, if you don't want that camera to be able to see you. The finger vein sensor sits on the inside of the handle in a small groove that you would slip your finger into naturally as you grasp the handle. A small, button near the bottom of the lock serves as a doorbell button for visitors.
Wireless charging comes from a small module that you would place on a table within four meters of the lock, though a Lockin representative told me owners can mount it on a wall. They also said it works best positioned directly in front of the lock, rather than at an angle. The V7 Max will be Matter-compatible, which makes it usable with any major smart home platform that supports the universal standard. Finally, the V7 Max is neither a normal door handle nor a deadbolt replacement; it's a mortise lock, which is more common in commercial buildings and would require significant rejiggering to install on the front of your house; unless you're extremely handy, you'll want a professional to put it in.
The Veno Pro Wireless is a redesigned version of the existing Veno Pro, which also offers palm vein and fingerprint scanning, doubles as a video doorbell, and is Matter compatible. The Veno Pro Wireless will be an easier sell for most people since it's a simple deadbolt replacement and shouldn't require any costly modification to install. Lockin hasn't yet revealed specific pricing for any of the locks, but in an email to Gizmodo, Lockin says the Veno Pro Wireless will be around the same price as the $380 Veno Pro.
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Removing part or all of the breast during breast cancer treatment is a potential outcome for some people. Reconstructive surgical procedures often involve prosthetic implants or transplanted tissue from elsewhere in the body. So, researchers reporting in ACS Applied Bio Materials developed a prototype injectable paste derived from human skin cells that could help restore breast volume after tumor removal, with less scarring and shorter healing time than current options.
By promoting blood vessel growth and tissue remodeling while keeping inflammation low and reducing capsular contracture, the injectable acellular matrix could make breast reconstruction safer, less invasive and more accessible, thereby improving long-term comfort and cosmetic outcomes for patients."
Pham Ngoc Chien, one of the study's lead researchers
During breast cancer treatment, cancerous cells and damaged tissue are often taken out, sometimes resulting in complete removal of the breast. For those who want to keep their breast volume, physicians turn to breast-conserving surgical techniques, where the remaining tissue is rearranged to account for space left by the tumor removal. Sometimes, skin and fat are even donated from other parts of the body to fill in the gaps left behind, like a skin graft. Though this technique preserves the shape of the breast for the patient, it leaves a scar where the tissue was donated from.
An alternative strategy involves acellular dermal matrix (ADM) - skin that has been processed to remove the outermost layer. This leaves a material with important cellular components for healing, including collagen, elastin and growth factors. Currently, ADM is available primarily in sheet form for tendon repair or plastic surgery, but Chien, Chan-Yeong Heo and colleagues wanted to create an injectable form of ADM that would be suitable for space-filling reconstructive breast surgery.
The researchers took a sample of skin donated by a living female participant and processed it through a series of steps including decellularizing, freezing and pulverizing to form small ADM particles. Then they added water to the particles to form a thick paste. The team injected small amounts of this paste into rats to test its biocompatibility and compared it to two commercially available ADM products. After a six-month period, the rats presented no adverse health effects. In fact, the animals treated with the new ADM paste had thinner layers of tissue form around the injected material than the rats treated with the commercially available product. Thinner tissue layers are preferable in breast implant procedures because they're less likely to cause complications such as infections or hematomas.
Longer-term safety trials and more complex tests are necessary before this material could be considered for clinical use. But the researchers say that this work highlights the potential of their ADM implant to improve breast reconstruction surgery.
American Chemical Society
Le, L. T. T., et al. (2025). Development and Evaluation of an Injectable Acellular Dermal Matrix for Breast Reconstruction. ACS Applied Bio Materials. doi: 10.1021/acsabm.5c01538. https://pubs.acs.org/doi/10.1021/acsabm.5c01538
Posted in: Device / Technology News | Medical Procedure News | Medical Science News
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GLP-1 agonists are pivotal in obesity care, promoting weight loss and addressing related health issues, with a focus on personalized, holistic treatment.
Guillaume Bentzinger, Luis Carrillo, Philippe Robin, and Alejandro Bara-Estaún
Discover how AI, flow chemistry, and NMR come together in the PiPAC project to revolutionize scalable and autonomous API production.
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More than half of the world's population speaks more than one language-but there is no consistent method for defining "bilingual" or "multilingual." This makes it difficult to accurately assess proficiency across multiple languages and to describe language backgrounds accurately.
A team of New York University researchers has now created a calculator that scores multilingualism, allowing users to see how multilingual they actually are and which language is their dominant one.
The work, which uses innovative formulas to build the calculator, is reported in the journal Bilingualism: Language and Cognition.
Multilingualism is a very broad label. These new formulas provide a clear, evidence-based way to understand your language strengths and how multilingual you truly are, bringing scientific clarity to an everyday part of life for millions of people."
Esti Blanco-Elorrieta, assistant professor of psychology and neural science at NYU and paper's senior author
The calculator works in nearly 50 languages, including American Sign Language, and allows users to fill in an unlisted language.
Blanco-Elorrieta and Xuanyi Jessica Chen, an NYU doctoral student and the paper's lead author, developed the formulas-embedded in a multilingual calculator that users can deploy to measure their multilingualism and language dominance-that are drawn from two primary variables:
Age of language acquisition for listening, reading, speaking, and writing
Self-rated language proficiency for listening, reading, speaking, and writing
The calculator then yields a multilingualism score, which indicates how multilingual a person is on a scale from monolingual to perfect polyglot. The language-dominance is separately tabulated by calculating the difference in ability between languages.
The authors-both multilingual speakers-note that past research has shown that self-rated language proficiency is, in fact, an accurate and efficient measure of actual language proficiency. The researchers also implemented other statistical controls to minimize self-rating bias. They add that, similarly, age of language acquisition has been shown to be a predictor of abilities: the earlier one learns a language, the more likely it is they will be able to master native-like proficiency in that language.
The researchers validated their measure by testing it in two distinct populations: healthy young bilinguals and older bilinguals with language impairments. They compared their results to those obtained from existing methods that rely on acquiring much more extensive language background information. Across both groups, the formulas produced language-dominance results that were nearly identical to those generated by more complicated measures, showing that the new approach is both simple and accurate.
"Rather than just labeling someone as 'bilingual' or 'monolingual,' this tool quantifies how multilingual one is," notes Chen.
"This calculator offers a transparent, quantitative tool that researchers, clinicians, and educators can adopt to better characterize multilingual populations, ultimately improving research quality and real-world applications-from language education to clinical assessment," concludes Blanco-Elorrieta.
The research was supported by grants from the National Institutes of Health (R00DC019973) and the National Science Foundation (2446452).
New York University
Chen X. J., & Blanco-Elorrieta E. (2025) A theoretically driven and empirically grounded calculation for language dominance and degree of multilingualism. Bilingualism: Language and Cognition. doi:10.1017/S1366728925100849. https://www.cambridge.org/core/journals/bilingualism-language-and-cognition/article/theoretically-driven-and-empirically-grounded-calculation-for-language-dominance-and-degree-of-multilingualism/76757921DA38601C02D9E9D0FA5FE899
Posted in: Medical Science News | Medical Research News
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The Alliance for Clinical Trials in Oncology has launched a randomized phase III clinical trial called RECIPROCAL (Alliance A032304) to explore whether doctors can optimize the timing of targeted radiation therapy to minimize side effects while preserving efficacy in men with advanced prostate cancer.
Our goal in this trial is to strategically improve both survival and quality of life for men living with advanced prostate cancer. We hope to prove we can safely adjust the therapy based on an individual's cancer instead of sticking to a rigid schedule, thus maintaining the effectiveness of targeted radiation therapy while reducing side effects."
Thomas Hope, MD, Alliance study chair, nuclear medicine physician and Professor in Residence, University of California, San Francisco
The current standard of care for men with metastatic castration-resistant prostate cancer includes Lutetium-177 Prostate Specific Membrane Antigen (PSMA) targeted Radioligand Therapy (RLT), a targeted radiation therapy attached to a drug molecule and injected into the bloodstream. Once in the body, PSMA RLT binds to cancer cells, killing them cells while minimizing harm to healthy tissue.
While PSMA RLT improves survival, it can cause side effects, such dry mouth, fatigue and gastrointestinal issues. Serious side effects can include blood disorders, kidney damage or liver problems.
In the trial, clinicians will enroll about 1,500 participants. All participants will start by receiving two infusions of PSMA RLT every six weeks. During this time, if a patient's prostate specific antigen (PSA) level falls, they will be randomized into one of two groups:
Standard arm
Adaptive arm
Follow‑up schedule
Our goal with RECIPROCAL is to show that treatment can be smarter, not just stronger. By tailoring therapy to each patient's PSA response, we aim to reduce unnecessary toxicity and diminish side effects while still delivering the same survival benefit. Ultimately, we want men with advanced prostate cancer to not only live longer, but to also feel better during their treatment."
Deaglan McHugh, MD, lead medical oncologist on the trial and Assistant Professor at Memorial Sloan Kettering Cancer Center
Alliance for Clinical Trials in Oncology
Posted in: Men's Health News | Drug Trial News
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An international research team identified hundreds of genes essential for the development of brain cells, including one gene linked to a severe neurodevelopmental disorder not previously described. The study published in Nature Neuroscience offers a new approach to identifying genes involved in neurodevelopmental disorders, including autism.
Which genes are required for turning embryonic stem cells into brain cells, and what happens when this process goes wrong? In a new study published today in Nature Neuroscience, researchers led by Prof. Sagiv Shifman from The Institute of Life Sciences at The Hebrew University of Jerusalem, in collaboration with Prof. Binnaz Yalcin from INSERM, France, used genome-wide CRISPR knockout screens to identify genes that are needed for early brain development.
The study set out to answer a straightforward question: which genes are required for the proper development of brain cells?
Using CRISPR-based gene-editing methods, the researchers systematically and individually "switched off" roughly 20,000 genes to study their role in brain development. They performed the screen in embryonic stem cells and while the cells changed into brain cells. By disrupting genes one by one, the team could see which genes are required for this transition to proceed normally.
Using this approach, the team mapped key steps in neural differentiation and identified 331 genes that are essential for generating neurons. Many of these genes had not previously been linked to this process, and the findings may help clarify the genetic basis of neurodevelopmental conditions, including altered brain size, autism, and developmental delay.
One of the study's central findings is the identification of PEDS1 as the cause of a previously undescribed neurodevelopmental disorder.
PEDS1 is required for the production of plasmalogens, a specialized class of membrane phospholipids that are enriched in myelin, the fatty sheath that insulates nerve fibers. In their genetic screen, the researchers also found that PEDS1 plays an important role in nerve cell formation and that its loss leads to reduced brain size. Based on these results, the team hypothesized that PEDS1 deficiency could also disrupt human brain development.
Genetic testing in two unrelated families identified a rare PEDS1 mutation associated with a severe developmental disorder in two children, marked by developmental delay and a smaller brain.
To test causality, the researchers inactivated PEDS1 in experimental models. These experiments confirmed that PEDS1 is essential for normal brain development, including the generation and migration of nerve cells, findings that may help explain the clinical features observed in the affected children.
Prof. Sagiv Shifman of the Faculty of Mathematics and Natural Sciences at Hebrew University explains: "By tracking the differentiation of embryonic stem cells into neural cells and systematically disrupting nearly all genes in the genome, we created a map of the genes essential for brain development. This map can help us better understand how the brain develops and identify genes linked to neurodevelopmental disorders that have yet to be discovered. Identifying PEDS1 as a genetic cause of developmental impairment in children, and clarifying its function, opens the door to improved diagnosis and genetic counseling for families, and may eventually support the development of targeted treatments."
The researchers found that inheritance patterns in neurodevelopmental syndromes may be predicted by the biological pathways involved. For genes that regulate other genes, such as those involved in regulating transcription and chromatin, disorders are often dominant, meaning a mutation in just one copy of the gene can be enough to cause disease. By contrast, disorders linked to metabolic genes (including PEDS1) are often recessive and require mutations in both copies of the gene, typically with each parent carrying one altered copy. This relationship between the biological pathway and inheritance could help clinicians and researchers recognize and prioritize candidate disease genes.
The team's "essentiality map," which shows when genes are required during development, also helped clarify differences between the mechanisms underlying autism and developmental delay. Genes that are broadly essential were more strongly associated with developmental delay, while genes that are specifically critical during the stages of nerve cell formation were more strongly associated with autism. This helps explain how disruptions in different pathways can lead to overlapping symptoms and supports the view that changes in early brain development can contribute to autism.
The research was supported by the Israel Science Foundation (ISF), the ISF–Broad Institute Program, and the MAVRI Biomedical Research Program.
To help advance neurodevelopmental research, the team has also launched an open online database that includes the experiment's results, making the data accessible to researchers worldwide.
Prof. Shifman added: "This was an excellent idea from PhD student Alana Amelan, who carried out a large part of the study and also created the website. We wanted our findings to serve the entire scientific community, supporting ongoing work on the genes we identified and helping researchers pinpoint additional genes involved in neurodevelopmental disorders."
The study provides a comprehensive map of genes involved in early nervous system development and highlights molecular mechanisms underlying a developmental disorder that affects the developing brain.
These insights may improve genetic diagnosis of neurodevelopmental disorders and help lay the groundwork for medical research into new approaches to prevention and treatment.
The Hebrew University of Jerusalem
Amelan, A., et al. (2026). CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment. Nature Neuroscience. doi: 10.1038/s41593-025-02165-0. https://www.nature.com/articles/s41593-025-02165-0
Posted in: Genomics | Medical Science News | Medical Research News
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Dr Bryony Henderson
GLP-1 agonists are pivotal in obesity care, promoting weight loss and addressing related health issues, with a focus on personalized, holistic treatment.
Guillaume Bentzinger, Luis Carrillo, Philippe Robin, and Alejandro Bara-Estaún
Discover how AI, flow chemistry, and NMR come together in the PiPAC project to revolutionize scalable and autonomous API production.
Dr. Raj Singh
Learn how digital connectivity and the PathoVerse are improving pathology workflows and accelerating access to expert diagnostics.
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A drug mimicking the hormone progesterone has anti-cancer activity when used together with conventional anti-estrogen treatment for women with breast cancer, a new Cambridge-led trial has found.
A low dose of megestrol acetate (a synthetic version of progesterone) has already been proven as a treatment to help patients manage hot flushes associated with anti-estrogen breast cancer therapies, and so could help them continue taking their treatment. The PIONEER trial has now shown that the addition of low dose megestrol to such treatment may also have a direct anti-cancer effect.
Around three-quarters of all breast cancers are ER-positive. This means the tumors are abundant in a molecule known as an estrogen receptor, 'feeding' on the estrogen circulating in the body. These women are usually offered anti-estrogens, medication that reduces level of estrogen and hence deprives the cancer of estrogen and inhibits its growth. However, reducing estrogen levels can bring on menopause-like symptoms, including hot flushes, joint and muscle pain, and potential bone loss.
In the PIONEER trial, post-menopausal women with ER-positive cancers were treated with an anti-estrogen with or without the progesterone mimic, megestrol. After two weeks of treatment, those that received the combination saw a greater decrease in tumor growth rates compared to those treated with an anti-estrogen only.
Although further work is required in larger patient cohorts and over a longer period of time to confirm the findings, researchers at the University of Cambridge say the trial suggests that megestrol could help improve the lives of thousands of women for whom anti-estrogen medication causes uncomfortable side-effects and can lead to some women stopping taking the medication.
PIONEER was led by Dr Richard Baird from the Department of Oncology at the University of Cambridge and Honorary Consultant Medical Oncologist at Cambridge University Hospitals NHS Foundation Trust (CUH). He said: "On the whole, anti-estrogens are very good treatments compared to some chemotherapies. They're gentler and are well tolerated, so patients often take them for many years. But some patients experience side effects that affect their quality of life. If you're taking something long term, even seemingly relatively minor side effects can have a big impact."
Some ER-positive breast cancer patients also have high levels of another molecule, known as progesterone receptor (PR). This group of patients also respond better to the anti-estrogen hormone therapy.
To explain why, Professor Jason Carroll and colleagues at the Cancer Research UK Cambridge Institute used cell cultures and mouse models to show that the hormone progesterone stops ER-positive cancer cells from dividing by indirectly blocking ER. This results in slower growth of the tumor. When mice treated with anti-estrogen hormone therapy were also given progesterone, the tumors grew even more slowly.
Professor Carroll, who co-leads the Precision Breast Cancer Institute, said: "These were very promising lab-based results, but we needed to show that this was also the case in patients. There's been concern that taking hormone replacement therapy – which primarily consists of estrogen and synthetic versions of progesterone (called progestins) – might encourage tumor growth. Although we no longer think this is the case, there's still been residual concern around the use of progesterone and progestins in breast cancer."
To see whether targeting the progesterone receptor in combination with an anti-estrogen could slow tumor growth in patients, Dr Baird and Professor Carroll designed the PIONEER trial, which tested adding megestrol, a progestin, to the standard anti-estrogen treatment letrozole.
A total of 198 patients were recruited at ten UK hospitals, including Addenbrooke's Hospital in Cambridge, and randomised into one of three groups: one group received only letrozole; one group received letrozole alongside 40mg of megestrol daily; and the third group received letrozole plus a much higher daily dose of megestrol, 160mg. In this 'window of opportunity' trial, treatment was given for two weeks prior to surgery to remove the tumor. The percentage of actively growing tumor cells was assessed at the start of the trial and then again before surgery.
In findings published today in Nature Cancer, the team showed that adding megestrol boosted the ability of letrozole to block tumor growth, with comparable effects at both the 40mg and 160mg doses.
In the two-week window that we looked at, adding a progestin made the anti-estrogen treatment more effective at slowing tumor growth. What was particularly pleasing to see was that even the lower dose had the desired effect.
Although the higher dose of progesterone is licenced as an anti-cancer treatment, over the long term it can have side effects including weight gain and high blood pressure. But just a quarter of the dose was as effective, and this would come with fewer side effects. We know from previous trials that a low dose of progesterone is effective at treating hot flushes for patients on anti-estrogen therapy. This could reduce the likelihood of patients stopping their medication, and so help improve breast cancer outcomes. Megestrol – the drug we used – is off-patent, making it a cost-effective option."
Dr. Rebecca Burrell, joint first author from the Cancer Research UK Cambridge Institute and CUH
Because women in the trial were only given megestrol for a short period of time, follow-up studies will be needed to confirm whether the drug would have the same beneficial effects with reduced side-effects over a longer period of time.
The research was funded by Anticancer Fund, with additional support from Cancer Research UK, Addenbrooke's Charitable Trust and the National Institute for Health and Care Research Cambridge Biomedical Research Centre.
Personalized and precise cancer treatments underpin the focus of care at the future Cambridge Cancer Research Hospital. The specialist facility planned for the Cambridge Biomedical Campus will bring together world-leading researchers from the University of Cambridge and its Cancer Research UK Cambridge Centre and clinical excellence from Addenbrooke's Hospital under one roof in a brand-new NHS hospital.
University of Cambridge
Burrell, R. A., et al. (2026). Evaluating progesterone receptor agonist megestrol plus letrozole for women with early-stage estrogen-receptor-positive breast cancer: the window-of-opportunity, randomized, phase 2b, PIONEER trial. Nature Cancer. doi: 10.1038/s43018-025-01087-x. https://www.nature.com/articles/s43018-025-01087-x
Posted in: Drug Trial News | Women's Health News
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GLP-1 agonists are pivotal in obesity care, promoting weight loss and addressing related health issues, with a focus on personalized, holistic treatment.
Guillaume Bentzinger, Luis Carrillo, Philippe Robin, and Alejandro Bara-Estaún
Discover how AI, flow chemistry, and NMR come together in the PiPAC project to revolutionize scalable and autonomous API production.
Dr. Raj Singh
Learn how digital connectivity and the PathoVerse are improving pathology workflows and accelerating access to expert diagnostics.
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A couple of years ago, Matthew Hurley got the kind of text people fear.
It said: "When was the last time you were STD tested?"
Someone Hurley had recently had unprotected sex with had just tested positive for HIV.
Hurley went to a clinic and got tested. "Luckily, I had not caught HIV, but it was a wake-up call," they said.
That experience moved Hurley to seek out PrEP, shorthand for preexposure prophylaxis. The antiretroviral medication greatly reduces the chance of getting HIV, the virus that causes AIDS. The therapy is 99% effective at protecting people against sexual transmission when taken as prescribed.
Hurley started PrEP and all was well for the first nine months - until their health insurance changed and they started seeing a new doctor: "When I brought PrEP up to him, he said, 'What's that?' And I was like, oh boy."
Hurley, who is a librarian, went into teaching mode. They explained that the PrEP regimen they'd been on required daily pills and lab work every three months to look out for breakthrough infections or other health issues.
Hurley was surprised they knew more about PrEP than the physician. The FDA approved the first drug, Truvada, back in 2012, and Hurley lives in the San Francisco Bay Area, a place with one of the highest concentrations of LGBTQ+ people in the nation and a deep history of HIV and health care activism. Hurley said older friends and acquaintances who survived the AIDS epidemic shared the horror of living through a time when there was no effective treatment or drugs for prevention. Deciding to take PrEP felt like an empowering way to protect their health and their community.
So Hurley pushed the doctor, and after the physician did his own research, he agreed to prescribe PrEP.
Hurley got the care they needed, but they had to be the expert in the exam room.
"That's a big burden," said Beth Oller, a family medicine physician and board member of GLMA, a national organization of LGBTQ+ and allied health care professionals focused on health equity. "You really want someone you can just go in and talk [to] about your health concerns without feeling like you are having to educate and advocate for yourself at every turn."
Oller said many queer people have had negative experiences during health care visits.
"I have a lot of patients who had not done preventive care for years because of the medical stigma," she said.
Clearing the access hurdles to HIV prevention medicine was just the beginning. Hurley started receiving a string of bills for PrEP-related care. Blood test: $271.80. Office visit: $263.
Again, Hurley was surprised. They knew - even if the billing office didn't - that under the Affordable Care Act most private insurance plans and Medicaid expansion programs are required to cover PrEP and ancillary services, like lab tests, as preventive with no cost sharing.
The bills for doctor visits and blood draws piled up.
Hurley would appeal the bill and get a denial almost every time. Then, they would appeal again.
Hurley shared a series of appeal letters for one service, in which the billing office acknowledged that blood work had been initially incorrectly coded as diagnostic. Once that was corrected, Hurley said, the insurer paid for the service.
That might sound quick or easy to resolve, but Hurley said it took "forever to get through the process." They dealt with at least six incorrect bills over several months. Hurley estimated they spent more than 60 hours contesting the bills.
During that time, Hurley said, the billing department "is continuing to send me emails and bills that are saying, You're overdue. You're overdue. You're overdue."
Fed up with the hassles, Hurley decided to find a health provider (and billing office) better informed about PrEP. They settled on the AIDS Healthcare Foundation. The care team there was able to discuss the pros and cons of different PrEP regimens and knew how to navigate the formulary for Hurley's insurance.
Hurley hasn't gotten an unexpected bill since.
But siloing sexual health care and PrEP off from primary care hasn't been ideal.
"I have multiple organizations that I have to deal with to get my holistic health dealt with," Hurley said.
A provider doesn't need to be an HIV specialist, an infectious disease expert, or a physician to prescribe PrEP. The Centers for Disease Control and Prevention encourages primary care providers to treat PrEP like other preventive medications.
To avoid some of the headaches Hurley faced, try these tips:
The CDC estimates 2.2 million Americans could benefit from HIV prevention drugs, but just over a quarter of that group have been prescribed them.
"Not enough people know about PrEP, and there are a number of people who know about PrEP but do not realize it's for them," said Jeremiah Johnson, executive director of PrEP4All, an organization dedicated to universal access to HIV prevention and medication.
According to the CDC's clinical guidelines, PrEP can be prescribed as part of a preventive health plan to anyone who's sexually active. It's especially recommended for people who don't use condoms consistently, intravenous drug users who share needles, men who have sex with men, and people in relationships with partners living with HIV or whose HIV status is unclear.
The vast majority of PrEP users are men. There are big race, gender, and geographical disparities in the distribution of HIV and the populations taking the prevention medicine. For example, based on the patterns of new infection in the U.S., a group that would benefit from PrEP is cisgender Black women, whose gender identity aligns with their sex assigned at birth.
If your doctors aren't well informed, start by educating yourself. There are also clinical guidelines and information you can share with your provider. Check your state or local health department for a how-to guide for prescribing PrEP. For example, the New York State Department of Health AIDS Institute has information for providers.
The CDC also has PrEP guidelines, but many of the agency's websites dealing with LGBTQ+ health are in flux. Under the Trump administration, some HIV/AIDS resources have been taken down from federal websites. Others now have headers saying: "This page does not reflect biological reality and therefore the Administration and this Department rejects it."
Johnson said Hurley's experience with billing mistakes is common. "The lab expenses in particular end up being very tricky," Johnson said.
For example, a doctor's office may mistakenly code the lab work required for PrEP as a diagnostic test instead of preventive care. Patients like Hurley can end up with a bill they shouldn't have to pay. If your doctor's office is making mistakes, share the PrEP billing and coding guide from NASTAD, an association of public health officials who administer HIV and hepatitis programs.
Try to get your lab work done in-network. If the lab is out-of-network, Johnson said, it can be difficult to appeal.
If the bills keep coming, appeal them. And if you can't resolve the dispute, Johnson said, file a complaint with the agency that regulates your insurance plan.
There are different kinds of PrEP. There are lower-cost, generic versions of Truvada, for example, sold as emtricitabine/tenofovir disoproxil fumarate, often shortened to FTC/TDF. Newer PrEP drugs Apretude and Yeztugo have list prices in the thousands of dollars. Check your insurance formulary and ask your doctor to prescribe medicine your plan will cover.
With many health care premiums dramatically increasing and millions at risk of losing Medicaid coverage, many people may go without health insurance this year. Drug manufacturers such as Gilead and ViiV have assistance programs for qualifying patients. If you have to pay out-of-pocket, prescription price comparison websites, like GoodRx, can help you find the pharmacies with the cheapest price.
Telehealth is an increasingly popular option if you don't live near an affirming provider or are looking for a more private way to get PrEP. In 2024, roughly 1 in 5 people on PrEP used telemedicine. Online pharmacies like Mistr and Q Care Plus offer PrEP without an in-person appointment, and lab work can be done at home. Some telehealth options have ways to lower the cost if you're uninsured.
Telehealth can also broaden the number of doctors who are ready to prescribe PrEP. And some patients say speaking with a remote provider feels like a safer setting to talk about sexual health. "They're in the comfort of their own bedroom or living room but can interface virtually with a provider. It can open up a lot of doors for honesty and trust," said Alex Sheldon, executive director of GLMA.
GLMA created the LGBTQ+ Healthcare Directory, a searchable database of health care providers across the nation who identify as queer-friendly. As Hurley discovered, living in a major metro area is no guarantee your doctor is up to date on LGBTQ+ health care.
Ask locals you trust for recommendations. You might be surprised to find good options nearby.
Health Care Helpline helps you navigate the health system hurdles between you and good care. Send us your tricky question and we may tap a policy sleuth to puzzle it out. The crowdsourced project is a joint production of NPR and KFF Health News.
KFF Health News
Posted in: Disease/Infection News | Healthcare News
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Dr Bryony Henderson
GLP-1 agonists are pivotal in obesity care, promoting weight loss and addressing related health issues, with a focus on personalized, holistic treatment.
Guillaume Bentzinger, Luis Carrillo, Philippe Robin, and Alejandro Bara-Estaún
Discover how AI, flow chemistry, and NMR come together in the PiPAC project to revolutionize scalable and autonomous API production.
Dr. Raj Singh
Learn how digital connectivity and the PathoVerse are improving pathology workflows and accelerating access to expert diagnostics.
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IntroductionVitamins, fiber, and bioactive compoundsHow golden berries prevent inflammationMetabolic effects on insulin resistanceHow are golden berries consumed?ConclusionsReferencesFurther reading
Golden berries (Physalis peruviana) are a nutrient-dense fruit rich in steroidal lactones, polyphenols, and fiber with demonstrated anti-inflammatory and metabolic effects in preclinical models. Evidence from cellular and animal studies indicates modulation of NF-κB signaling, reduced cytokine levels, and improved insulin sensitivity and lipid metabolism.
Image Credit: Maria Castellanos / Shutterstock.com
Golden berries (Physalis peruviana) are native to the Andean highlands of Peru and Ecuador, with commercial production in Colombia, South Africa, the United States, and New Zealand. Golden berries are rich in polyunsaturated fatty acids, vitamins A, B1, B2, B3, C, K1, and E, phytosterols like campesterol, beta-sitosterol, and stigmasterol, as well as minerals including potassium and phosphorus, antioxidant polyphenols, and dietary fiber.1
Goldenberry fruit and calyx contain different “signature” bioactives: fruit extracts are notable for steroidal lactones (physalins/physalin derivatives and related withanolides), while calyx extracts are typically richer in phenolic acids and flavonoids. Golden berries concentrate rare steroidal lactones called withanolides and related physalins, which contribute antimicrobial, anti-inflammatory, and antiproliferative activities. In one compositional and bioactivity study, physalin derivatives and a withanolide were tentatively identified in the fruit extract, while calyx extracts showed antioxidant activity in cell-based models and inhibited nitric oxide production and advanced glycation end-products (AGEs) formation in vitro.2
Rather than relying on limited human evidence, current “metabolic” mechanistic support for goldenberry comes primarily from in vitro enzyme/AGE-inhibition assays and animal studies.2 For example, calyx preparations have been evaluated for α-glucosidase inhibition and AGE-formation inhibition in vitro - two targets that are relevant to postprandial glycemia and glycation-associated tissue stress.2
Golden berries elicit anti-inflammatory effects by limiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and downstream cytokine production. In lipopolysaccharide (LPS)-stimulated murine macrophages, golden berry extract reduced nitric oxide, IL-6, IL-1β, TNF-α, and PGE2 levels.3
Mechanistically, golden berry extract was reported to reduce NF-κB signaling by preventing IκBα degradation and reducing p65 nuclear translocation in LPS-stimulated macrophages, consistent with lowered production of pro-inflammatory mediators.3
In vivo, dietary supplementation with golden berry extract in a DSS colitis model reduced disease severity, improved colon metrics, and supported tissue restoration. Oxidative stress also declined, as demonstrated by reduced MPO activity, neutrophil infiltration, and ROS levels.3
While observational and intervention studies in humans have linked higher overall fruit intake (as a dietary pattern) to lower levels of common inflammatory biomarkers such as CRP and cytokines, targeted clinical trials that isolate goldenberry-specific effects on these endpoints are still needed.3
In a rat model designed to mimic obesity/insulin-resistance features, goldenberry was incorporated into the diet, and outcomes were assessed at the end of the experiment (post-day 16), including glycemia, lipid profile, organ/adipose weights, and metabolic gene expression. In an obese rat model of metabolic syndrome, a high-fat diet combined with daily golden berry intake reduced fasting blood glucose levels and improved insulin signaling, as demonstrated by higher INSR and PPARγ expression, as well as lower levels of FASN and LPL.4
Liver weight decreased with golden berry supplementation, suggesting lower hepatic fat accumulation, whereas brown adipose tissue mass increased, which is consistent with improved energy expenditure potential. Visceral and subcutaneous fat pads were lighter, with overall weight gain attenuated as compared to control rats consuming a high-fat diet alone.
In addition to glycemia, the same intervention reported improvements in the plasma biochemical profile (including cholesterol, triglycerides, LDL, and HDL), alongside shifts in metabolic genes linked to insulin signaling/adipogenesis.4
Image Credit: Brent Hofacker / Shutterstock.com
Fresh golden berries are tart-sweet and often consumed as a snack, in fruit salads, salsa for fish or poultry, or as a garnish. Although you can keep the husk on until use, it is advised to remove, rinse, and dry the berry immediately before eating.2,5
Dried golden berries are often incorporated into trail mixes, baked goods, and compotes, or rehydrated for sauces. Drying reduces water activity into the microbial-safe range of 0.23-0.52, thereby improving shelf stability at room temperature when stored in airtight packaging away from light.5
Microwave drying under reduced pressure yields lower water activity, higher polyphenol and carotenoid content, and better antioxidant capacity than conventional hot-air drying. Thus, dried golden berry products made with gentle and rapid dehydration retain more bioactive compounds.2,5
Powdered golden mixes can be incorporated into smoothies, yogurt, oatmeal, and baked goods. Golden berry powders should similarly be stored in moisture-proof, opaque containers and refrigerated or frozen after opening to slow vitamin loss.2,5
Golden berries are routinely processed into jams, juices, syrups, and savory or sweet appetizers. Various food industries manufacture products containing golden berries in their beverages, compotes, and pastry products like pies and cakes.2,3,4
Goldenberry contains multiple classes of potentially functional compounds, particularly steroidal lactones (physalin/withanolide-related compounds), phenolics, carotenoids, vitamin C, and fiber, with preclinical evidence supporting anti-inflammatory and metabolic effects. Golden berries contain numerous bioactive compounds, including withanolides, carotenoids, vitamin C, and fiber, that mitigate inflammation, support glucose control, and improve triglyceride handling. Preclinical models suggest that golden berry intake inhibits NF-κB, reduces cytokine levels and oxidative stress, while conferring improvements in insulin pathways, lipids, and hepatic fat.2
While promising, rigorous randomized human trials with standardized preparations and doses are needed to confirm efficacy, define safety for long-term intake, and guide evidence-based recommendations for metabolic and inflammatory health.
Further ReadingAll Superfood ContentAmla (Indian Gooseberry) Health Benefits: From Vitamin C to Anti-Aging EvidenceWhy Pomegranate Is Good for You: Evidence-Based Insights Into Its Health BenefitsGoji Berries: Health Benefits for Immunity, Vision, and MetabolismDo Superfoods Really Exist?More...
Last Updated: Jan 4, 2026
Written by
Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.
Please use one of the following formats to cite this article in your essay, paper or report:
APA
Kumar Malesu, Vijay. (2026, January 04). Golden Berry (Physalis peruviana): Anti-Inflammatory Properties and Emerging Evidence for Metabolic Health. News-Medical. Retrieved on January 05, 2026 from https://www.news-medical.net/health/Golden-Berry-(Physalis-peruviana)-Anti-Inflammatory-Properties-and-Emerging-Evidence-for-Metabolic-Health.aspx.
MLA
Kumar Malesu, Vijay. "Golden Berry (Physalis peruviana): Anti-Inflammatory Properties and Emerging Evidence for Metabolic Health". News-Medical. 05 January 2026.
IntroductionMechanisms of gut and immune supportClinical evidenceForms and dosageSafety notesReferencesFurther reading
How an ancient Mediterranean resin is reshaping modern understanding of gut lining resilience, immune signaling, and microbiota-driven inflammation.
Image Credit: rawf8 / Shutterstock.com
Mastiha is a natural resin obtained from the stems and branches of the Pistacia lentiscus tree, particularly the Chios variety. Mastiha has been used throughout the Mediterranean region for over 2,500 years, with historical records from Hippocrates, Dioscorides, and Galen describing its use in managing gastrointestinal complaints such as dyspepsia, gastralgia, and peptic ulcers.
Mastiha is rich in phenolic compounds, phytosterols, and arabinogalactan proteins, with approximately 30% of its composition consisting of the natural polymer poly-β-myrcene. Among these compounds, terpenes are particularly abundant, with monoterpenes like α-pinene, β-pinene, and β-myrcene, as well as triterpenes including mastihadienonic and isomastihadienonic acids.1,2
Rather than acting as a classical fermentable prebiotic fiber, mastiha appears to exert microbiota-modulating effects through selective antimicrobial activity and host–microbe immune signaling, indirectly supporting microbial diversity and gut homeostasis.3,4
Therapeutic potentials of Chios Mastic.4
Preclinical and clinical evidence indicate that mastiha modulates gut microbial composition rather than directly stimulating bacterial proliferation. In a murine non-alcoholic steatohepatitis (NASH) model, mastiha supplementation improved hepatic steatosis and fibrosis while enhancing gut microbiota diversity. In human NAFLD trials, mastiha supplementation altered beta-diversity, downregulated pro-inflammatory taxa such as Flavonifractor, and reduced bile acid–related and phospholipid metabolites, suggesting indirect microbiota remodeling.3,4
Mastiha enhances mucosal barrier integrity and reduces gut permeability. In dextran sodium sulfate (DSS)-induced colitis, oral mastiha protects against colon injury and attenuates expression of pro-inflammatory cytokines, including TNF-α and IL-6, alongside adhesion molecules such as ICAM-1.7,8
Mechanistic studies demonstrate that mastiha triterpenes activate antioxidant defense pathways (including Nrf2-mediated glutathione synthesis) while suppressing NF-κB and MAPK signaling cascades. In Sprague-Dawley rats with colitis, oral mastiha resin oil at 400 mg/kg/day decreased the total colitis index, while intrarectal administration significantly reduced TNF-α, with efficacy comparable to that of prednisolone. Across experimental colitis models, mastiha consistently downregulates TNF-α and IL-6, supporting its role as an immunomodulatory adjunct rather than a direct immunosuppressant.5–8
Mastiha exhibits notable antimicrobial activity against Helicobacter pylori. Clinical trials demonstrate partial eradication rates and significant reductions in bacterial load, rather than complete eradication. Broad antibacterial and antifungal activity against Staphylococcus, Streptococcus, and Candida species further supports its adjunctive role in digestive and oral immune health.4,9
In a randomized controlled trial of adults with functional dyspepsia, 350 mg of mastiha resin three times daily for 21 days significantly improved epigastric pain and dyspeptic symptoms compared with placebo. These benefits are attributed to local antioxidant and anti-inflammatory effects on the gastric mucosa rather than acid suppression.1,10
Although direct IBS-specific trials are limited, extrapolation from IBD studies suggests benefit in symptoms driven by low-grade inflammation and barrier dysfunction. In a double-blind trial of 60 patients with IBD, 2.8 g/day of mastiha for three months improved IBDQ quality-of-life scores, reduced fecal lysozyme, and lowered oxidative stress biomarkers, without inducing clinical immunosuppression.8,10,11
Smaller clinical studies report that four-week supplementation with 2.2 g/day in patients with active Crohn's disease reduced CRP, IL-6, and TNF-α levels. Symptom improvement occurred in a subset of participants and should be interpreted cautiously due to the limited sample size.12–15
In quiescent IBD, six-month supplementation prevented increases in plasma free amino acids, an early metabolic marker of mucosal stress, without altering remission rates. Additional mechanistic studies demonstrate modulation of miRNA-155–Th17 signaling, preservation of tight junction proteins such as ZO-1, and shifts in fecal metabolites linked to epithelial resilience rather than direct disease remission.10–15
Mastiha is available in several forms used across clinical and traditional settings. Chewing gum or whole resin pieces represent the oldest mode of intake. Powdered mastiha and encapsulated resin are most commonly used in clinical trials for dosing consistency.4,16
Clinically studied doses range from ~1 g/day for dyspepsia and H. pylori adjunct therapy to 2.2–2.8 g/day in IBD trials. Higher intakes (≥4 g/day) appear primarily in older or exploratory studies and are not routinely recommended. Trial durations typically range from 2 to 12 weeks, with more extended observational use requiring medical supervision.3,4
Clinical trials consistently report that mastiha is well-tolerated, with adverse events comparable to those observed with placebo. Allergic reactions are rare but possible, particularly in individuals with known sensitivities to Pistacia or Anacardiaceae.
Animal toxicity findings occur at exposures far exceeding human supplemental doses. Long-term safety data in pregnancy, lactation, and pediatric populations remain insufficient; therefore, routine use is not recommended in these groups.4,16
Further ReadingAll Antioxidant ContentBest Antioxidant Foods for Health and LongevityWhat are AntioxidantsAntioxidant: The Oxidative Challenge In BiologyAntioxidant MetabolitesMore...
Last Updated: Jan 4, 2026
Written by
Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.
Please use one of the following formats to cite this article in your essay, paper or report:
APA
Toshniwal Paharia, Pooja Toshniwal Paharia. (2026, January 04). Mastiha Resin Benefits for Gut Health, Inflammation, and Immune Function. News-Medical. Retrieved on January 05, 2026 from https://www.news-medical.net/health/Mastiha-Resin-Benefits-for-Gut-Health-Inflammation-and-Immune-Function.aspx.
