"4chan, down for more than a week after hackers got in through an insecure script that handled PDFs, is back online," notes BoingBoing. (They add that Thursday saw 4chan's first blog postin years — just the words "Testing testing 123 123...") But 4chan posted a much longer explanation on Friday," confirming their servers were compromised by a malicious PDF upload from "a hacker using a UK IP address," granting access to their databases and administrative dashboard.

The attacker "spent several hours exfiltrating database tables and much of 4chan's source code. When they had finished downloading what they wanted, they began to vandalize 4chan at which point moderators became aware and 4chan's servers were halted, preventing further access."

While not all of our servers were breached, the most important one was, and it was due to simply not updating old operating systems and code in a timely fashion. Ultimately this problem was caused by having insufficient skilled man-hours available to update our code and infrastructure, and being starved of money for years by advertisers, payment providers, and service providers who had succumbed to external pressure campaigns. We had begun a process of speccing new servers in late 2023. As many have suspected, until that time 4chan had been running on a set of servers purchased second-hand by moot a few weeks before his final Q&A [in 2015], as prior to then we simply were not in a financial position to consider such a large purchase. Advertisers and payment providers willing to work with 4chan are rare, and are quickly pressured by activists into cancelling their services. Putting together the money for new equipment took nearly a decade...

The free time that 4chan's development team had available to dedicate to 4chan was insufficient to update our software and infrastructure fast enough, and our luck ran out. However, we have not been idle during our nearly two weeks of downtime. The server that was breached has been replaced, with the operating system and code updated to the latest versions. PDF uploads have been temporarily disabled on those boards that supported them, but they will be back in the near future. One slow but much beloved board, /f/ — Flash, will not be returning however, as there is no realistic way to prevent similar exploits using .swf files.

We are bringing on additional volunteer developers to help keep up with the workload, and our team of volunteer janitors & moderators remains united despite the grievous violations some have suffered to their personal privacy.
4chan is back. No other website can replace it, or this community. No matter how hard it is, we are not giving up.

[ Read more of this story ]( https://tech.slashdot.org/story/25/04/27/0252257/4chan-returns-details-breach-blames-funding-issues-ends-shockwave-board?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

Some patches for Linux 6.15-rc4 (updating the kernel driver for the Bcachefs file system) triggered some "straight-to-the-point wisdom" from Linus Torvalds about case-insensitive filesystems, reports Phoronix.

Bcachefs developer Kent Overstreet started the conversation, explaining how some buggy patches for their case-insensitive file and folder support were upstreamed into the Bcachefs kernel driver nearly two years ago:

When I was discussing with the developer who did the implementation, I noted that fstests should already have tests. However, it seems I neglected to tell him to make sure the tests actually run... It is _not_ enough to simply rely on the automated tests. You have to have eyes on what your code is doing.
Overstreet added "There's a story behind the case insensitive directory fixes, and lessons to be learned." To which Torvalds replied.... "No."
"The only lesson to be learned is that filesystem people never learn."

Torvalds: Case-insensitive names are horribly wrong, and you shouldn't have done them at all. The problem wasn't the lack of testing, the problem was implementing it in the first place. The problem is then compounded by "trying to do it right", and in the process doing it horrible wrong indeed, because "right" doesn't exist, but trying to will make random bytes have very magical meaning.

And btw, the tests are all completely broken anyway. Last I saw, they didn't actually test for all the really interesting cases — the ones that cause security issues in user land. Security issues like "user space checked that the filename didn't match some security-sensitive pattern". And then the shit-for-brains filesystem ends up matching that pattern *anyway*, because the people who do case insensitivity *INVARIABLY* do things like ignore non-printing characters, so now "case insensitive" also means "insensitive to other things too"....
Dammit. Case sensitivity is a BUG. The fact that filesystem people *still* think it's a feature, I cannot understand. It's like they revere the old FAT filesystem _so_ much that they have to recreate it — badly.

And this led to a very lively back-and-forth discussion.

Slashdot's summary of the highlights:

[ Read more of this story ]( https://linux.slashdot.org/story/25/04/27/0547245/linus-torvalds-expresses-his-hatred-for-case-insensitive-file-systems?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

80-year-old George Lucas appeared this week at a 45th anniversary screening of The Empire Strikes Back, reports CNN — and finally gave a good explanation for why Yoda speaks the way he does. "He explained that it came about in order to ensure that the little alien's usually profound messages really landed with audiences."
"Because if you speak regular English, people won't listen that much," Lucas said at the 2025 TCM Classic Film Festival, per Variety . "But if he had an accent, or it's really hard to understand what he's saying, they focus on what he's saying." Yoda was "basically the philosopher of the movie," the filmmaker added. "I had to figure out a way to get people to actually listen — especially 12-year-olds."