MLA
Toshniwal Paharia, Pooja Toshniwal Paharia. "Mastiha Resin Benefits for Gut Health, Inflammation, and Immune Function". News-Medical. 05 January 2026.
New study reveals that bacteria can survive antibiotic treatment through two fundamentally different "shutdown modes," not just the classic idea of dormancy. The researchers show that some cells enter a regulated, protective growth arrest, a controlled dormant state that shields them from antibiotics, while others survive in a disrupted, dysregulated growth arrest, a malfunctioning state marked by vulnerabilities, especially impaired cell membrane stability. This distinction is important because antibiotic persistence is a major cause of treatment failure and relapsing infections even when bacteria are not genetically resistant, and it has remained scientifically confusing for years, with studies reporting conflicting results. By demonstrating that persistence can come from two distinct biological states, the work helps explain those contradictions and provides a practical path forward: different persister types may require different treatment strategies, making it possible to design more effective therapies that prevent infections from coming back.
Antibiotics are supposed to wipe out harmful bacteria. Yet in many stubborn infections, a small number of bacterial cells manage to survive, only to re-emerge later and cause relapse. This phenomenon, known as antibiotic persistence, is a major driver of treatment failure and one reason infections can be so difficult to fully cure.
For years, persistence has largely been blamed on bacteria that shut down and lie dormant, essentially going into a kind of sleep that protects them from antibiotics designed to target active growth. But new research led by PhD student Adi Rotem under the guidance Prof. Nathalie Balaban from Hebrew University reveals that this explanation tells only part of the story.
The study shows that high survival under antibiotics can originate from two fundamentally different growth-arrest states, and they are not just variations of the same "sleeping" behavior. One is a controlled, regulated shutdown, the classic dormancy model. The other is something entirely different: a disrupted, dysregulated arrest, where bacteria survive not by protective calm but by entering a malfunctioning state with distinct vulnerabilities.
"We found that bacteria can survive antibiotics by following two very different paths," said Prof. Balaban. "Recognizing the difference helps resolve years of conflicting results and points to more effective treatment strategies."
The researchers identified two archetypes of growth arrest that can both lead to persistence, but for very different reasons:1) Regulated growth arrest: A protected dormant stateIn this mode, bacteria intentionally slow down and enter a stable, defended condition. These cells are harder to kill because many antibiotics rely on bacterial growth to be effective.2) Disrupted growth arrest: Survival through breakdownIn the second mode, bacteria enter a dysregulated and disrupted state. This is not a planned shutdown, but a loss of normal cellular control. These bacteria show a broad impairment in membrane homeostasis, a core function needed to maintain the integrity of the cell.That weakness could become a key treatment target.
Antibiotic persistence plays a role in recurring infections across a wide range of settings, from chronic urinary tract infections to infections tied to medical implants. Yet despite intense research, scientists have struggled to agree on a single mechanism explaining why persister cells survive. Different experiments have produced conflicting results about what persisters look like and how they behave.
This study offers an explanation: researchers may have been observing different types of growth-arrested bacteria without recognizing they were distinct.
By separating persistence into two different physiological states, the findings suggest a future where treatments could be tailored, targeting dormant persisters one way, and disrupted persisters another.
The team combined mathematical modeling with several high-resolution experimental tools, including:
Together, these approaches revealed clear biological signatures distinguishing regulated growth arrest from disrupted growth arrest, along with the specific vulnerabilities of the disrupted state.
Hebrew University of Jerusalem
Rotem, A., et al. (2026). Differentiation between regulated and disrupted growth arrests allows tailoring of effective treatments for antibiotic persistence. Science Advances. doi: 10.1126/sciadv.adt6577. https://www.science.org/doi/10.1126/sciadv.adt6577
Posted in: Medical Science News | Medical Research News | Disease/Infection News
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Dr Bryony Henderson
GLP-1 agonists are pivotal in obesity care, promoting weight loss and addressing related health issues, with a focus on personalized, holistic treatment.
Guillaume Bentzinger, Luis Carrillo, Philippe Robin, and Alejandro Bara-Estaún
Discover how AI, flow chemistry, and NMR come together in the PiPAC project to revolutionize scalable and autonomous API production.
Dr. Raj Singh
Learn how digital connectivity and the PathoVerse are improving pathology workflows and accelerating access to expert diagnostics.
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on this website is designed to support, not to replace the relationship
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Self-harming and self-sabotaging behaviors, from skin picking to ghosting people, all stem from evolutionary survival mechanisms, according to a compelling new psychological analysis.
Clinical psychologist Dr. Charlie Heriot-Maitland, in his new book Controlled Explosions in Mental Health, explores the biological necessities behind harmful behaviors.
He argues that although these behaviors seem counterintuitive, the brain uses these small harms as a protective dose to prevent further harms. For example, someone may procrastinate starting a project, causing themselves harm, but trying to prevent a higher-stakes harm of failure or rejection.
Our brain is a survival machine. It is programmed not to optimize our happiness and well-being, but to keep us alive. It needs us to exist in a predictable world. It does not like surprises. It does not want us to be caught off guard."
Dr. Charlie Heriot-Maitland, clinical psychologist
"Being exposed to threats and dangers is bad enough, but the most vulnerable state for us humans is being exposed to unpredictable threat. Our brain cannot allow this, and will intervene to give us more controlled, predictable versions of threat. Our brain would rather we were the arbiter of our own downfall than risk being floored by something external. It would rather we were well-rehearsed in receiving internally-created hostility than risk being unprepared for it from others," explains Dr Heriot-Maitland.
This protective mechanism operates on a fundamental principle: the brain would rather deal with the certainty of a controlled, known threat, than cope with the possibility of an out-of-control, unknown threat.
The science behind this theory is based on how the human brain evolved, that is primarily for survival rather than happiness. Brains are hardwired to spot danger everywhere, which helped the species survive. However, it now means we are extra attuned to any potential hurts on the horizon – physical or emotional.
Dr Heriot-Maitland suggests this evolutionary tactic of 'better safe than sorry', signifies that even though we know it might not be sensible to eat a share bag of chocolates, we do it anyway to avoid the bigger shame of failure. Another example is even when someone does not really hate us, we might still avoid them anyway instead of facing the bigger potential rejection.
"Our brains have evolved to favour perceiving threat, even when there isn't one, in order to elicit a protective response in us. We have all inherited a highly sensitive threat-detection and threat-response system," he explains.
Common self-sabotaging behaviors include procrastination, perfectionism and pessimism.
Perfectionism operates similarly to procrastination, but through different mechanisms. While procrastination diverts attention away from tasks, perfectionists might show a hyper-focus and attention to detail with the hope of ensuring that errors are not being made. The primary motivation is often to avoid failure, but this puts the perfectionist at risk of stress and burnout.
Self-criticism represents another form of self-sabotage, whether trying to self-improve or self-blame to create a feeling of agency and control – these behaviors all involve a neurological hijacking in which the brain's threat-response system co-opts higher cognitive functions, such as imagination and reasoning.
The threat system utilises these cognitive functions, he explains, which is why when experiencing fear, our imagination can become instantly flooded with fear-related predictive scenarios.
One problem with self-sabotaging behaviors, Dr Heriot-Maitland points out, is that they often become self-fulfilling prophecies.
"If we think we are not very good at something, we may not try our best and then end up performing worse than we would have had we made a different prediction," he explains."Or if we think someone doesn't like us, and we avoid them, then our fear of rejection may have stood in the way of creating a relationship."
Even if we can acknowledge these behaviors aren't helpful, addressing them requires to first understand their protective function rather than simply trying to eliminate them.
Using the metaphor of self-sabotaging behavior as 'controlled explosions', he explains: "The bomb squad are not our enemies. They are protecting something big; something hurt; something wounded or painful.
"In many cases, it may be linked to a difficult life experience – a threat, a trauma or a tragedy. The controlled explosions do harm us though – we must not lose sight of that either."
Effective psychological interventions focus on processing the underlying emotional pain, he says, although acknowledges this is a 'tough choice' and unlikely to be a 'quick fix'.
Dr Heriot-Maitland explains: "Resolving underlying harm can often involve both of these two aspects: creating safeness around the feared situation and feeling; grieving the loss of having a core need in that situation that was unmet, denied or dismissed."
Ultimately, the way out of the self-sabotage loop is not through more self-criticism, which compounds the well-worn neural pathways, but through self-compassion, Dr Heriot-Maitland adds.
To utilise the brain's neuroplasticity and learn new, less harmful habits, people must deliberately choose to recognise and understand the behavior first, he argues: "To instil these compassionate motivations into a process like this is not just 'a given'. It takes time, effort, and intentionality."
By understanding the evolutionary basis for self-sabotage first, he suggests, this offers the chance to recognises the protective function it served, while addressing the harm it has caused without judgement.
Heriot-Maitland concludes: "We don't want to fight these behaviors, but nor do we want to appease them and let them carry on controlling, dictating, and sabotaging our lives. There are choices we have here."
Taylor & Francis Group
Heriot-Maitland, C. (2026). Controlled Explosions in Mental Health. DOI: 10.4324/9781003559924. https://www.taylorfrancis.com/books/mono/10.4324/9781003559924/controlled-explosions-mental-health-charlie-heriot-maitland
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Dr Bryony Henderson
GLP-1 agonists are pivotal in obesity care, promoting weight loss and addressing related health issues, with a focus on personalized, holistic treatment.
Guillaume Bentzinger, Luis Carrillo, Philippe Robin, and Alejandro Bara-Estaún
Discover how AI, flow chemistry, and NMR come together in the PiPAC project to revolutionize scalable and autonomous API production.
Dr. Raj Singh
Learn how digital connectivity and the PathoVerse are improving pathology workflows and accelerating access to expert diagnostics.
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Circadian rhythms that are weaker and more fragmented are linked to an increased risk of dementia, according to a new study published on December 29, 2025, in Neurology®, the medical journal of the American Academy of Neurology. The study also found that circadian rhythm levels that peaked later in the day, rather than earlier, were also linked to an increased risk. The study does not prove that these factors cause dementia, it only shows an association.
Circadian rhythm is the body's internal clock. It regulates the 24-hour sleep-wake cycle and other body processes like hormones, digestion and body temperature. It is guided by the brain and influenced by light exposure.
With a strong circadian rhythm, the body clock aligns well with the 24-hour day, sending clear signals for body functions. People with a strong circadian rhythm tend to follow their regular times for sleeping and activity, even with schedule or season changes. With a weak circadian rhythm, light and schedule changes are more likely to disrupt the body clock. People with weaker rhythms are more likely to shift their sleep and activity times with the seasons or schedule changes.
Changes in circadian rhythms happen with aging, and evidence suggests that circadian rhythm disturbances may be a risk factor for neurodegenerative diseases like dementia. Our study measured these rest-activity rhythms and found people with weaker and more fragmented rhythms, and people with activity levels that peaked later in the day, had an elevated risk of dementia."
Wendy Wang, MPH, PhD, study author, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, Texas
The study involved 2,183 people with an average age of 79 who did not have dementia at the start of the study. Of participants, 24% were Black people and 76% were white people.
Participants wore small heart monitors that adhere to the chest to measure rest and activity for an average of 12 days. Researchers used data from the monitors to track the strength and patterns of people's circadian rhythms. Participants were then followed for an average of three years and during that time 176 people were diagnosed with dementia.
Researchers reviewed heart monitor data for various measures to determine circadian rhythm strength. These measures included relative amplitude, which is a measure of the difference between a person's most active and least active periods. High relative amplitude signified stronger circadian rhythms.
Researchers divided participants into three groups, comparing the high group to the low group. A total of 31 of 728 people in the high group developed dementia, compared to 106 of the 727 people in the low group. After adjusting for factors such as age, blood pressure and heart disease, researchers found when compared to people in the high group, those in the low, weaker rhythm group had nearly 2.5 times the risk of dementia, with a 54% increased risk of dementia for every standard deviation decrease in relative amplitude.
Researchers also found people who experienced a peak of activity later in the afternoon, 2:15 p.m. or later, compared to earlier in the afternoon, 1:11 p.m.-2:14 p.m., had a 45% increased risk of dementia. Seven percent of those in the early group developed dementia, compared to 10% of those in the high group.
Having a later peak of activity means there could be a difference between the body clock and environmental cues such as later hours and darkness.
"Disruptions in circadian rhythms may alter body processes like inflammation, and may interfere with sleep, possibly increasing amyloid plaques linked to dementia, or reducing amyloid clearance from the brain," said Wang. "Future studies should examine the potential role of circadian rhythm interventions, such as light therapy or lifestyle changes, to determine if they may help lower a person's risk of dementia."
A limitation of the study was that researchers did not have information on sleep disorders, like sleep apnea, which could affect the results.
American Academy of Neurology
Wang, W., et al. (2025). Association Between Circadian Rest-Activity Rhythms and Incident Dementia in Older Adults. Neurology. doi: 10.1212/wnl.0000000000214513. https://www.neurology.org/doi/10.1212/WNL.0000000000214513
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Dr Bryony Henderson
GLP-1 agonists are pivotal in obesity care, promoting weight loss and addressing related health issues, with a focus on personalized, holistic treatment.
Guillaume Bentzinger, Luis Carrillo, Philippe Robin, and Alejandro Bara-Estaún
Discover how AI, flow chemistry, and NMR come together in the PiPAC project to revolutionize scalable and autonomous API production.
Dr. Raj Singh
Learn how digital connectivity and the PathoVerse are improving pathology workflows and accelerating access to expert diagnostics.
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IntroductionThe role of sulfur in healthKey dietary sources of sulfurHow does sulfur prevent aging?Garlic-specific evidenceBrassicas and cancer preventionPractical guidanceDietary combinations to enhance absorptionReferencesFurther reading
From garlic allicin to broccoli sulforaphane, discover how dietary sulfur compounds switch on the body's core repair systems and shape long-term resilience against aging and disease.
Image Credit: Ekaterina Bondaretc / Shutterstock.com
This article discusses the importance of sulfur for various physiological processes, including nuclear factor erythroid 2-related factor 2 (Nrf2) activation and hydrogen sulfide (H₂S) signaling, while offering practical ways to maximize allicin and sulforaphane intake for healthy aging.
As the primary source of cysteine for glutathione (GSH), sulfur is an essential element involved in the detoxification of reactive oxygen species and the conjugation of xenobiotics. In proteins, sulfur-containing residues enable catalysis, redox sensing, and structural regulation.
Sulfur-containing amino acids (SAAs) like cysteine and methionine form disulfide bonds and undergo reversible S-glutathionylation, S-nitrosylation, and S-persulfidation that contribute to peroxidase, dehydroascorbate reductase, and transcription factor activity, thereby stabilizing the glutathione-to-glutathione disulfide (GSSG) redox couple. SAAs also support protein folding, repair oxidized targets, and rebuild damaged macromolecules, sustaining resilience under oxidative or metal stress.1,2
Garlic, onions, and leeks are alliaceous vegetables rich in organosulfur compounds such as cysteine sulfoxides and their enzymatic breakdown products. Cruciferous vegetables like broccoli, kale, and cauliflower contain high levels of glucosinolates, whose concentration varies widely by species, cultivar, tissue, and processing rather than constituting a fixed percentage of total dry weight.3,6
Researchers have identified various organosulfur compounds in fish, chicken, and minced beef. Eggs, pasta, and rice primarily provide sulfur in the form of SAAs. Chicken, beef, and fish exhibit similarly high levels of SAA, with proportions ranging from 74% to 97%.3
Inorganic sulphate can also be found in tap water, with concentrations varying globally. Whereas the Netherlands reports levels below 260 mg/L, higher levels of up to 22 mmol/L have been measured in parts of central Canada.3
H2S functions as a gasotransmitter that supports longevity through its role in mitochondrial respiration, redox signaling, and stress adaptation. By modulating mitochondrial electron transport and preserving thiol redox balance, H2S enhances stress resistance and maintains proteostasis during aging.4
Nrf2 binds antioxidant response elements (AREs) and induces phase II detoxification enzymes, including glutathione S transferases (GSTs), nicotinamide adenine dinucleotide (phosphate) hydrogen [NAD(P)H] quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), and enzymes for GSH synthesis. This limits oxidative damage, sustains redox homeostasis, and protects long-lived tissues.4
GSH and thioredoxin (Trx) directly neutralize electrophiles and recycle oxidized proteins. Cysteine-rich dietary isothiocyanates also attenuate nuclear factor kappa B (NF-κB) signaling and inflammasome activation, thereby lowering chronic inflammation that accelerates biological aging.4,6
Sulfur metabolism stabilizes one-carbon flux and S-adenosylmethionine (SAM) availability for DNA and histone methylation. Protein persulfidation further protects catalytic cysteine residues from irreversible oxidation, preserving enzyme function under stress conditions.2
Crushing fresh garlic converts S-allyl-L-cysteine sulfoxide (alliin) to allicin through the enzyme alliinase. Allicin is transient and rearranges into organosulfur compounds such as diallyl disulfide, diallyl trisulfide, ajoene, and dithiins, with concentrations varying by preparation method, including powders, oils, or aged extracts.7
Cardiovascular evidence suggests that garlic derivatives can reduce low-density lipoprotein cholesterol and blood pressure, inhibit platelet aggregation, and attenuate early atherogenic processes. Garlic-derived compounds have also been shown to reduce vascular inflammation markers, such as vascular cell adhesion molecule-1 (VCAM-1), in vivo; however, clinical outcomes remain heterogeneous across trials.5,7
Garlic compounds modulate cytokine profiles, often decreasing tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), while increasing interleukin-10 (IL-10). Enhanced activity of natural killer cells and γδ T cells can support mucosal immunity and secretory immunoglobulin A (IgA) responses.5
Allicin and related thiosulfinates exhibit broad antibacterial and antiparasitic actions. In vivo, allicin supports host defense by promoting macrophage activation and interferon-γ (IFN-γ) signaling.5
Brassica vegetables like broccoli, kale, and cabbage are rich in glucosinolates that, upon tissue disruption, convert to sulforaphane from glucoraphanin and indole-3-carbinol from glucobrassicin. Sulforaphane activates Nrf2, inducing detoxification enzymes such as glutathione S-transferases and NAD(P)H:quinone oxidoreductase 1.6
Sulforaphane also inhibits histone deacetylases, promotes cell cycle arrest and apoptosis, and suppresses NF-κB signaling. Indole-3-carbinol forms diindolylmethane in the stomach, activates the aryl hydrocarbon receptor, shifts estrogen metabolism toward 2-hydroxylation, and induces cytochrome P450 1A1.6
In vitro studies report anti-cancer effects of sulforaphane and indole-3-carbinol, including suppression of proliferation and enhancement of apoptosis. In rodents, broccoli sprouts or purified isothiocyanates reduce carcinogen-induced tumor burden across multiple tissues and decrease polyp formation in adenomatous polyposis coli multiple intestinal neoplasia (ApcMin) models.
In clinical trials, consumption of broccoli sprout beverages increased urinary excretion of airborne toxin conjugates and supported glutathione S-transferase activity. Higher crucifer intake correlates with reduced risk of colorectal, lung, and prostate cancer, although effect sizes vary by population and genetic background.6
Image Credit: Bondar Illia / Shutterstock.com
To maximize allicin formation, fresh garlic should be crushed, minced, or grated to allow alliinase activation before heating. Heating intact cloves first inactivates alliinase and prevents allicin generation.
When cooking, lightly crushed garlic should be exposed only to moderate heat for short durations, as prolonged heating beyond approximately 10 minutes reduces bioactivity. Adding garlic toward the end of cooking or off heat helps preserve sulfur compounds. Pre-crushed garlic gently warmed in oil favors ajoene formation, whereas higher temperatures shift products toward allyl sulfides.7
Acidic pickling inhibits alliinase while producing minimal allicin. Aged garlic extract provides stable, water-soluble sulfur compounds such as S-allyl cysteine with favorable bioavailability.7
Preparations that preserve plant enzymes maximize the production of bioactive sulfur metabolites. For crucifers, boiling, frying, blanching, and high-power microwaving reduce glucosinolates, whereas steaming better preserves myrosinase activity.
Allowing endogenous myrosinase to act increases conversion of glucosinolates to isothiocyanates. Raw crucifers or sprouts yield higher sulforaphane exposure than myrosinase-free supplements, although gut microbial β-thioglucosidases can partially compensate for enzyme loss.
Finely chopping allium vegetables activates alliinase, rapidly generating allicin and downstream sulfides. High-temperature processing significantly decreases organosulfur bioavailability, emphasizing the value of low-heat and minimal-water techniques.8
Further ReadingAll Functional Food ContentIs Nutmeg Good for You? Evidence-Based Benefits for Brain, Heart, and ImmunityAmla (Indian Gooseberry) Health Benefits: From Vitamin C to Anti-Aging EvidenceWhy Pomegranate Is Good for You: Evidence-Based Insights Into Its Health BenefitsLychee Health Benefits: Antioxidant, Neuroprotective, and Anti-Cancer InsightsMore...
Last Updated: Jan 4, 2026
Written by
Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.
Please use one of the following formats to cite this article in your essay, paper or report:
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Kumar Malesu, Vijay. (2026, January 04). Sulfur-Rich Foods for Longevity: How Garlic and Cruciferous Vegetables Support Cellular Repair. News-Medical. Retrieved on January 05, 2026 from https://www.news-medical.net/health/Sulfur-Rich-Foods-for-Longevity-How-Garlic-and-Cruciferous-Vegetables-Support-Cellular-Repair.aspx.
MLA
Kumar Malesu, Vijay. "Sulfur-Rich Foods for Longevity: How Garlic and Cruciferous Vegetables Support Cellular Repair". News-Medical. 05 January 2026.
IntroductionDietary componentsComparison to Mediterranean dietMechanisms supporting heart healthEvidence baseDisease-risk reductionHow to adopt the Adriatic dietConclusionsReferences Further reading
A closer look at how a traditional Adriatic way of eating translates Mediterranean heritage into measurable cardiovascular protection through diet, lifestyle, and long-term adherence.
Image Credit: kudla / Shutterstock.com
The Adriatic diet is a regional expression of the Mediterranean dietary pattern practiced in Slovenia, Croatia, Montenegro, and other regions along the Adriatic coast. Like the Mediterranean diet, the Adriatic diet emphasizes the consumption of fruits, vegetables, whole grains, legumes, nuts, and olive oil, with regular fish intake, moderate dairy consumption, and limited red and processed meats.1,2
Consuming oily fish two to three times every week provides sufficient omega-3 polyunsaturated fatty acids to lower triglyceride levels and modestly improve blood pressure, while also reducing inflammation. Legumes like beans, chickpeas, and lentils provide low-glycemic protein and fiber, with higher intakes associated with improved lipid profiles and cardiometabolic risk markers. Extra-virgin olive oil is rich in monounsaturated fat and phenolic compounds, particularly hydroxytyrosol, which support endothelial function and reduce oxidative stress.2
Whole grains are high in fiber, which improves cholesterol regulation, inflammation, and weight management. Seasonal wild greens and vegetables provide potassium, dietary nitrates, and flavonoids that support vascular health and satiety. Moderate wine intake with meals reflects traditional practice, although cardioprotective benefits are context-dependent and not required for cardiovascular risk reduction.2,4
The Adriatic diet aligns with the Mediterranean Diet through a plant-forward pattern, emphasizing extra-virgin olive oil as the primary fat, abundant vegetables and cereals, frequent fish, legumes, and a lifestyle that values seasonality, biodiversity, conviviality, and culinary tradition.3
Adriatic meals frequently feature ‘blue' oily fish, such as anchovies, prepared with olive oil and herbs. Regional culinary traditions include wild edible plants and bitter greens prepared with olive oil, reflecting historical food availability and cultural heritage rather than distinct nutritional advantages over other Mediterranean sub-patterns. Premium local virgin olive oils with Protected Designation of Origin (PDO) further define flavor profiles and are commonly paired with vegetables, pulses, crudités, and fish.3
Image Credit: Dina Saeed / Shutterstock.com
High omega-3 intake from non-fried fish reduces triglyceride levels and exerts anti-inflammatory and antithrombotic effects, contributing to lower cardiovascular risk. Antioxidants abundant in extra-virgin olive oil, herbs, and vegetables, especially phenolics like hydroxytyrosol and oleuropein, reduce oxidative stress markers and post-prandial inflammatory signaling.2
The Mediterranean dietary pattern reduces vascular inflammation, modulates pro-atherogenic gene expression, and decreases platelet aggregation. These cardioprotective effects are associated with reduced incidence of myocardial infarction and stroke in randomized trials.2,4
High fiber intake from whole grains, legumes, nuts, fruits, and vegetables improves metabolic health by lowering LDL cholesterol, improving glycemic responses, promoting satiety, and reducing blood pressure. Fiber also supports gut microbiome diversity, which is associated with lower production of pro-atherogenic metabolites such as trimethylamine N-oxide.4
Classic cohort studies from Mediterranean regions linked traditional dietary patterns rich in olive oil, fish, legumes, grains, fruits, and vegetables with low cardiovascular mortality despite relatively high total fat intake. Subsequent randomized trials, including the Lyon Diet Heart Study and PREDIMED, demonstrated fewer major cardiovascular events and lower mortality with Mediterranean dietary patterns, supporting both primary and secondary prevention.2,6
A 2024 systematic review and meta-analysis of randomized pediatric trials reported modest improvements in triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, and systolic blood pressure among children and adolescents following Mediterranean diet interventions.5
In the PREDIMED trial, Mediterranean-style diets enriched with extra-virgin olive oil or nuts were associated with improved blood pressure control and a lower incidence of major cardiovascular events, with a reduction in stroke risk representing the most consistent individual outcome. Olive oil–rich dietary patterns are also associated with improved endothelial function and reduced vascular inflammation, contributing to favorable cardiometabolic risk profiles.2,6
The Adriatic diet is rich in olive oil, vegetables, fruits, legumes, nuts, whole-grain cereals, and pasta, with regular fish and moderate dairy consumption. Individuals following the Adriatic diet often limit sweets, commercially baked pastries, and fast food. Irregular breakfast patterns and lower breakfast quality have been observed among Adriatic youth and are associated with poorer adherence to the Mediterranean diet.7
An Adriatic-style week typically includes fruit once to twice daily and vegetables daily, fish two to three times weekly, legumes at least once weekly, nuts two to three times weekly, and pasta or rice about five days per week. Higher adherence scores among Croatian coastal youth are associated with regular meals, family eating practices, and higher physical activity levels.7
With an emphasis on extra-virgin olive oil, vegetables, whole grains, legumes, nuts, and frequent fish consumption, the Adriatic diet reflects a regional Mediterranean pattern associated with improved lipid profiles, lower blood pressure, reduced inflammation, and better vascular function. Evidence from cohort studies and randomized trials of Mediterranean dietary models aligns biomarker improvements with fewer major cardiovascular events, particularly stroke. Distinct regional culinary traditions enhance palatability, cultural continuity, and long-term adherence.
Further ReadingAll Diet & Nutrition ContentWhat Is Angelica Root? Benefits, Nutrition, and How It Supports Women's HealthIs Watermelon a Superfood? Examining the Scientific EvidenceThe MIND Diet Explained: Foods That Fight Cognitive DeclineHow an Anti-Inflammatory Diet Lowers Chronic Disease RiskMore...
Last Updated: Jan 4, 2026
Written by
Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.
Please use one of the following formats to cite this article in your essay, paper or report:
APA
Kumar Malesu, Vijay. (2026, January 04). Adriatic Diet Explained: Cardiovascular Benefits and Scientific Evidence. News-Medical. Retrieved on January 05, 2026 from https://www.news-medical.net/health/Adriatic-Diet-Explained-Cardiovascular-Benefits-and-Scientific-Evidence.aspx.
MLA
Kumar Malesu, Vijay. "Adriatic Diet Explained: Cardiovascular Benefits and Scientific Evidence". News-Medical. 05 January 2026.
Brenden Aaronson's coach has already had to defend him from fan abuse this season — twice.
But things appear to be changing at Leeds for the U.S. men's national soccer team attacker, who with each passing week looks more like the solution and less like the problem for the Premier League outfit.
His latest contribution might have been his most significant. Aaronson showed just about everything that makes him valuable on one play against Manchester United, scoring a vital goal as Leeds stretched its unbeaten run to seven.
The American's heroics at Elland Road kick off this week's Five.
Brenden Aaronson has found his footing in the Premier League.
The Leeds attacker scored his side's only goal in a 1-1 draw with Manchester United on Sunday, making it two goals and three assists in his last 11 Premier League appearances.
It's a modest hot streak, but it's a massive improvement when considering Aaronson had one goal and three assists in his previous 44 Premier League games. The 25-year-old has become a key player this season for Leeds, which is now eight points clear of the relegation zone.
Aaronson's goal typified everything that he's about. The USMNT midfielder chased down a 50-50 ball, getting in behind United's defense and then showing the quality and composure to bury his chance.
"Sometimes you have to take a chance," Aaronson said after the game. "The ball came to me. I think that the center back didn't know that I was going to be kind of running off his shoulder like that. It was a good touch. And then it is just about putting it on target."
Leeds manager Daniel Farke was full of praise after the game for a player he has stuck with despite many calls for his removal from the lineup.
"He deserves all the plaudits at the moment," Farke said. "Great finish. There's more clarity in his play. He embodies what we are about in creating chances and working hard off the ball."
Weston McKennie playing a new position is hardly earth-shattering news, but the Juventus man's latest shift is noteworthy in the context of his USMNT role.
McKennie was moved into a trequartista – or attacking midfield – role against Lecce on Saturday, a similar spot to where he played under USMNT boss Mauricio Pochettino in October.
Playing further up the pitch, McKennie found a pocket of space and converted his first Serie A goal of the season in a 1-1 draw. Though it was his first league goal, McKennie now has three goals and two assists in his past nine games in all competitions.
After he was surprisingly omitted from two of three fall rosters for the USMNT, McKennie's proficiency as a trequartista served as a timely reminder for Pochettino.
"It's not a new position for me," McKennie said after the game. "I'm always available for the coach and the team and I try to give 100 percent wherever I play.
"I like the trequartista role because you can help both defensively and offensively."
Yunus Musah isn't yet a key player for Atalanta, but the midfielder's role is trending in the right direction.
Musah has now played in four consecutive Serie A games for La Dea, coming off the bench for the last 30 minutes of Saturday's 1-0 win over Roma.
After Musah was an unused sub in seven of eight matches, he has finally started to prove his worth to manager Raffaele Palladino. It certainly doesn't hurt that Atalanta has won three of its past four games either.
"In the middle, he's a buzzing presence who brings freshness and keeps the midfield under Atalanta's control," read an assessment from Gazzetta dello Sport this week. "His rise within the team hierarchy continues."
Musah found himself on the outside of the USMNT picture in 2025, making just two appearances. If he can find a way to continue his mini-surge at Atalanta, there might still be a way back before the World Cup.
There was no build-up period for Antonee Robinson. When he was back from injury, it was full speed ahead.
After nearly three months on the sideline with knee problems, the Fulham left back has now played every minute of six consecutive games, including Sunday's thrilling 2-2 draw against Liverpool.
Robinson was excellent against Arne Slot's side, and could have had multiple assists with better finishing from his teammates.
The 28-year-old was a major concern for Pochettino just a couple months ago, but he's once again locked in as a vital player for the Cottagers. If he continues in this manner, Robinson will undoubtedly regain the same status with the USMNT in 2026.
Very few, if any, games in La Liga history will have had so much Jersey as Sunday's match between Real Sociedad and Atlético Madrid.
New Jersey-born coach Pellegrino Matarazzo made history in his Sociedad debut, becoming the first American manager in La Liga.
New Jersey-born midfielder Johnny Cardoso, meanwhile, played the final half hour for Atlético in a 1-1 draw. It's been an injury-hit debut campaign for the 24-year-old, who made just his seventh appearance of the season Sunday.
For Matarazzo, securing a draw against a top-four opponent is an auspicious beginning at a club mired in a relegation fight.
First minister announces plan for bank holiday on Monday 15 June after opening game against Haiti
Football fans needn't worry about the hangover when they celebrate, or otherwise, into the wee hours after Scotland's first match in the 2026 World Cup – because the day after the 2am UK time fixture looks likely to be a national bank holiday there.
The first minister, John Swinney, announced that Monday 15 June will be designated a national bank holiday to mark Scotland's participation in the tournament for the first time since 1998.
The anticipation among Tartan Army fans has been building since their team qualified for the men's football World Cup for the first time in more than a quarter of a century after a breathtaking 4-2 win against Denmark at Hampden Park in November.
Swinney said: “I am taking steps to ensure the Monday after our opening game should be a national bank holiday so that – no matter the outcome of the match – we can all come together to share the occasion.”
Bank holidays can be appointed in Scotland by royal proclamation, with the first minister advising the privy council on proclamations that are then designated by the king. It means that public-sector employees whose work is managed by the Scottish government will get a day off, with the decision at the discretion of other employers.
Scotland men's national team will play their first fixture against Haiti on Sunday 14 June, with a kick-off at 2am UK time. This will be followed by other late-night starts at 11pm, including against Brazil, who beat Scotland 2-1 in Scotland's last World Cup outing back in 1998.
The significant time difference, as well as the expense of tickets precluding travel for many fans, has prompted industry calls for extended pub opening hours and fan zones on the days Scotland are playing.
Swinney said: “Scotland qualifying for the men's World Cup was a remarkable achievement and a landmark moment, and the reaction to the dramatic win against Denmark reminded us all what football means to the country.
“This year, we want to make the most of this huge opportunity for Scotland and ensure as many people as possible have the opportunity to celebrate the team's success.
“Not only is this an historic sporting event, it's also a chance for Scotland to be on the world stage, to attract business development, create tourism interest within the country and to make cultural and sporting connections.”
Manchester United have finally put Ruben Amorim out of his misery. On Monday morning, the 20-time champions of England announced that the Portuguese had "departed his role as head coach" and that the decision had been "reluctantly" made to "give the team the best opportunity of the highest possible Premier League finish". Of course, the table doesn't make for particularly poor reading for United.
They're sixth in the standings, and just three points off Liverpool in fourth, so, in that sense, progress had been made, given the Red Devils finished 15th last season. However, United had only won one of their previous five league games under Amorim, who continued to confuse with his stubborn tactical approach and bizarre substitutions.
So, when he went public with his frustration with the set-up at Old Trafford after Sunday's 1-1 draw at Leeds, his exit became somewhat inevitable. Indeed, Amorim departs with the lowest win ratio of any United manager in the Premier League era (32%), with his time in charge characterised by almost constant disappointment.
Below, GOAL runs through the worst 10 moments of a truly woeful reign...
Before the Manchester derby on September 14, 2025, Amorim was asked whether he or Pep Guardiola had bigger problems to resolve, given United were actually above City in the standings after three games of the new season.
"To compare me with the situation of Pep is just a joke," Amorim said. "I think we have bigger problems." He was right, too, as all of United's issues were laid bare during a 3-0 defeat to a team that had lost their previous two league games.
As well as lacking a real cutting edge (just two of their 12 shots were on target), United were once again wide open at the back, prompting further criticism of Amorim's preferred formation.
"When Ruben Amorim first came I was heartened by them playing three at the back," former United right-back Gary Neville said on Sky Sports. "But every single game he changes the back three, which tells me he is not sure which back three he should play.
"It was a nothing game from United. They are 14th in the league only four games in and we all said that they can't be getting to October where they are 14th or 15th in the league or the manager will be in trouble. There are a few games to go but they have to start winning quickly."
By the tail end of last season, it was clear that Amorim was almost solely focused on the Europa League - as it represented United's only hope of Champions League qualification. However, the nature of the performances in the league were still disturbing, with the 4-1 loss to Newcastle on April 13 the most obvious case in point.
Despite dropping Andre Onana, United still turned in another disastrous defensive display at St. James Park as they slumped to a defeat that meant the club would definitely post their lowest-ever Premier League points haul. Worryingly, Amorim had no real explanation for all of the mistakes his players were making.
"It's a little bit of everything," he said. "It's hard to point to one thing. So, I understand [the criticism] but I don't care. Nothing is worse than losing games. People can say whatever they want to say. But I don't want to defend myself or anything like that. If you look at our position in the table, it says it all."
Despite their dire league form, the FA Cup actually felt like a realistic target for Amorim's United - and particularly after they followed up their shock third-round elimination of Arsenal at the Emirates with a 2-1 win over Leicester City.
However, the Red Devils were dumped out of the competition - and in their own back yard - after being beaten by Fulham in a shootout after a 1-1 draw at Old Trafford.
It represented a 10th defeat for Amorim in 24 games - a startling statistic made all the more remarkable for the fact that his much-maligned predecessor, Erik ten Hag, hadn't hit that figure until his 55th match in charge. Nonetheless, Amorim insisted that he was starting to get to grips with the job.
"The goal is to win the Premier League," he told the BBC. "I know that we are losing games, but the goal is to win the Premier League again. I don't know how long it will take but we have a goal and we continue forward no matter what. It's impossible to know when but you start understanding the players are better and we understand the league. So, we'll see in the future."
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Bryan Mbeumo did not enjoy a happy return to the Gtech Community Stadium in September, as Manchester United were beaten 3-1 by his former club. However, while the home fans revelled in the opportunity to mock the Cameroon international for moving to Old Trafford during the summer, with chants of 'You should have stayed at a big club' ringing around the game, Mbeumo wasn't the one held responsible for United's defeat.
Had Bruno Fernandes converted a second-half penalty, the visitors would have left London with at least a point, but even the captain wasn't cast as the main culprit. As far as Match of the Day pundit Micah Richards was concerned, Amorim was to blame for United failing to win an eighth consecutive league game on the road.
"The system is hampering [the players]," the former Manchester City defender said. "They're not sure where they're meant to be.
"In terms of the goals, there were individual errors. Harry Maguire was trying to play offside for the first one - there's no point gambling there. But, for the second, Matthijs de Ligt doesn't know where's he's going and Maguire isn't sure where to position himself. It's 100 percent confusion caused by playing that system. It doesn't suit the players."
A dramatic derby win at the Etihad on December 15, 2024 was portrayed as a statement victory for Amorim just over a month into his tenure. However, United were brought crashing back down to earth by three consecutive defeats, against Bournemouth, Wolves and Newcastle, and without scoring a single goal.
It meant that only bottom side Southampton had lost more times since Amorim's first game in charge on November 24, and also resulted in his side dropping to 14th in the table - the club's lowest position at the turn of the year since 1989.
Nonetheless, it still came as a surprise to hear Amorim admit that relegation was a "possibility" for one of the richest clubs in world football. "It is also my fault," he told reporters, "because the team is not improving. It is a little bit lost in this moment and it is a bit embarrassing to be Manchester United coach and lose a lot of games.
"But I think people are tired of excuses at this club. This club needs a shock."
United began 2025 showing some fight, as they came from behind to claim a 2-2 draw at Liverpool thanks to Amad Diallo, who then hit a 12-minute hat-trick to earn a 3-1 win over Southampton on January 16.
Just three days later, though, and it felt like United were back to square one after a humbling 3-1 loss at home to Brighton. Indeed, a disillusioned Amorim even went so far as to claim that his team was maybe "the worst" in United's history.
"In [the past] 10 games in the Premier League, we won two," he pointed out. "Imagine what this is for a fan of Manchester United. Imagine what this is for me. We are getting a new coach who is losing more than the last coach. I have full knowledge of that.
"I know you [the media] want headlines but I am saying [we are the worst] because we have to acknowledge that and to change that. Here you go: your headlines!"
Things appeared to be finally picking up for Amorim in October, after he managed to oversee three successive Premier League wins for the first time. However, November opened with back-to-back 2-2 draws with Nottingham Forest and Tottenham that exposed United's usual defensive frailties.
Worse was to come, though, in their third and final fixture of the month, as Amorim's men lost 1-0 at home to Everton despite playing more than 77 minutes of the game against 10 men following Idrissa Gueye's remarkable dismissal for striking his own team-mate.
Funnily enough, the United manager felt that the incident illustrated the kind of passion and commitment to the cause that his team often lacks.
"Fighting is not a bad thing," he reasoned. "Fighting doesn't mean that they don't like each other. Fighting means that when you lose the ball and 'I will fight you because we will suffer a goal.' I hope my players, when they lose the ball, fight each other.
"Old Trafford was there saying to us 'we are all here to give a big step up', but I felt that we were not ready. Again, these five weeks, when everyone is praising our evolution, I'm always saying the same things. We are not even near what we're supposed to be in this club."
When asked about his very unhappy anniversary as United boss, Amorim also tellingly admitted, "I feel afraid of returning to the [negative] feeling of last season. That is my biggest concern. We need to work together. We are going to work together. The players are trying but we need to be better."
A hard-fought Boxing-day win over Newcastle with an under-strength side had lifted the spirits at Old Trafford as the turn of the year approached. However, on December 30, United were held at home by the Premier League's basement boys Wolves, who had arrived in Manchester on an 11-game losing streak.
Worse still, Wolves had actually appeared the more likely winners of the game before the hosts had a late strike from Patrick Dorgu disallowed for offside.
Again, Amorim had been shorn of the services of some key players but he at least conceded that United had lacked fluidity, quality and creativity. Still, he was adamant that United were "going to be a strong team" as soon as they got back to full-strength.
"There is no doubt in mind," Amorim said, just six days before his dismissal.
Amorim's one saving grace last season was United's thrilling run to the final of the Europa League, with the 5-4 last-eight second-leg win over Lyon undoubtedly one of the most incredible European nights Old Trafford had ever witnessed. However, all anyone remembers now is United losing 'El Crapico', the showdown at San Mames between two of the worst-performing teams in the Premier League.
In fairness to Amorim, his side dominated the game against Tottenham in Bilbao. However, despite having 73% possession and 16 shots to Tottenham's three, United ended up being beaten by their opponents' only shot on target all evening, from Brennan Johnson. It was an awful goal to concede, too, but rather indicative of United's often comically bad defending under Amorim.
However, despite squandering a golden opportunity to sneak his side into the Champions League, Amorim insisted that he remained the right man for the job.
"I know the patience of the fans will be really short in the next season, but I guarantee you I will not quit and I will not go away," he declared. "I am really confident I am still the guy, more than in the beginning."
Any hope that United might improve after overhauling their attack during the summer was quickly dispelled after an utterly humiliating Carabao Cup second-round shootout loss at Grimsby Town.
The visitors had actually done well to force penalties, after finding themselves 2-0 down inside half an hour at Blundell Park, but Amorim was disgusted that he'd even had to bring on the likes of Bruno Fernandes, Bryan Mbeumo and Matthijs de Ligt to turn around a game against League Two opposition.
"I think this is a little bit the limit," the Portuguese admitted. "I think something has to change. I think the team and the players spoke really loud today. I think the best team won, the only team that was on the pitch. The way we start the game without any intensity, we were completely lost."
Unfortunately for Amorim, he also looked out of his depth - particularly as he once again couldn't bring himself to watch the shootout.
However, the most damaging image of the night - and arguably the defining image of his tenure - was the manager frantically moving pieces around a tactics board as he tried to get to grips with Grimsby during a opening hour for United!
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The 2026 FIFA World Cup™ tournament is set to kick off in mid-June. As the North America-hosted event inches closer, the fervor for "the beautiful game" continues to grow thanks to the help from global institutions like The LEGO Group.
In addition to prepping a 2,482-piece LEGO® version of the World Cup™ trophy, the creativity-oriented company has put together a 1,498 piece soccer ball (football) block set. Instead of recreating the upcoming tournament's adidas Trionda Official Match Ball, the new set opts for a more generic look. Multiple panels come together across the build, donning hits of pink, blue, and white. The LEGO® set's most defining characteristic, however, is the miniature stadium hidden inside. Fan-filled stands surround a pitch and winning team, looking ahead to World Cup™ Final.
Enjoy a closer look at the $130 set ahead. The item should land on LEGO.com soon.
For more product news, check out the latest Nike Running shoes: Structure Plus and Vomero Premium.
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Brenden Aaronson scoring against Manchester United and Weston McKennie celebrating his goal against Lecce Getty Images
Weston McKennie continues to let his football do the talking as he waits for a new deal from Juventus, teenager Cole Campbell seeks first-team football in Germany with a loan move, and Brenden Aaronson proves his worth to Leeds United in a huge derby match.
It was quite the weekend for a selection of American players in Europe. Welcome to this week's USMNT Player Tracker.
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Weston McKennie has missed more games than he has played for the United States men's national team under Mauricio Pochettino.
His absences have been due to injury or his coach resting him to try lesser-known options. Pochettino rates him and made that clear when he left the 27-year-old out of his November roster for friendlies against Paraguay and Uruguay.
But while the U.S. have other promising midfield players, including Aidan Morris, Sebastian Berhalter, Diego Luna and Malik Tillman, Pochettino can be confident that, in McKennie, he has an ace to play.
World Cup squads need the right mix of experience and youth, and McKennie has the pedigree and reassuring consistency at the highest level with Juventus, one of Europe's biggest clubs.
McKennie was at it again on Saturday, scoring his first Serie A goal of the season in Juventus' 1-1 draw with Lecce, and excelling, as usual, in a different position. It's the type of tactical flexibility that will be a bonus to Pochettino for the summer.
Instead of playing wing-back in a 3-5-2 — where he has played often under Juve manager Luciano Spalletti and his predecessor Igor Tudor — McKennie was deployed in an advanced midfield role.
To top off his performance, he was in the right place at the right time to ensure the hosts came from behind to secure a point. And it could have been all three for the home side, but McKennie's Canadian team-mate, Jonathan David, had a penalty saved.
After the match, McKennie spoke of the positional switch. “For me, it's not a new position. I'm at the manager's and the team's disposal, and I try to give 100 per cent in every role,” the Texan said via Il Bianconero.
“I like playing as a trequartista (attacking midfielder) because you can both defend and attack.”
Cole Campbell's potential has been discussed for some time at Borussia Dortmund, where he has been on the bench for the Bundesliga side five times this term. But the 19-year-old has played only 16 minutes, and has now gone on loan to fifth-placed Hoffenheim to chase more game time.
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On Sunday, he left Dortmund's winter training camp in Marbella, Spain, to complete the move until the end of the season. Hoffenheim are believed to have agreed an option to make the deal permanent in the summer for around €10million-€12million (about £9.5m; $13m).
“Cole is a young player with a lot of potential, but for various reasons he has not been able to show that recently,” Dortmund sporting director Sebastian Kehl told the club's official website.
“He has high expectations of himself and was unhappy with his current role. That is one of the reasons we agreed to this loan and believe that he will get more playing time at Hoffenheim in the second half of the season than he has recently had with us. We wish him every success.”
The Athletic's German football correspondent Seb Stafford-Bloor believes it could be a good move. “Hoffenheim are having a dramatic turnaround, based on excellent, low-cost recruitment and a team that have become one of the most athletically dominant in the Bundesliga this season,” he said.
“They're top, or otherwise second, in every meaningful running category. That's what Cole Campbell is joining.”
Brenden Aaronson continues to prove his own worth in the Premier League.
Last week, he got a vital assist for resurgent Leeds United in a 1-1 draw with Sunderland. Yesterday, he went one better with a wonderful goal to give his side the lead against Manchester United at Elland Road. Daniel Farke's side had to settle for a draw in the end, but it pulled them eight points away from the relegation place.
“It is tough because you are fighting the whole game to get good chances,” Aaronson told the club website media after the match, “Man United have great players and they are tough to break down. So, you get the chance to score, but then it is about trying to keep the lead.”
The 25-year-old said he relied on instinct in the lead-up to his second goal of the Premier League campaign. “When I see Dom (Calvert-Lewin) going up for headers, I try to run off him,” Aaronson added. “I was just running in behind to see if I could get lucky.
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“Sometimes you have to take a chance. The ball came to me. I think that the centre-back didn't know that I was going to be running off his shoulder like that. It was a good touch. And then it is just about putting it on target.”
In France, Folarin Balogun's assist for Monaco failed to make much difference as Tanner Tessmann's Lyon ran out 3-1 winners. Balogun was bundled over in the break that produced Mamadou Coulibaly's strike, but his contribution counts as an assist.
Unfortunately for the hosts, that goal to make it 1-1 was as good as it got.
Tessmann, meanwhile, came on as a 66th-minute substitute, while rumours in Italy suggest that Fiorentina are keen to bring the former Venezia man back to Serie A during the January transfer window.
(All kick-offs Eastern Time)
Christian Pulisic made a rare drop to the bench for Milan's 1-0 win over Cagliari on Friday. See if he is back in the starting XI as Milan take on Genoa in Serie A on Thursday (2:45pm, Paramount +). While tomorrow (Tuesday), McKennie and Juventus head to Sassuolo (2:45pm, Paramount +).
The following day sees a resurgent Antonee Robinson, who was excellent in Fulham's 2-2 draw with Liverpool on Sunday, take on Chelsea in a west London derby (2:30pm, Wednesday, Peacock Premium). Later the same day, Aaronson and Leeds go to St James' Park to face Newcastle United (3:15pm, Peacock Premium).
On Saturday, Tillman and Bayer Leverkusen, who are in third place in the Bundesliga, will look to make it three consecutive wins when they face Stuttgart (12:30pm, ESPN+).
Greg O'Keeffe is a senior writer for The Athletic covering US soccer players in the UK & Europe.
Previously he spent a decade at the Liverpool Echo covering news and features before an eight-year stint as the paper's Everton correspondent; giving readers the inside track on Goodison Park, a remit he later reprised at The Athletic.
He has also worked as a news and sport journalist for the BBC and hosts a podcast in his spare time. Follow Greg on Twitter @GregOK
2026 is here and so too is the World Cup year, making the next few months all more important for American players across the globe.
While several leagues, including the American-heavy Bundesliga and Eredivisie, have yet to resume from their winter breaks, others are already in full stride in the new year, with some U.S. men's national team players already having played two games since the calendar flipped.
It was a memorable weekend in Europe for American players, with important goals, milestone-moments and defensive masterclasses taking center stage. Here, Sports Illustrated ranks the top four performances of the week from Mauricio Pochettino's players across the globe.
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West Bromwich Albion's George Campbell is putting himself in contention for a USMNT role at some point in 2026, even if it may not be for the 2026 World Cup. Unfortunately for the American center back, he is impressing in an area of depth. None of that, however, takes away from his impressive week, which saw him score off a set piece in a 2–1 midweek win over QPR and play a full 90 minutes in a 1–0 loss to Swansea City. The match against Swansea saw him shift to an unusual right back position, but he continued to deliver, getting more involved in the attack with a pair of shots and three passes into the final third. The 24-year-old is in a spell of good form. Could it be enough to attract Mauricio Pochettino's eye in the lead up to the World Cup?
Antonee Robinson continued to play heavy minutes for Fulham on the weekend, going the full 90 in a blockbuster 2–2 draw with Liverpool, which featured a goal for either side in second-half stoppage time. The 28-year-old continues to show his tenacity in getting involved in the attack, a good sign for the back three or back five the USMNT is likely to play. Robinson had two passes into the final third, created a chance and chipped in with six defensive contributions, often matched up against Dominik Szoboszlai down the wing. The match was the sixth straight game that saw him play all 90 minutes, after only having a single previous substitute appearance in his return to Premier League action on Sept. 28.
Brenden Aaronson's opener was cancelled out by Matheus Cunha just 3 minutes later as the two clubs split the points pic.twitter.com/GhquMfkox0
Brenden Aaronson is playing some of the best soccer of his career right now for Leeds United and brought his goal tally on the season to three with a strike in a 1–1 draw with Manchester United on Sunday. The goal marked his third goal contribution in the last six matches, after picking up an assist on a stellar team goal against Sunderland and his first helper of the productive run in a 3–3 draw with Liverpool on Dec. 6.On Sunday, he bolted up the pitch before sprinting between Ayden Heaven and Leny Yoro and finishing his shot past Senne Lemmens between the sticks. “I was kind of just running in behind to see if I could get lucky and sometimes you have to take a chance,” Aaronson said postgame. “The ball came to me. I think that the center back didn't know that I was going to be running off his shoulder like that. I had a good touch, and then it's just about putting the shot on target.”While he has nine goals in 56 USMNT caps and has not played consistently at the international level as of late, Aaronson is nearing a spot on the World Cup roster and a potential starting role if he keeps up his current form.
Il gol del pareggio di Wes in #JuveLecce ⚽️Gli highlights della sfida sul nostro canale su Youtube 📺 https://t.co/dvlzYq5ZiD pic.twitter.com/SIowCXFqBR
Weston McKennie is proving an invaluable piece for Juventus and started 2026 on the best personal note possible, with his first Serie A goal of the season in a 1–1 draw with Lecce on Saturday. Making his 205th appearance for the club, the 27-year-old took on a more attacking role than usual, playing in his eighth position this season under manager Luciano Spalletti's versatile demands.While the Bianconeri will rue a missed penalty from Jonathan David, McKennie's performance was promising. In addition to his goal, he created three chances and had two shots. Riding a wave of form with five goal contributions across his last nine games in all competitions, McKennie will look to lead fourth-place Juventus to a win in their next match against 10th-place Sassuolo on Tuesday.
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Ben Steiner is an American-Canadian journalist who brings in-depth experience, having covered the North American national teams, MLS, CPL, NWSL, NSL and Liga MX for prominent outlets, including MLSsoccer.com, CBC Sports, and OneSoccer.
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2026 World
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Entering 2026, the U.S. men's national team is trending upward. After months of apathy and doubt, optimism is suddenly abundant. But that does not mean the USMNT is anything close to a finished product. With a home World Cup six months away, its roster and its starting 11 are far from settled.
Some of the biggest USMNT stories of early 2026, therefore, will be battles that play out remotely. The national team will gather only once between now and the naming of a World Cup roster in late May. Players, whether in MLS or abroad, will have to prove their worth at their clubs.
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Some, surely, have already done that. Christian Pulisic, for example, leads the Italian Serie A in goals plus assists per 90 minutes (and across all of Europe's Big Five leagues, he's second to only Harry Kane). He will start for the U.S. on June 12 against Paraguay, if healthy.
But other spots — in the 11, in head coach Mauricio Pochettino's rotation, and on the 26-man roster — are up for grabs. Questions remain unanswered. Who will start in midfield? Who will play right back, or right center back and wingback? Is there room on the roster, or even on the field, for Gio Reyna? And what about the strikers behind Folarin Balogun?
The following is a breakdown of those questions and others, and the key personnel dilemmas that remain unsolved as the World Cup nears.
The evolution of the national team over the past seven months had an enormous impact on what the position battles look like across the field, and it has reshaped how we think about the U.S. midfield entirely.
After operating through most of the last cycle and the first half of this cycle in a 4-3-3, the U.S. now plays in a hybrid 3-4-2-1/4-4-2 setup. That tweak means the U.S. will likely start with two attacking midfielders on the field along with two central midfielders. And the group of players being considered for those four spots grew after the Gold Cup and fall friendlies.
Pochettino is thus weighing two elements to the midfield: what's the best pairing for midfielders in front of a back line that, when the U.S. has the ball, plays out of a back three; and who are the two best attacking midfielders to complement the wingback/wingers and No. 9.
Let's tackle the deeper-lying position battle first.
Tyler Adams feels like a natural starter as one of those two players, but while Adams was often seen as the No. 6 in the U.S.'s 4-3-3, with Weston McKennie and Yunus Musah playing in front of him, there is a real argument to be made that allowing Adams to roam and attack in midfield is the better use of his skill set. Thus, Pochettino could be looking at players such as Tanner Tessmann, Cristian Roldan, Aidan Morris, and Johnny Cardoso as fighting it out at the No. 6.
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Adams, then, holds down the top spot on the depth chart in that box-to-box role, but Pochettino has also coaxed fantastic performances out of players such as Sebastian Berhalter, McKennie, Tessmann — and even Timmy Tillman — in that role.
McKennie is maybe the personification of how the math in midfield has changed. Whereas he was always seen as a natural midfield partner for Adams, tucked in behind Pulisic in a 4-2-3-1, or as a more advanced central midfielder in the 4-3-3, he now might be a better fit as one of the dual No. 10s in the 3-4-2-1 formation rather than playing behind the attacking line. Or even as a substitute for Adams in the box-to-box role.
And then, of course, there's the question of Adams' health. The Bournemouth midfielder left a 4-4 draw against Manchester United on Dec. 15 with a torn MCL and will miss up to three months. That would put Adams back on the field in March, so he should have time to recover ahead of the World Cup, but his injury is a reminder that the math in midfield can swing dramatically based on the health of any one player.
Our current depth chart for the two central midfield roles:
The question about the two attacking midfield roles has to begin with Gio Reyna's health, form and availability.
Reyna, 23, was once considered the best American prospect ever. His early seasons at Dortmund made him look like the natural follow-up to Pulisic, but the last four seasons have been marred by injury. Reyna totaled just 2,925 minutes across all competitions with his club team since 2021-22 — an average of 731.25 per season. There are real concerns about whether he can stay healthy for a full season and also get back to his previous levels of production.
There is a glimmer of hope. Reyna started four consecutive games for Borussia Monchengladbach in December, the first time he's completed that feat at club level since August 2021. His 372 minutes in the Bundesliga this year surpass his output for all of last season with Dortmund. Reyna has yet to score or assist for Gladbach, but he did pick up a goal and assist in his return with the U.S. in November.
That adds intrigue to the battle in attacking midfield.
Pulisic is a locked-in starter for the U.S. The Milan man is turning in yet another fantastic season in Italy. Pulisic has eight goals and two assists in 12 league games for Milan this season, two goals behind Lautaro Martínez for the Serie A lead.
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That makes for a three-way battle at the other spot. In the mix: Malik Tillman, one of the U.S.'s standouts in 2025; McKennie, who has been sharp for Juventus this year, with two Champions League goals; Reyna; Diego Luna, a Pochettino favorite; and Tim Weah, who is an option as a right back/right wingback/winger, but can also play inside.
How many midfielders will Pochettino bring to the World Cup? That could be impacted by the versatility of players elsewhere and the fact that the flexibility of the lineup puts an emphasis on players who can help in multiple spots.
The current depth chart:
What even is a right back in this current system? It depends on who you ask and when you ask.
It is notable, however, that Sergiño Dest started alongside Alex Freeman in the 5-1 win over Uruguay, and while Freeman sometimes looked like a third center back, he was actually considered the right back while Dest was a winger.
That sums up the possibilities for Pochettino at the World Cup. In a system in which the U.S. builds out with three but often defends in a four, the outside backs have become sort of hybrid wingers/wingbacks/fullbacks, depending on the size and balance of the team.
Over the past few months, that means Max Arfsten has played as a left back/left wingback, while the right back — whether it was Dest, Tim Weah or Freeman — has been more of a winger than a defender.
Will that look the same when and if Antonee Robinson is back healthy and in the U.S. lineup again? Or will he be asked to push higher up the field? That's something we might learn in March. But the battle of the right backs has become an interesting study in the different ways the U.S. can beat you. Freeman's ability to play as a hybrid third center back/right back is especially intriguing because it adds another attacking element for the U.S.
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Pochettino might opt to start three center backs in the back line, as he has before with Chris Richards, Tim Ream and Miles Robinson or Mark McKenzie. He might opt instead to start a right back in that spot, as he has with Joe Scally and Freeman. If he opts for the latter, it gives the U.S. some different looks to unbalance the opponent.
Here's how we think things stand right now in the pecking order:
Goalkeeper has been a position of uncertainty ever since Matt Turner's club minutes vanished in Europe. Freese got an opportunity in June, won the job, and has played every single minute of every match since. So, is the competition closed? Or could Turner win back his place if he re-finds his 2022 form in MLS this spring?
He still has more upside than Freese. He also has World Cup experience. The only scenario where the goalkeeper position isn't viewed as something of a weakness for the USMNT in June is the one where Turner, now back with the New England Revolution, becomes the shot-stopping machine he was a few years back.
Freese, though, has proven himself to Pochettino. And like Turner, he's sharp and well-liked by teammates. He's clearly the frontrunner for the No. 1 shirt, but U.S. coaches will surely be watching both Matts (and other goalkeepers) once the MLS season begins in February.
Balogun has almost cemented himself as the USMNT's starting striker, but beyond him, the depth chart remains in flux. Haji Wright has performed well for both Coventry City and the national team. Ricardo Pepi was performing well a year ago before his knee injury, and he has recaptured that goalscoring form with goals in four straight Eredivisie games and in three of his last four Champions League appearances (all off the bench).
Meanwhile, Patrick Agyemang (six goals in his debut season at Derby County in the EFL Championship) endeared himself to Pochettino at this summer's Gold Cup and brings a physical presence that this striker group would otherwise lack. And yes, although Josh Sargent has likely fallen off the roster bubble, he — or another forward — could always play his way back into the mix.
The question for Pochettino, then, is twofold:
The answers, as always with strikers, depend on form. Pepi feels like the biggest wild card. Agyemang is probably on the outside looking in, but could fill a unique role — if he continues playing well enough for Derby County. Plenty remains up in the air.
World Cup
2026 World
Cup Prep
John Dorton / ISI Photos / USSF
Entering 2026, the U.S. men's national team is trending upward. After months of apathy and doubt, optimism is suddenly abundant. But that does not mean the USMNT is anything close to a finished product. With a home World Cup six months away, its roster and its starting 11 are far from settled.
Some of the biggest USMNT stories of early 2026, therefore, will be battles that play out remotely. The national team will gather only once between now and the naming of a World Cup roster in late May. Players, whether in MLS or abroad, will have to prove their worth at their clubs.
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Some, surely, have already done that. Christian Pulisic, for example, leads the Italian Serie A in goals plus assists per 90 minutes (and across all of Europe's Big Five leagues, he's second to only Harry Kane). He will start for the U.S. on June 12 against Paraguay, if healthy.
But other spots — in the 11, in head coach Mauricio Pochettino's rotation, and on the 26-man roster — are up for grabs. Questions remain unanswered. Who will start in midfield? Who will play right back, or right center back and wingback? Is there room on the roster, or even on the field, for Gio Reyna? And what about the strikers behind Folarin Balogun?
The following is a breakdown of those questions and others, and the key personnel dilemmas that remain unsolved as the World Cup nears.
The evolution of the national team over the past seven months had an enormous impact on what the position battles look like across the field, and it has reshaped how we think about the U.S. midfield entirely.
After operating through most of the last cycle and the first half of this cycle in a 4-3-3, the U.S. now plays in a hybrid 3-4-2-1/4-4-2 setup. That tweak means the U.S. will likely start with two attacking midfielders on the field along with two central midfielders. And the group of players being considered for those four spots grew after the Gold Cup and fall friendlies.
Pochettino is thus weighing two elements to the midfield: what's the best pairing for midfielders in front of a back line that, when the U.S. has the ball, plays out of a back three; and who are the two best attacking midfielders to complement the wingback/wingers and No. 9.
Let's tackle the deeper-lying position battle first.
Tyler Adams feels like a natural starter as one of those two players, but while Adams was often seen as the No. 6 in the U.S.'s 4-3-3, with Weston McKennie and Yunus Musah playing in front of him, there is a real argument to be made that allowing Adams to roam and attack in midfield is the better use of his skill set. Thus, Pochettino could be looking at players such as Tanner Tessmann, Cristian Roldan, Aidan Morris, and Johnny Cardoso as fighting it out at the No. 6.
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Adams, then, holds down the top spot on the depth chart in that box-to-box role, but Pochettino has also coaxed fantastic performances out of players such as Sebastian Berhalter, McKennie, Tessmann — and even Timmy Tillman — in that role.
McKennie is maybe the personification of how the math in midfield has changed. Whereas he was always seen as a natural midfield partner for Adams, tucked in behind Pulisic in a 4-2-3-1, or as a more advanced central midfielder in the 4-3-3, he now might be a better fit as one of the dual No. 10s in the 3-4-2-1 formation rather than playing behind the attacking line. Or even as a substitute for Adams in the box-to-box role.
And then, of course, there's the question of Adams' health. The Bournemouth midfielder left a 4-4 draw against Manchester United on Dec. 15 with a torn MCL and will miss up to three months. That would put Adams back on the field in March, so he should have time to recover ahead of the World Cup, but his injury is a reminder that the math in midfield can swing dramatically based on the health of any one player.
Our current depth chart for the two central midfield roles:
The question about the two attacking midfield roles has to begin with Gio Reyna's health, form and availability.
Reyna, 23, was once considered the best American prospect ever. His early seasons at Dortmund made him look like the natural follow-up to Pulisic, but the last four seasons have been marred by injury. Reyna totaled just 2,925 minutes across all competitions with his club team since 2021-22 — an average of 731.25 per season. There are real concerns about whether he can stay healthy for a full season and also get back to his previous levels of production.
There is a glimmer of hope. Reyna started four consecutive games for Borussia Monchengladbach in December, the first time he's completed that feat at club level since August 2021. His 372 minutes in the Bundesliga this year surpass his output for all of last season with Dortmund. Reyna has yet to score or assist for Gladbach, but he did pick up a goal and assist in his return with the U.S. in November.
That adds intrigue to the battle in attacking midfield.
Pulisic is a locked-in starter for the U.S. The Milan man is turning in yet another fantastic season in Italy. Pulisic has eight goals and two assists in 12 league games for Milan this season, two goals behind Lautaro Martínez for the Serie A lead.
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That makes for a three-way battle at the other spot. In the mix: Malik Tillman, one of the U.S.'s standouts in 2025; McKennie, who has been sharp for Juventus this year, with two Champions League goals; Reyna; Diego Luna, a Pochettino favorite; and Tim Weah, who is an option as a right back/right wingback/winger, but can also play inside.
How many midfielders will Pochettino bring to the World Cup? That could be impacted by the versatility of players elsewhere and the fact that the flexibility of the lineup puts an emphasis on players who can help in multiple spots.
The current depth chart:
What even is a right back in this current system? It depends on who you ask and when you ask.
It is notable, however, that Sergiño Dest started alongside Alex Freeman in the 5-1 win over Uruguay, and while Freeman sometimes looked like a third center back, he was actually considered the right back while Dest was a winger.
That sums up the possibilities for Pochettino at the World Cup. In a system in which the U.S. builds out with three but often defends in a four, the outside backs have become sort of hybrid wingers/wingbacks/fullbacks, depending on the size and balance of the team.
Over the past few months, that means Max Arfsten has played as a left back/left wingback, while the right back — whether it was Dest, Tim Weah or Freeman — has been more of a winger than a defender.
Will that look the same when and if Antonee Robinson is back healthy and in the U.S. lineup again? Or will he be asked to push higher up the field? That's something we might learn in March. But the battle of the right backs has become an interesting study in the different ways the U.S. can beat you. Freeman's ability to play as a hybrid third center back/right back is especially intriguing because it adds another attacking element for the U.S.
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Pochettino might opt to start three center backs in the back line, as he has before with Chris Richards, Tim Ream and Miles Robinson or Mark McKenzie. He might opt instead to start a right back in that spot, as he has with Joe Scally and Freeman. If he opts for the latter, it gives the U.S. some different looks to unbalance the opponent.
Here's how we think things stand right now in the pecking order:
Goalkeeper has been a position of uncertainty ever since Matt Turner's club minutes vanished in Europe. Freese got an opportunity in June, won the job, and has played every single minute of every match since. So, is the competition closed? Or could Turner win back his place if he re-finds his 2022 form in MLS this spring?
He still has more upside than Freese. He also has World Cup experience. The only scenario where the goalkeeper position isn't viewed as something of a weakness for the USMNT in June is the one where Turner, now back with the New England Revolution, becomes the shot-stopping machine he was a few years back.
Freese, though, has proven himself to Pochettino. And like Turner, he's sharp and well-liked by teammates. He's clearly the frontrunner for the No. 1 shirt, but U.S. coaches will surely be watching both Matts (and other goalkeepers) once the MLS season begins in February.
Balogun has almost cemented himself as the USMNT's starting striker, but beyond him, the depth chart remains in flux. Haji Wright has performed well for both Coventry City and the national team. Ricardo Pepi was performing well a year ago before his knee injury, and he has recaptured that goalscoring form with goals in four straight Eredivisie games and in three of his last four Champions League appearances (all off the bench).
Meanwhile, Patrick Agyemang (six goals in his debut season at Derby County in the EFL Championship) endeared himself to Pochettino at this summer's Gold Cup and brings a physical presence that this striker group would otherwise lack. And yes, although Josh Sargent has likely fallen off the roster bubble, he — or another forward — could always play his way back into the mix.
The question for Pochettino, then, is twofold:
The answers, as always with strikers, depend on form. Pepi feels like the biggest wild card. Agyemang is probably on the outside looking in, but could fill a unique role — if he continues playing well enough for Derby County. Plenty remains up in the air.
First Minister John Swinney made the announcement during his New Year election pitch to voters in Glasgow on Monday morning.
Scotland reporter
@Jenster13
Monday 5 January 2026 15:26, UK
Scotland's first minister has proposed a national bank holiday to mark the men's football team playing in its first World Cup since 1998.
Scotland's opening game is against Haiti in Boston, with kick-off scheduled to take place at 2am UK time on Sunday 14 June.
John Swinney has proposed that Monday 15 June be designated a national bank holiday in celebration.
The first minister said 2026 is "shaping up to be a very exciting year" for Scotland - with the Commonwealth Games returning to Glasgow and the men's national football team securing their spot in the FIFA World Cup this summer.
Mr Swinney said: "The whole nation will come to a standstill in June. Even more so in July once we've seen off Brazil and progressed to the knockout stages.
"This is a moment 28 years in the waiting - and I want as many people as possible to share the occasion.
"So, friends, I can confirm today that I have written to the Privy Council, proposing that the Monday - the day after our opening game - be designated a bank holiday in Scotland.
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"That will mean that supporters across the country can watch our men's team in their first World Cup match for almost 30 years and share in the chance for Scotland to be on the world stage, to attract business development, to create tourism and hospitality interest within the country, and to make deep and lasting cultural and sporting connections."
The proposal will be formally confirmed once rubberstamped by the King.
Mr Swinney made the announcement during his New Year election pitch to voters in Glasgow on Monday morning.
Ahead of the Holyrood election in May, the first minister said the SNP will "offer Scotland hope for a better future".
He added: "We've all been on the doorsteps a lot in recent months. Voters everywhere are telling us the same thing.
"The UK economy is broken. Living standards are flat as a pancake. Far too many people are living in poverty. Far too many people are struggling to make ends meet.
"Energy costs in energy-rich Scotland are scandalously high. These are the fundamental issues holding Scotland back."
Mr Swinney claimed the UK is "lurching further and further to the right" as he described the language around immigration and asylum "nothing short of disgraceful".
He added: "In this election, there are those who will seek to obtain power by spreading fear and insecurity. There are those who will seek to divide us.
"And there are those who don't care about Scotland and instead seek to use the election to further their own interests. Not the SNP."
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The first minister claimed the best way to support the nation's NHS, bring down energy bills and make daily life more affordable for people "is for Scotland to become an independent country".
However, Mr Swinney is yet to reveal a clear plan on how his party intends to deliver Scottish independence if the UK government continues to refuse requests for a second referendum.
Mr Swinney said: "To become independent, we need a referendum that will be recognised by the international community.
"In 2011, Scotland secured a referendum when the SNP won a majority. It worked in 2011 - and it will work in 2026."
Mr Swinney admitted it was an "ambitious task" as he called for a "fresh start with independence".
He said: "Let 2026 be a year when we rightly celebrate all that we are - but also imagine what we could be."
Adding: "Where others try and tell people in Scotland that they can't, let us demonstrate that we can."
During his speech, Mr Swinney also addressed the US raid on Venezuela saying he was "deeply concerned" about the situation.
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Scottish Labour leader Anas Sarwar also spoke to supporters on Monday morning.
Mr Sarwar said: "I know the prime minister and the UK Labour government are not popular with the public right now.
"So, I am not running to be Scotland's first minister in denial of the truth. I am running to be Scotland's first minister in defiance of it."
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Mr Sarwar said the "SNP have had their chance" but "blew it".
He took aim at both the SNP and Reform UK, claiming they "both play the politics of fear and blame".
He said: "The truth is, Nigel Farage does not care about Scotland. He does not understand Scotland, and he does not want to fix Scotland."
Mr Sarwar added: "I want to build something better here in Scotland. But we must confront the reasons pushing people towards Reform.
"When people feel ignored, when services fail, and when trust drains away, it creates space for those who want to divide us."
Later on Monday, Scottish Tory leader Russell Findlay pledged to cut taxes if his party gets into power this year.
Mr Findlay said the Scottish Conservatives would raise the threshold at which Scots pay income tax, as well as for those paying the higher rate of tax amid accusations the SNP and Labour favour "stealth taxes" by freezing income tax rates.
Freezing rates means those who see an increase in wages can be pulled into higher tax brackets.
Mr Findlay said: "I believe, this year, the cost of living crisis will and should define the Holyrood election.
"It's the number one concern for every family, every business, every worker, every community, indeed, the whole country.
"2026 will be the cost of living election.
"The public will have the choice between five more miserable years of SNP tax rises and wasteful spending or a new era of hope with a common sense focus on bringing down bills through economic growth."
Mr Findlay said his party would "fight to bring down bills", help Scotland's economy to thrive, lower NHS waiting lists, and raise standards in schools.
He also claimed that the Scottish welfare system "incentivises idleness" and warned that social security spending was unsustainable.
Mr Findlay said: "Scotland cannot afford to continue to park more people on benefits street."
Real Madrid have been offered the chance to sign Crystal Palace sensation Adam Wharton, but Los Blancos will face fierce competition for his signature. Premier League giants Liverpool, Manchester City, Manchester United and Chelsea are all tracking the midfielder, who will reportedly cost at least €70 million and is demanding a huge salary to leave Selhurst Park.
The race to sign one of England's most prodigious midfield talents has taken a continental twist, with reports in Spain saying that Wharton has been offered to Madrid. The 21-year-old, who has enjoyed a meteoric rise since swapping Blackburn Rovers for Crystal Palace in January 2024, has established himself as a linchpin in the Eagles' midfield, drawing admiring glances from the elite of European football.
According to Spanish outlet AS, intermediaries acting on behalf of the player have made contact with the reigning European champions to gauge their interest in bringing the Englishman to the Santiago Bernabeu. While Real Madrid have focused heavily on recruiting French and Brazilian talent in recent years - alongside the marquee signing of Jude Bellingham - the opportunity to pair Wharton with his international teammate is an intriguing proposition for the Spanish hierarchy.
However, the report suggests that while Madrid are attentive to the market, they have not yet made a definitive move. The club is currently weighing up their options as they look to future-proof their engine room, but the financial package required to land the Palace ace could prove to be a stumbling block even for a club of their stature.
Any club wishing to prise Wharton away from South London will need to possess incredibly deep pockets. Crystal Palace, who have a strong track record of developing and protecting the value of their assets, have absolutely no intention of letting their star man leave on the cheap. AS states that the Eagles have slapped a minimum price tag of €70 million (£58m) on the midfielder, a figure that would represent a massive profit on the initial £18m they paid Blackburn just two years ago.
Perhaps more significant than the transfer fee, however, are the reported wage demands. The Spanish publication claims that Wharton is seeking a "Galactico salary" to facilitate a move. This suggests the player is aware of his soaring stock and expects to be remunerated as a top-tier starter immediately, rather than stepping onto a developmental wage structure.
For Real Madrid, who manage their wage bill meticulously to accommodate superstars like Kylian Mbappe and Vinicius Junior, these demands could necessitate a significant departure from their usual policy for signing young players.
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If Madrid do decide to pass on the opportunity, Wharton will not be short of suitors closer to home. The report highlights that the entire 'Big Four' of interested parties - Liverpool, Manchester City, Manchester United and Chelsea - remain firmly in the hunt.
Liverpool have long admired Wharton's ability to break lines and dictate tempo, seeing him as a potential long-term successor to their current midfield anchors. Meanwhile, City are perpetually in the market for technically secure midfielders who can operate in Pep Guardiola's complex system, with Wharton's profile fitting the mould of a City player perfectly.
United, under the INEOS regime, are prioritising young, domestic talent, making Wharton a prime target for their continued rebuild at Old Trafford. Chelsea, true to form, are also monitoring the situation, having spent the last few years aggressively acquiring the best young talent in world football.
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Despite the noise surrounding his future, Crystal Palace find themselves in a strong negotiating position with Wharton under a long-term contract at Selhurst Park. The midfielder's calm demeanour on the pitch has been matched by his sensible approach to his career off it. Since arriving in the Premier League, he has shown a maturity beyond his years, forcing his way into the England setup for Euro 2024, though he remained an unused substitute throughout, and becoming one of the first names on the team sheet in South London.
Whether he moves to the bright lights of Madrid or stays in the Premier League to fight for titles, one thing is certain: Wharton is now considered elite property, and it will take a monumental financial package to secure his services in 2026. The bidding war has effectively begun, and the numbers being mentioned suggest it will be one of the sagas of the year.
Fans heading to the Fifa World Cup can expect more than just a game, as I discovered at an Inter Miami match last month
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Thinking about heading to the Fifa World Cup this year? The fact that the tournament takes place across three countries – United States, Canada and Mexico – should make it a bucket list experience for football fans. Unfortunately, the ticket prices reflect that reality: with even the cheapest tickets priced at multiples of the last tournament, and final tickets going for over $3,000.
As someone who has been to several “soccer” games on the other side of the pond, I wasn't that surprised by the prices. When I attended an Inter Miami game earlier this month, the cheapest seats were north of £200, with the better seats going for well into the four figures.
Though the higher prices might not be the only surprise awaiting British fans heading over the pond. Here are a few other things to be aware of.
We all know Americans don't do things by halves – and football matches are no exception. If you are going to a game in the States, you can expect a lot more pageantry that you might get in Europe. The whole focus is on making the entire thing into an afternoon or evening-long spectacle.
Don't worry: it isn't a total abomination. There are no cheerleaders or rodeo cowboys during the half-time break. But you can expect lots of snazzy video packages on the big screen, deafening pyrotechnic displays just before kick off, and even those “fan cams” they have at baseball games. Though don't expect the old school “kiss cam”: these days it's been retired due to PC sensibilities.
There's also a healthy dose of patriotism with the national anthem played before all games. Attendees are expected to stand up and remove their hats, though singing along is optional.
There is one thing you can always say about watching sport in America: you're unlikely to go hungry. Visit most stadiums and you will find a veritable smorgasbord of different food concessions, either on the inner perimeter of the stadium or just outside.
Tacos, fried chicken, pizza, poke bowls – you name it. And often from recognised brands and award-winning street food vans, rather than in-house stadium slop. Honestly, the sheer variety on offer makes the typical British stadium hospitality – pies and nachos – feel like something from the Soviet Union.
You can booze too, including during the action. Walk around the stadium and you'll find dozens of enthusiastic vendors hawking beers from their ice-filled cool boxes. One word of warning though: it's common for them to only sell the massive 700ml cans of US beer. Given the hot weather, I've never managed to finish one without the last bit going warm.
Oh and you'll also pay hefty prices for the privilege of all that hospitality. When I last watched Inter Miami play, I paid around £20 for a single beer (including tip) and £30 for a burrito before the game.
If you find the prices a little steep, why not try “tailgating” – the American practice of firing up impromptu BBQs and knocking back a few beers in the parking lot before the game. The tradition began with American football but has been carried over to the beautiful game as well. And provided it stays within the stadium car park (or parking lot), it's all legal.
Be careful about wandering out of the designated area carrying a drink, though, as there's every chance you could be fined under the ubiquitous “open container” laws.
There's a persistent stereotype that US football fans are a bit clueless and passionless. In my experience, that's far from true. If anything, American soccer fans are often totally obsessed, and their knowledge of the Premier League can be impressive.
It's definitely true that games are much more family-friendly than you might find in Europe. You'll see lots of families with young children. But every MLS team also has its share of hardcore partisan fans too. In general, they tend to sit in one particular terrace, where they can make as much noise as they like.
In those areas there's a carnival atmosphere: expect big drums and trumpets, coloured smoke bombs, and lots of coordinated chanting. The vibe is very rarely aggressive, but I have seen witless opposition fans being shoved out of the enclosure after wandering in out of curiosity.
In all my time in the US, I've never got my head around this one. MLS games routinely kick off several minutes after their advertised starting time. And for no particular reason: the stadiums are usually full before the scheduled time rolls around.
Maybe that will change with the World Cup, which presumably has strict rules about these things due to the broadcast deals. Then again, given the ongoing bromance between Donald Trump and Gianni Infantino, who knows who will be calling the shots.
This one is hardly exclusive to America, but it bears repeating anyway. When 25,000 football fans leave the stadium at once, the vast majority of them travelling by car, all those eight-lane freeways count for nothing: even the most sprawling US city can be brought to an instant standstill.
I've experienced this a few times. In pint-sized Cincinnati, I was lucky to be able to walk back to my hotel, feeling slightly smug as I walked past all the stationary vehicles. By contrast, in soccer-mad Miami, I ended up enduring one of the slowest, and most expensive, Uber rides of my life, as it took more than an hour to crawl a few miles.
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The jig is up for Ruben Amorim. After 14 unforgettable months as head coach, he has been sacked by Manchester United. He broke many records for the wrong reasons, lost a European final to Tottenham and was dumped out of the Carabao Cup by fourth-tier side Grimsby Town. Yet it is only now that those upstairs at Old Trafford have decided to pull the trigger.
After his final game in charge, a credible 1-1 draw at rivals Leeds United, Amorim couldn't help himself, targeting his superiors in a rant that he wanted to be "the manager, not the coach". Though United claim his firing was more down to results, even with a mediocre team sitting a modest sixth in the Premier League table, do you think we'd really be here talking about Amorim's replacements if he just kept quiet in that press conference instead of running his mouth?
Darren Fletcher is now in charge of the first team on an interim basis, with a caretaker reportedly then coming in until the end of the season, while the club search for a permanent replacement. But who should that person be? Who could United get that's happy to be the head coach, not the manager? GOAL ranks the top contenders:
Every time the United job becomes vacant, Zinedine Zidane is linked to it. He is merely here as an obligation to keeping the tradition alive.
The former Real Madrid boss will not be heading to Old Trafford. If he is to return to management again, it's almost certainly going to be with the France national team, not in the Premier League.
"I will definitely return to coaching. In the future, I don't know, one of my goals is to coach the French national team. We'll see," he said back in October, one month before French media began reporting he would indeed succeed Didier Deschamps.
Unai Emery has done brilliantly to rebuild his reputation in English football. He was deemed a failure at Arsenal after taking on the unenviable job of succeeding Arsene Wenger, but after a short stint back home in Spain with Villarreal - which included beating United in the 2021 Europa League final - he is back at the top of his game.
Having found Aston Villa in a relegation scrap, Emery has turned them into consistent top-four contenders and rebuilt the club in his image. Therein lies why he probably won't be heading to Old Trafford. Villa will give everything in order to keep Emery, and United probably won't be able to offer the same level of power and autonomy he currently enjoys in the West Midlands.
Eddie Howe feels like the INEOS sporting philosophy bottled in a football manager, focusing on mindset and self-improvement. That, plus millions and millions of pounds, is what has made his Bournemouth and Newcastle teams so dynamic.
The Magpies haven't quite hit expectations this season, but they're still likely to reach the Champions League knockout stages and well in with a shout for a top-four finish. Unless those on Tyneside decide now is the time to part company with Howe and move in a new direction, he won't be in the frame for the United gig.
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The one manager, the one person altogether, who's even more INEOS-coded than Howe is Sir Gareth Southgate. Marginal gains and committing to culture while ultimately not actually winning championships anyway? Yeah, that's the good stuff.
Southgate and INEOS have long been said to have a great relationship, but the ex-England boss has made clear he's not going to return to management just for the sake of it.
"I am not desperate to stay in football," he said in November. "I have had 37 years in football. You can never say never, because I have just seen Martin O'Neill at his age go to Celtic, but it is not something that is high on my agenda at the moment. I am enjoying the work around leadership. I am enjoying my work with young people. I am very determined to try and make a difference there. And so, I am very relaxed about not being in football at the moment."
The Three Lions role suited Southgate to a tee, but the cut-and-thrust of the Premier League with one of the most scrutinised clubs in the world wouldn't.
United confirmed on Monday that former midfielder Fletcher has been placed in interim charge of the first team. The Scot returned to the club in 2021 as a technical director and last summer was given the Under-18s manager's job.
There's half a chance this experience both upstairs and on the training ground could help Fletcher get the full-time job, putting together a string of results a la Ole Gunnar Solskjaer in 2018-19, but it's still an improbable outcome nonetheless. United's best hope is Fletcher makes the team loom competent and the sum of its parts again before deciding on a permanent successor to Amorim, but could they be swayed to keep him if they go on a run and secure Champions League qualification?
Unlike many of the names on this list, ex-midfielder Michael Carrick actually has experience of managing United. He was a key member of Solskjaer's backroom staff until the Norwegian's sacking in November 2021, after which Carrick took caretaker charge prior to Ralf Rangnick's arrival until the end of that season.
Carrick, to his credit, won two and drew one of his three games in the dugout, and they weren't exactly easy games either. A 1-1 draw away at title-chasing Chelsea was followed by a last-gasp win away at Villarreal in the Champions League. His final match saw United beat Arsenal 3-2 at Old Trafford.
Deciding to pursue his career as a head coach rather than an assistant, Carrick left and was appointed Middlesbrough manager in 2022, guiding them to the Championship play-offs in his first season, and they remained contenders for promotion before his sacking last summer.
To paraphrase every middle-aged pundit ever, Carrick knows the club. Would that be enough to convince INEOS?
If United do want a short-term option to bring them back to stability, then picking up the phone and convincing Solskjaer to return might not be the worst idea in the world.
He's done it before, he loves the club and probably wouldn't be under any illusions over the length of his tenure this time around. There was even talk of that post-Ten Hag and pre-Amorim. The optics of such a return would be difficult for the top brass to stomach though, and that's before you think of the potential parallels to Frank Lampard heading back to Chelsea in 2023 and winning only once in his 11 games.
The best candidate of Solskjaer's former staff is undoubtedly Kieran McKenna, who has worked miracles as manager of Ipswich Town. He found them squandering in League One back in 2021, but back-to-back promotions starting from his first full season saw the Tractor Boys return to the Premier League in the span of two years.
They were relegated at the end of 2024-25 without much of a fight, but you could hardly blame McKenna for not keeping a team which still had plenty of players from their days in the third tier for not staying up. Ipswich seem primed to be promoted back to the top-flight this season, too.
Again, the issue here is public perception. Could United really get away with appointing a Championship manager to solve this crisis?
After his abrupt exit from Brighton in 2024, Roberto De Zerbi was one of several candidates spoken to by United's new hierarchy as they weighed up the future of Erik ten Hag. The plus side of the Italian was the style of play he preaches, often praised by other managers as one of the game's best tacticians and thinkers. The negatives were how combustible and temperamental he could be.
In the end, they opted to stick with Ten Hag for a few months more, while De Zerbi, who claimed to have even received a contract offer from United, headed to France to manage Marseille. Though you'd imagine he'd be keen on a Premier League return, it's hard to envisage the Red Devils' powerbrokers wanting someone so fiery to lead them through this stage of their project, despite their continued admiration of the Italian.
With seemingly every chance he gets, Mauricio Pochettino talks up returning to Tottenham one day. The United States boss hasn't hidden from his desire to manage in the Premier League again, particularly if the opportunity came with Spurs.
But there's a history between Pochettino and United that just won't go away. When Jose Mourinho was sacked in 2018, the Argentine was the immediate favourite to replace him. Tottenham were rattled so much that they even asked journalists not to ask questions on the subject. The job went to Solskjaer on that occasion, but when the Norwegian left a couple of years later, Pochettino was pitted in a direct head-to-head with Ajax's Ten Hag. Again, Pochettino lost out.
Pochettino wouldn't be available until after the U.S.' World Cup campaign on home soil this summer, but his insistence on managing in England once more means he has to be a contender for United again after Fletcher's interim spell.
The second of three managers who won't be an option until the World Cup concludes, Thomas Tuchel is another name who has held talks over the United job before. Like De Zerbi, the club decided against furthering discussions in order to stand by Ten Hag.
Of all the coaches on this list, Tuchel is both the most accomplished and the most qualified. There aren't many better active managers in all of football. But can United really go back to him with their tails between their legs and say they were wrong to overlook him two years ago? Could they ask Tuchel to come and sort them out 24 months behind schedule? It might be worth a try if they want to be successful.
In retrospect, Xavi's tenure as Barcelona head coach was pretty successful. He took over in 2021 with them ninth in La Liga and still reeling from Lionel Messi's summer departure, but led them back to second place that season before winning the title the following year, all the while continuing to promote and trust in youth. That was against the backdrop of Barca's financial crisis and the relentless pressure of the Spanish press.
That hounding clearly took a toll on Xavi, who seemed drained by the time he left the club in 2024. The English press is much tamer in comparison, while he has previously suggested he would love to test himself in the Premier League. United might be able to provide him with that opportunity, with reports in recent months claiming the 45-year-old would relish such a chance.
On paper, Julian Nagelsmann is the exact sort of head coach that United in the INEOS era should be chasing. He's tactically flexible, modern in every sense and proven both at massive teams (Germany and Bayern Munich) and those looking to break into the established elite (RB Leipzig and Hoffenheim).
Still only 38 and at the top of his game, Nagelsmann feels destined to manage in the Premier League one day. As with Pochettino and Tuchel, that may not come until after the World Cup, but if he can give United his word that he will take the job as soon as Germany's tournament is over, he would almost definitely be worth waiting for.
Imagine time travelling back to Christmas Day and say that the unemployed Enzo Maresca would be in the running to succeed the sacked Amorim. What a wild start it's been to 2026!
Given how many Manchester City alumni are already making the big decisions at United, from CEO Omar Berrada to director of football Jason Wilcox, you'd think they'd already have Maresca, their former U23s coach, on their radar. But talks about succeeding Pep Guardiola across town, plus his Chelsea dismissal being almost parallel to Amorim's, means it would be hard to sell Maresca on a project where he again doesn't play a larger and more important role. Maybe those existing relationships with the Old Trafford hierarchy could make that an easier for him to swallow, however.
If United want a modern, proven head coach who's happy to play his part as a cog in the system on the training pitch and in the dugout, then Andoni Iraola should be in their thinking. Bournemouth, despite losing all of their best players year on year, remain the most entertaining team in the Premier League, not least showcased by their thrilling 4-4 draw at Old Trafford just last month. They have a clear style and philosophy regardless of which players are on the pitch.
The appointment of Amorim proved to be a failure because he wasn't suited to the week-to-week pressures of the Premier League and wanted to have a bigger say in club matters. It didn't fall apart because of the club's ambition. A swing on Iraola, someone with two-and-a-half years of positive experience in England and has recognised his standing as only the head coach of a mid-table team like Bournemouth, may be seen as similarly radical, but there would at least be method behind that madness this time around.
Crystal Palace's successful 2025 using a similar 3-4-3 system to Amorim's which crashed and burned saw Oliver Glasner heavily linked to the United post. With the Austrian unlikely to stay at Selhurst Park beyond the expiration of his contract this summer, expect these stories to return to the news cycle again.
With United partway to constructing a 3-4-3 that has more square pegs in square holes, you can understand if the board pivot to Glasner to pick up where Amorim left off and work from there. Promise him what Steve Parish can't at Palace and he might make the step up to an elite-level manager.
Glasner might be at that level already having already won the Europa League and FA Cup, and sooner or later a top club will give him a go. Why can't that be United? And, judging by reporting from the Daily Telegraph who say he's indeed their top target, why won't that be United?
Alejandro Garnacho has publicly revelled in Ruben Amorim's sacking by Manchester United. The Portuguese tactician has been relieved of his duties at Old Trafford as a forgettable 14-month tenure is brought to a close. Garnacho was among those to be frozen out of the Red Devils fold by Amorim, leading to him leaving for Chelsea, and the Argentina international appears to have taken great delight in seeing his former boss dismissed.
Amorim inherited the managerial reins at Old Trafford in November 2024. He made it clear from the off that he would be implementing the 3-4-3 system that had served him so well during a title-winning spell at previous club Sporting.
That formation did not play to the strengths of several wingers that were tied to United at the time. Brazil international Antony, homegrown star Marcus Rashford and England forward Jadon Sancho were all phased out - with all of them currently plying their club trade outside of Manchester.
Garnacho, another product of the Red Devils' fabled academy system, also struggled to win over Amorim. Questions were asked of the 21-year-old's attitude, with it becoming apparent at the end of the 2024-25 campaign that there was no future for him at United under the Portuguese tactician.
A £40 million ($54m) transfer to Chelsea was subsequently completed, allowing Garnacho to start afresh at Stamford Bridge. While that new challenge has been embraced, the tricky winger continues to keep an eye on events at Old Trafford.
On January 5, it was revealed that Amorim had been forced through the exits in Manchester. He took in just 63 games at the helm and has paid the price for inconsistency on the field and public blasts at the United board off the pitch.
Garnacho hinted after the 2025 Europa League final, which saw United suffer a 1-0 defeat to domestic rivals Tottenham, that he was ready to walk away from Amorim's reign in Manchester. He said: “Up until the final I played every round helping the team, and today I play 20 minutes, I don't know. The final will influence [my decision] but the whole season, the situation of the club. I'm going to try to enjoy the summer and see what happens afterwards.”
His brother, Roberto, posted on social media: “Working as no-one else, helping every round, coming from two goals in the last two finals, just to be on the pitch for 19 mins and get thrown under the bus.”
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Garnacho is not prepared to forgive and forget when it comes to Amorim. It was quickly noted by fans that he had liked an Instagram post from transfer guru Fabrizio Romano that confirmed the departure of another manager from the Manchester United hotseat.
Garnacho said of severing ties with United when linking up with Enzo Maresca at Chelsea: “Sometimes in life you have to change things to maybe take a step forward or to improve as a player. It was the right moment, also the right club, so it was an easy decision.
“I spoke with [Maresca, before joining], he explained everything to me. Now working together I think we are doing well, we are going to improve with time. He trusts me. So that's the most important [thing] — we have confidence and we are going to improve.
“The most important thing [a coach can give] is confidence. He speaks with me every week and I think we're going to be better — me as a player and the team all together, with time. There's confidence between manager and player.”
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Garnacho is no longer working with Maresca, as the Italian tactician is another of those to have been sacked by a Premier League heavyweight early in 2026. The Blues are expected to hand the reins to former Derby and Hull City boss Liam Rosenior, who will be eager to see what Garnacho has to offer.
United have announced that Darren Fletcher will be taking charge of first-team affairs at Old Trafford on an interim basis. Maresca is among the names being linked with the Red Devils, with it possible that he will make an immediate return to top-flight management in England.
It was a mic drop moment that came out of the blue and yet seemed to have been brewing for a long time. Ruben Amorim was getting through a potentially difficult press conference after drawing at Leeds with little fuss, giving the assembled journalists little to feed on. But then came the bombshell moment which has led to him ultimately being sacked just 14 months after taking over at Old Trafford.
Amorim had looked downbeat and despondent in his last pre-match briefing, clearly upset about something but unwilling to say what it was as he repeated, "I don't want to talk about it" three times when asked if anything had changed between him and sporting director Jason Wilcox. But when asked right at the end of the press conference at Elland Road if he still felt the confidence from the board of directors, he didn't just take the bait, he bit the line off.
"To start with that, I noticed that you received selective information about everything," he began. "I came here to be the manager of the Manchester United, not to be the coach of Manchester United. And that is clear. I know that my name is not [Thomas] Tuchel, it's not [Antonio] Conte, it's not [Jose] Mourinho, but I'm the manager of Manchester United. And it's going to be like this for 18 months, or when the board decides to change."
With one answer, a routine post-game press conference suddenly felt like a scene from a television drama. And Amorim did not stop there, repeating that he wanted to be "the manager, not the coach" twice more before delivering the show-stopping line: "In every department - the scouting department, the sporting director needs to do their job, I will do mine for 18 months and then we move on."
But instead of another 18 months, Amorim only got another 19 hours in the job as he was sacked on Monday morning. He could hardly have been surprised given his press conference at Leeds felt like a resignation statement. Despite his often strained relationship with the media, Amorim was using them to speak out against the board who had hired him. And as Enzo Maresca had just witnessed at Chelsea and Nuno Espirito Santo found with Nottingham Forest, once you do that, there is usually only one winner.
Amorim has had no shortage of critics during his time in charge of United, be it rival pundits such as Jamie Carragher or Red Devils' legends Wayne Rooney, Gary Neville and Paul Scholes. But he always felt the support of the board, despite presiding over the club's lowest league finish in 51 years and failing to qualify for Europe for the first time in 11 years after losing the Europa League final to a very poor Tottenham team.
In October, Sir Jim Ratcliffe said he would be happy to give Amorim three years to "demonstrate he is a good coach", comparing him to Mikel Arteta and how the Gunners gave the Spanish coach time to get things right after a difficult first three seasons.
Previously in June, chief executive Omar Berrada had compared Amorim to Pep Guardiola, whom he had worked with at Manchester City, as the Portuguese, "stuck to his principles and given what he'd won, he had an enormous amount of credit in the bank."
"He was allowed that first year to be below-par by his standards. The club backed him that summer, the team started winning and created this winning cycle that lasted until this season," Berrada added on Guardiola's City tenure.
The top brass were the only allies Amorim could rely on, which is why it was so surprising to see him point the finger at them at Elland Road.
Immediately after Amorim was sacked, United sources were keen to point out that he had unwavering support from everyone within the club and insisted that there had been no power struggles or ultimatums. But there was clearly unease between the coach and sporting director Wilcox, who was believed to have encouraged him to move away from the 3-4-2-1 shape he had used in almost every game.
Amorim's strict adherence to his beloved formation has proved to be his undoing, as many predicted it would. It held the team back on the pitch and it ultimately led to a rift between him and the club's hierarchy.
A source who had previously worked with Amorim was not surprised when he saw the coach lash out in the press conference, as Amorim does not like to be questioned or have anyone interfere with his choices for the team. At Sporting CP, he always had full trust from the board and absolute power over team selection and new signings, but it was becoming clear that was no longer the case at United.
United sources claim that Amorim has been sacked as the club had not seen enough signs of evolution or progress. Leaving aside for a second the misguided decision the Red Devils made in appointing Amorim in the middle of last season when he wanted to wait until the summer, it is difficult to argue against their reasoning.
In his 14 months in charge, Amorim won just 24 out of 63 matches, leaving him with a win percentage of just 38.7. It is comfortably the worst record of any manager in the post-Sir Alex Ferguson era, with Louis van Gaal, Erik ten Hag, Ole Gunnar Solskjaer, Jose Mourinho and David Moyes all winning at least 52% of their games.
It is the worst record of any United coach since Frank O'Farrell in the early 1970s. And unlike Moyes, who at least had the excuse of being given just £27 million to spend on Marouane Fellaini in his first transfer window and arrived just after chief executive David Gill had departed alongside Ferguson, Amorim cannot say he was not backed in the transfer market or allowed to reshape the squad.
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Within two months of Amorim arriving, United signed Patrick Dorgu to boost their wing-back options. More significantly, the new boss was allowed to bomb Marcus Rashford out of the squad and then the club, an episode which has become more embarrassing as the striker has rebuilt his career first at Aston Villa and now at Barcelona, also returning to the England squad.
Over the summer, United shelled out £216m on new signings, including ready-made Premier League players such as Matheus Cunha and Bryan Mbeumo, a new goalkeeper in Senne Lammens and the highly-coveted Benjamin Sesko, who was also targeted by Newcastle and Arsenal and was the most expensive signing of the lot at £74m.
That made United the fifth-biggest spenders in the Premier League and the third-highest net spenders, only behind Arsenal and Liverpool, a fact that United sources were also keen to point out when Amorim was let go. They also stressed that he was fully aligned with the plan to prioritise signing three forwards over a midfielder last summer.
Having been given a much more dangerous attack, United also had a crucial advantage over all the other top clubs they were competing with this season: they have no European football to worry about. They 'earned' even more time on the training ground and even fewer games to drain players' energy when they were knocked out of the Carabao Cup by Grimsby Town, the club's first-ever defeat to a fourth-division side.
But United did not use it to their advantage. They sit in sixth place in the Premier League table after 20 games, with every team above them playing European football.
It is really a miracle that United are still within striking distance of Champions League football given their recent run of results. They have won just three of their last 11 fixtures, only facing one top-five rival in that period in Aston Villa, who beat them. They played five of the teams in the bottom six, failing to beat all of them, including a Wolves side who at the time had the worst record in English top-flight history and a dismal West Ham who were rolled over by Wolves at the weekend.
Their home form has been most infuriating. They have taken six points from their last five matches at Old Trafford, losing against 10-man Everton before drawing with each Wolves, West Ham and Bournemouth. Their one win in that period, against Newcastle, was slightly fortunate too, with the Magpies dominating the second half.
Results matter more than anything and Amorim did not get enough good ones. But beyond that, his leadership of the club has been poor in many other aspects. He has been dismissive of the club's academy, hounding out Rashford and Alejandro Garnacho while barely playing Kobbie Mainoo. He also made less than complimentary comments about youngsters such as Chido Obi and Harry Amass, which eroded a lot of his support among fans of a club that prides itself on trusting homegrown players.
Then there were the the brutal comments Amorim made which undermined the squad. He sensationally claimed he would rather field his goalkeeping coach Jorge Vital, who is in his 60s, instead of Rashford while also describing his squad as "maybe the worst team in the history of Manchester United".
Christian Eriksen recently described how badly that went down with the players: "I don't think that helped the players at all. Some stuff you can say inside and it's not too clever to say outside, to put extra pressure and put an extra label on the players who were already trying to do their best. I don't think that helped at all, no. Then if he's right or wrong, whatever, but I think for us it was a bit of like, ‘Oh, here we go again. Another headline'."
There were too many headlines during Amorim's era and they were rarely good ones. Even though 14 months seems like a short amount of time, many fans and pundits believe he should have been removed far earlier. The Europa League final defeat to Tottenham - who sacked Ange Postecoglou despite winning a first trophy in 17 years - would have been an obvious moment to change course. The defeat at Brentford in September - after which GOALcalled for him to be sacked - was another.
Amorim clung on thanks to the board's faith in him, but when he pointed the finger back at them, there was no place to hide.
Based on the author's interpretations and judgments of facts, data and events
Gianni Infantino, the president of FIFA, awards U.S. President Donald Trump the newly established FIFA Peace Prize at the Kennedy Center, in Washington, on December 5, 2025.
Scott Stinson is a journalist based in suburban Toronto.
Scott Stinson is a journalist based in suburban Toronto.
Gianni Infantino, the president of FIFA, finally spoke up about sky-high ticket prices for the 2026 World Cup, described as “extortionate” and “scandalous” by football supporters' groups in Europe and elsewhere.
Showing that he has learned something from his budding friendship with U.S. President Donald Trump, Infantino gave an explanation that was equal parts shameless and ridiculous.
Ticket prices starting at several hundred dollars for the cheap seats — many times what FIFA originally said when the World Cup was announced for the United States, Canada and Mexico — were simply necessary for the good of the sport, Infantino said.
Without the billions of dollars FIFA will rake in this year, he claimed, there “would be no football in 150 countries.”
Do you want to pay thousands of dollars to attend a World Cup game, or do you want soccer to go broke?
It is true that FIFA sends much of its revenues back to its 211 member associations — the governing bodies of soccer for nations around the world — for investment in the sport. But there is simply no reason for FIFA to increase the scale at the levels planned for this summer's tournament, which is of course being supported by hundreds of millions of public dollars.
When member nations received their ticket allotments and prices in early December, supporters were outraged to discover that group-stage games began at about US$270, more than eight times the amount charged at Euro 2024. Lower-bowl seats were listed for more than US$700. Those figures reflect a doubling of ticket prices since the last World Cup, in Qatar, in 2022.
In its 2018 bid document for this year's event, FIFA said it expected ticket prices for the group stages in North America would range between US$21 and $230. The umbrella group Football Supporters Europe said last month that the announced prices for 2026 were “a monumental betrayal of the tradition of the World Cup.”
The huge hike means that FIFA, not surprisingly, expects huge revenue increases. According to a report in The Athletic, FIFA will book more than US$2 billion in ticketing income in the four-year cycle ending with the 2026 World Cup, more than triple the previous four-year cycle. The same report says Infantino's FIFA will end up with cash reserves of more than US$4 billion by the end of this cycle.
These are staggering amounts for a non-profit organization, and it's obvious that FIFA could still generate considerable revenue while offering reasonable ticket prices. The expanded 2026 World Cup has more games, and in larger stadiums, than previous editions, so the potential for increased revenue was already baked in.
That, evidently, wasn't enough. And it all comes back to Infantino, the man who has blazed new trails of obsequiousness with his sucking up to Trump. All that revenue FIFA hoards can then be doled out back to the member nations who, in turn, will eventually vote to keep Infantino in his job.
Would it surprise you to learn that amounts paid out to member associations have more than quadrupled over the past decade? I'm guessing it would not, just as it was no surprise to anyone when Infantino's predecessor Sepp Blatter was ousted in a corruption and bribery scandal that involved, literally, stacks of cash paid out in brown paper envelopes. These guys don't even bother to do their grifting in the shadows.
Will some of FIFA's vast World Cup income make it back to the countries that need it for youth development and pitch maintenance, especially in poorer parts of the world? Of course. But you don't have to be a cynic to recognize that all those billions sloshing around in FIFA's coffers will make it that much easier for certain cronies and swells to justify their five-star hotels and private-jet jaunts.
FIFA will say its prices are justified, given the high demand for World Cup tickets. But they mean a tournament that could have been welcoming to all will instead be open only to the wealthiest among us.
No wonder Infantino and Trump seem to be hitting it off so well.
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Scott Stinson is a journalist based in suburban Toronto.
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Kudermetova claimed unapproved quotes about Rune aired on the former WTA doubles No. 1's “Spring is Calling” podcast.ByDavid KanePublished Jan 05, 2026 copy_link
Published Jan 05, 2026
Elena Vesnina addressed comments made by Veronika Kudermetova after her former doubles partner claimed parts of a 2025 interview given on Vesnina's “Spring is Calling Весна зовёт\]” podcast [aired without her consent.“My interview with Veronika was one of the first I had done for my podcast last year,” the former WTA doubles No. 1 said in an exclusive statement to TENNIS.com. “I would have never posted anything that my guest had a problem with or asked for me to remove, nor would my production team have put it on the air.”Kudermetova attempted to walk back an anecdote shared in the cold open for Vesnina's podcast, in which the married world No. 30 revealed ATP player Holger Rune had slid into her DMs on social media.
“My interview with Veronika was one of the first I had done for my podcast last year,” the former WTA doubles No. 1 said in an exclusive statement to TENNIS.com. “I would have never posted anything that my guest had a problem with or asked for me to remove, nor would my production team have put it on the air.”Kudermetova attempted to walk back an anecdote shared in the cold open for Vesnina's podcast, in which the married world No. 30 revealed ATP player Holger Rune had slid into her DMs on social media.
Kudermetova attempted to walk back an anecdote shared in the cold open for Vesnina's podcast, in which the married world No. 30 revealed ATP player Holger Rune had slid into her DMs on social media.
“It was just a private conversation between me and Elena Vesnina while we were setting up the cameras before the interview; I didn't think they would include it in the final version,” Kudermetova claimed in an interview with Tatar-Inform, a Russian-language publication. “That is, the story about Rune was off-camera. I even asked them not to include that segment. But in the end, the podcast was released, and it turned out to be quite provocative.”Vesnina, who partnered Kudermetova to reach the 2021 Wimbledon women's doubles final, has become a full-time analyst and podcaster since officially retiring from tennis in 2024, and pushed back on the accusation when asked for comment over the weekend.“We discussed the comments with her straight away after the interview and she didn't tell us there was anything couldn't publish,” Vesnina said. “But this situation has gotten out of control. For me, it was not necessary to bring so much attention to this situation.”
Vesnina, who partnered Kudermetova to reach the 2021 Wimbledon women's doubles final, has become a full-time analyst and podcaster since officially retiring from tennis in 2024, and pushed back on the accusation when asked for comment over the weekend.“We discussed the comments with her straight away after the interview and she didn't tell us there was anything couldn't publish,” Vesnina said. “But this situation has gotten out of control. For me, it was not necessary to bring so much attention to this situation.”
“We discussed the comments with her straight away after the interview and she didn't tell us there was anything couldn't publish,” Vesnina said. “But this situation has gotten out of control. For me, it was not necessary to bring so much attention to this situation.”
We discussed the comments with her straight away after the interview and she didn't tell us there was anything couldn't publish For me, it was not necessary to bring so much attention to this situation. Elena Vesnina
Kudermetova expressed regret that Rune received criticism and mocking as a result of the story, one that was echoed by fellow player Anna Kalinskaya in a later interview with another former WTA player, Anna Chakvetadze.“Veronika is not the only player to have told a story like this,” Vesnina said. “I think we've all learned something from this. When it comes to Holger, I think it was a good lesson for him to be more careful.”A two-time Olympic medalist and four-time Grand Slam doubles champion, Vesnina has become an active part of the tennis media ecosystem, going viral last fall when pressing world No. 1 Carlos Alcaraz about his relationship status during the ATP Finals.“I'm free!” smiled Alcaraz.Vesnina plans to be on site—and asking more questions—at tournaments throughout the 2026 season.
“Veronika is not the only player to have told a story like this,” Vesnina said. “I think we've all learned something from this. When it comes to Holger, I think it was a good lesson for him to be more careful.”A two-time Olympic medalist and four-time Grand Slam doubles champion, Vesnina has become an active part of the tennis media ecosystem, going viral last fall when pressing world No. 1 Carlos Alcaraz about his relationship status during the ATP Finals.“I'm free!” smiled Alcaraz.Vesnina plans to be on site—and asking more questions—at tournaments throughout the 2026 season.
A two-time Olympic medalist and four-time Grand Slam doubles champion, Vesnina has become an active part of the tennis media ecosystem, going viral last fall when pressing world No. 1 Carlos Alcaraz about his relationship status during the ATP Finals.“I'm free!” smiled Alcaraz.Vesnina plans to be on site—and asking more questions—at tournaments throughout the 2026 season.
“I'm free!” smiled Alcaraz.Vesnina plans to be on site—and asking more questions—at tournaments throughout the 2026 season.
Vesnina plans to be on site—and asking more questions—at tournaments throughout the 2026 season.
Get ready for a massive day of tennis across the Tasman. From Aryna Sabalenka's first match of 2026 to Venus Williams' season kickoff and a winner-take-all United Cup showdown between Australia and Czechia, we have the storylines to watch.
But for one match, Aryna Sabalenka would have a perfect 14-0 record at the Brisbane International.
The World No. 1 hasn't forgotten.
“Of course, remembering [the 2024] final,” Sabalenka said, “I really want to do just a little bit better.”
Elena Rybakina knocked out a 6-0, 6-3 win in that championship match, which in retrospect cost Sabalenka the chance to win three consecutive titles in Brisbane. Sabalenka can make it three in four years with a win in this stacked WTA Tour Driven by Mercedes-Benz 500 event.
Her journey begins Tuesday with a match against Cristina Bucsa, who was a three-set winner over qualifier Anna Bondar in the first round. Sabalenka is familiar with her game because their only previous meeting came at last year's US Open, when she defeated Bucsa 6-1, 6-4 in the fourth round.
As it turns out, Rybakina also kicks off her new year on Tuesday when she faces Zhang Shuai. Rybakina owns a 2-1 head-to-head record, but she lost to Zhang at the 2022 Australian Open when she retired.
Rybakina, the No. 3 seed, could meet Sabalenka in the semifinals. She has a perfect 5-0 record playing Brisbane.
“I know the courts well,” Rybakina told reporters. “I know the conditions. So I really like that also we have a roof, which helps on couple of courts.
“Yeah, I really enjoy always my time here. I think the courts, since it's fast, it's good for my game, so I'm just looking forward to start.”
Sabalenka, who has appeared in three straight Australian Open finals, winning two of them, also has the kind of power game that thrives Down Under.
“I always enjoy coming here,” Sabalenka told reporters on Saturday. “I always show my best tennis here. I enjoy playing in front of all of the people. I'm really excited to be back and really hope to do well again.”
The first match at Patrick Rafter Arena features 2024 Australian Open champion Madison Keys opposite fellow American McCartney Kessler, who was a 6-1, 6-3 winner over Emiliana Arango.
Three-time Brisbane champion Karolina Pliskova withdrew from the singles draw with a right lower leg injury and was replaced by Lucky Loser Yulia Putintseva, who scored a 6-2, 6-4 first-round victory over Hailey Baptiste.
Pat Rafter Arena: starts 11:00 a.m. (8 p.m. ET)
Show Court 1: starts 11:00 a.m.
Show Court 2: starts 11:00 a.m.
Meanwhile, in Sydney Australia and Czechia, both 1-0, will battle for the Group D title.
When Australia's Maya Joint came up ill, Storm Hunter stepped in and scored two points, defeating Malene Helgo in singles and teaming with John-Patrick Smith in mixed doubles to defeat Norway 2-1. Hunter, ranked No. 428 in singles, was ecstatic.
“Super, super happy,” Hunter said afterward. “Just glad that I could do my part tonight. Just wanted to go out there and, yeah, give it a good crack.”
Team captain Lleyton Hewitt said he isn't sure if Joint will be available for her singles match against Barbora Krejcikova; if not, it would again be Hunter.
It was Krejcikova, who came through for Czechia against Norway on Monday, tallying a singles win over Helgo and adding a mixed doubles victory with Adam Pavlasek.
The team that wins will meet either Germany or Poland in the quarterfinals.
The Group D scenarios are straightforward: The winner of Australia vs. Czechia wins the group. The loser finishes second.
In Group B action, 1-0 Canada can secure a quarterfinal berth with a win over Belgium (0-1). To get there, Victoria Mboko and Felix Auger-Aliassime swept to a 3-0 victory over China.
Group B: Canada (1-0) vs. Belgium (0-1)Start time: 10:30 a.m. local / 2:30 a.m. ET
Group D: Australia (1-0) vs. Czechia (1-0)Start time: Not before 5 p.m. local / 4 a.m. ET
In Group C, it's 0-1 Italy versus 0-1 France with the winner finishing second.
Group C: Italy (0-1) vs. France (0-1)Start time: 10 a.m. local / 9 p.m. ET
Things are heating up in Auckland, with top-seeded Elina Svitolina plays her first match of the season, against Varvara Gracheva.
No. 4 Alexandra Eala faces Donna Vekic and No. 5 Magda Linette goes up against 45-year-old wild card Venus Williams.
Centre Court: starts 11:30 a.m.
Grandstand: starts 11:30 a.m.
Get ready for a massive day of tennis across the Tasman. From Aryna Sabalenka's first match of 2026 to Venus Williams' season kickoff and a winner-take-all United Cup showdown between Australia and Czechia, we have the storylines to watch.
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Gauff has tried to clarify her comments about American tennis fans on social media just before her United Cup singles match against Spain's Jessica Bouzas Maneiro.ByAssociated PressPublished Jan 05, 2026 copy_link
Published Jan 05, 2026
© AP
PERTH, Australia (AP)—Coco Gauff dropped a post on social media just before she started her United Cup singles match Monday, hoping to add context to her recent comments about American tennis fans.The match didn't go well for the No. 4-ranked Guaff, who lost the first five games and struggled in a 6-1, 6-7 (3), 6-0 loss to No. 42 Jessica Bouzas Maneiro in Perth.It gave Spain a 1-0 lead over the defending champion U.S. team in the Group A contest. But then Taylor Fritz saved a match point on the way to winning the men's singles match and Gauff combined with Christian Harrison in the mixed doubles to clinch victory for the Americans."I‘m going to clarify because people are dragging this out of context," Gauff said in the pre-match morning social media post, referring to the "worst" comment she made earlier at the tournament when comparing support for players from smaller countries with the kind of support American players receive on foreign soil.
The match didn't go well for the No. 4-ranked Guaff, who lost the first five games and struggled in a 6-1, 6-7 (3), 6-0 loss to No. 42 Jessica Bouzas Maneiro in Perth.It gave Spain a 1-0 lead over the defending champion U.S. team in the Group A contest. But then Taylor Fritz saved a match point on the way to winning the men's singles match and Gauff combined with Christian Harrison in the mixed doubles to clinch victory for the Americans."I‘m going to clarify because people are dragging this out of context," Gauff said in the pre-match morning social media post, referring to the "worst" comment she made earlier at the tournament when comparing support for players from smaller countries with the kind of support American players receive on foreign soil.
It gave Spain a 1-0 lead over the defending champion U.S. team in the Group A contest. But then Taylor Fritz saved a match point on the way to winning the men's singles match and Gauff combined with Christian Harrison in the mixed doubles to clinch victory for the Americans."I‘m going to clarify because people are dragging this out of context," Gauff said in the pre-match morning social media post, referring to the "worst" comment she made earlier at the tournament when comparing support for players from smaller countries with the kind of support American players receive on foreign soil.
"I‘m going to clarify because people are dragging this out of context," Gauff said in the pre-match morning social media post, referring to the "worst" comment she made earlier at the tournament when comparing support for players from smaller countries with the kind of support American players receive on foreign soil.
"Those from smaller countries come with their colors and flags and it is clear on who they are supporting." Gauff said in her post. "I was just speaking from my perspective. I understand the financial aspect of things and know tennis is not accessible for everyone, it was more of a comment for those who are already attending and how I wish they were as passionate as those from other countries."The 21-year-old Gauff, a two-time major winner, said her initial comments were in response to a question at a news conference."I was asked and it was simply an observation I noticed about other countries vs. mine that is all," she said. "Nevertheless I am grateful for any support no matter how big or small it is."In a clip of the news conference posted on X, Gauff said: "I feel like we're definitely in the tennis department the worst when it comes to that.
The 21-year-old Gauff, a two-time major winner, said her initial comments were in response to a question at a news conference."I was asked and it was simply an observation I noticed about other countries vs. mine that is all," she said. "Nevertheless I am grateful for any support no matter how big or small it is."In a clip of the news conference posted on X, Gauff said: "I feel like we're definitely in the tennis department the worst when it comes to that.
"I was asked and it was simply an observation I noticed about other countries vs. mine that is all," she said. "Nevertheless I am grateful for any support no matter how big or small it is."In a clip of the news conference posted on X, Gauff said: "I feel like we're definitely in the tennis department the worst when it comes to that.
In a clip of the news conference posted on X, Gauff said: "I feel like we're definitely in the tennis department the worst when it comes to that.
She added that at previous team events she'd noticed that players from other countries get more animated support from their fans than the American tennis players do, but attributed that to the U.S. sports fans having so many successful teams and athletes to support.Guaff said there was always good support for the Americans from fans who travel to the Australian Open in Melbourne, "but I would like to see some more Americans if we make it to Sydney (United Cup finals) in Sydney than there were last year."The U.S. team is 2-0 after wins over Spain and Argentina and has clinched a spot in the quarterfinals.
Guaff said there was always good support for the Americans from fans who travel to the Australian Open in Melbourne, "but I would like to see some more Americans if we make it to Sydney (United Cup finals) in Sydney than there were last year."The U.S. team is 2-0 after wins over Spain and Argentina and has clinched a spot in the quarterfinals.
The U.S. team is 2-0 after wins over Spain and Argentina and has clinched a spot in the quarterfinals.
lol I ‘m going to clarify because people are dragging this out of context. I ‘m not expecting people to travel to tournaments to watch us play. But there are many tournaments that we have in america and abroad where americans are already attending regardless of who is playing… https://t.co/AqutxKTZYy
It was close call against Spain. Fritz, struggling with knee pain, produced a 7-6 (4), 3-6, 7-6 (6) win over No. 38 Jaume Munar. He missed two match points on Munar's serve in the 12th game of the third set and then saved one in the tiebreaker before sealing the win to level the contest.Gauff and Harrison won the doubles 7-6 (5), 6-0 and finished the session signing autographs and posing for photographs with fans, including some waving the American flags.At a later news conference Gauff was asked if the reaction to her comments on social media had put her off her game."No," she said. "And I don't think it was piling on. I was just trying to clarify what I meant. I wrote everything that I had to say on that."Fritz supported Gauff, saying the reaction to his teammate's comments were an example of people wanting to "assume the absolute worst."I was here and I know exactly what she meant," Fritz said. "And she said nothing wrong."
Gauff and Harrison won the doubles 7-6 (5), 6-0 and finished the session signing autographs and posing for photographs with fans, including some waving the American flags.At a later news conference Gauff was asked if the reaction to her comments on social media had put her off her game."No," she said. "And I don't think it was piling on. I was just trying to clarify what I meant. I wrote everything that I had to say on that."Fritz supported Gauff, saying the reaction to his teammate's comments were an example of people wanting to "assume the absolute worst."I was here and I know exactly what she meant," Fritz said. "And she said nothing wrong."
At a later news conference Gauff was asked if the reaction to her comments on social media had put her off her game."No," she said. "And I don't think it was piling on. I was just trying to clarify what I meant. I wrote everything that I had to say on that."Fritz supported Gauff, saying the reaction to his teammate's comments were an example of people wanting to "assume the absolute worst."I was here and I know exactly what she meant," Fritz said. "And she said nothing wrong."
"No," she said. "And I don't think it was piling on. I was just trying to clarify what I meant. I wrote everything that I had to say on that."Fritz supported Gauff, saying the reaction to his teammate's comments were an example of people wanting to "assume the absolute worst."I was here and I know exactly what she meant," Fritz said. "And she said nothing wrong."
Fritz supported Gauff, saying the reaction to his teammate's comments were an example of people wanting to "assume the absolute worst."I was here and I know exactly what she meant," Fritz said. "And she said nothing wrong."
"I was here and I know exactly what she meant," Fritz said. "And she said nothing wrong."
Coco Gauff bounced back from her singles defeat by partnering with Christian Harrison for the clinching mixed-doubles win as the United States eliminated Spain from the United Cup.
Coco Gauff redeemed herself on the mixed-doubles court to send the United States into the United Cup quarterfinals in Perth on Monday, teaming with Christian Harrison for a 7-6 (5), 6-0 win over Inigo Cervantes and Yvonne Cavalle-Reimers. The pair rallied from an early break in the opening set, and the result eliminated Spain from the competition.
Earlier, World No. 9 Taylor Fritz saved a match point against Jaume Munar to keep the defending champions' hopes alive after Gauff lost the opening singles match in three sets to World No. 42 Jessica Bouzas Maneiro -- the biggest win of Bouzas Maneiro's career by ranking and an early jolt to Gauff's 2026 season on the WTA Tour driven by Mercedes-Benz.
The comeback ensured the United States topped Group A and advanced.
United Cup: Scores | Standings
"Obviously it wasn't a great match for me," Gauff said to reporters on the defeat to Bouzas Maneiro. "I tried my best to fight back with what I had in that moment. Once it was over, I kind of just sat in the bathroom for a little bit -- I had a lot of confidence in Taylor -- so I was just trying to make sure that I was ready for mixed.
"I think that's the beauty of this event that you have other people could pick you up on your off days."
Taking the court after Gauff's three-set loss, Fritz knew the defending champions would not win the group if he dropped his second match of the tournament, having already lost his opener to Sebastian Baez.
Fritz earned his first break points of the match at 5-6 in the third set but couldn't convert either match point. He then saved a match point in the deciding tiebreak before closing out a 7-6 (4), 3-6, 7-6 (6) victory in 3 hours, 14 minutes.
"It was a crazy match," Fritz said on-court. "I thought Jaume played very well. I felt I was in a lot of his service games, but he played so well on so many of the big points.
"I had to come up with a lot to keep myself in the match or convert any of the big points. It was really tough, really physical."
Fritz took a seven-minute medical timeout at 4-all in the third set to treat a bloodied toe after a long slide chasing a drop shot. He saved a break point in the following game. Fritz is hoping for a repeat of last year's United Cup run, when he also dropped his opening match before winning four in a row to guide the Americans to their second title in three years.
He entered the tournament after intensive offseason rehab on his knee for what he described as "pretty serious tendonitis," but he didn't give an inch to Munar in a series of grinding baseline exchanges. The World No. 9 also fired 16 aces, adding to the 22 he hit against Baez.
It was a monumental effort from Fritz, required only because Bouzas Maneiro -- who enjoyed a breakout 2025 highlighted by her first Grand Slam fourth round and a career-high ranking of No. 40 -- stunned Gauff earlier in the day.
Seemingly intent on carrying her 2025 breakthrough into the new season, the Spaniard upset Gauff in convincing fashion, 6-1, 6-7 (3), 6-0, at RAC Arena. It was Gauff's first United Cup loss in 10 career matches across singles and doubles; she entered the day 6-0 in singles and 9-0 overall.
The victory marked Bouzas Maneiro's first career Top 5 win and gave Spain a 1-0 lead over the United States ahead of the men's singles match between Fritz and Munar.
"I know Coco and she's a fighter," Bouzas Maneiro on-court said after the match. "She's there all the time in the match, so I knew that I had to be there, and even if I'm 4-1 up, I have to be there. And yeah, she won the second set, and I went to the bathroom and was trying to focus just to take it point by point.
"And that was my mentality in the third set. To be [there] with power every point because even if you are [up] 3-0 or 4-0, you have to be ready."
Bouzas Maneiro set the tone immediately, breaking the World No. 4 in the opening game en route to a 5-0 lead. She went on to break the American in all four of her service games in the first set and nine times overall.
Her forehand -- which produced 11 winners in the match -- fueled her early surge, but her return game, paired with Gauff's serving struggles, defined the rest of the match. It was a stark contrast to Gauff's dominant performance earlier in the week against Argentina's Solana Sierra.
Gauff landed just 60% of her first serves and won just under 60% of those points. She was further undone by 14 double faults and 54 unforced errors. Bouzas Maneiro could only match Gauff's first-serve numbers but managed her unforced errors more effectively (41) and converted 9-of-12 break points.
Ultimate teamwork 🤩 pic.twitter.com/PWA1Y9hwyR
Still, Gauff refused to go quietly. She rallied from 4-1 down to take the second set in a tiebreak and appeared poised for a remarkable comeback. But Bouzas Maneiro broke to open the decider and never looked back, racing to a 4-0 lead after saving two break points in a five-deuce game.
After 2 hours and 12 minutes, Bouzas Maneiro closed out the match with a third-set bagel, earning a bit of redemption after being blanked in a deciding set by Sierra earlier in the week, and secured the biggest win of her career despite her country's elimination.
"It's just good to experience those pressure moments early in the season, especially since this is my only event before Australia," Gauff said. "I would prefer to win in straights, but it doesn't hurt to go three -- more so when you're on the winning side of it."
Coco Gauff bounced back from her singles defeat by partnering with Christian Harrison for the clinching mixed-doubles win as the United States eliminated Spain from the United Cup.
Thanasi Kokkinakis did not expect a first-round doubles match at the Brisbane International presented by ANZ could move him to tears.
But it did just that. The 29-year-old Australian, who underwent a radical and unprecedented pectoral surgery in February, is back competing on home soil in Brisbane, where he teamed with Nick Kyrgios to earn a three-set win over Matthew Ebden and Rajeev Ram.
“I've never really teared up from a doubles match, even when we won,” Kokkinakis said. “What I have gone through the past 12 months is crazy, speaking to a lot of surgeons, a lot of doctors. I spoke to Rafa's doctor and he wasn't quite sure what was going on. It was pretty crazy.”
For much of the past year, Kokkinakis had been trapped in a frustrating medical grey area. Chronic issues around his shoulder and chest left him in pain but without a clear diagnosis or treatment plan, forcing him to bounce between specialists while his season slipped away.
“No physio or doctor that I saw was really comfortable and confident of which was the right way to go,” he said. “But I said I didn't want to keep doing what I was doing. In the past I'd play one match and maybe have a big win, and my arm was shot for the next couple of rounds. I was almost like ‘I don't care if I don't play again, I'm not doing that again', because it's almost like a tease of what I can do and then I just have to pull out.”
That cycle — flashes of form followed by forced withdrawals — ultimately pushed Kokkinakis toward a drastic decision. After years of managing damaged tissue, he agreed to undergo a surgery few tennis players had ever attempted.
“I essentially cut half my pec off,” explained the former No. 65 player in the PIF ATP Rankings. “I had a bald scar tissue that I was playing with for five or so years. I saw a bunch of surgeons that didn't want to operate on it. They thought it's risky, never been done in tennis. Essentially I have an Achilles allograft — or a dead person's Achilles — in my arm trying to attach my pec to my shoulder.”
The unprecedented nature of the procedure made the comeback process even more daunting. Unlike common knee or ankle injuries, there was no established route back in, no familiar timelines, and no peers who had walked the same path.
“It's really hard coming back from that process, because you don't really have anyone to speak to because no one's done it,” said Kokkinakis. “A lot of people do ACLs and Achilles ruptures, which are brutal, terrible injuries. But with those, a lot of people have had them, so you know who to speak to and what to do.”
Even reaching the start line in Brisbane required careful management. Kokkinakis acknowledged that simply being fit enough to contest doubles felt like a milestone after months of stop-start progress.
Throughout the long rehabilitation, the Australian summer remained his motivation. Kokkinakis has fond memories of this period, having won his sole ATP Tour title in 2022 in Adelaide, the city where he was born.
“There's a lot of unknowns, but I have just done a lot of training to try and get myself in a position where I can even play a doubles match,” Kokkinakis said. “It's been very stop/start. I don't know how my future is going to go, what it holds, but I've done everything I can to give myself at least a chance. I'm taking it day by day.”
The Aussie endured isolated winter training sessions in Melbourne with the vision of returning to court in front of home fans.
“I was so sick of training, and just being in Melbourne in the winter with no one to really train with and trying to motivate myself for the Aussie summer,” Kokkinakis said. “That was always the carrot at the end, just trying to look forward to that moment, not knowing if I can actually play.
“Just doing everything I can. Endless injections, cortisones, trying to get myself to a spot where I can take the court. It's a feeling that is very hard to replicate. I'm not taking it for granted, and I know that's what I will miss the most when eventually I stop playing.
“All my rehab and everything I was doing was focused on trying to get back in front of a crowd in Australia and being competitive. So I'm really, really happy.”
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The United States has qualified for the United Cup quarter-finals in Perth after a complicated group-stage victory over Spain Monday.
World No. 9 Taylor Fritz had to save a match point against Jaume Munar to keep alive the defending champion's hopes of topping Group A after Coco Gauff suffered a shock three-set loss to World No. 42 Jessica Bouzas Maneiro in the day's opening match.
The United States' conquest of Group A was only complete when Gauff found redemption on the mixed doubles court, partnering Christian Harrison to a 7-6(5), 6-0 win over Inigo Cervantes and Yvonne Cavalle-Reimers after they rallied from an early break in the first set. Spain has now been eliminated from the tournament.
In the second match of the day, World No. 9 Fritz saved a match point in a do-or-die clash with Munar, who would have sent Argentina to the quarter-finals had he upset the American.
Seeing his first break points of the match at 5-6 in the third, Fritz failed to convert both match point opportunities and later saved a match point on his serve in the tie-break before winning 7-6(4), 3-6, 7-6(6) in three hours and 14 minutes.
"It was a crazy match," Fritz said. "I thought Jaume played very well. I felt I was in a lot of his service games but he played so well on so many of the big points.
"I had to come up with a lot to keep myself in the match or convert any of the big points. It was really tough, really physical."
Fritz took a seven-minute medical time-out at 4-all in the third set to treat a bloodied toe after a long slide chasing a drop shot. He saved a break point in the following game.
The United States won Group A with a 2-0 record after its initial win over Argentina. Had they lost the mixed, the Americans would have finished runner-up in Group A and would only have claimed a quarter-final berth if they had a better record than the other two Group runners-up.
Fritz came into the tournament after intensive rehab in the offseason on his knee for what he described as “pretty serious tendonitis”. But he didn't give an inch to Munar in a series of lengthy baseline exchanges. He also fired 16 aces to add to the 22 against Baez.
"The knee is something I'm going to be dealing with for a while," he said. "... I started feeling it towards the end of the first set but it didn't get any worse. Typically I start feeling it and it gets worse and worse and worse until I can't even bend it. So I'm really happy with the fact that it stayed at the level it was at and it wasn't bad enough to stop me from playing through."
Jessica Bouzas Maneiro is coming off a breakout 2025 season in which she set a career-high ranking of No. 40, reached the fourth round of a Grand Slam for the first time at Wimbledon and made her first WTA 1000 quarterfinal in Montreal.
On Monday at the United Cup, the Spaniard carried that momentum into 2026, upsetting World No. 4 Coco Gauff in dominant fashion, 6-1, 6-7 (3), 6-0 at RAC Arena. The loss is Gauff's first at the United Cup in 10 matches across singles and doubles; she entered the day 6-0 in singles and 9-0 overall.
The win marks Bouzas Maneiro's first career Top-5 victory.
“I know Coco and she's a fighter,” Bouzas Maneiro said after the match. “She's there all the time in the match, so I knew that I had to be there, and even if I'm 4-1 up, I have to be there. And yeah, she won the second set and I went to the bathroom and I was trying to focus just to take it point by point.
“And that was my mentality in the third set. To be [there] with power every point because even if you are [up] 3-0 or 4-0, you have to be ready.”
Bouzas Maneiro set the tone immediately, breaking Gauff in the opening game en route to a 5-0 lead. She went on to break the American in all four of her service games in the first set and nine times overall.
Her forehand -- which produced 11 winners in the match -- fueled her early surge, but her return game, paired with Gauff's serving struggles, defined the rest of the match. It was a stark contrast to Gauff's dominant performance earlier in the week against Argentina's Solana Sierra.
Gauff landed just 60% of her first serves and won just under 60% of those points. She was further undone by 14 double faults and 54 unforced errors. Bouzas Maneiro could only match Gauff's first-serve numbers but managed her unforced errors more effectively (41) and converted 9 of 12 break points.
Still, Gauff refused to go quietly despite her struggles. She rallied from 4-1 down to take the second set in a tiebreak and appeared poised for a remarkable comeback. But Bouzas Maneiro broke to open the decider and never looked back, racing to a 4-0 lead after saving two break points in a five-deuce game.
After 2 hours and 12 minutes, Bouzas Maneiro closed out the match with a third-set bagel, earning a bit of redemption after being blanked in a deciding set by Sierra earlier in the week, and secured the biggest win of her career.
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Barbora Krejcikova steadied after a slow start to take the opening point before Jakub Mensik backed it up with a composed win over Casper Ruud, as Czechia completed a sweep and eliminated Norway from United Cup contention.
Two first-time United Cup participants -- Barbora Krejcikova and Jakub Mensik -- led Czechia to a win over Noway at the United Cup in Sydney on Monday.
Two-time Grand Slam singles champion Krejcikova triumphed over Norway's Malene Helgo to give Czechia an early 1-0 lead in Group D Sydney action, before Mensik clinched the victory by downing fellow Top 20 star Casper Ruud 7-5, 7-6(6). Krejcikova, alongside Adam Pavlasek, won mixed doubles to secure the sweep.
United Cup: Scores | Standings
Former World No. 2 Krejcikova comes into the 2026 WTA Tour Driven by Mercedes-Benz season ranked No. 65 in the rankings after another bout with injury to close 2025. She reached the quarterfinals of the US Open in September -- a watershed moment in a season that only began in May after dealing with a recurring back injury.
But as quickly as she was healthy, Krejcikova was dealing with physical problems again after she suffered a knee injury against McCartney Kessler in the third round of the China Open. She retired from that match, later revealing her injury was worse that previously thought, and also retired from her first match at the WTA 125 in Limoges in December.
A season-opening a match against World No. 532 Helgo proved to be just what the doctor ordered for Krejcikova to find some match fitness -- and to shake hands healthy.
A post shared by United Cup (@unitedcuptennis)
"I'm very excited I can be here, that I can play, that I'm fit to play, that I can start the season from the beginning, which last year I wasn't," Krejcikova said to reporters. "I'm also really happy that I'm part of this event, this nice competition where we have a team. I think we have a really good atmosphere on the team, and it's been working really well."
The 26-year-old Oslo native has punched above her weight in United Cup in the past -- she pushed both Caroline Garcia and Donna Vekic to three sets at the event in 2024 -- and she took advantage of a slow start by Krejcikova to open up an early 3-1 lead.
But after the Czech, who played the 1 hour, 38-minute match with supportive sleeve on her left knee, erased a break point opportunity in a five-deuce fifth game, she righted the ship by winning eight of the next nine games and never trailed again.
"The knee is better. It took some time, but it's improving every day and I'm very happy with that," Krejcikova added at her on-court interview.
Making his United Cup debut and playing his first match of the season, Mensik's win also eliminated Norway, which fell to 0-2 this week.Mensik held his nerve late in both sets, earning a crucial break at 5-5 in the opener before serving for a one-set advantage. Mensik later rebounded from failing to serve out the match at 5-4 in the second set. He trailed 5-3 in the second-set tiebreak, yet won five of the next six points to survive. The winner of last year's ATP Masters 1000 event in Miami, Mensik crushed a forehand pass cross-court when facing a set point at 6-5 in the second-set tie-break.“First match of the season, it's never easy,” Mensik said during his on-court interview. “It's been a great fight. I'm grateful for the win. I managed in both sets to find the power at the end, that was the most important thing.”
A post shared by United Cup (@unitedcuptennis)
At 20 years and four months, Mensik is the second-youngest man to record a singles win in United Cup history, behind an 18-year-old Stefanos Sakellaridis in 2023. The World No. 18 in the PIF ATP Rankings improved to 2-0 in his Lexus ATP Head2Head series with Ruud, whom Mensik beat at last year's Australian Open in the second round.Mensik crushed 16 aces and won 78% of his first-serve points, according to Infosys ATP Stats, compared to Ruud's 56%.Australia and Czechia are both 1-0 in Group D action, and will face each other Jan. 6 at Ken Rosewall Arena in Sydney.
Barbora Krejcikova steadied after a slow start to take the opening point before Jakub Mensik backed it up with a composed win over Casper Ruud, as Czechia completed a sweep and eliminated Norway from United Cup contention.
Not only is it the 24-year-old's career Top 3 debut, she's also the new American No. 1 now.ByJohn BerkokPublished Jan 05, 2026 copy_link
Published Jan 05, 2026
© 2025 Robert Prange
There weren't any tournaments last week, but with some adjustments to the rankings this week, we've got some movement—including one very notable one.Amanda Anisimova moves up from No. 4 to a new career-high of No. 3, which isn't just her Top 3 debut, but she's also the new American No. 1 now—she switches spots with Coco Gauff, who dips from No. 3 to No. 4.Even though there were no points on offer last week, the flip-flop comes after points from Week 1 of 2025 drop off the WTA rankings this week. Anisimova, who fell in the first round of Auckland a year ago, stays at 6,287 ranking points, while Gauff, who led Team USA to the United Cup title a year ago, sees her points drop from 6,763 to 6,273.And so, Anisimova is now the highest-ranked American player on either the ATP or WTA rankings, with Gauff now the second-highest-ranked American player.
Amanda Anisimova moves up from No. 4 to a new career-high of No. 3, which isn't just her Top 3 debut, but she's also the new American No. 1 now—she switches spots with Coco Gauff, who dips from No. 3 to No. 4.Even though there were no points on offer last week, the flip-flop comes after points from Week 1 of 2025 drop off the WTA rankings this week. Anisimova, who fell in the first round of Auckland a year ago, stays at 6,287 ranking points, while Gauff, who led Team USA to the United Cup title a year ago, sees her points drop from 6,763 to 6,273.And so, Anisimova is now the highest-ranked American player on either the ATP or WTA rankings, with Gauff now the second-highest-ranked American player.
Even though there were no points on offer last week, the flip-flop comes after points from Week 1 of 2025 drop off the WTA rankings this week. Anisimova, who fell in the first round of Auckland a year ago, stays at 6,287 ranking points, while Gauff, who led Team USA to the United Cup title a year ago, sees her points drop from 6,763 to 6,273.And so, Anisimova is now the highest-ranked American player on either the ATP or WTA rankings, with Gauff now the second-highest-ranked American player.
And so, Anisimova is now the highest-ranked American player on either the ATP or WTA rankings, with Gauff now the second-highest-ranked American player.
And there's more.Anisimova is just the third player born in the 2000s to reach the Top 3 in WTA rankings history, and the fifth player to do it in either WTA or ATP rankings history.PLAYERS BORN IN THE 2000s TO REACH THE TOP 3 (ATP or WTA rankings):Iga Swiatek, career-high No. 1 [born in 2001]Carlos Alcaraz, career-high No. 1 [born in 2003]Jannik Sinner, career-high No. 1 [born in 2001]Coco Gauff, career-high No. 2 [born in 2004]Amanda Anisimova, career-high No. 3 [born in 2001]She's also just the 15th American woman ever to reach the Top 3, since WTA rankings were established in 1975.AMERICANS TO REACH TOP 3 IN WTA RANKINGS HISTORY (since 1975):No. 1s (8): Chris Evert, Martina Navratilova, Tracy Austin, Monica Seles, Lindsay Davenport, Jennifer Capriati, Venus Williams, Serena WilliamsNo. 2s (3): Billie Jean King, Andrea Jaeger, Coco GauffNo. 3s (4): Pam Shriver, Sloane Stephens, Jessica Pegula, Amanda AnisimovaAnd just to compare, 11 American men have reached the Top 3, since ATP rankings were established in 1973.
Anisimova is just the third player born in the 2000s to reach the Top 3 in WTA rankings history, and the fifth player to do it in either WTA or ATP rankings history.PLAYERS BORN IN THE 2000s TO REACH THE TOP 3 (ATP or WTA rankings):Iga Swiatek, career-high No. 1 [born in 2001]Carlos Alcaraz, career-high No. 1 [born in 2003]Jannik Sinner, career-high No. 1 [born in 2001]Coco Gauff, career-high No. 2 [born in 2004]Amanda Anisimova, career-high No. 3 [born in 2001]She's also just the 15th American woman ever to reach the Top 3, since WTA rankings were established in 1975.AMERICANS TO REACH TOP 3 IN WTA RANKINGS HISTORY (since 1975):No. 1s (8): Chris Evert, Martina Navratilova, Tracy Austin, Monica Seles, Lindsay Davenport, Jennifer Capriati, Venus Williams, Serena WilliamsNo. 2s (3): Billie Jean King, Andrea Jaeger, Coco GauffNo. 3s (4): Pam Shriver, Sloane Stephens, Jessica Pegula, Amanda AnisimovaAnd just to compare, 11 American men have reached the Top 3, since ATP rankings were established in 1973.
PLAYERS BORN IN THE 2000s TO REACH THE TOP 3 (ATP or WTA rankings):Iga Swiatek, career-high No. 1 [born in 2001]Carlos Alcaraz, career-high No. 1 [born in 2003]Jannik Sinner, career-high No. 1 [born in 2001]Coco Gauff, career-high No. 2 [born in 2004]Amanda Anisimova, career-high No. 3 [born in 2001]She's also just the 15th American woman ever to reach the Top 3, since WTA rankings were established in 1975.AMERICANS TO REACH TOP 3 IN WTA RANKINGS HISTORY (since 1975):No. 1s (8): Chris Evert, Martina Navratilova, Tracy Austin, Monica Seles, Lindsay Davenport, Jennifer Capriati, Venus Williams, Serena WilliamsNo. 2s (3): Billie Jean King, Andrea Jaeger, Coco GauffNo. 3s (4): Pam Shriver, Sloane Stephens, Jessica Pegula, Amanda AnisimovaAnd just to compare, 11 American men have reached the Top 3, since ATP rankings were established in 1973.
She's also just the 15th American woman ever to reach the Top 3, since WTA rankings were established in 1975.AMERICANS TO REACH TOP 3 IN WTA RANKINGS HISTORY (since 1975):No. 1s (8): Chris Evert, Martina Navratilova, Tracy Austin, Monica Seles, Lindsay Davenport, Jennifer Capriati, Venus Williams, Serena WilliamsNo. 2s (3): Billie Jean King, Andrea Jaeger, Coco GauffNo. 3s (4): Pam Shriver, Sloane Stephens, Jessica Pegula, Amanda AnisimovaAnd just to compare, 11 American men have reached the Top 3, since ATP rankings were established in 1973.
AMERICANS TO REACH TOP 3 IN WTA RANKINGS HISTORY (since 1975):No. 1s (8): Chris Evert, Martina Navratilova, Tracy Austin, Monica Seles, Lindsay Davenport, Jennifer Capriati, Venus Williams, Serena WilliamsNo. 2s (3): Billie Jean King, Andrea Jaeger, Coco GauffNo. 3s (4): Pam Shriver, Sloane Stephens, Jessica Pegula, Amanda AnisimovaAnd just to compare, 11 American men have reached the Top 3, since ATP rankings were established in 1973.
And just to compare, 11 American men have reached the Top 3, since ATP rankings were established in 1973.
In 2024, 🇺🇸 Amanda Anisimova made the biggest year-on-year jump into the Top 50 of the year, soaring from #359 to #36. 📈And her momentum hasn't stopped. 🔥🔥🔥In 2025 she made the biggest year-on-year jump INTO THE TOP 10 of the year, from #36 to #4:https://t.co/l8i5iJ4OQm
Other notable moves on the new WTA rankings include Linda Noskova rising from No. 13 to a new personal best of No. 12, after Clara Tauson dips from No. 12 to No. 14 (Noskova lost her second match in Brisbane a year ago, while Tauson captured the title in Auckland).And Spain's Cristina Bucsa makes her Top 50 debut, rising from No. 51 to No. 50, after Anastasia Potapova drops from No. 50 to No. 55 (Bucsa lost first round in Brisbane last year, while Potapova reached the third round).On the ATP rankings, the most notable shift comes inside the Top 10, as Taylor Fritz drops from No. 6 to No. 9—and everyone in between moves up a spot, Alex de Minaur rising from No. 7 back to his career-high of No. 6, Lorenzo Musetti rising from No. 8 to No. 7 and Ben Shelton from No. 9 to No. 8, regaining his status as American men's No. 1, which he briefly achieved late last year for the first time.
And Spain's Cristina Bucsa makes her Top 50 debut, rising from No. 51 to No. 50, after Anastasia Potapova drops from No. 50 to No. 55 (Bucsa lost first round in Brisbane last year, while Potapova reached the third round).On the ATP rankings, the most notable shift comes inside the Top 10, as Taylor Fritz drops from No. 6 to No. 9—and everyone in between moves up a spot, Alex de Minaur rising from No. 7 back to his career-high of No. 6, Lorenzo Musetti rising from No. 8 to No. 7 and Ben Shelton from No. 9 to No. 8, regaining his status as American men's No. 1, which he briefly achieved late last year for the first time.
On the ATP rankings, the most notable shift comes inside the Top 10, as Taylor Fritz drops from No. 6 to No. 9—and everyone in between moves up a spot, Alex de Minaur rising from No. 7 back to his career-high of No. 6, Lorenzo Musetti rising from No. 8 to No. 7 and Ben Shelton from No. 9 to No. 8, regaining his status as American men's No. 1, which he briefly achieved late last year for the first time.
Jakub Mensik clinched Czechia's victory against Norway at the United Cup on Monday, when he downed fellow Top 20 star Casper Ruud 7-5, 7-6(6) in Sydney.
Making his United Cup debut and playing his first match of the season, Mensik's win followed Barbora Krejcikova's victory against Malene Helgo to give Czechia a 2-0 win in the Group D tie, eliminating Norway, which fell to 0-2 this week.
Mensik held his nerve late in both sets, earning a crucial break at 5-5 in the opener before serving for a one-set advantage. Mensik later rebounded from failing to serve out the match at 5-4 in the second set. He trailed 3/5 in the second-set tie-break, yet won five of the next six points to survive. The winner of last year's ATP Masters 1000 event in Miami, Mensik crushed a forehand pass cross-court when facing a set point at 5/6 in the second-set tie-break.
“First match of the season, it's never easy,” Mensik said during his on-court interview. “It's been a great fight. I'm grateful for the win. I managed in both sets to find the power at the end, that was the most important thing.”
At 20 years and four months, Mensik is the second-youngest man to record a singles win in United Cup history, behind an 18-year-old Stefanos Sakellaridis in 2023. The World No. 18 in the PIF ATP Rankings improved to 2-0 in his Lexus ATP Head2Head series with Ruud, whom Mensik beat at last year's Australian Open in the second round.
Mensik crushed 16 aces and won 78 per cent of his first-serve points, according to Infosys ATP Stats, compared to Ruud's 56 per cent.
Earlier, two-time major singles champion Krejcikova scored a winning United Cup debut in a 6-4, 6-3 triumph over Norway's Helgo.
The former World No. 2 comes into the 2026 WTA Tour Driven by Mercedes-Benz season ranked No. 65 in the PIF WTA Rankings after another bout with injury to close 2025. She reached the quarter-finals of the US Open in September, a watershed moment in her season that only began in May after dealing with a recurring back injury.
Putting Team Czechia on the scoreboard 📋 pic.twitter.com/EihT4A8bFV
Krejcikova then unfortunately dealt with physical problems again, suffering a knee injury against McCartney Kessler in the third round of the China Open. She retired from that match, later revealing her injury was worse than previously thought. Krejcikova also retired from her first match at the WTA 125 in Limoges in December.
Krejcikova's season-opening match against World No. 532 Helgo proved to be an ideal return.
“I didn't play for a long period, and the injury that I had was really tough and very unfortunate," Krejcikova said. "I'm really happy that I'm here, that I can play, that I can enjoy it, that I can compete, and I'm really happy that I can finally finish a match."
Helgo, 26, has punched above her weight in the United Cup in the past. She pushed both Caroline Garcia and Donna Vekic to three sets in 2024 and took advantage of a slow start by Krejcikova to open up an early 3-1 lead.
But then, Krejcikova, who played the one-hour, 38-minute match with supportive wrapping on her left knee, erased a break point opportunity in a five-deuce fifth game and righted the ship by winning eight of the next nine games.
“The knee is better. It took some time, but it's improving every day and I'm very happy with that," Krejcikova said.
Australia and Czechia are both 1-0 in Group D action. Mixed doubles between Czechia and Norway is up next at Ken Rosewall Arena.
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The Serbian shared "ongoing concerns regarding transparency, governance, and the way my voice and image have been represented" were behind the decision.ByTENNIS.comPublished Jan 04, 2026 copy_link
Published Jan 04, 2026
© 2025 Tullio Puglia
In 2019, Novak Djokovic co-founded the Professional Tennis Players Association (PTPA) with fellow ATP Tour competitor Vasek Pospisil.The initiative officially launched at the height of the pandemic during the 2020 US Open, with Pospisil proclaiming, “The PTPA did not emerge to be combative, to disrupt, or to cause any issues within or outside the tennis tour. Simply to unify the players, have our voices heard & have an impact on decisions being made that effect our lives & livelihoods.”
The initiative officially launched at the height of the pandemic during the 2020 US Open, with Pospisil proclaiming, “The PTPA did not emerge to be combative, to disrupt, or to cause any issues within or outside the tennis tour. Simply to unify the players, have our voices heard & have an impact on decisions being made that effect our lives & livelihoods.”
After careful consideration, I have decided to step away completely from the Professional Tennis Players Association. This decision comes after ongoing concerns regarding transparency, governance, and the way my voice and image have been represented.
More than five years since the PTPA officially took shape, Djokovic has announced he is fully severing ties from the organization after revealing the two sides no longer share common ground.“After careful consideration, I have decided to step away completely from the Professional Tennis Players Association. This decision comes after ongoing concerns regarding transparency, governance, and the way my voice and image have been represented,” Djokovic wrote on X Sunday evening.“I am proud of the vision that Vasek and I shared when founding the PTPA, giving players a stronger, independent voice - but it has become clear that my values and approach are no longer aligned with the current direction of the organization.“I will continue to focus on my tennis, my family, and contributing to the sport in ways that reflect my principles and integrity. I wish the players and those involved the best as they move forward, but for me, this chapter is now closed.”
“After careful consideration, I have decided to step away completely from the Professional Tennis Players Association. This decision comes after ongoing concerns regarding transparency, governance, and the way my voice and image have been represented,” Djokovic wrote on X Sunday evening.“I am proud of the vision that Vasek and I shared when founding the PTPA, giving players a stronger, independent voice - but it has become clear that my values and approach are no longer aligned with the current direction of the organization.“I will continue to focus on my tennis, my family, and contributing to the sport in ways that reflect my principles and integrity. I wish the players and those involved the best as they move forward, but for me, this chapter is now closed.”
“I am proud of the vision that Vasek and I shared when founding the PTPA, giving players a stronger, independent voice - but it has become clear that my values and approach are no longer aligned with the current direction of the organization.“I will continue to focus on my tennis, my family, and contributing to the sport in ways that reflect my principles and integrity. I wish the players and those involved the best as they move forward, but for me, this chapter is now closed.”
“I will continue to focus on my tennis, my family, and contributing to the sport in ways that reflect my principles and integrity. I wish the players and those involved the best as they move forward, but for me, this chapter is now closed.”
Ten months ago, the PTPA filed an antitrust lawsuit that named the ATP and WTA Tours, International Tennis Federation (ITF) and International Tennis Integrity Agency (ITIA) as defendants.The men's tour responded by stating, “We strongly reject the premise of the PTPA's claims, believe the case to be entirely without merit, and will vigorously defend our position. ATP remains committed to working in the best interests of the game - towards continued growth, financial stability, and the best possible future for our players, tournaments, and fans.”Before forming the PTPA, Djokovic served as ATP Player Council president from 2016-20.The 38-year-old is coming off a year where he reached the semifinals of all four Grand Slam events and surpassed 100 career titles. Djokovic is due to make his 2026 debut at the Adelaide International ahead of this month's Australian Open.We'll continue to monitor this developing story.
The men's tour responded by stating, “We strongly reject the premise of the PTPA's claims, believe the case to be entirely without merit, and will vigorously defend our position. ATP remains committed to working in the best interests of the game - towards continued growth, financial stability, and the best possible future for our players, tournaments, and fans.”Before forming the PTPA, Djokovic served as ATP Player Council president from 2016-20.The 38-year-old is coming off a year where he reached the semifinals of all four Grand Slam events and surpassed 100 career titles. Djokovic is due to make his 2026 debut at the Adelaide International ahead of this month's Australian Open.We'll continue to monitor this developing story.
Before forming the PTPA, Djokovic served as ATP Player Council president from 2016-20.The 38-year-old is coming off a year where he reached the semifinals of all four Grand Slam events and surpassed 100 career titles. Djokovic is due to make his 2026 debut at the Adelaide International ahead of this month's Australian Open.We'll continue to monitor this developing story.
The 38-year-old is coming off a year where he reached the semifinals of all four Grand Slam events and surpassed 100 career titles. Djokovic is due to make his 2026 debut at the Adelaide International ahead of this month's Australian Open.We'll continue to monitor this developing story.
We'll continue to monitor this developing story.
Plus: Big men's matches include Ruud vs. Mensik, Zverev vs. Hurkacz, and Fritz vs. Munar.ByTENNIS.comPublished Jan 04, 2026 copy_link
Published Jan 04, 2026
© 2026 Robert Prange
Stan Wawrinka may be wondering what he got himself into when he announced his 2026 retirement tour. At this rate, it may not last until the end of January. Over the last two nights in the United Cup, the 40-year-old has played two marathon three-set matches against significantly younger opponents. He won the first, over Arthur Rinderknech, 7-6 in the third, and almost won the second, against 23-year-old Flavio Cobolli, before finally running out of gas at the finish line and falling by the same score.Elsewhere, it was a fairly one-sided night in the team competition. Germany beat the Netherlands 3-0, Canada beat China 3-0, Great Britain beat Japan 2-1. The most notable non-Stan result may have been Naomi Osaka's second straight defeat, to 276th-ranked Katie Swan, who was filling in for an injured Emma Raducanu.What's next in Sydney and Perth? Here's a look at Monday's lineup. Stan, it seems safe to say, will be happy to have the night off.
Elsewhere, it was a fairly one-sided night in the team competition. Germany beat the Netherlands 3-0, Canada beat China 3-0, Great Britain beat Japan 2-1. The most notable non-Stan result may have been Naomi Osaka's second straight defeat, to 276th-ranked Katie Swan, who was filling in for an injured Emma Raducanu.What's next in Sydney and Perth? Here's a look at Monday's lineup. Stan, it seems safe to say, will be happy to have the night off.
What's next in Sydney and Perth? Here's a look at Monday's lineup. Stan, it seems safe to say, will be happy to have the night off.
SydneyCzechia vs. Norway (10:30 A.M. local time; 6:30 P.M. ET)Germany vs. Poland (5:30 P.M. local time; 1:30 A.M. ET)PerthUSA vs. Spain (10:00 A.M. local time; 9:00 P.M. ET)Great Britain vs. Greece (5:00 local time; 4:00 A.M. ET)
Czechia vs. Norway (10:30 A.M. local time; 6:30 P.M. ET)Germany vs. Poland (5:30 P.M. local time; 1:30 A.M. ET)PerthUSA vs. Spain (10:00 A.M. local time; 9:00 P.M. ET)Great Britain vs. Greece (5:00 local time; 4:00 A.M. ET)
Germany vs. Poland (5:30 P.M. local time; 1:30 A.M. ET)PerthUSA vs. Spain (10:00 A.M. local time; 9:00 P.M. ET)Great Britain vs. Greece (5:00 local time; 4:00 A.M. ET)
PerthUSA vs. Spain (10:00 A.M. local time; 9:00 P.M. ET)Great Britain vs. Greece (5:00 local time; 4:00 A.M. ET)
USA vs. Spain (10:00 A.M. local time; 9:00 P.M. ET)Great Britain vs. Greece (5:00 local time; 4:00 A.M. ET)
Great Britain vs. Greece (5:00 local time; 4:00 A.M. ET)
Jakub Mensik vs. Casper Ruud: The 20-year-old Mensik is one of the bigger question marks of the coming season: Will he be the guy who won a Masters 1000 in Miami, or the guy who failed to make another semifinal the rest of the year? He'll start his 2026 with a high-profile encounter against Ruud, who looked good in a win over Alex de Minaur two nights ago. Mensik won their only previous meeting, at the Australian Open last year.Alexander Zverev vs. Hubert Hurkacz: The Pole returns to the court after knee surgery ended his 2025 early. Zverev leads their head to head 3-1.Iga Świątek vs. Eva Łys: On paper, Świątek should have a smooth start to her new year. She has played Lys three times and surrendered just seven games in total. But the 23-year-old Ukrainian-German is improving.
Alexander Zverev vs. Hubert Hurkacz: The Pole returns to the court after knee surgery ended his 2025 early. Zverev leads their head to head 3-1.Iga Świątek vs. Eva Łys: On paper, Świątek should have a smooth start to her new year. She has played Lys three times and surrendered just seven games in total. But the 23-year-old Ukrainian-German is improving.
Iga Świątek vs. Eva Łys: On paper, Świątek should have a smooth start to her new year. She has played Lys three times and surrendered just seven games in total. But the 23-year-old Ukrainian-German is improving.
Coco Gauff vs. Jessica Bouzas Maneiro: Round 2 for Coco, and her serve should get a proper test. The American and the 40th-ranked Spaniard have never played.Taylor Fritz vs. Jaume Munar: This should be an interesting stylistic clash, between server and grinder. Fritz won their only meeting, in a third-set tiebreaker in Indian Wells, back in 2022.Maria Sakkari vs. Emma Raducanu: Stick a question mark by Raducanu's name. She pulled out of her match on Sunday with a lingering foot issue, and may or may not be ready for this one. Whoever she faces, Sakkari will be looking to back up her impressive straight-set win over Naomi Osaka in her opener.
Taylor Fritz vs. Jaume Munar: This should be an interesting stylistic clash, between server and grinder. Fritz won their only meeting, in a third-set tiebreaker in Indian Wells, back in 2022.Maria Sakkari vs. Emma Raducanu: Stick a question mark by Raducanu's name. She pulled out of her match on Sunday with a lingering foot issue, and may or may not be ready for this one. Whoever she faces, Sakkari will be looking to back up her impressive straight-set win over Naomi Osaka in her opener.
Maria Sakkari vs. Emma Raducanu: Stick a question mark by Raducanu's name. She pulled out of her match on Sunday with a lingering foot issue, and may or may not be ready for this one. Whoever she faces, Sakkari will be looking to back up her impressive straight-set win over Naomi Osaka in her opener.
Czechia d. Norway 2-1Poland d. Germany 2-1USA d. Spain 3-0Greece d. Great Britain 3-0
Poland d. Germany 2-1USA d. Spain 3-0Greece d. Great Britain 3-0
USA d. Spain 3-0Greece d. Great Britain 3-0
Greece d. Great Britain 3-0
Plus, Ella Langley earns her first Hot 100 top 10.
By
Gary Trust
Taylor Swift's “The Fate of Ophelia” tops the Billboard Hot 100 for a ninth week, besting “Anti-Hero” as the sole longest-leading hit among her 13 career No. 1s.
“The Fate of Ophelia” surges back to the Hot 100's summit from No. 28 as holiday hits recede from the chart's upper reaches, a week after they claimed a weekly-best top 24 positions. The lead single from Swift's album The Life of a Showgirl reigned in its first eight weeks on the ranking, dating to its mid-October debut. “Anti-Hero” claimed its eight-week No. 1 run upon its start in November 2022.
Elsewhere, Ella Langley lands her first Hot 100 top 10, as “Choosin' Texas” vaults 48-5. It leads the Hot Country Songs chart for a sixth week.
Check out the full rundown of this week's Hot 100 top 10 below.
The Hot 100 blends all-genre U.S. streaming (official audio and official video), radio airplay and sales data, the lattermost metric reflecting purchases of physical singles and digital tracks from full-service digital music retailers; digital singles sales from direct-to-consumer (D2C) sites are excluded from chart calculations. All charts (dated Jan. 10, 2026) will update on Billboard.com tomorrow, Jan. 6. For all chart news, you can follow @billboard and @billboardcharts on both X, formerly known as Twitter, and Instagram. Plus, for all chart rules and explanations, click here.
Luminate, the independent data provider to the Billboard charts, completes a thorough review of all data submissions used in compiling the weekly chart rankings. Luminate reviews and authenticates data. In partnership with Billboard, data deemed suspicious or unverifiable is removed, using established criteria, before final chart calculations are made and published.
“The Fate of Ophelia” drew 18.3 million official streams (up 9% week-over-week) and 60.7 million radio airplay audience impressions (up 12%) and sold 30,000 (up 779%) in the United States Dec. 26-Jan. 1.
The single adds an eighth week at No. 1 on the Streaming Songs chart; falls to No. 3 from its No. 2 high on Radio Songs; and lifts 5-4 on Digital Song Sales after six weeks at No. 1. It's the highest-selling song of the week overall, with 26,000 in physical singles, via vinyl versions that shipped during the tracking week, and 4,000 downloads.
As “The Fate of Ophelia” one-ups “Anti-Hero” for Swift's longest Hot 100 rule, here's a recap of her signature 13 No. 1s, ranked by most weeks at the summit.
“The Fate of Ophelia” contributes to Swift's eight Hot 100 No. 1s totaling 27 weeks on top in the 2020s — both the most among all artists this decade.
Overall, Swift's 13 No. 1s tie her for the fourth-most in the Hot 100's history. She has spent 45 weeks atop the chart, eighth-best all-time.
With the latest Hot 100 dated Jan. 10, 2026, Swift has now placed at No. 1 in 11 distinct years (per chart dates), encompassing her 13 leaders: 2012, 2014-15, 2017, 2020-24 and, thanks to “The Fate of Ophelia,” 2025-26.
Among the six acts that have each spent time atop the Hot 100 in 10 or more individual years, Swift now solely boasts the second-best total:
Ella Langley achieves her first Hot 100 top 10, as “Choosin' Texas” soars 48-5 (topping its prior No. 11 peak before the holidays). It totaled 15.7 million streams (up 5%), 25 million in radio reach (up 2%) and sold 5,000 (up 1%) in the tracking week.
The trad-country single rebounds 4-1 for a second week atop Digital Song Sales, as it leads the multimetric Hot Country Songs chart for a sixth week, dating to its first in early December.
Meanwhile, Langley and Beyoncé are the lone stars with Hot 100 top 10s that name-check Texas in song titles. Prior to Langley (who's from Alabama), Houston's own Beyoncé logged two weeks at No. 1 in 2024 with “Texas Hold ‘Em.” (One other such song has hit the top 40: Waylon Jennings' classic “Luckenbach, Texas [Back to the Basics of Love]” reached No. 25 in 1977.)
HUNTR/X's “Golden,” from Netflix's KPop Demon Hunters, flies 28-2 on the Hot 100, after eight weeks at No. 1 beginning in August.
Alex Warren's “Ordinary,” which ruled the Hot 100 for 10 weeks starting in May, returns at No. 3, tying for the highest reentry in the chart's archives (reflecting rules related, in part, to the fall of holiday songs). It adds a 24th week at No. 1 on Radio Songs (67.8 million, up 24%).
Olivia Dean's “Man I Need” blasts back, from No. 36, to its No. 4 Hot 100 high.
Kehlani's “Folded” rises to a new No. 6 Hot 100 best, from No. 51. It tops the multimetric Hot R&B/Hip-Hop Songs and Hot R&B Songs charts for a fourth week each.
Sombr's “Back to Friends” bounds 52-7 for a new Hot 100 high, as it adds a 13th week at No. 1 on Hot Rock & Alternative Songs.
Swift's “Opalite” revisits the Hot 100's top 10 (54-8), after hitting No. 2, and two more songs reenter the chart in the tier: Leon Thomas' “Mutt,” at No. 9 after reaching No. 6, and Justin Bieber's “Daisies,” at No. 10 after peaking at No. 2.
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Though the 2026 Critics Choice Awards certainly felt business as usual, with comedian Chelsea Handler hosting for the fourth straight year at the ceremony's third consecutive year at the Barker Hangar in Santa Monica, they did also represent the ongoing identity crisis that most televised awards shows are currently facing.
While much has been said by the team here at IndieWire about SAG's Actors Awards now streaming on Netflix and the Oscars heading to YouTube in 2029, the most pressing thing about the Critics Choice Awards is not its broadcast partner as much as it's the ceremony's relationship to the Golden Globes.
How that comes up immediately is that this go-round, the shows swapped weekends, so that the Critics Choice Awards became the first major televised awards show of the year. For attendees, the benefit of that is to re-enter awards season off of holiday break in a more casual setting (again, this awards show is inside a hangar, the Golden Globes are at the Beverly Hilton's International Ballroom).
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There's a level of relief on the organizer's side too, given that, just two years ago, the CCAs were jam-packed into a marathon week of awards shows that had been delayed by the strikes. Last year, the ceremony was delayed until February, much further into Oscars season because of the Los Angeles wildfires. The latter ended up working to the show's benefit, as “Anora” winning Best Picture started the tide shift that clued everyone in on the film being the Oscars frontrunner.
This time, being first out the gate, the CCAs got to set the tone the way that the Globes usually do, and here lies that identity crisis.
Both awards are voted on by entertainment journalists, with the Golden Globes having more of an international focus than the widely American voting body for Critics Choice. Back in the more controversial years, before its 2023 revamp, the Golden Globes had a reputation for being more populist, wanting to give their awards to the most famous awards contenders, while Critics Choice developed a reputation as the awards show that was more predictive of who would win the Oscars.
However, just as they switched show dates this year, Golden Globes and CCAs have also switched what the perception of what their winners are. Consider this: the Golden Globes leaning into being the more international awards body puts them more in tune with the Academy Awards.
The love for “I'm Still Here” in particular was very influential on Oscars voters, especially when, as a result of the fires, they were given more time to watch films before choosing nominees. But the wins for fellow International Feature “Emilia Peréz” were also a bellwether for what was to come.
Meanwhile, the 2025 Critics Choice Awards winners were way more spread out, and arguably more populist, with the biggest surprise being that “Wicked” helmer Jon M. Chu won Best Director. He would go on to not even be nominated at the Oscars for directing the first half of the recent movie musical box office phenomenon.
When put in the position to develop the momentum for awards season winners, the 2026 Critics Choice Awards zigged in a lot of categories that even voters thought they would zag.
“One Battle After Another” winning Best Picture came as a surprise to almost no one. “Marty Supreme” star Timothée Chalamet winning Best Actor and “Hamnet” star Jessie Buckley winning Best Actress makes sense from an Oscar predictions standpoint, but many other influential critics circles have been voting in other ways. Many were predicting either “The Secret Agent” star Wagner Moura or “Blue Moon” star Ethan Hawke to win the former, and “If I Had Legs I'd Kick You” star Rose Byrne to win the latter award. “Frankenstein” star Jacob Elordi and “Weapons” star Amy Madigan winning the supporting categories were the only film acting awards that felt climactic.
That said, 12 films won awards across 23 categories, so few people inside the ceremony could come off as unsatisfied. If there was one core issue with the telecast, it was which awards were given off-camera. The TV categories don't have any craft awards, so only Best Animated Series, Best Foreign Language Series, Best Comedy Special, and Best Variety Series were given off-air.
But on the film side, while we were still in a time where it felt like certain categories were anyone's game, the CCAs chose not to air the two major director contenders Ryan Coogler and Paul Thomas Anderson winning Best Original Screenplay and Best Adapted Screenplay, respectively, for “Sinners” and “One Battle After Another.” While Anderson got to speak elsewhere, the primary representatives for “Sinners” onstage ended up being Best Young Actor/Actress winner Miles Caton and Best Casting/Ensemble winner Francine Maisler.
The even more baffling omission was no Best Foreign Language Film, which had “The Secret Agent” win a slight upset. Even if Oscar frontrunner “Sentimental Value” was not actually nominated in the category, the Best Foreign Language Film included several other nominees that are still in the conversation for a Best Picture Oscar nomination, including the other three Neon contenders: “It Was Just an Accident,” “No Other Choice,” and “Sirāt.”
Best Picture presenters Moura and his “The Secret Agent” director Kleber Mendonça Filho had one of the best jokes of the night, saying how that category would be the “foreign” one in their native Brazil. But comparing the 10 Best Picture nominees at the CCAs, where “Sentimental Value” is the only film not in English, to the 12 films nominated for Drama or Musical/Comedy at the Golden Globes, almost half of which are not in English, it does feel like the latter awards body is more in line with how the Oscars, which have had at multiple international Best Picture nominees the last two years is evolving.
In terms of highlights from the room, Elordi stood up for “Adolescence” star Owen Cooper when he won for the Netflix limited series, as the teen actor plays the younger version of Elordi's character in the upcoming Warner Bros. Pictures release “Wuthering Heights.” Despite the perception that his fellow nominees seemed unenthused at him winning, “Train Dreams” star Joel Edgerton immediately went to Chalamet's table afterwards to congratulate him.
And super-producer Amy Pascal, who is believed to be an inspirational figure for the show, did stop by “The Studio” table to catch up with her former Sony colleague Seth Rogen, and the name “James Bond” was mentioned.
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By
Simon Vozick-Levinson
When Lucy Dacus walked onstage at the Jan. 1 inauguration of New York's new mayor, Zohran Mamdani, music fans watching at home perked up with excitement. Dacus herself was feeling some big jitters. “I was so nervous, because I can't think of a higher-stakes stage that I've been on,” she says. “You can mess up your own things, but it's really not cool to mess up somebody else's thing.”
In fact, Dacus nailed that moment with a stirring rendition of “Bread and Roses,” an early-20th-century anthem of the labor and women's suffrage movements. A couple of days later, she called Rolling Stone to take us behind the scenes of a historic day in New York.
Her City Hall appearance, which was not announced until the day of the inauguration, came together in just a few weeks, after the mayor-elect's office reached out in early December. They went back and forth on what to perform — “It would have felt weird to get up and sing one of my own songs,” she says — before Mamdani's team suggested the storied protest song they went with.
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Lucy Dacus performing ‘Bread and Roses' today at Zohran Mamdani's Inauguration Ceremony today in New York City! pic.twitter.com/s2Lvm5S1DI
Dacus was familiar with “Bread and Roses” because of a performance she did with Julien Baker and Phoebe Bridgers, her boygenius bandmates, back in 2021 at a San Francisco benefit for the nonprofit organization of the same name. “It's such a beautiful sentiment,” she says. “The idea that you're not just fighting for your sustenance — you're fighting for your joy.”
Although Dacus is based in Los Angeles, she's one of many people around the country who found something inspiring in Mamdani's promise to work toward a better life for all New Yorkers. In September, ahead of the mayoral election, she brought the popular progressive candidate out as a surprise guest during her set at the All Things Go festival in Forest Hills, Queens, just a few months after he made a similar appearance at one of MJ Lenderman's shows in Brooklyn.
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“I feel such love and joy in the crowd this evening, and this is what our city should feel like,” Mamdani told the crowd at All Things Go. “It should be a city where trans New Yorkers are cherished, a city where our queer neighbors are celebrated, and a city where each and every New Yorker can be the fullest version of themselves. And it has to be a city that all of us can afford, whether you're an artist, or a dreamer, or someone who works the night shifts. And that city, that city is within reach, if we're willing to fight for it.”
On the frigid afternoon of the inauguration, Dacus walked onstage to join keyboardist Sarah Goldstone and looked out at the people assembled in front of City Hall. “It doesn't feel like that big of a crowd, actually,” she says. “It's not even as many people as I'd have at one of our concerts. But then, all of the cameras, you realize this is a global event.” She tried not to think too much about that, and focused on visualizing the images that went with poet James Oppenheim's lyrics as she sang.
After finishing the song, she exchanged a hug with New York's new first lady, visual artist Rama Duwaji. “And on the way off the stage, I tried to fist-bump Bernie Sanders, which maybe confused him,” she adds. “But he said that I did a good job.”
She also took the chance to chat with Broadway legend Mandy Patinkin, whose performance of “Somewhere Over the Rainbow” was another highlight of the inauguration. “His voice is so iconic to me,” she says. (Hamilton star Javier Muñoz and Punjabi Canadian musician Babbulicious were also part of the festivities.)
Ultimately, Dacus thinks it's no coincidence that Mamdani's vision for New York connected with so many creative artists. “When you make art, you realize that it's not a luxury,” she says. “People that make art know the value of having the time and presence to focus on your interests.” That connects with the theme of “Bread and Roses,” too: “I think people need to not look at organizing or participating as something that is only going to be draining. It's something that gives back a lot of purpose and beauty.”
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Mamdani himself has a background in the arts, having grown up as the son of noted filmmaker Mira Nair and, famously, put in some work as indie rapper Mr. Cardamom before entering politics at the suggestion of Das Racist's Himanshu Suri.
“I wonder if being creative is a great attribute for a politician, because when you're creative, you make something because you aren't satisfied that it doesn't exist,” Dacus continues, thinking out loud. “If he's bringing a creative approach to policy, I'm glad. Maybe more politicians should be creative.”
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Rolling Stone is a part of Penske Media Corporation. © 2026 Rolling Stone, LLC. All rights reserved.
By Nellie Andreeva
Co-Editor-in-Chief, TV
On the heels of Mayor of Kingstown‘s bloody Season 4 finale, the Paramount+ crime drama starring Jeremy Renner has been renewed for a fifth. It will be the final installment of the series, created by Taylor Sheridan and Hugh Dillon, and will consist of eight episodes, down from 10 for Seasons 1-4, with recent cast addition Edie Falco returning alongside Renner.
This is the first ongoing Sheridan series to set an end date since the regime change at Paramount+. In the months following Skydance's acquisition of the streamer's parent Paramount Global in August, Paramount+ has ordered new seasons of Sherdian's Landman, Tulsa King and Lioness. (Paramount's new streaming chief Cindy Holland in August called the the Taylor Sheridan universe “a really great foundation” for Paramount+; in October, the prolific creator set a 2029 move to NBCUniversal.)
Mayor of Kingstown has been a solid draw on Paramount+. It also has steadily improved its standing with critics, going from 33% on Rotten Tomatoes for Season 1 to 100% for the most recent fourth season featuring Emmy winner Falco as a new lead opposite Oscar nominee Renner.
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Still, Mayor of Kingstown‘s ratings performance has not been on the level of other Sheridan dramas, especially recently. Season 4 of Mayor of Kingstown overlapped with new seasons of Landman (Season 2) and Tulsa King (Season 3) being released on Paramount+. Both Landman and Tulsa King have charted on Nielsen's weekly Top 10 of streaming originals, with Landman also making waves as a Top 3 series on the overall Nielsen chart.
Meanwhile, Mayor of Kingstown, which — like most Sheridan series — is expensive to make, has not broken into Nielsen's originals Top 10 with its fourth season having done so with previous installments.
Still, it is a Paramount+ legacy show being part of the Taylor Sheridan universe, which led to the decision to pick up a final season, with a six-episode order reportedly discussed before the two sides settled on eight installments.
In Season 4 of Mayor of Kingstown, Mike's (Renner) control over Kingstown is threatened as new players compete to fill the power vacuum left in the Russians' wake, compelling him to confront the resulting gang war and stop them from swallowing the town. Meanwhile, with those he loves in more danger than ever before, Mike must contend with a headstrong new Warden (Falco) to protect his own while grappling with demons from his past.
The season ended with the gang war in Kingstown escalating to a violent climax in the finale. Sheridan and Dillon will now have eight more episodes to examine the aftermath and tell the rest of the story, which Dillon previously shared they had been prepared to take to seven seasons.
“[Sheridan] has an ending for it in Season 7. Whether it goes that far or that's where we get [who knows], but he has an ending, and everyone knows about it,” Dillon said in a Screen Rant interview last year. “Our goal is to get to that Season 7, because that's as far as we can get, because that's where he's always had it. 15 years ago, he had it. 15 years ago, ‘So, here's how it's starting, Mitch is going to get killed off in the first 10 pages, and season 7, episode 10, this is where Mike's going to be.”
Mitch, played by Kyle Chandler, was Mike's (Renner) older brother who was famously shot dead in the series' opening episode.
In addition to Renner and Falco, the latest season stars Lennie James, Laura Benanti, Dillon, Taylor Handley, Tobi Bamtefa, Derek Webster, Hamish Allan-Headley and Nishi Munshi.
Mayor of Kingstown is produced by Paramount Television Studios, 101 Studios and Bosque Ranch Productions. Sheridan executive produces with Dillon, Renner, Antoine Fuqua, David C. Glasser, Ron Burkle, David Hutkin, Bob Yari, Michael Friedman, Dave Erickson, Christoph Schrewe, Wendy Riss, Evan Perazzo and Keith Cox. Erickson also serves as showrunner. The series is distributed by Paramount Global Content Distribution.
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I hope the s5 is as ‘satisfying' as Sheridan etc is claiming
The original vision of 7 seasons is gone
Take Yellowstone second part s6(?) when Costner was killed off
What a fg mess that was IMHO.
Why in the world would you end a show when it's top of the list?? It's a great show but the 10 shows every year or more is ridiculous. Go back to what really is the standard 20-23 weeks a season. You completely lose interest after that short a season and that long between seasons. Keep it on the air and fix it!!
Not surprised. Glad they get to wrap things up though.
I have a feeling this has more to do with Jeremy Renner's back problems than with ratings. I hope he continues to recover from his accident.
Love the show by far my favorite on Paramount.
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By Erik Pedersen
Managing Editor
Netflix's KPop Demon Hunters leads the way with 13 nominations for the 2026 Annie Awards, followed by Pixar's Elio with 10. Disney Animation Studios' Zootopia 2 and Gkids' Little Amélie or the Character of Rain are next with five each.
Those four titles will compete with DreamWorks Animation's The Bad Guys 2 for the marquee Best Feature Prize. Up for Best Feature – Independent are Arco, I'm Frankelda, Lost In Starlight, A Magnificent Life and Scarlet. See the full list of noms below
ASIFA-Hollywood revealed its Annie noms in 32 categories on Monday. Winners will be feted during the 53rd Annie Awards ceremony on February 21 at UCLA's Royce Hall.
Since the Best Animated Feature Oscar category was launched in 2002, 14 of the 23 winners of the Annies' marquee Best Feature prize – and seven of the past 13 – went on to claim the golden statuette. But last year bucked the trend as the Academy Award went to Flow over The Wild Robot, which dominated the 2025 Annies with seven nods. Flow, however, did win the Annie for Best Independent Feature back in February, along with Best Writing.
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ASIFA-Hollywood also has set the winners of its 2026 Juried Awards, honoring “unparalleled achievement and exceptional contributions to animation.”
The Winsor McCay Award in recognition of lifetime or career contributions are being presented to animator, writer and director Michaël Dudok de Wit, filmmakers Christopher Miller and Phil Lord and writer-director Chris Sanders.
The June Foray Award for significant and benevolent impact to the animation community will be awarded to Sandy Rabins, animation and live action producer and the founding guiding light for the AnimAID effort to assist and support those in the animation industry who were affected by the L. A. wildfires.
The Ub Iwerks Award for technical advancement affecting the animation industry will be presented to Wacom, manufacturer of the Cintiq graphics tablet and other products that have become an integral part of animation production worldwide.
RELATED: 2026 Awards Season Calendar: Dates For Oscars, Guilds, Grammys, Tonys & More
The Special Achievement Award acknowledging unique and outstanding achievement not recognized within the existing award category structure will be presented to LightBox Expo, the annual event that brings the creative animation community of filmmakers together with animation students and fans.
Here are the nominees for the 2026 Annie Awards:
BEST FEATURE
ElioPixar Animation Studios
KPop Demon HuntersSony Pictures Animation for Netflix
Little Amélie or the Character of RainMaybe Movies, Ikki Films, Distributed by Gkids
The Bad Guys 2DreamWorks Animation
Zootopia 2Walt Disney Animation Studios
BEST FEATURE – INDEPENDENT
A Magnificent LifeMediawan, What the Prod and Bidibul productions
ArcoRemembers, MountainA France, France 3 Cinéma
I'm FrankeldaCinema Fantasma, Warner Bros. Discovery, Woo Films, Cine Vendaval
Lost In StarlightNetflix / Climax Studio
ScarletStudio CHIZU
BEST SPECIAL PRODUCTION
A Loud House Christmas Movie: Naughty or NiceNickelodeon Animation Studio & Jam Filled Entertainment
Adult Swim's The ElephantTitmouse and Williams Street
Not Just a GoofVenturia Animation Studios ® for CNEK Films LLC
Snoopy Presents: A Summer MusicalWildBrain Studios in association with Apple
The Night Before Christmas in WonderlandLupus Films, Universal Pictures Content Group
BEST SHORT SUBJECT
CardboardLocksmith Animation
Ovary-ActingKlipp og Lim, Jante Films, Apparat Filmproduktion AB
PillowzzzAnimoshe
Snow BearThe Art of Aaron Blaise
The Girl Who Cried PearlsNational Film Board of Canada
BEST SPONSORED
Animated Short: “Trek” | Honkai: Star RailFLiiiP Design
Fortnite x The Simpsons: Apocalypse D'Oh!A Gracie Films Production in Association with 20th Television Animation
LouiMax Dreams of Being An AdultImagine Create Media Inc. in conjunction with Maileg APS
Olipop YetiScreen Novelties & Passion Pictures
Sonic Racing: CrossWorlds – The AnimationSEGA of America in association with GXS Productions
BEST TV/MEDIA – PRESCHOOL
Eva The OwletEpisode: Welcome to TreetopingtonBrown Bag Films / Scholastic Entertainment in association with Apple
Kindergarten: The Musical! Episode: Gotta Go!Oddbot Entertainment, Disney Branded Television
The Tiny Chef ShowEpisode: Tiny Chef's Spooky Stump SpectacularImagine Entertainment, Tiny Chef Productions and Nickelodeon Productions
Wow LisaEpisode: Rainy DayPunkrobot
Xavier Riddle and the Secret Museum Episode: I am Jackie Robinson9 Story Media Group, Brown Bag Films
BEST TV/MEDIA – CHILDREN
My Melody & KuromiEpisode: All For Our Best FriendSanrio Company for Netflix
Spice Frontier: Escape From Veltegar Episode: 1Steamroller Animation
Tales of the Teenage Mutant Ninja Turtles Episode: Rise of the Night NinjaNickelodeon Animation Studios and PointGrey Pictures
The Wonderfully Weird World of Gumball Episode: The RewriteHanna-Barbera Studios Europe
Wylde PakEpisode: SungandeulNickelodeon Animation Studios / Jam Filled Entertainment
BEST TV/MEDIA – MATURE
Bob's BurgersEpisode: Grand Pre-Pre-Pre Opening20th TV
Common Side Effects Episode: PilotGreen Street Pictures, Bandera Entertainment and Williams Street Productions
Haha, You ClownsEpisode: 107 – Duncan Holds a BabyWilliams Street
Il BaracchinoEpisode: Claudia entra in un caffèLuckyred, Megadrago
South ParkEpisode: Sermon on the ‘MountComedy Central LLC
BEST TV/MEDIA – LIMITED SERIES
Asterix & Obelix: The Big Fight Episode: Episode IIINetflix / Banijay Productions France / Légende Films
Eyes of WakandaEpisode: Into The Lion's DenMarvel Studios
Marvel Zombies Episode: 2Marvel Studios
Star Wars: Visions – Volume 3 Episode: BLACKdavid production
Win Or LoseEpisode: Episode 8: HomePixar Animation Studios
BEST STUDENT FILM
A Sparrow's SongStudent director: Tobias EckerlinStudent producer: Tobias EckerlinSchool: Filmakademie Baden-Württemberg GmbH
AcrobatsStudent directors: Eloïse Alluyn, Hugo Danet, Anna Despinoy, Antonin Guerci, Alexandre Marzin, Shali ReddySchool: Gobelins
Jour de ventStudent directors: Martin Chailloux, Ai Kim Crespin, Elise Golfouse, Chloé Lab, Hugo Taillez, Camille TrudingSchool: École des Nouvelles Images
The Undying Pain of Existence Student director: Oscar JacobsonStudent producers: Franz Rügamer, Nadiia YunatskaSchool: Filmakademie Baden-Württemberg GmbH
TRASHStudent directors: Maxime Crançon, Alexis Le RalStudent producers: Robin Delaporte, Romain Fleischer, Mattéo DurandSchool: ESMA
BEST FX – TV/MEDIA
Marvel Zombies Episode: Episode 4Production Company: Marvel AnimationFX Production Company: Stellar Creative Lab, Inc.Emma Badia, Tristan Fairclough, Jimmy Dumont, Sheng Hung, Arth Vasavada
Prehistoric Planet: Ice Age Episode: The Big FreezeProduction Company: BBC Studios Natural History UnitFX Production Company: FramestoreEdward Ferrysienanda, Kevin Christensen, Guy Shuleman , Benedikt Roettger, Kevin Tarpinian
Spice Frontier Episode: 1Production Company: Steamroller AnimationFX Production Company: Steamroller AnimationSteamroller Animation Effects Department
Star Wars: Visions – Volume 3 Episode: The Bird of ParadiseProduction Company: Polygon PicturesFX Production Company: Polygon PicturesTakashi Okamoto, Kohei Yamamoto, Genyo Sasaki, Chizuru Nakamura, Erika Matsui
WONDLAEpisode: LostProduction Company: Skydance AnimationFX Production Company: ICON Creative StudioEP 209 ICON Creative Studio FX Team
BEST FX – FEATURE
ElioProduction Company: Pixar Animation StudiosFX Production Company: Pixar Animation StudiosFerdi Scheepers, Shaun Galinak, Alyssa Lee, Nate Skeen, Gary Bruins
In Your DreamsProduction Company: Netflix, Kuku StudiosFX Production Company: Sony Pictures ImageworksDmitriy Kolesnik, Stephen Paschk, David Sellares, Stephanie McNair
KPop Demon HuntersProduction Company: Sony Pictures Animation for NetflixFX Production Company: Sony Pictures ImageworksFilippo Macari, Nicola Finizio, Simon Lewis, Naoki Kato, Daniel La Chapelle
The Bad Guys 2Production Company: DreamWorks AnimationFX Production Company: DreamWorks AnimationLandon Gray, Michael Losure, Zachary Glynn, Chris Wombold, Olivier Malric
Zootopia 2Production Company: Walt Disney Animation StudiosFX Production Company: Walt Disney Animation StudiosLe Joyce Tong, Shamintha Kalamba Arachchi, Dimitre Berberov, Chris Carignan, Cristiana Covone
BEST CHARACTER ANIMATION – TV/MEDIA
Asterix & Obelix: The Big Fight Episode: Episode IIINetflix / Banijay Productions France / Légende FilmsFloriane Caseiro
Forevergreen Special ProductionNathan Engelhardt and Jeremy SpearsBrendan Gottlieb
Snoopy Presents: A Summer Musical Special ProductionWildBrain Studios in association with AppleChris Derochie
The Simpsons Various EpisodesA Gracie Films Production in Association with 20th Television AnimationNik Ranieri
Win Or Lose Various EpisodesPixar Animation StudiosAlli Sadegiani
BEST CHARACTER ANIMATION – FEATURE
ElioPixar Animation StudiosJonah Sidhom
KPop Demon HuntersSony Pictures Animation, NetflixRyusuke Furuya
Little Amélie or the Character of RainMaybe Movies, Ikki Films, Distributed by GkidsJuliette Laurent
The Bad Guys 2DreamWorks AnimationLudovic Bouancheau
Zootopia 2Walt Disney Animation StudiosTony Smeed
BEST CHARACTER ANIMATION – LIVE ACTION
A Minecraft MovieProduction Company: Warner Bros. Pictures, Legendary Pictures, Mojang Studios, Vertigo Entertainment, On the RoamFX Production Company: Weta FXKevin Estey, Anthony McIndoe, Jade Lorier, Caroline Ting, Luisma Lavin Peredo
Captain America: Brave New WorldProduction Company: Marvel Studios, Walt Disney Studios Motion PicturesFX Production Company: Weta FXSidney Kombo-Kintombo, Andrew William Park, Marco Röth, Paul Seyb, Thien Ly
How To Train Your DragonProduction Company: DreamWorks AnimationFX Production Company: FramestoreKayn Garcia, Jean-Denis Haas, Meena Ibrahim, Nathan McConnel, Nick Tripodi
Prehistoric Planet: Ice AgeProduction Company: BBC Studios Natural History UnitFX Production Company: FramestoreAdrien Annesley, Alvise Avati, Riyad Chalakkara, Daniel Mizuguchi, Liam Russell
SupermanProduction Company: DC StudiosFX Production Company: FramestoreLoic Mireault, Michael Elder, Philipp Winterstein, Victor Dinis, Diego De Paula Pereira Batista
BEST CHARACTER ANIMATION – VIDEO GAME
Bye Sweet CaroleLittle Sewing MachineChris Darril
Death Stranding 2: On the BeachKojima ProductionsHideo Kojima, Masaaki Kawata, Kojima Productions, PlayStation Studios XDEV
Ghost of YōteiSucker Punch ProductionsSucker Punch Productions Animation Team
KeeperDouble Fine ProductionsZach Baharov, Alex Turner, Jerry Matsko, Anne-Sophie Savard, Geneviève Desbiens
South of MidnightCompulsion GamesMike Jungbluth, Sebastien Dussault, Vincent Schneider, Remi Edmond
BEST CHARACTER DESIGN – TV/MEDIA
Asterix & Obelix: The Big Fight Episode: Episode IVNetflix / Banijay Productions France / Légende FilmsBorja Montoro
Bat-FamEpisode: A Knight at the MoviesAmazon MGM Studios, Warner Bros. Animation, DC EntertainmentBenjamin Tong
Love, Death + Robots Episode: 400 BoysBlur Studio for NetflixRobert Valley
Wednesdays with Gramps Short FilmDreamWorks AnimationSeth St. Pierre
Win Or LoseEpisode: Episode 8, HomePixar Animation StudiosLou Hamou-Lhadj
BEST CHARACTER DESIGN – FEATURE
ElioPixar Animation StudiosMatt Nolte, Yingzong Xin, James Woods, Kaleb Rice, Bob Pauley
FixedSony Pictures Animation for NetflixCraig Kellman
KPop Demon HuntersSony Pictures Animation for NetflixScott Watanabe, Ami Thompson
The SpongeBob Movie: Search for SquarePantsParamount Animation / Nickelodeon MoviesAdam Paloian, Thaddeus Couldron, Alvi Ramirez
The TwitsNetflix Presents / The Roald Dahl Story CompanyKei Acedera, Tristan Poulain, Jules Rigolle, Fernando Peque, Remi Salmon
BEST DIRECTION – TV/MEDIA
Common Side Effects Episode: Cliff's EdgeGreen Street Pictures, Bandera Entertainment and Williams Street ProductionsVincent Tsui
DAN DA DANEpisode: Clash! Space Kaiju vs. Giant Robot!Science SARU, Mainichi Broadcasting System, Distributed by GkidsFuga Yamashiro, Abel Góngora
Not a Box Episode: It's a BoatSilver Creek Falls Entertainment / Passion Pictures in association with AppleSiri Melchior
Tales of the Teenage Mutant Ninja Turtles Episode: Rise of the Night NinjaNickelodeon Animation Studios and PointGrey PicturesJJ Conway, Kevin Molina-Ortiz
The Quinta's Ghost Short FilmMartirio Films & Illusorium filmsJames A. Castillo
BEST DIRECTION – FEATURE
ArcoRemembers, MountainA France, France 3 CinémaUgo Bienvenu, Adam Sillard, Anaëlle Saba
Chainsaw Man – The Movie: Reze ArcMAPPA StudiosTatsuya Yoshihara
KPop Demon HuntersSony Pictures Animation for NetflixMaggie Kang, Chris Appelhans
Little Amélie or the Character of RainMaybe Movies, Ikki Films, Distributed by GkidsMaïlys Vallade, Liane-Cho Han
ScarletStudio CHIZUMamoru Hosoda
BEST MUSIC – TV/MEDIA
Common Side Effects Episode: Lakeshore LimitedGreen Street Pictures, Bandera Entertainment, and Williams Street ProductionsNicolas Snyder
Devil May CryEpisode: The First CircleA Netflix Series / Studio Mir / Adi Shankar Animation / CapcomPower Glove, Alex Seaver
ÉiruShort FilmCartoon SaloonLeo Pearson, Ceara Conway
Snoopy Presents: A Summer Musical Special ProductionWildBrain Studios in association with AppleBen Folds, Jeff Morrow, Alan Zachary, Michael Weiner
Win Or LoseEpisode: Episode 6, Mixed SignalsPixar Animation StudiosRamin Djawadi, Shane Eli, Johnny Pakfar
BEST MUSIC – FEATURE
ArcoRemembers, MountainA France, France 3 CinémaArnaud Toulon
ElioPixar Animation StudiosRob Simonsen
KPop Demon HuntersSony Pictures Animation for NetflixKPop Demon Hunters Music Team
Little Amélie or the Character of RainMaybe Movies, Ikki Films, Distributed by GkidsMari Fukuhara
Zootopia 2Walt Disney Animation StudiosShakira, Ed Sheeran, Blake Slatkin, Michael Giacchino
BEST PRODUCTION DESIGN – TV/MEDIA
Asterix & Obelix: The Big Fight Episode: Episode IINetflix / Banijay Productions France / Légende FilmsAurélien Prédal
Forevergreen Special ProductionNathan Engelhardt and Jeremy SpearsJeremy Spears, Gregory Culp
Love, Death + RobotsEpisode: How Zeke Got ReligionBlur Studio for NetflixGigi Cavenago
ParaNorman: The Thrifting Special ProductionLAIKAThibault Leclercq, Santiago Montiel, Jung Woonyoung, Stephanie Bray-Lee
Wednesdays with Gramps Short FilmDreamWorks AnimationFrederic Stewart
BEST PRODUCTION DESIGN – FEATURE
ElioPixar Animation StudiosHarley Jessup, Ernesto Nemesio, Maria Lee, Kristian Norelius, Kyle Jones
KPop Demon HuntersSony Pictures Animation for NetflixHelen Chen, Dave Bleich, Wendell Dalit, Scott Watanabe, Celine Kim
The Bad Guys 2DreamWorks AnimationLuc Desmarchelier, Floriane Marchix
The TwitsNetflix Presents / The Roald Dahl Story CompanyEstefania Pantoja, Alexandre Diboine, Clement Dartigues, Fernando Peque, Remi Salmon
Zootopia 2Walt Disney Animation StudiosCory Loftis, Limei Z. Hshieh
BEST STORYBOARDING – TV/MEDIA
Love, Death + RobotsEpisode: How Zeke Got ReligionBlur Studio for NetflixEdgar Martins
ParaNorman: The Thrifting Special ProductionLAIKAColeton Palmer, Katherine Jay Myong, Heewon Jeong
Snow Bear Short FilmThe Art of Aaron Blaise, LLC.Aaron Blaise
Tales of the Teenage Mutant Ninja Turtles Episode: Rise of the Night NinjaNickelodeon Animation Studios and PointGrey PicturesRichard Chi, Matthew Kim, Sheldon Vella, Lyndsay Simpson
Win Or LoseEpisode: Episode 8, HomePixar Animation StudiosEsteban Bravo
BEST STORYBOARDING – FEATURE
ArcoRemembers, MountainA France, France 3 CinémaUgo Bienvenu
ElioPixar Animation StudiosTony Rosenast
Little Amélie or the Character of RainMaybe Movies, Ikki Films, Distributed by GkidsNicolas Pawlowski
The Bad Guys 2DreamWorks AnimationAnthony Holden, Young Ki Yoon
Zootopia 2Walt Disney Animation StudiosHikari Toriumi
BEST VOICE ACTING – TV/MEDIA
Bob's BurgersEpisode: Don't Worry Be Hoopy20th TVDan Mintz (Character: Tina Belcher)
Hazbin HotelEpisode: Behind Closed DoorsAmazon MGM Studios, A24, Bento Box EntertainmentErika Henningsen (Character: Charlie Morningstar)
Long Story Short Episode: Shira Can't CookTornante Television and ShadowMachine for NetflixAbbi Jacobson (Character: Shira Schwooper)
Smiling Friends Episode: ShmalooglesWilliams StreetZach Hadel (Character: Evil Wizard)
The Wonderfully Weird World of Gumball Episode: The AmadainHanna-Barbera Studios EuropeAlkaio Thiele (Character: Gumball Watterson)
BEST VOICE ACTING – FEATURE
Dog ManDreamWorks AnimationLil Rey Howery (Character: Chief)
ElioPixar Animation StudiosRemy Edgerly (Character: Glordon)
In Your DreamsNetflix Presents a Kuku Studios Production / Sony Pictures ImageworksCraig Robinson (Character: Baloney Tony)
KPop Demon HuntersSony Pictures Animation for NetflixArden Cho (Character: Rumi)
The TwitsNetflix Presents / The Roald Dahl Story CompanyMaitreyi Ramakrishnan (Character: Beesha)
BEST WRITING – TV/MEDIA
#1 Happy Family USAEpisode: Episode 101: NINE TENAmazon MGM Studios, A24, Cairo CowboyRamy Youssef, Pam Brady
Adult Swim's The Elephant Special ProductionTitmouse and Williams StreetPendleton Ward, Ian Jones-Quartey, Rebecca Sugar, Patrick McHale
Common Side Effects Episode: PilotGreen Street Pictures, Bandera Entertainment, and Williams Street ProductionsJoe Bennett, Steve Hely
Lulu is a Rhinoceros Special ProductionBento Box and Propagate in association with AppleAllison Flom
Win Or LoseEpisode: Episode 4, PicklePixar Animation StudiosCarrie Hobson, Michael Yates
BEST WRITING – FEATURE
ElioPixar Animation StudiosJulia Cho, Mark Hammer, Mike Jones
KPop Demon HuntersKPop Demon Hunters Editorial TeamDanya Jimenez , Hannah McMechan, Maggie Kang, Chris Appelhans
Little Amélie or the Character of RainMaybe Movies, Ikki Films, Distributed by GkidsLiane-Cho Han, Aude Py, Maïlys Vallade, Eddine Noël
ScarletStudio CHIZUMamoru Hosoda
Zootopia 2Walt Disney Animation StudiosJared Bush
BEST EDITORIAL – TV/MEDIA
Asterix & Obelix: The Big Fight Episode: Episode IIINetflix / Banijay Productions France / Légende FilmsDavid Boyadjian
Common Side Effects Episode: RaidGreen Street Pictures, Bandera Entertainment, and Williams Street ProductionsTony Christopherson, Joie Lim
Haunted HotelEpisode: The Acolytes of AbaddonTitmouse for NetflixBenjamin Morse, Benjamin Martian, Marshall Wetta
Invincible S3Episode: I Thought You'd Never Shut UpAmazon MGM Studios, Skybound AnimationLuke Asa Guidici, Matt Michael, Lea Carosella, Liam Johnson
Tom Clancy's Splinter Cell: Deathwatch Episode: Up From the GraveUbisoft Film & TelevisionThomas Belair, Nicolas Bourgeois, Julien Perez
BEST EDITORIAL – FEATURE
ArcoRemembers, MountainA France, France 3 CinémaNathan Jacquard
ElioPixar Animation StudiosAnna Wolitzky, Steve Bloom, Noah Newman, Greg Snyder, Ben Morris
KPop Demon HuntersSony Pictures Animation for NetflixKPop Demon Hunters Editorial Team
Little Amélie or the Character of RainMaybe Movies, Ikki Films, Distributed by GkidsLudovic Versace
Olivia & las NubesCine Chani, Historias de Bibi & Guasábara CineTomás Pichardo Espaillat
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Label a film a “zombie movie” and our genre-trained brains zip right to the question of whether it will feature fast-moving or slow-moving iterations of the undead. With that trope so embedded into the modern DNA of this particular horror subgenre, it's refreshing when a filmmaker puts it on the backburner and explores something more interior, which is what writer-director Zak Hilditch (1922) does with We Bury The Dead.
The Australian filmmaker uses the sparseness of his home country as a haunting backdrop for this intimate examination of a woman on a journey to understand her humanity. Ava Newman (Daisy Ridley) is an American, compelled to travel to Tasmania in the wake of an accidental American detonation of “something” off the coast of the remote island. More than 300,000 are now dead, and that may include Ava's husband Mitch (Matt Whelan), who was attending a corporate retreat on the island and hasn't touched base since all communications went dead.
Adrift in a fugue state, Ava arrives on the island to volunteer, assigned to one of many body retrieval teams organized by the Australian military. Their mission is to go into all of the rural communities that are furthest away from the impact zone to remove bodies from residences so they can be buried. Ava's seemingly selfless call to action actually masks her true intention to eventually branch out on her own to find out if her husband is alive or dead. Only after she lands does she find out that there could be a third option: A by-product of this modern catastrophe is that some victims are waking up, then quickly culled by the military.
Hilditch does a fine job laying out the necessary specifics of the event, the repercussions, and the unexpected undead twist which begins more as a mystery than an overt threat. More importantly, all of the setup is used in service of Ava's physical and mental journey into this foreign reality. As she engages in the bleak, voyeuristic work of intruding into these abandoned homes to recover the dead, Ava is forced to knock on her own doors, confronting and acknowledging the unresolved complexities of her marriage. It's through a series of flashbacks framed as Ava's remembrances that the audience gets a more truthful taste of who she and Mitch were together before. A once blissful marriage is increasingly laid bare as desperately complicated and damaged by years of infertility issues, blame, and guilt.
Initially, Ridley conveys much of Ava's numbness and interior conflict through her amply expressive face, with little dialogue and to great success. The opening third of We Bury The Dead provides her a rich succession of scenes that are allowed to breathe as she finds her moorings in this disturbing wasteland of lost futures and abrupt endings. Ridley's work is supported by rich sound design which provides space for Ava's solitude while also gently building an aural tapestry for this island—which includes the spine-chilling noises associated with the “waking,” including their signature teeth-grinding. It's sparse in execution but intensely effective in conjuring immediate tension whenever they appear.
Hilditch and his editor Merlin Eden set an unhurried pace for Ava's journey that might seem antithetical to modern horror, but it facilitates the way this place changes her—slowly, but thoroughly, so she'll be ready to face the answers awaiting her. The inclusion of two challenging male characters also allows us to see how Ava holds herself when placed under the eyes of others. With fellow body retriever Clay (Brenton Thwaites), she develops an unconventional bond as he is bracingly candid and seemingly apathetic about the death around them. His lack of social niceties allows Ava to shed the less attractive parts of her own nature. And with Riley (Mark Coles Smith), a soldier who is also mourning the loss of a spouse, comes a disturbing encounter that grounds the story in the realities of a woman traversing any landscape alone. It's the most terrifying horror sequence of the film.
As for those awoken by this disaster, Hilditch takes the existential path. That means there are plenty of unanswered questions, but questions which bolster Ava's quest to determine what she wants out of life now that she may be alone. She's remarkably unafraid of those who now straddle the living and the dead and more intrigued by what she can still recognize in an ambling corpse, or a newly woken father that bestows one last act of love to his dead family. If these recently dead can still hold onto the best of themselves, what keeps the living from doing the same? For those looking to delve into more philosophical horror, We Bury The Dead is a thoughtful trek into the unknown. As Ava moves towards her own discovery, she ends up finding more truth in what remains unresolved—by experiencing what grief dredges up in the living.
Director: Zak Hilditch
Writers: Zak Hilditch
Starring: Daisy Ridley, Mark Coles Smith, Brenton Thwaites, Matt Whelan
Release Date: January 2, 2025
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By
Jon Blistein
Björk shared a note of solidarity with the people of Greenland after Donald Trump and his admin revived threats of taking over the country following the capture of Venezuelan president Nicolas Maduro.
“I wish all Greenlanders blessing in their fight for independence,” Björk wrote on Instagram Monday (Jan. 5), adding: “Colonialism has repeatedly given me horror chills up my back, and the chance that my fellow Greenlanders might go from one cruel colonizer to another is too brutal to even imagine. ‘Úr öskunni í eldinn,' like we say in Icelandic.” (That phrase translates to “From the ashes into the fire.”)
Though the Icelandic musician's allusion to the U.S.'s threats was clear, much of Björk's note actually focused on Greenland's relationship with Denmark. Greenland hasn't been a Danish colony since the 1950s, but it's still a semi-autonomous district of Denmark, with its own local government and two representatives in Danish parliament. Denmark also continues to control Greenland's foreign affairs and defense, and contributes more than half the country's public budget.
Iceland, Bjök's home country, also has a colonial past with Denmark, dating back to the first half of the 20th century. Iceland became independent in 1944, with Björk writing that her fellow citizens are “extremely relieved that they managed to break from the Danish” and “didn't lose our language.”
She went on to share two harrowing stories about Denmark's control over Greenland. One referred to a lawsuit over 140 Greenlandic women filed in 2024, accusing Denmark of fitting them with IUDs without their consent or knowledge in an effort to reduce Greenland's population. It's believed that nearly 4,500 women and girls were affected between 1966 and 1970.
“They are my age and younger … childless,” Björk wrote.
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She also mentioned the “parenting competency” tests that Denmark subjected Greenlandic people to for years, until they were finally banned last May. These tests, though frequently used in Denmark as part of child protection investigations, were criticized as inappropriate and unsuitable for the people of Greenland and other minorities. Björk's post mentioned a Greenlandic mother who saw her daughter taken from her just two hours after her birth in 2024; despite the tests being banned since then, mother and child still have not been reunited.
In closing her note, Björk wrote, “Dear Greenlanders, declare independence !!!! Sympathetic wishes from your neighbors. Warmthness.”
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Rolling Stone is a part of Penske Media Corporation. © 2026 Rolling Stone, LLC. All rights reserved.
Kylie Jenner is kicking off awards season with a bang.
Attending the 2026 Critics' Choice Awards on the arm of boyfriend Timothée Chalamet Sunday night, the reality TV star and beauty mogul chose a vintage Versace look for the occasion.
Jenner chose a metallic lace and chainmail gown from Versace's Fall/Winter 1996 collection, making the vintage piece a year older than the 28-year-old makeup mogul.
Jenner's gown featured a low bustier neckline, sheer black lace down the sides, with spaghetti straps that crossed at her back.
The archival piece hails from Tab Vintage and, while currently unavailable on the popular store's site, there is a similar listing on 1st Dibs for the same dress, ringing in at a whopping nearly $10,000.
The reality star kept things simple in terms of jewelry, wearing nothing but a large pear-shaped solitaire diamond ring on her left pinky finger.
Chalamet, meanwhile, wore a double-breasted Givenchy pinstriped suit and floral tie. The “Dune” actor nabbed
Chalamet, who won a Critics' Choice Award for Best Actor in “Marty Supreme” that evening, chose a 1950s tailoring vibe, slipping into a double-breasted navy pinstripe suit from Givenchy. With a crisp white button-down, he, too, looked to the archives, opting for a vintage pink flowered tie from the design house.
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While accepting his award, Chalamet thanked Jenner: “my partner of three years.”
“Thank you for our foundation,” he shared, adding, “I love you … I couldn't do this without you. Thank you from the bottom of my heart.”
Jenner was seen replying, “I love you,” back.
Vintage Versace chainmail seems to be her comfort choice as Chalamet's awards show date; she wore a similar look in silver to last year's Golden Globe Awards.
The 1999 gown, however, featured a dangerously low back — and the delicate look even appeared to split near her thigh.
We're expecting many head-turning looks on the red carpet from this A-list couple in the weeks to come.
By Dade Hayes
Business Editor
Amazon is overhauling the Fire TV interface in an effort to reduce the time viewers spend searching for streaming content.
Along with the new UI, the tech giant is also releasing the Ember Artline, a “lifestyle TV” designed to showcase artwork and photos.
The twin announcements were made Monday as CES ramps up in Las Vegas. The main exhibits start Tuesday, but Monday's docket is full of panel conversations and corporate events.
In a blog post, Amazon said the Fire TV revamp aims to be “cleaner, faster, and better organized, helping customers spend less time searching and more time watching.” It cited research from Nielsen subsidiary Gracenote indicating that U.S. streaming viewers spend an average of 12 minutes searching for something to watch, up from 10 1/2 minutes in 2023.
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With the new Fire TV, it is “faster and easier to find movies, TV shows, sports, news, and live content,” the blog post said, giving the example of a user browsing movies. In that use case, titles from all apps the viewer uses are displayed. Amazon's own research found as much of a 20% to 30% boost in search speed with the new interface.
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The number of apps Fire TV users can pin to the home screen is increasing from six to 20.
The Ember Artline is a 4K QLED TV whose matte screen is just an inch-and-a-half thick and is designed to display art and photos with reduced glare.
The set also has far-field microphones enabling voice commands, and also has an “ambient experience” that turns on and off when people enter or leave the room. More than 2,000 pieces of free art are provided with the Ember Artline, with an AI feature helping owners get help from the set itself, with recommendations for artwork that will match a given room's style and decor.
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The 2025-2026 awards season had its first major event of the latter year last night. On Sunday, the 31st Critics Choice Awards were held in Santa Monica and broadcast on E! and USA, and the critics had good news for One Battle After Another and Frankenstein, in particular. The former film snagged the awards for both Best Picture and Best Director, though both supporting actor contenders Sean Penn and Benicio Del Toro lost out to Frankenstein‘s Jacob Elordi. The Guillermo del Toro-directed film also snagged the awards for production design, costume design, and make up.
Elsewhere, Timothée Chalamet earned another victory in his year-long campaign for Marty Supreme, which sure looks good for the rest of his awards season hopes. Jessie Buckley of Hamnet took home the award for Best Actress, potentially cementing her as the frontrunner of the category for the rest of the season, while Amy Madigan of Weapons woke up Monday morning with a Critics Choice Award of her own.
On the TV side of things, The Pitt, The Studio, and Adolescence continue their own dominant streaks that began at the Emmy Awards in September. Jimmy Kimmel Live! and South Park, two shows that have frequently been in the news this year for their skirmishes with the Trump administration, took home trophies for Best Talk Show and Best Animated Series, respectively. You can check out the entire list of winners below.
One Battle After Another
Bugonia
Frankenstein
Hamnet
Jay Kelly
Marty Supreme
Sentimental Value
Sinners
Train Dreams
Wicked: For Good
Timothée Chalamet – Marty Supreme
Leonardo DiCaprio – One Battle After Another
Joel Edgerton – Train Dreams
Ethan Hawke – Blue Moon
Michael B. Jordan – Sinners
Wagner Moura – The Secret Agent
Jessie Buckley – Hamnet
Rose Byrne – If I Had Legs I'd Kick You
Chase Infiniti – One Battle After Another
Renate Reinsve – Sentimental Value
Amanda Seyfried – The Testament of Ann Lee
Emma Stone – Bugonia
Jacob Elordi – Frankenstein
Benicio Del Toro – One Battle After Another
Paul Mescal – Hamnet
Sean Penn – One Battle After Another
Adam Sandler – Jay Kelly
Stellan Skarsgard – Sentimental Value
Amy Madigan – Weapons
Elle Fanning – Sentimental Value
Ariana Grande – Wicked: For Good
Inga Ibsdotter Lilleaas – Sentimental Value
Wunmi Mosaku – Sinners
Teyana Taylor – One Battle After Another
Miles Caton – Sinners
Everett Blunck – The Plague
Cary Christopher – Weapons
Shannon Mahina Gorman – Rental Family
Jacobi Jupe – Hamnet
Nina Ye – Left-Handed Girl
Paul Thomas Anderson – One Battle After Another
Ryan Coogler – Sinners
Guillermo del Toro – Frankenstein
Josh Safdie – Marty Supreme
Joachim Trier – Sentimental Value
Chloé Zhao – Hamnet
Ryan Coogler – Sinners
Noah Baumbach, Emily Mortimer – Jay Kelly
Ronald Bronstein, Josh Safdie – Marty Supreme
Zach Cregger – Weapons
Eva Victor – Sorry, Baby
Eskil Vogt, Joachim Trier – Sentimental Value
Paul Thomas Anderson – One Battle After Another
Clint Bentley, Greg Kwedar – Train Dreams
Park Chan-wook, Lee Kyoung-mi, Don Mckellar, Jahye Lee – No Other Choice
Guillermo del Toro – Frankenstein
Will Tracy – Bugonia
Chloé Zhao, Maggie O'Farrell – Hamnet
Francine Maisler – Sinners
Nina Gold – Hamnet
Douglas Aibel, Nina Gold – Jay Kelly
Jennifer Venditti – Marty Supreme
Cassandra Kulukundis – One Battle After Another
Tiffany Little Canfield, Bernard Telsey – Wicked: For Good
Adolpho Veloso – Train Dreams
Claudio Miranda – F1
Dan Laustsen – Frankenstein
Łukasz Żal – Hamnet
Michael Bauman – One Battle After Another
Autumn Durald Arkapaw – Sinners
Tamara Deverell, Shane Vieau – Frankenstein
Kasra Farahani, Jille Azis – The Fantastic Four: First Steps
Fiona Crombie, Alice Felton – Hamnet
Jack Fisk, Adam Willis – Marty Supreme
Hannah Beachler, Monique Champagne – Sinners
Nathan Crowley, Lee Sandales – Wicked: For Good
Best Editing
Stephen Mirrione – F1
Kirk Baxter – A House of Dynamite
Ronald Bronstein, Josh Safdie – Marty Supreme
Andy Jurgensen – One Battle After Another
Viridiana Lieberman – The Perfect Neighbor
Michael P. Shawver – Sinners
Kate Hawley – Frankenstein
Malgosia Turzanska – Hamnet
Lindsay Pugh – Hedda
Colleen Atwood, Christine Cantella – Kiss of the Spider Woman
Ruth E. Carter – Sinners
Paul Tazewell – Wicked: For Good
Mike Hill, Jordan Samuel, Cliona Furey – Frankenstein
Flora Moody, John Nolan – 28 Years Later
Siân Richards, Ken Diaz, Mike Fontaine, Shunika Terry – Sinners Kazu Hiro, Felix Fox, Mia Neal – The Smashing Machine
Leo Satkovich, Melizah Wheat, Jason Collins – Weapons
Frances Hannon, Mark Coulier, Laura Blount – Wicked: For Good
Joe Letteri, Richard Baneham, Eric Saindon, Daniel Barrett – Avatar: Fire and Ash
Ryan Tudhope, Nikeah Forde, Robert Harrington, Nicolas Chevallier, Eric Leven, Edward Price, Keith Dawson – F1
Dennis Berardi, Ayo Burgess, Ivan Busquets, José Granell – Frankenstein
Alex Wuttke, Ian Lowe, Jeff Sutherland, Kirstin Hall – Mission: Impossible – The Final Reckoning
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Let's be clear, right up top, that the age-defying, “hotness”-imposing wonder drug in Ryan Murphy's latest FX provocation The Beauty is not The Substance. The Substance made a Margaret Qualley crawl out of your back and run around while you took a nice bathroom nap; The Beauty, as far as we can tell, just makes you look like a permanent Instagram filter—or maybe Ashton Kutcher—and is also some kind of biological zombie plague.
Still, it's hard not to draw some parallels, even as the trailer for the upcoming show puts a lot more focus on the people creating the titular, uh, product, notably Kutcher, whose character is billed, irritatingly, only as “The Corporation.” (The Corporation apparently hangs out a lot with a very contemptuous Isabella Rossellini, in what we can only assume is low-key Death Becomes Her reference; meanwhile, we're going to give the show the benefit of the doubt and not presume Kutcher was cast entirely because of his past connections with Demi Moore—although they're certainly distracting.) When the new drug starts spreading like a virus, and turning people into some kind of ostensibly hot monsters, a pair of FBI agents (Evan Peters and Rebecca Hall) search for answers, while a character billed as The Assassin (played by Anthony Ramos, with a serious assist from a goofy metal eyepatch) goes around shooting people and threatening them with little hatchets.
If the general incoherence of the above description didn't make it clear, this looks like an extremely Ryan Murphy-ass show, with Murphy, in this case, working with 9-1-1 and Glee alum Matthew Hodgson to crank up the chaos. Say what you like about it, it's undeniably energetic, in that way that some of Murphy's more deranged ideas are; Kutcher's clearly having a pretty good time, preening in exotic locales and secretive superlabs and dropping lines like “It's an STD that people will actually want.”
The Beauty debuts on FX and Hulu on Wednesday, January 21; the series co-stars Jeremy Pope, Bella Hadid, Ben Platt, Jessica Alexander, and Vincent D'Onofrio.
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By Dessi Gomez
SEO Staff Writer
With everything now “Rightside Up” for Netflix's Stranger Things, the streamer is ready to take viewers behind the scenes of Season 5's production in a documentary arriving Jan. 12.
Directed by Martina Radwan, the documentary will dive into the years of work on the final season of the Duffer brothers' supernatural coming of age series. The MakeMake Production is produced by Angs Wall, Terry Leonard and Kent Kubena.
The trailer for the film, released this morning, teases an emotional Matt and Ross Duffer wrapping up the Netflix tentpole show that took 10 years to make. Shots of the cast crying also bring home the reality of saying goodbye to characters they gave a good chunk of their lives to.
“Writing the last lines that these characters would ever say,” one brother (Matt?) says at the beginning of the clip. “It was really hard to do.”
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“There was a debate in terms of Eleven's fate,” he adds later as he can be seen saying “God I don't know how to play this. Is she really gonna go through with this?”
Right after that, Millie Bobby Brown can be heard saying “I'm not ready to let go.”
Radwan spent a full year on set with Matt ad Ross Duffer, documenting their creative process along with cast and long-time collaborators.
RELATED: ‘Stranger Things 5': Duffer Brothers Unpack Emotional Series Finale From [SPOILER]'s Death To That 40-Minute Epilogue, Those Needle Drops & A Spinoff Hint
“I'm endlessly grateful to the Duffer Brothers for trusting me with a front-row seat to this incredible journey. Being able to get close and watching them bring this beloved show to life in real time, was pure joy. I only wish I could travel back and document Seasons 1 through 4,” she said. “Everyone welcomed me with remarkable generosity, openly sharing their personal and collective experiences from a decade of creative filmmaking, always pushing the boundaries. The Duffers inspire everyone to be better, including myself, their process and the show represents everything I love about filmmaking.”
The series finale rang in 2026 on New Year's Eve arriving both on the streamer and in theaters. After about an hour or so of action in their last battle with Vecna (Jamie Campbell Bower) and a supersized Mind Flayer, the original Hawkins crew got their somewhat happy ending with The Party graduating from high school as the class of 1989 and the young adult characters heading off to college but meeting back up to share their lives. Hopper (David Harbour) proposed to Joyce (Winona Ryder) and suggested they move to Montauk, Long Island in a nod to the original title and setting for what became Stranger Things.
See behind-the-scenes stills from the documentary below and watch the trailer above:
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The show died, so Will could “live”.
Lol, ok.
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Ryan Murphy's latest Evan Peters vehicle, “The Beauty,” is coming to FX in late January, and like all of the “American Horror Story” and “Monster” creator's projects, it promises to be a glossy affair filled with jutting cheekbones, addictive beats, and a surplus of campy vibes.
This time, the Golden Globe-winning “Dahmer” star is playing an FBI agent who, along with his partner, played by Rebecca Hall, is sent to Paris to look into a pattern of international supermodels dying in mysterious and gruesome ways. When the agents arrive in the City of Light, they discover the existence of “a sexually transmitted virus that transforms ordinary people into visions of physical perfection, but with terrifying consequences,” according to the show's synopsis.
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That leads them to a shadowy tech billionaire who goes by “The Corporation,” played by Ashton Kutcher, who has been manufacturing a miracle drug nicknamed “The Beauty.” Against the backdrop of Paris, Venice, Rome, and New York, the agents work to keep the virus from spreading further, while The Corporation tries to get his money-making injection in the hands of as many people as possible.
The twisty series also stars Anthony Ramos as an assassin working for The Corporation, and Jeremy Pope as “a desperate outsider” who gets caught up in the chaos unleashed by the billionaire's Substance-like creation.
In the first trailer for “The Beauty,” viewers get a taste of the very Murphy-esque new series and its many guest stars, which include Bella Hadid, Isabella Rossellini, Ben Platt, Jessica Alexander and Vincent D'Onofrio. The snippet opens with Kutcher and Rossellini trading barbs onboard a yacht as The Corporation celebrates his business savvy and then widens to the rest of the world in various states of unrest over The Beauty, which we find out has a serious bug or two.
The first three episodes of “The Beauty,” which is co-written and co-created by Matthew Hodgson, air on FX and Hulu January 21, 2026. Hall, who recently played opposite Ben Whishaw in “Peter Hujar's Day,” is also set to appear in the fourth installment of “Monster,” which will focus on the murderess Lizzie Borden.
Watch the trailer for “The Beauty” below.
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Amy Schumer feels pretty.
The actress put her weight loss transformation on display in a slew of bathing suits over the weekend.
“My mom took these photos of me while I was packing for a trip,” the comedian captioned an Instagram carousel Sunday.
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The slideshow kicked off with a smiling shot of the star in a strapless red bikini top and matching bottoms with “no makeup” and “no filter.”
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The newly-single star, 44, modeled a black one-piece, a strappy purple number and a black bikini in subsequent snaps.
After showing off two dresses and a pair of pajamas, Schumer concluded the social media upload with an airport selfie.
“The last photo I'm on the trip,” she told her followers, adding that 2026 “is about self care and self love.”
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The “Trainwreck” star concluded, “Let's all appreciate our health our families our friends and have the best year of our lives. Moving forward with no regrets. Just love. #notf–kingaround.”
Schumer's A-list pals gushed over her appearance in the comments section.
“You look 🔥,” model Paulina Porizkova wrote, while “Friends” alum Courteney Cox praised the “gorgeous” Emmy winner.
Schumer shared her mindset for the new year on the heels of her headline-making split from husband Chris Fischer.
Divorce speculation swirled in November 2025, with the “Last Comic Standing” alum confirming their breakup the following month.
“Blah blah blah Chris and I have made the difficult decision to end our marriage after 7 years. We love each other very much and will continue to focus on raising our son,” she wrote in December 2025, referencing 6-year-old son Gene.
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Earlier that same month, Schumer cryptically clarified via Instagram that “whatever ends up happening” with Fischer, 45, had “nothing to do with” her recent weight loss.
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The Golden Globe winner, notably, dropped 50 pounds with the help of Mounjaro, years after a “horrible” experience with Wegovy.
Schumer issued an apology to those “let down” by her slimdown last month, writing, “Sorry for whatever feeling it's giving you.”
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These days, “Good Will Hunting” co-writers Matt Damon and Ben Affleck do a film together just about every few years, which means that Netflix's “The Rip” is arriving right on time. The action-thriller written and directed by “Smokin' Aces” filmmaker Joe Carnahan, and starring the best-friend duo, will release globally on the streaming platform in mid-January, foregoing a theatrical run.
The logline for the film, which takes its name from a slang term for seizing illegal goods, reads: “Upon discovering millions in cash in a derelict stash house, trust among a team of Miami cops begins to fray. As outside forces learn about the size of the seizure, everything is called into question — including who they can rely on.”
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Joining Damon and Affleck's seasoned Miami officers — who, based on the just-released trailer, have plenty of life left in them — are younger cops played by Steven Yeun and Teyana Taylor, who is still collecting accolades for her performance in Paul Thomas Anderson's “One Battle After Another.”
“The Rip,” which is said to be inspired by real events, is billed as a “gritty, throwback action-thriller,” but it more specifically invites comparison to stunt-heavy heist films like “The Fast and the Furious” and corrupt-cop movies like “Training Day,” which makes sense given Carnahan's breakout film was 2002's Ray Liotta-led “Narc.”
The film, which marks the first collaboration between Netflix and Damon and Affleck's production company Artists Equity, even comes complete with a femme fatale type, played by “The Flash” star Sasha Calle, who gets mixed up with the swaggering team of cops when she's present at the raid.
“The Rip,” which releases on Netflix January 16, also features performances from Catalina Sandino Moreno, Scott Adkins, and Kyle Chandler. The streamer released a sneak peek of the film on Christmas Day, and now you can watch the full trailer below.
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Amy Schumer has welcomed 2026 with optimism and a fresh outlook. Schumer's Instagram posts have been refreshingly honest as she embraces her ‘self-love' era with honesty and self-acceptance, all while keeping her signature sense of humor.
On Sunday, January 4, the “I Feel Pretty” star shared a series of makeup-free bikini photos on Instagram, offering a candid glimpse into her mindset as she moves forward personally and professionally.
The post focused on Schumer's pre-vacation trip planning, but with a twist. The 44-year-old “Trainwreck” star posted photos taken before and during a recent getaway.
The photos showed her wearing bikinis and swimwear. “My mom took these photos of me while I was packing for a trip,” Schumer wrote. “And the last photo I'm on the trip. This year is about self-care and self-love.”
She also added in the caption that she was not wearing any makeup in the photos and chose to share them without filters.
The post wasn't just a regular one highlighting her stunning physical transformation. Schumer shared a more important message of resilience with her fans and followers.
“Let's all appreciate our health, our families, our friends, and have the best year of our lives,” she wrote. “Moving forward with no regrets. Just love.”
Schumer addressed her split from husband Chris Fischer on December 12. “Blah blah blah , Chris and I have made the difficult decision to end our marriage after 7 years,” she wrote, as per Entertainment Weekly. “We love each other very much and will continue to focus on raising our son.
In her post, she added, “We would appreciate people respecting our privacy at this time. blah blah blah not becisse I dropped some lbs and thought I could bag s basket and not because he's a hot Janlmes beard award winning chef who can still pull some hot tail. Amicable and all love and respect! Family forever [sic].”
As the couple faces a complicated chapter, Schumer's statement focused on their mutual commitment to raising their son, Gene, whom they welcomed in May 2019.
On New Year's Eve, Schumer joked about being newly single in an Instagram Story, crossing her eyes and holding a plate of spaghetti. “Who's kissing this at midnight?” she captioned the image, as reported by Page Six.
Schumer's noticeable weight loss over the past few years has drawn widespread attention and prompted questions about how she achieved it. While in March she confirmed using the weight loss medication Mounjaro, she has also been clear that serious health concerns drove her decision to lose weight.
She has previously explained that the change followed a medical diagnosis.
“I had a disease that makes your face extremely puffy that can kill you, but the internet caught it, and the disease has cleared,” Schumer wrote, referencing her diagnosis, as reported by People.
In a December 1 Instagram update, she confirmed that she had lost 50 pounds and stressed that her motivation was survival, not appearance. “Not to look hot, which does feel fun and temporary,” she wrote, “to survive.”
All her recent Instagram posts suggest one thing: for Schumer, this chapter is less about weight loss and more about well-being.
Still Looks Like SHIT! LOL!
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By Max Goldbart
International TV Co-Editor
After the runaway success of The Last of Us and A Minecraft Movie, the studios have been aggressive with video game IP, but there is plenty more out there.
British research firm Ampere Analysis has dug deep into the world of gaming to come up with what it believes are the four next titles ripe for adaptation.
Ampere floated BAFTA 2024 best game winner Baldur's Gate III, Black Myth: Wu Kong, Hollow Knight: Silksong, and Sons of the Forest as the quad of video games that could be coming to a big or small screen next, noting that they each have “strong popularity,” are “recent releases,” and contain “distinctive worlds.”
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Off the back of a super five years for video game IP, Ampere searched through the gaming archives leading on eight key characteristics to come up with its list. Characteristics included a defined narrative, adaptation style, franchise popularity and addressable audience.
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“Studios have moved quickly to secure the biggest and most obvious game franchises, but our research shows there is still significant untapped potential in the market,” said Ronald Santa-Cruz, Research Manager and Games Subject Matter Expert at Ampere Analysis. “For studios willing to look beyond the usual suspects, there remains a strong pipeline of game IP that could translate into the next major transmedia success.”
Some of the biggest shows and movies of the previous few years started life as video games and Ampere said commissions of IP have increased by an average 30% since 2019. Major studios, including Warner Bros. Discovery, Paramount, Netflix, Comcast, and Amazon have already secured rights to 10 marquee game franchises, with the likes of Mortal Kombat, Street Fighter and Legend of Zelda all coming up.
Driven by the recent success of high-profile titles such as The Last of Us and A Minecraft Movie, the market has shifted decisively towards live-action adaptations and away from animation, added the research firm. In 2025, 69% of commissioned adaptations were live action, more than double the share from the previous year. In the second half of 2025 alone, 18 new game adaptations were commissioned, with 78% of these live action.
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By
Emily Zemler
Ariana Grande offered an update on her highly-anticipated Eternal Sunshine tour while attending the Critics Choice Awards on Sunday night.
“I've been working on the set list for months now,” she told E! News on the red carpet outside the Barker Hangar in Los Angeles. “It's in a good place, but we'll never know until we get into the rehearsals — which are starting very soon — and we put things on their feet if it'll make sense or not.”
When asked if she could share any details, Grande played it coy. “I want to let it be a surprise,” she said.
The outlet also asked Grande if she feels like she's a different person while on tour. “I think it's the same person,” she responded. “I am grateful to work and I'm excited for the tour.”
E! asks Ariana Grande if she'll incorporate Glinda in the ‘eternal sunshine' tour set list:“We'll see” pic.twitter.com/ZvjB4237Og
Grande's tour kicks off next June with two dates in Oakland, California, before moving to Los Angeles (both the Crypto.com Arena and Kia Forum). The singer will also perform in Austin; Grande's native Sunrise, Florida; Atlanta; Brooklyn; Boston; and Montreal. She'll conclude the U.S. run with two nights at Chicago's United Center on Aug. 3 and 5. The trek will then jump the Atlantic for five nights at London's O2 arena.
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Similar to 2019's Sweetener world tour, the newly announced slate of performances will span two albums: Eternal Sunshine and Positions, the R&B opus Grande released in late 2020. “I think that I was buying myself time — I didn't want to do that,” she told the Zach Sang Show earlier this year, referring to the idea of taking two albums on the road again. “I was like, yeah, and then the album will never happen, and then the tour will never — no, no, no. I'm kidding.”
In November, Grande confirmed she has no plans for another tour in the foreseeable future. “The last 10 or 15 years will look very different to the ones that are coming up,” she said in an interview on Amy Poehler‘s Good Hang podcast. “I don't want to say anything definitive.”
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She continued, “I do know that I'm very excited to do this small tour, but I think it might not happen again for a long, long, long, long, long time. I'm going to give it my all and it's going to be beautiful. I think that's why I'm doing it because I'm like, ‘One last hurrah!'”
A couple of months after the tour wraps, the long awaited fourth movie in the Meet the Parents franchise — Focker In-Law — will hit theaters. Grande stars in the film alongside returning cast members Robert De Niro, Ben Stiller, Owen Wilson, Blythe Danner, and Teri Polo.
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By
Emily Zemler
After a clearly-effective marketing campaign, Timothée Chalamet won Best Actor at the annual Critics Choice Awards on Sunday night for his performance in Marty Supreme.
Chalamet took the stage at the Barker Hangar in Los Angeles to accept the award, which is voted on by a body of film critics, and used the opportunity to thank a number of people in his life for their support. He first called out his fellow nominees, including Michael B. Jordan, who was up for his dual performance in Sinners.
“Michael, man, unbelievable,” Chalamet said. “Just rewatched Sinners. [I] hadn't seen the after-credit scene. I'm happy I stuck around the second time.”
He then thanked Marty Supreme filmmaker Josh Safdie for “crafting a role and a story” for him, admitting, “I'm more nervous than I thought I'd be.”
“You made a story about a flawed man with a relatable dream, and you didn't preach to the audience about what's right and wrong,” the actor told Safdie. “I think we should all be telling stories like that. Thank you for this dream.”
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Notably, Chalamet also thanked his girlfriend, Kylie Jenner, whom he rarely speaks about publicly despite her presence with him at various film-related events.
“Thank you to my partner of three years,” Chalamet said sincerely. “Thank you for our foundation. I love you. I couldn't do this without you. Thank you from the bottom of my heart.”
As the camera cut to Jenner, she mouthed “I love you” in response.
Timothée Chalamet thanks Kylie Jenner during his Best Actor speech at the Critics Choice Awards:“Thank you to my partner of three years. Thank you for our foundation. I love you. I couldn't do this without you.” pic.twitter.com/MzFjVIAqve
Chalamet went on a promotional rampage for Marty Supreme, which hit theaters on Dec. 25. Last month, he shared an 18-minute Zoom video featuring the “marketing team” for the film. During the clip, he shared his ideas for, as he put it, “one of the most important things that happens on Planet Earth this year. Marty Supreme. Christmas Day.”
He later went on The Tonight Show to pitch audiences on why they should see the film. “This is a movie about sacrifice in pursuit of a dream,” he said. “And it's something I can relate to deeply. And we live in a bleak time, especially for young people, so this film is an attempted antidote to that. And to continue to believe in yourself and to continue to dream big and to follow your dreams and not take no for an answer. That's the spirit of Marty Supreme, out on Christmas Day.”
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In a final stunt, Chalamet ascended the Las Vegas Sphere, which had been transformed into a giant orange ping-pong ball.
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The actor was also recently awarded a spotlight award at the Palm Springs International Film Festival Awards. He was accompanied to that event by Jenner as well.
“At some point, I realized the film industry isn't an institution,” Chalamet said in his acceptance speech. “Great roles aren't printed on a conveyor belt. Great auteurs and directors don't fall from a tree. Every day to wake up in good health and have the opportunity to make things for the world, that's truly a gift in every sense of the word.”
Timothée Chalamet accepts the Spotlight Actor of the Year Award at the Palm Springs International Film Festival Awards:“Every day, to wake up in good health and have the opportunity to create things for the world… is truly a gift.”(Source: @Variety) pic.twitter.com/34daaVj5Mr
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The campaign went live on Sunday (Jan. 4) with a $100,000 goal and raised just over $1,500 within its first six hours.
By
Jessica Lynch
Mickey Rourke has launched a GoFundMe campaign as he faces a possible eviction from his Los Angeles home after allegedly falling nearly $60,000 behind on rent.
According to The Hollywood Reporter, the fundraiser was organized by Rourke's friend and a member of his management team, Liya-Joelle Jones. The campaign went live on Sunday (Jan. 4) with a $100,000 goal and raised just over $1,500 within its first six hours.
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The GoFundMe page states that Rourke has given his “full permission” for funds to be used to “help cover immediate housing-related expenses” and prevent eviction. The campaign describes a period of prolonged financial and health struggles following the actor's decision to step away from Hollywood at the height of his career.
“At the height of his success, he stepped away from Hollywood in search of truth and authenticity, choosing risk over comfort,” the campaign reads. “Boxing—real and punishing—left lasting physical and emotional scars, and the industry that once celebrated him moved on quickly.”
The page continues, “Fame does not protect against hardship, and talent does not guarantee stability. What remains is a person who deserves dignity, housing, and the chance to regain his footing.”
Speaking to THR, Jones said, “Mickey is going through a very difficult time right now, and it's been incredibly touching to see how many people care about him and want to help.”
According to People, Rourke was served a notice on Dec. 18 demanding payment of $59,100 in back rent or that he vacate the property within three days. The notice was reportedly posted on the home and mailed to the actor because he was not present at the time.
A complaint filed on Dec. 29 alleges that Rourke “failed to comply with the requirements of” the notice.
The three-bedroom, 1,600-square-foot home was rented under a lease Rourke signed in March 2025 for $5,200 per month, which was later increased to $7,000. In addition to back rent, the landlord, Eric Goldie, is reportedly seeking attorney fees and the forfeiture of the rental agreement.
Rourke began renting the home shortly before pursuing legal action against Celebrity Big Brother UK over an alleged pay dispute following his exit from the series in April 2025. At the time, his manager Kimberly Hines said in a statement shared with People that the show had disrespected the actor and failed to compensate him as agreed.
“There's no question that when Big Brother booked Mickey Rourke, they were fully aware of both his public persona and how it aligned with his Hollywood rebel image,” Hines said, adding that producers knew his presence would be “explosive, controversial and attention-grabbing — and that's exactly what they got, and more.”
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Some love stories are not meant just for the screen. For Adam Sandler, the most remarkable love story he has ever been in is his own. The actor truly believes some things in life are meant to be.
While accepting a major career honor this weekend, the actor reflected on love, fate, and the life he might have lived had he taken a very different path. Sandler, 59, was honored with the Chairman's Award at the Palm Springs International Film Festival gala on Saturday, January 3, in Palm Springs, California.
The honor celebrated his dramatic performance in “Jay Kelly,” marking a complete shift from the comedic roles that made him a household name.
The award was presented following an introduction from Laura Dern, one of Sandler's co-stars in the film. While accepting his speech, he gave a sweet nod to his loving wife of over 20 years.
During his acceptance speech, Sandler shared his most honest feelings about how his life might have unfolded had he chosen to work for his father as an electrical engineer rather than pursue acting.
“I sometimes think about it, [if] I didn't click that year and I did go work for my dad, what my life would be right now,” he said, as reported by People. “First off, I'm thinking I'd probably still be married to my wife, Jackie. That's destiny. Nothing stops that.”
He followed the heartfelt moment with humor, adding, “But we definitely [would] have a different house. Probably, like, 10 less bathrooms and [fewer] statues of me.”
Sandler married Jackie Sandler in June 2003. The couple shares two daughters, Sadie, born in 2006, and Sunny, born in 2008.
In “Jay Kelly,” directed and co-written by Noah Baumbach, Adam Sandler takes on the role of Ron Sukenick, a worn-down manager navigating the pressures of Hollywood while representing a larger-than-life movie star played by George Clooney.
The film has received strong critical acclaim and has become one of Sandler's most widely discussed performances in recent years, firmly placing him in this season's awards race. His work in the film has earned recognition from major awards, including nominations at the Critics' Choice Awards and the Golden Globes. There is a strong Oscar buzz for his performance in the film, too.
Sandler was one of several high-profile honorees at this year's festival.
The movie also stars Miley Cyrus, Timothée Chalamet, Leonardo DiCaprio, Amanda Seyfried, Kate Hudson, Michael B. Jordan, and more. “Jay Kelly,” which also stars Dern, Billy Crudup, Greta Gerwig, Riley Keough, and Emily Mortimer.
The film is currently streaming on Netflix.
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The ‘Marty Supreme' star took his time onstage, saying, "I don't know if I'll be up here again."
By
Nicole Fell
Assistant Editor
Timothée Chalamet scored his first win of the 2026 awards season, taking home the award for best actor at Sunday's 2026 Critics Choice Awards.
The 30-year-old Marty Supreme star looked extremely surprised when his name was called, leaning over to kiss girlfriend Kylie Jenner.
The actor has been earnestly upfront about his desire for recognition in this role, which he carried over into his awards speech. “I got a lot of people to thank. I don't know if I'll be up here again, so give me a second,” Chalamet told the gathered crowd as he went down his list of those to thank.
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Chalamet was visibly shaken by the win, stumbling over his words a few times. “Damn, I'm more nervous than I thought I'd be,” he said, correcting his mistake.
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The actor thanked his fellow nominees, singling out Michael B. Jordan in particular. “Michael, man, unbelievable. Just rewatched Sinners. [I] hadn't seen the after-credit scene. I'm happy I stuck around the second time.”
He also thanked Marty Supreme director Josh Safdie for “crafting a role and a story” for him. “You made a story about the relatable dream and you didn't preach to the audience about what's right and wrong. I think you should all be telling stories like that, so thank you for this dream,” he said.
Given the pair have been attending more events together, it's no surprise Chalamet thanked long-term girlfriend Kylie Jenner, the camera panning over to the reality star while he spoke. “Thank you to my partner of three years. Thank you for our foundation,” he said. “I love you. I couldn't do this without you.”
The couple didn't attend Sunday's pre-show carpet, arriving after the show had already begun. Hacks' Paul W. Downs and Meg Stalter were the talk of the night thanks to their outfits, which were an exact match to Chalamet and Jenner's looks at the Marty Supreme L.A. premiere.
The 31st Critics Choice Awards ceremony aired live from Santa Monica's Barker Hangar on E! and USA Network. The list of the 2026 Critics Choice film and TV nominees can be found here. Check out the stars' arrivals and looks.
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'Jimmy Kimmel Live!' won best talk show over Stephen Colbert's 'Late Show,' 'Late Night With Seth Meyers' and 'The Daily Show,' with Kimmel joking the other shows, save Sean Evans' 'Hot Ones,' "did not care enough to be here with you tonight."
By
Hilary Lewis
Deputy Editor, East Coast
Jimmy Kimmel said he was surprised to win best talk series at the 2026 Critics Choice Awards, but he still came equipped with a number of sharp barbs and a comically long written acceptance speech, which he unrolled onstage.
Kimmel quipped that he would have preferred a “FIFA peace prize,” referring to the award President Donald Trump received at the, now renamed, Kennedy Center during the World Cup draw last month.
After that, Kimmel unrolled a comedically long written acceptance speech as he said he “really didn't expect this,” and thanked the critics, calling out three specific reviewers by name, including Jeffrey Howard from KCLV-TV in Las Vegas, whom Kimmel, a Sin City native, said he went to high school with.
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He went on to thank “our friends at Disney,” naming CEO Bob Iger, entertainment co-chairman Dana Walden and even OpenAI boss Sam Altman, who, Kimmel said, “who now owns my voice and face. Please don't do anything weird with it.”
Kimmel's remarks about Altman appear to be a reference to Disney's recent $1 billion investment in OpenAI that included striking a licensing deal with the Altman-run AI powerhouse. The latter agreement would allow users of OpenAI's Sora to create clips using characters from the Marvel, Pixar and Star Wars franchises.
Kimmel was nominated alongside his late night competitors The Late Show With Stephen Colbert, Late Night With Seth Meyers, The Daily Show and Watch What Happens Live With Andy Cohen as well as YouTube's Hot Ones. Kimmel joked that his fellow nominees, save Hot Ones‘ Sean Evans, who was shown onscreen laughing at Kimmel's acceptance speech, “did not care enough to be here with you tonight.”
Of Evans, Kimmel joked that one day he'd be “the only one left.” Questions have emerged in recent months about the future of late-night TV after CBS canceled The Late Show for what the network claimed were financial reasons. Meanwhile, Trump has gone after Colbert, Kimmel and Meyers, saying they all should be taken off the air.
Kimmel's win comes after ABC briefly suspended him this fall after he made comments about Charlie Kirk's killer that led Trump's FCC chair to threaten ABC affiliates' licenses.
Since returning to the air, Kimmel and wife and co-head writer Molly McNearney, who joined Kimmel onstage Sunday night, have spoken out in support of free speech, and Kimmel took time on Sunday night to address the issue and Trump.
“Thanks to all the writers and actors and producers and union members, many of you who are in this room, who supported us, who really stepped forward us and reminded us that we do not take free speech for granted in this city or in this country,” Kimmel said. “Your actions were important, and we appreciate them.”
He later added, “Most of all I wanna thank our president, Donald Jennifer Trump. Without whom, we'd be going home empty-handed tonight. So thank you, Mr. President for all the many ridiculous things you do each and every day. It's been a banner couple of weeks, and we can't wait to get back on the air tomorrow night to talk about them.”
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He also appeared in ‘Cinderella Liberty,' ‘The Day of the Dolphin' and ‘The Front Page' and spent the past 17 years teaching at the Stella Adler Studio of Acting.
By
Mike Barnes
Senior Editor
Jon Korkes, the veteran character actor and acting teacher who worked for director Alan Arkin in Little Murders on stage and screen and portrayed the doomed turret gunner opposite him in Mike Nichols' Catch-22, has died. He was 80.
Korkes died peacefully in his New York apartment on New Year's Eve, his cousin Nancy Drinkwater told The Hollywood Reporter.
In other notable '70s films, Korkes played an undercover bad guy in Nichols' The Day of the Dolphin (1973) and a reporter in Billy Wilder's version of The Front Page (1974), and he showed up in Mark Rydell's Cinderella Liberty (1973) and Larry Peerce's Two-Minute Warning (1976) as well.
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For television, he appeared on everything from All in the Family to Law & Order: Criminal Intent and recurred as corrections officer Tom Robinson on six episodes of Oz during the HBO drama's final three seasons (2001-03).
In 1968, Korkes was working as a reader in auditions for Jules Feiffer's off-Broadway production of Little Murders when he was cast by director Arkin to play the brother of Marcia Rodd's character in the Fred Willard-starring black comedy about unrelenting decay in New York City.
He reprised the role of Kenny Newquist alongside Rodd (and other returnees Vincent Gardenia and Elizabeth Wilson as their parents) in the 1971 Fox film version that also was helmed by Arkin and starred Elliott Gould in Willard's role of a photographer.
In perhaps his most notable part — though his screen time was limited — he portrayed the young turret gunner Snowden, whose slow, bloody death haunts Arkin's bombardier Capt. John Yossarian throughout Catch-22 (1970).
As a teacher at the Stella Adler Studio of Acting in Manhattan from 2008 until November, Korkes “brought decades of experience across film, television and theater into the classroom, meeting each student exactly where they were,” reads a statement from the school on Facebook. “He loved teaching, and his students knew it.”
For him, it was all about paying it forward. “Nichols and Arkin and Feiffer and all those people started me. They were like the slightly older kids who let me play ball with them, and they showed me things and they didn't kick me out,” Korkes said in a video on the school's website. “You don't forget that.”
Born in Lynn, Massachusetts, on Dec. 4, 1945, Jonathan David Korkes was raised in nearby Marblehead, where he graduated from Marblehead High School. He made his onscreen debut as a small-time crook in The Out-of-Towners (1970), directed by Arthur Hiller and starring Jack Lemmon in another movie about a crumbling New York.
Meanwhile, he appeared on Broadway in 1969 in The Penny Wars, directed by Barbara Harris, and in 1971 in the one-act Unlikely Heroes.
Korkes' résumé also included the movies The Outside Man (1972), Between the Lines (1977), Jaws of Satan (1981), Getting Away With Murder (1996), Riding in Cars With Boys (2001) and The Double (2013) and stints on TV on The Mary Tyler Moore Show, The Rookies, The Larry Sanders Show, Homicide: Life on the Street and three Law & Order series.
He also taught a master class for actors in Rio de Janeiro.
8:40 a.m. Jan. 5: Added details of his death.
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All the red carpet looks from Ariana Grande and more Sunday night at Santa Monica Airport's Barker Hangar.
By Laurie Brookins, Tristan Cassel
January 4, 2026 4:00pm
Will the reshuffling of the event calendar enhance the anticipation for Sunday night's kickoff of the 2026 awards season? That question is among many that promise to be answered as the red carpet opens for the 2026 Critics Choice Awards, taking place at the Barker Hangar at Santa Monica Airport.
For the first time in nine years, the Critics Choice Awards has leapfrogged to the front of the awards season schedule, enabling this organization of film, TV and streaming journalists to help set the narrative for the coming months and perhaps nurture a buzz for films and actors in contention for the season's most coveted trophies. That includes Timothée Chalamet for Marty Supreme and Leonardo DiCaprio for One Battle After Another, as well as Jesse Buckley for Hamnet and Amanda Seyfried for The Testament of Ann Lee. (Keep up with the winners as they are announce live.)
It's also the first opportunity to get a sense of who will emerge as the year's most-discussed style stars on the awards season red carpet. Frankenstein's Jacob Elordi and Sentimental Value's Elle Fanning traditionally scored best-dressed nods for their sartorial choices during previous seasons, but One Battle After Another's Teyana Taylor also should top many lists, as the actress is firmly a designer favorite who's worn Balmain and Tom Ford by Haider Ackermann in recent months.
Ultimately, from high-profile films and TV shows to viral moments in high fashion, a variety of game plans and campaigns will be established Sunday night at the Barker Hangar. Here's a look at all of the night's arrivals, which The Hollywood Reporter will update throughout the evening.
Leighton Meester in Carolina Herrera and Chopard with Adam Brody in a Jaeger-LeCoultre timepiece
Teyana Taylor in Saint Laurent by Anthony Vaccarello with Tiffany & Co. jewels
Ariana Grande in Alberta Ferretti with Bucherer Fine Jewellery and Jimmy Choo shoes
Diego Luna in Zegna and an Omega timepiece
Adam Sandler and Jackie Sandler
Elle Fanning in archival Ralph Lauren with Cartier jewels and Manolo Blahnik shoes
Seth Rogen in Zegna and David Yurman jewels
Joel Edgerton in Louis Vuitton
Ryan Coogler in Louis Vuitton with Zinzi Coogler in diamonds by Zales
Jacob Elordi in Bottega Veneta with Cartier jewels and Oliver Peoples sunglasses
Noah Hawley
Matthew Rhys in Giorgio Armani with Keri Russell
Stellan Skarsgård in Dior with an Omega timepiece
Amanda Seyfried in Valentino with Tiffany & Co. jewels
Jessica Biel in Lanvin with Cartier jewels
Michael B. Jordan in Louis Vuitton and Christian Louboutin boots
Nick Offerman
Ludwig Göransson in Zegna with Boucheron jewels
David Alan Grier
Jeff Goldblum in a Blancpain timepiece
Shawn Hatosy in Paul Smith
Odessa A'zion in Ott Dubai and Jimmy Choo shoes
Patricia Arquette
Chelsea Handler in Monique Lhuillier and Jennifer Meyer jewelry
Jean Smart in Saidian jewels
Hannah Einbinder in Louis Vuitton
Sarah Snook in Akris with Chopard jewels
Tramell Tillman in Anamika Khanna and Lagos jewels
Ginnifer Goodwin and Josh Dallas, both in Giorgio Armani
Mark Sonnenblick, Rei Ami and EJAE with Audrey Nuna, who is wearing Marc Jacobs
Kathy Bates
Lisa Ann Walter in a Solangel gown with jewels by A.Jaffe, Anabela Chan and Le Vian and a handbag by Marina Raphael
Paul W. Downs and Megan Stalter in looks by Erica D. Schwartz
Adam Scott
Ethan Hawke in Bode
Rhea Seehorn in custom Louis Vuitton
Jen Statsky
Carrie Preston
Benicio del Toro in Giorgio Armani and an Omega timepiece
Jimmy Kimmel and Molly McNearney
Quinta Brunson in Chloé
Jon M. Chu
Denée Benton in Bach Mai with Baetyl jewels
Tom Pelphrey in Saint Laurent by Anthony Vaccarello with Kaley Cuoco in Simkhai with Pomellato jewels and Jimmy Choo shoes
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Whether it's forcing Brigitte Macron to prove that she is a woman or wildly speculating about Charlie Kirk's murder, the far-right podcaster and conspiracy theorist has millions of listeners hooked on her unique brand of dangerous misinformation. So, how has Candace Owens been allowed to become so powerful, asks Katie Rosseinsky
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For right-wing firebrand Candace Owens, conspiracy theories are a form of “mind yoga”, a way of bending the mind “like a pretzel”. They're also extremely compelling, for her millions of social media followers and podcast listeners at least, and extremely lucrative, helping the 36-year-old American build a staggering media empire in under a decade.
Coronavirus and the vaccines. The moon landings. Climate change. The #MeToo case against Harvey Weinstein. Blake Lively and Justin Baldoni's legal battle. All these disparate subjects have received Owens's signature treatment. On her eponymous podcast, she is the queen of the “just asking questions” approach: positioning herself as an investigating crusader who is bold enough to probe the topics that she believes the mainstream media don't want you to know about.
She is part one-woman outrage machine, part millennial version of a medieval mystic; she has certainly worked out how to cleverly monetise the human impulse to “uncover” so-called “truths” and to feel like we are somehow in possession of a secret knowledge that explains how the world works. But her latest forays into so-called “mind yoga” are tying her in ever more complex knots that set her apart from even the most fact-averse of her fellow microphone-toting far-right truthers.
Last summer, French president Emmanuel Macron and his wife Brigitte filed a defamation lawsuit against Owens, who has regularly and fervently spouted bizarre claims that the first lady was born male; the couple have accused her of mounting “a campaign of global humiliation” and “relentless bullying on a worldwide scale”. Their civil suit followed separate criminal prosecutions in France against 10 people accused of making malicious comments about the first lady's gender and sexuality. On Monday (5 January), a Paris court found the eight men and two women guilty of cyberbullying, describing their claims as “particularly degrading, insulting and malicious”; their penalties ranged from cyberbullying awareness training to eight-month suspended prison sentences.
In November, Owens made the even stranger allegations that the Macrons had attempted to orchestrate her assassination (the National Gendarmerie Intervention Group, the organisation that Owens claimed was involved in the “plot”, told French media that these allegations were fake news).
And towards the end of last year, Owens dragged herself and her followers even further down the rabbit hole by stirring up conspiracies around the death of her one-time boss, Charlie Kirk, the right-wing activist and founder of conservative student group Turning Point, who was shot dead in September. Among her inflammatory claims? The suggestion that his death was somehow an “inside job” involving Turning Point employees.
Her claims prompted Kirk's longtime producer, Blake Neff, to finally call Owens out for spending months “attacking Charlie's closest friends”, who, he said, “have had to endure harassment from people who have gotten whipped up by what Candace is saying”. Owens is now playing an even higher stakes game, running the risk of finally alienating one-time allies on her end of the political spectrum, while also surely aware that her most devoted core of fans will expect wilder theories to come.
So how did Owens become one of the most influential – and arguably, one of the most dangerous – women on the internet? Her early days didn't exactly lay obvious foundations for a hard-right pivot. The third of four children, she spent her childhood in Stamford, Connecticut and, following her parents' divorce, was brought up by her grandparents. At school, she experienced racist bullying; when she was in her senior year, she received death threats from some white classmates, including the son of Stamford's then-mayor. Her family sued the Stamford Board of Education, eventually gaining a $37,500 settlement.
Around this time, she developed “an abiding interest in current affairs”, as a Tatler profile would later put it, with her political sympathies initially skewing towards the Democrats. After dropping out of a journalism degree at the University of Rhode Island, Owens interned in the fashion cupboard at American Vogue (“There was not some kind of formal hierarchy, but it was very clear that she was running the show,” a fellow intern recalled in Vanity Fair).
She then worked her way up the ranks in administration in a New York private equity firm before co-founding a marketing agency. Dig back into the agency's blog archives, and you will find Owens mouthing off about “the bat-s***-crazy antics of the Republican Tea Party”. But her politics would soon change drastically. In 2016, she launched a Kickstarter campaign for a platform called Social Autopsy, a searchable database of internet trolls (there is, of course, a certain irony to Owens initially touting herself as some kind of anti-cyberbullying champion).
She is part one-woman outrage machine, part millennial version of a medieval mystic
Inevitably, it stoked criticism: wouldn't this just amount to doxxing, the typically malicious act of posting another person's private details on the internet? Owens ended up on the receiving end of online hate herself, and blamed left-wing activists. “I became a conservative overnight,” she later reflected. “I realised that liberals were actually the racists. Liberals were actually the trolls.”
Not long after, she started posting on YouTube: her first video was a sketch in which she “came out” to her parents as a conservative. Owens positioned herself as a supporter of Donald Trump, who was then in the early stages of his first presidency, and decried ideas around identity politics, structural racism and the Black Lives Matter movement. She particularly vehemently opposed any suggestion that African-Americans should perceive themselves as victims – and still does.
Owens crossed paths with Kirk at a conservative conference in Florida late in 2017. “Within 30 seconds of seeing her on stage, I said to myself, ‘Oh my goodness, I have not seen a talent like this in my six years of politics,'” Kirk later told The Washington Post. He immediately hired her to work in communications for Turning Point, and they spent the next few years touring colleges, spreading the conservative gospel.
Around this time, Owens launched the Blexit Foundation, an organisation encouraging a “Black exit” from the Democrats, urging Black voters to throw their support behind the Republican Party instead. Kanye West publicly supported her, writing “I love the way Candace Owens thinks” on Twitter. And she and Kirk also took their Turning Point mission overseas.
At an event in London in December 2018, Owens ended up appearing to suggest that if Hitler had simply stuck to Germany, his policies would have been “fine”. “Whenever we say ‘nationalism', the first thing people think about, at least in America, is Hitler,” she said. “He was a national socialist, but if Hitler just wanted to make Germany great and have things run well, OK, fine.” The “problem”, she added, was that he “had dreams outside of Germany. He wanted to globalise.” Owens would later claim that her words had been taken out of context by “leftist journalists”, and stated that there is “no excuse or defence ever” for “everything that [Hitler] did”.
Owens left Turning Point in 2019, but her profile continued to grow and grow. 2021 saw the launch of Candace, an online show for the conservative platform Daily Wire, co-founded by another right-wing controversy magnet, Ben Shapiro; it featured sit-down interviews with the likes of Trump, but she also used her platform to weigh in on pop culture and lifestyle topics (such as her vehement belief that women should not wear leggings outside of the gym, because doing so is indicative of “the decline of our culture”).
But in 2024, Owens parted ways with Daily Wire, reportedly over her antisemitic comments (although she would later claim this was a “smear campaign” and a “ridiculous storyline”). Owens's great talent, though, is for turning controversy into content, and it wasn't long before she returned with her own venture, a self-titled podcast. Since launching in June of 2024, its ascent has been dizzying: in October 2025, it ranked as the No 1 show across platforms in terms of downloads and views per episode, with an average of around 3.5 million downloads per show, according to analytics from Podscribe.
The right-wing podcast sphere is booming in a way that the left can't seem to match. Just a quick glance at the US charts demonstrates the dominance of controversial conservative-skewing figures such as Joe Rogan, Tucker Carlson and Theo Von. According to a Media Matters report from 2024, right-leaning online shows had nearly five times as many followers and subscribers as their left-wing equivalents. Controversy and conspiracy pay off: the more outrageous the content, the more the listeners keep coming back (not for nothing was “rage bait” announced as the Oxford Dictionary's word of the year).
It's a model that Owens has honed to perfection. Outrage drives clicks, listens and views. It keeps fans coming back. And this in turn makes advertisers sit up and take note. Her husband, George Farmer, the British son of a multi-millionaire Tory peer and hedge fund manager, oversees the business side of the operation, and told Bloomberg that her advertisers “have reported seeing returns of two-to-one on dollars spent with us, and up to five-to-one reported in some cases”.
Her huge listener base means that the podcast can inevitably charge higher advertising rates; recent analysis from Fortune magazine suggested that her company generates up to $10m in revenues per year. And according to Farmer, only one advertiser has pulled out over the past year; the show now has almost 60 sponsors, Bloomberg reports. In 2023, her anti-trans YouTube videos were demonetised, and last year, she was temporarily suspended after violating hate speech policies, but she has since returned with a vengeance. And even if these bigger sites did ban her, she would probably follow in the footsteps of other “cancelled” right-wing figures and simply move to a new platform.
What's particularly shrewd, though, is the way Owens has a knack for throwing herself into topics that are guaranteed to creep onto your social feed. Take actor Blake Lively's legal battle against her It Ends with Us co-star and director Justin Baldoni. Owens covered the story in obsessive detail, responding to suggestions and “clues” from followers with all the zeal of a TikTok sleuth.
Elsewhere, she borrows the aesthetic of your classic lifestyle influencer. Her website, Club Candace, doesn't exactly look like the online home of a conservative firebrand; instead of Maga red and shouty graphics, it's all swirly, cursive fonts and glowing photos of Owens. But then you look closer at the merch she's selling: the “Candace Intelligence Agency” T-shirts ($35), the “we don't know-know, but we know” sweater ($60), a slogan that gets to the heart of Owens's fast-and-loose attitude to facts, and the “conspiracy theorist” mug ($16).
And yet with the Macron lawsuit looming, Owens may have met her match. For all the successes of her podcast, she is now facing a major legal battle. She has been asking fans to donate to her legal fund, and estimates she will need around $5m, but that feels like a conservative estimate. Should she lose, she could face millions in legal fees alone. The case of fellow right-wing podcaster and conspiracy theorist Alex Jones feels particularly pertinent here: Jones was ordered to pay around $1.4bn in total damages after the families of Sandy Hook elementary school shooting victims won two separate defamation suits against him. He has since been declared bankrupt (although he is still broadcasting).
In American defamation cases against public figures, though, the onus is on the plaintiff to prove “actual malice”, or essentially to show that the defendant knew the information they were sharing was untrue. This can be tricky to prove. In 2021, Owens was hit with a separate defamation suit by the former Republican congressional candidate Kimberly Klacik. She claimed that Owens had smeared her with false allegations of drug use, fraud and working as a “madame” in a strip club, but the case was tossed out by a judge; Klacik ended up being required to pay her $115,000 to cover legal fees.
Using Kirk's death as another trending topic to boost her profile looks like an ill-advised move, too. Owens is far from the only podcaster to indulge in bizarre conspiracy theories, but her personal link to Kirk, coupled with her willingness to exploit that for clicks and listens, makes the whole spectacle feel extremely murky. In aiming for Turning Point, too, she risks splitting her support base. Here, she is not going after the “establishment” or the “elite”, those bogey people of conspiratorial thinking, but her own political allies. And the signs are that Turning Point are not going to let her get away with it.
But Candace is unlikely to let this knock her off course. For her, a backlash is likely to be seen as just another opportunity. In this respect, she is the Trump era pundit par excellence: scandals that would have ended other careers only seem to give her more fodder to feed back to her devoted followers. Until now, Owens, with all her despicable theories, has made notoriety her superpower. In today's topsy-turvy cultural climate, being the ragebait queen has served her well. It remains to be seen, however, if they make her undefeatable.
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Jeff Bezos seemed to get a special delivery at his $165 million home in Beverly Hills: a UFO!
The odd, futuristic structure sits on the grounds near the cactus garden. Bezos, 61, has yet to reveal the contents of the shiny installation. Some speculate it's a sauna, but it also bears a striking resemblance to a made-to-order, stainless-steel statement piece designed by Timothy Oulton Studio.
The pod was designed as a scale replica of NASA's Apollo 11 space capsule, according to the studio's website, and can be utilized as “a private VIP seating lounge, a workspace meeting capsule or a dining pod.”
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Students on campus at Coastal Carolina University in Conway, South Carolina. (File photo courtesy of Coastal Carolina)
COLUMBIA — An unmanned underwater research vehicle, an event center to train hospitality students and an institute centered around federal defense research are among items on South Carolina colleges' budget wish list for the coming year.
In all, public universities and technical colleges are seeking $2.3 billion in additional state aid for the fiscal year starting in July, according to a review of budget requests.
Legislators won't approve colleges' full requests, but the plans are a preview of higher education priorities across the state.
Coastal Carolina students to build satellite in state's 1st college space program
For Coastal Carolina University, those priorities include a buildout of South Carolina's first university-run space program.
Since March 2023, Coastal Carolina professors and about 80 science and engineering students have worked to plan and build a satellite. Now it's time to launch the shoebox-sized satellite into orbit, where it will circle the planet 15 times a day from roughly 1,200 miles up.
The Conway-based college is asking legislators to set aside $450,000. But the school also wants to take things a step further, with a $900,000 underwater research vehicle.
The unmanned vehicle and satellite will work in tandem collecting images and data from above and below the Atlantic Ocean and South Carolina's blackwater estuaries.
“Coastal systems are vital to the state's economy and culture, supporting fisheries, ecotourism, and economic development,” the college's request reads. “The data collected will enhance our ability to assess ecosystem resilience and provide early warnings for environmental stressors.”
Coastal Carolina scientists and students will track environmental changes driven by storms, flooding, drought, and other natural events. They'll also monitor impacts to habitats and movements of key marine species, such as shrimp, crabs, oysters, red knots, red drum, sharks, turtles, dolphins, and whales, according to the college's request.
While Coastal Carolina's request appears out of the ordinary, it's far from the most expensive.
The technical college system is collectively seeking $743 million for projects across its 16 college campuses, accounting for a third of the total newly requested. Most of it would pay for construction projects.
High-dollar projects include $80 million to move the medical campus of Florence-Darlington Technical College out of downtown Florence, giving the college room to grow its training programs in high-demand health care fields.
Midlands Technical College and Spartanburg Community College are asking for $60 million and $65 million respectively to demolish and rebuild a student center and an administrative building, according to documents provided by the state Department of Administration.
And Denmark Technical College, the state's only historically Black tech school, is renewing a $35 million request for new lab and classroom space. The college, located 35 miles east of the Savannah River National Laboratory, wants to train more of the cybersecurity and energy professionals needed by the federal nuclear research lab in an effort to attract more students and grow the school's enrollment.
MUSC Health seeks $350M for new, top-tier cancer center
Budget asks from the Medical University of South Carolina and the University of South Carolina round out the top three largest requests.
Most of MUSC's $418 million request is for construction of a top-tier cancer center in downtown Charleston, the first of its kind in South Carolina.
And about half of USC's $307 million ask would go to further the flagship university's own health care ambitions.
That includes one-time money to move the pharmacy school to the university's new medical campus that's under construction in downtown Columbia's redeveloped BullStreet District.
The school also wants annually recurring dollars to operate the new, taxpayer-funded neurological hospital and a series of clinics across the state that specialize in diagnosing Alzheimer's disease and dementia.
USC to establish center for civics education, following national trend
Beyond money for the medical campus, USC is asking for annual operating dollars to run a newly-formed center focused on teaching civil debate and civics lessons. It wants more money to continue a four-way, multi-year research partnership between USC, Clemson University, South Carolina State University and the Savannah River National Laboratory. And it's asking for funds to continue and expand its efforts around artificial intelligence.
Across the USC system, other major requests include a new nursing education center in Beaufort, complete with simulation labs, and the renovation of an event center in Spartanburg to train hospitality students in the Upstate.
As for Clemson, its request tallies $193 million in additional aid.
That includes $20 million for its National Security Institute, with the goal of growing the $30 million in annual research it does with the U.S. Department of Defense.
In its request, Clemson highlighted its military roots. The school, originally known as Clemson Agricultural College, opened in July 1893 as an all-male, all-white military college. It wasn't until 1955 that the school began admitting non-military students and women.
Clemson also is renewing requests for projects the Legislature either didn't fund or partially funded. That includes $60 million for next-generation computing center, $35 million for a new science laboratory and $20 million to expand a genetics research lab.
by Jessica Holdman, SC Daily Gazette January 5, 2026
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Jessica Holdman writes about the economy, workforce and higher education. Before joining the SC Daily Gazette, she was a business reporter for The Post and Courier.
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The cast includes Catherine Buxton, Hannah Daly, Julia Jennings, Kathleen Lewis, Ronan Hope Riordan, Michael Dix Thomas, and Nate Stephenson.
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A reading of Emily Dickinson: Paranormal Investigator in Poe's Finest Hour comes to Portland Stage's Studio Theater this month. Performances are January 16, 17, and 18 at 7:30pm.
Join Fox Bramble for a staged reading of Emily Dickinson: Paranormal Investigator in Poe's Finest Hour, written and directed by Todd Brian Backus.
It's 1849 and New York is a gritty, grimy city filled with ghosts, ghouls, and irresponsible transcendentalists. After a string of curious incidents Emily Dickinson, New England's premier paranormal investigator, and her estranged mentor Edgar Allan Poe are on the case! Armed with esoteric knowledge and brass knuckles—not to mention a strong grasp on both blank and metered verse—they venture to Brooklyn on the trail of a horrifying new adversary.
Featuring: Catherine Buxton, Hannah Daly, Julia Jennings, Kathleen Lewis, Ronan Hope Riordan, Michael Dix Thomas, and Nate Stephenson.
Fox Bramble is a new Portland, ME theatre company interested in telling weird stories onstage, helmed by Todd Brian Backus and Beka Bryer. This staged reading will help raise funds for their debut production coming (hopefully) in Summer 2026.
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Donald Trump shared a post suggesting that Tim Walz ordered the killing in revenge for Melissa Hortman voting to strip healthcare from illegal immigrants
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The children of murdered Minnesota lawmaker Melissa Hortman have called for Donald Trump to take down a Truth Social post, which linked her killing to the state governor, Tim Walz.
Hortman and her husband, Mark, were murdered on June 14, 2025, along with their golden retriever, by a man impersonating a police officer.
Over the weekend, Trump re-shared a post suggesting that fellow Democrats targeted the Hortmans for “exposing a multi-billion dollar money laundering fraud going to illegal immigrants.”
Colin Hortman, the son of the murdered couple, begged Trump to take the post down in an emotional statement as the family continues to grieve.
“I am asking President Trump to remove the video that he shared and apologize to me and my family for posting this misinformation and for using my mother's own words to dishonor her memory,” he wrote in the statement, which was seen by NBC News.
Trump's post included a video that claimed that the alleged fraud case involved “child care” and “health care rackets,” run by Somali immigrants, whom the social media user claims came to the United States illegally.
It goes on to claim that the Hortman couple's alleged shooter, Vance Boelter, had been ordered to carry out the murder by Governor Tim Walz.
The motive given was that Hortman had voted against her party to strip taxpayer-funded health care coverage for illegal immigrants shortly before her death.
The evidence given by the original social media user was a letter, written by Boelter and mailed to FBI Director Kash Patel. In the document, Boelter claims that Walz instructed him to kill Amy Klobuchar, among some other redacted names.
Boelter, a former employee of Walz's, alleged that the governor would “hurt my family” if he did not “play ball.”
He also details an alleged meeting, organized by the governor, in which he met with a woman referred to as “Mel.”
According to Boelter, he carried out a double shooting shortly after.
Lawmakers maintain that Boelter first attempted to murder John Hoffman, a member of the Minnesota Senate, his wife, Yvette, and their daughter, Hope. According to the attorney's office, all three survived the attack.
Boelter allegedly travelled to the Hortman's residence shortly after, before killing the couple. He was caught two days later in the biggest manhunt in Minnesota state history.
Currently, he faces six federal charges in relation to the case, including stalking, murder, and attempted shooting. If found guilty, the Attorney's Office says that he faces life in prison or even death.
Governor Walz, who ran as a running mate with former Vice President Kamala Harris in the 2024 presidential election, has vehemently denied the suggestion that he ordered Boelter to commit the crime. He has also condemned the president for re-sharing the conspiracy theory on social media.
“Dangerous, depraved behavior from the sitting president of the United States,” Walz wrote. “In covering for an actual serial killer, he is going to get more innocent people killed. America is better than this.”
Meanwhile, the Hortman family has reiterated its call for Trump to take down the post. Sophie Hortman, Colin's sister, wrote that the post promotes a “false narrative.”
“The video being shared by the president is another hurdle our family must overcome in grieving the loss of my parents, Mark and Melissa, and their beloved [dog] Gilbert,” she added, in a statement also seen by NBC News. “I ask President Trump to please consider the pain and sadness we have faced, and to honor the spirit of the holidays we have just spent without our parents by taking down the post on Truth Social.”
In recent weeks, Trump has seized upon conspiracy theories about immigration to Minnesota by Somali migrants.
His administration recently shared an AI-generated trailer for an animated film entitled Minnesota Millionaires, which depicts Somali men travelling to the state in order to defraud the state's daycare program.
“We don't need to be pirates anymore. I found a better way. Government-funded daycare. We must go to Minnesota,” a character in the video says, referencing the fraud cases leveled against some daycare centres that support the children of Somali immigrants.
Amid the intense pressure put on the Minnesotan government by Trump over the daycare fraud allegations, Walz decided to drop out of the 2026 Minnesota Gubernatorial Race.
Speaking at a public statement today, Walz said that he could not give “give a political campaign my all” after an “extraordinarily difficult year for our state.”
He cited the childcare program investigations as a particular example of the pressures placed upon him, ever since he rocketed to fame as Kamala Harris's running mate in the 2024 election.
“Donald Trump and his allies – in Washington, in St. Paul, and online – want to make our state a colder, meaner place,” Walz said in a statement. “They want to poison our people against each other by attacking our neighbors. And, ultimately, they want to take away much of what makes Minnesota the best place in America to raise a family.”
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We call for a deliberate integration of astrobiological research with applied science. Knowledge gained from biological systems and study sites on Earth that guide investigation of planetary bodies in our solar system can inform strategies for carbon capture, low-carbon energy production, waste remediation, and biotechnology.
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Just as its name suggests, ‘Fireplace 10 hours full HD' is just 10 hours of a cozy fireplace burning away to the sound of crackling wood. It's definitely not the most spectacular clip ever uploaded to YouTube, but that didn't stop it from generating over 157 million views in under 10 years. Considering the video has been monetized since its upload in 2016, it is estimated that the creator has made over $1 million from this video alone.
YouTube is actually full of long clips, often recorded on a loop and meant to be played in the background without causing a distraction. It's a recipe that works, and most creators post multiple such videos to maximize earnings. But that is not the case with ‘Fireplace 10 hours full HD'. The channel, also named ‘Fireplace 10 Hours', has just one upload in the last decade, so the fact that it was able to generate over $1 million in ad revenue is crazy.
The fact that this is the only video on the channel has fueled a debate around the recipient of the ad revenue. Some have claimed that because the channel does not abide by YouTube's rule to have at least three uploads to even be considered for its partner program, the platform gets all the ad revenue from ‘Fireplace 10 hours full HD'. However, that rule only came into effect in 2023, so this 2016 channel should not be subject to it.
Regardless of who is entitled to the ad revenue, the fact that a 10-hour clip of a cozy fireplace has racked up over 157 million views on YouTube is proof that you don't have to come up with something new and exciting, hire editors, or post every day. All you have to do is satisfy a need, and you're set!.
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Rachael Funnell
Rachael Funnell
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Rachael has a degree in Zoology from the University of Southampton, and specializes in animal behavior, evolution, palaeontology, and the environment.
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Rachael has a degree in Zoology from the University of Southampton, and specializes in animal behavior, evolution, palaeontology, and the environment.View full profile
Rachael has a degree in Zoology from the University of Southampton, and specializes in animal behavior, evolution, palaeontology, and the environment.
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Oh Cooper, what have you gotten yourself into?
Image credit: Sean McGrath from Saint John, NB, Canada - Cooper and Styrofoam via Wikimedia Commons (CC BY 2.0)
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Parts of the world are experiencing the extremes of cold at this time of year, and with low temperatures comes a shocking phenomenon: cat zapping. If you've been trying to pet your cat only to wind up both getting a miniature shock, fear not. You aren't alone.
Cats are famously tied to static electricity. Don't believe me? Just check out the leading image for “static cling” on Wikipedia (oh Cooper, what a pickle you've found yourself in). Turns out, the static potential of cats in winter comes down to two key things: your petting approach, and humidity.
A 2024 study set out to answer a key question in our understanding of static electricity – what puts the “tribo” in triboelectricity? Triboelectrification is the process through which static electricity is generated by rubbing two things together.
It's a well-documented phenomenon, as anyone who's ever had a balloon rubbed on their hair only for it to stick can attest to (such as dear Nosey the cat). As for why that is? It's something we've only just got to grips with.
“For the first time, we are able to explain a mystery that nobody could before: why rubbing matters,” said Laurence Marks of Northwestern University in a statement, who led the 2024 study. “People have tried, but they could not explain experimental results without making assumptions that were not justified or justifiable.”
“We now can, and the answer is surprisingly simple. Just having different deformations – and therefore different charges – at the front and back of something sliding leads to current.”
Petting a cat involves sliding your hand across their fur. As your hand moves, both your hand and the cat's fur experience different amounts of stress because of the way surfaces resist motion. This difference causes electric charges to build up unevenly along your hand and the cat's fur.
As those charges build and flow, they can suddenly discharge in the form of that static zap you feel when touching your cat. So it's not touching the cat that creates static electricity, but the sliding motion involved in petting that produces uneven charges.
If you've noticed more zaps between you and your cat during cold weather, it's largely due to low humidity. Cold air holds less moisture, and indoor heating dries the air even further.
Moist air normally helps static charges slowly leak away, but when the air is dry, charges linger and build up more easily. That leaves both you and your cat primed for a static zap the next time you touch.
Ergo, it's not your fault! But good luck explaining that to them.
Written by Rachael Funnell
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After a grand successful Telugu release. #Shambala releasing in Hindi on 9th Jan'26
Unveiling the Hindi trailer - https://t.co/S1IUlDRVJz
All the best to @iamaadisaikumar and the entire team????@tweets_archana @ugandharmuni #RajasekharAnnabhimoju @ShiningPictures… pic.twitter.com/itnt68GNa2
RISHAB SHETTY UNVEILS *HINDI* TRAILER OF SUPERNATURAL THRILLER 'SHAMBHALA' – 9 JAN 2026 RELEASE IN *HINDI* MARKET... After winning hearts and emerging as a boxoffice success in its original #Telugu version, the supernatural thriller #Shambhala, starring #AadiSaiKumar, is all set… pic.twitter.com/RyrFUAq8iw
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LEGO's newest Creator release proves that big ideas come in compact packages. The Space Exploration Telescope (set 31378) landed on shelves January 1, 2026, with 278 pieces that transform into three completely different models: a fully adjustable telescope with spinning planets, a working microscope, or a posable UFO. At $34.99, this set sits comfortably in impulse-buy territory while delivering the kind of replay value that keeps kids engaged long after the initial build.
What makes this set particularly clever is how it uses a single light brick across all three models. The telescope projects celestial images onto walls, the microscope illuminates specimens, and the UFO beams light from its underside. Three decorated lenses featuring a planet, star, and Moon add educational depth that goes beyond typical building sets. For parents seeking STEM toys that actually encourage experimentation rather than collecting dust on a shelf, this Creator set deserves serious consideration.
Designer: LEGO
That primary telescope build is surprisingly robust for being one of three options. Standing over 10.5 inches (27 cm) tall, it has a decent presence, and the tripod design is stable enough for actual play. The accompanying solar system, with its seven spinning planets, is a fantastic kinetic detail that adds life to the model. The projection feature is the real engineering win here. It takes what would be a static display piece and gives it an interactive purpose that cleverly mimics what a real telescope does: show you images of space. It's a smart, elegant solution for a toy.
When you get tired of stargazing, the rebuild into a microscope shows the true genius of the part selection. The core housing for the light brick and lens assembly gets flipped vertically, and what was once a projection system becomes an illumination source. The same decorated lenses that projected planets now serve as makeshift slides, which is a brilliant way to teach kids about functional design and repurposing components. It's a solid B-model that feels complete and intentional, demonstrating how form follows function with just a few clever reconfigurations of the same 278 bricks.
The final build, a UFO, is the set's playful wild card. It shifts the entire theme from educational STEM hardware to pure science fiction. The designers did a great job creating a classic saucer shape with posable antennae and legs that flip out for landing. Here, the light brick serves as a simple beam underneath the craft, perfect for imaginative scenarios. This C-model provides an essential creative outlet, proving the set's versatility extends beyond scientific instruments. It's the build that lets kids take the parts and just have fun, which is arguably the most important function of any LEGO set.
The set is available now through LEGO's official website, Target, and authorized LEGO retailers for $34.99. Batteries for the light brick come included, which saves you a trip to the store or the inevitable disappointment of discovering you need them mid-build. The recommended age is 8 and up, though younger kids with building experience could handle it with minimal supervision. Digital instructions are accessible through the free LEGO Builder app, which lets you zoom, rotate, and track build progress on your phone or tablet. LEGO's website currently shows a 60-day shipping window, so if you're ordering online, factor that into your timeline.
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There's a particular kind of frustration that comes with a stubborn screw buried deep inside a chassis or tucked behind a piece of furniture. You…
A bunch of people have been working on a project called Artica, which is a natural cooling, ventilation and heat recovery system. The beauty of…
Keyshot's Material Graph offers the ability to go beyond simply tweaking a material's color, roughness, or refractive index. If Keyshot's material library is a restaurant…
This strikingly designed record player beautifully blurs the boundaries between digital and physical media! Packed full of carefully thought out design features, this is undeniably…
There's finally a robot for the home that's not just for sucking up dirt on the floor. Robots are coming, whether we like it or…
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