Also this week, the verified Instagram accounts for Disney+, Star Wars and LucasFilm — Lucas' film and television production company — posted clips of Yoda doing bloopers on the set of "Star Wars" films, with [Frank] Oz continuing to do the voice and manipulate the heavy Yoda puppet even on takes that were unusable. Suffice it to say: One for the ages, Yoda is.

Lucas also remembered how he'd "mounted a guerilla campaign to generate excitement" for the first Star Wars movie, reports Variety. ("I got the kids walking around Disneyland and the Comic Cons and all that kind of stuff... that's why Fox was so shocked when the first day the lines were all around the block.") And Variety says Lucas described a condition in his contract for Star Wars "that would again be life-changing, both for him and the entertainment industry as a whole."

"I said, 'besides that, I'd like licensing.' They went, 'What's licensing?'" Unimpressed by the film, and colored by the history of movie merchandising to that point, the studio capitulated to his demands. "They talked to themselves, and they went, 'He's never going to be able to do that. It takes them a billion dollars and a year to make a toy or make anything. There's no money in that at all.'"

[ Read more of this story ]( https://entertainment.slashdot.org/story/25/04/27/040248/yoda-bloopers-released---and-george-lucas-reveals-why-yoda-talks-backwards?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

"The U.S. and Canadian websites for Lenovo offered U.S. $140 and CAD $211 off on the same ThinkPad X1 Carbon model when choosing any one of the Linux-based alternatives," reports It's FOSS News:

This was brought to my attention thanks to a Reddit post... Others then chimed in, saying that Lenovo has been doing this since at least 2020 and that the big price difference shows how ridiculous Windows' pricing is...
Not all models from their laptop lineup, like ThinkPad, Yoga, Legion, LOQ, etc., feature an option to get Linux pre-installed during the checkout process. Luckily, there is an easy way to filter through the numerous laptops. Just go to the laptops section (U.S.) on the Lenovo website and turn on the "Operating System" filter under the Filter by specs sidebar menu.

The article end with an embedded YouTube video showing a VCR playing a videotape of a 1999 local TV news report... about the legendary "Windows Refund Day" protests.

Slashdot ran numerous stories about the event — including one by Jon Katz...

[ Read more of this story ]( https://linux.slashdot.org/story/25/04/27/0127203/lenovo-may-be-avoiding-the-windows-tax-by-offering-cheaper-laptops-with-pre-installed-linux?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

The university blamed it on "the significant number of students" who violated their coding competition's rules.
Long-time Slashdot reader theodp quotes this report from The Logic: Finding that many students violated rules and submitted code not written by themselves, the University of Waterloo's Centre for Computing and Math decided not to release results from its annual Canadian Computing Competition (CCC), which many students rely on to bolster their chances of being accepted into Waterloo's prestigious computing and engineering programs, or land a spot on teams to represent Canada in international competitions. "It is clear that many students submitted code that they did not write themselves, relying instead on forbidden external help," the CCC co-chairs explained in a statement. "As such, the reliability of 'ranking' students would neither be equitable, fair, or accurate."

"It is disappointing that the students who violated the CCC Rules will impact those students who are deserving of recognition," the univeresity said in its statement. They added that they are "considering possible ways to address this problem for future contests."

[ Read more of this story ]( https://news.slashdot.org/story/25/04/26/238243/canadian-university-cancels-coding-competition-over-suspected-ai-cheating?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

"Not so long ago, working in tech meant job security, extravagant perks and a bring-your-whole-self-to-the-office ethos rare in other industries," writes the Wall Street Journal.

But now tech work "looks like a regular job," with workers "contending with the constant fear of layoffs, longer hours and an ever-growing list of responsibilities for the same pay."

Now employees find themselves doing the work of multiple laid-off colleagues. Some have lost jobs only to be rehired into positions that aren't eligible for raises or stock grants. Changing jobs used to be a surefire way to secure a raise; these days, asking for more money can lead to a job offer being withdrawn.

The shift in tech has been building slowly. For years, demand for workers outstripped supply, a dynamic that peaked during the Covid-19 pandemic. Big tech companies like Meta and Salesforce admitted they brought on too many employees. The ensuing downturn included mass layoffs that started in 2022...

[S]ome longtime tech employees say they no longer recognize the companies they work for. Management has become more focused on delivering the results Wall Street expects. Revenue remains strong for tech giants, but they're pouring resources into costly AI infrastructure, putting pressure on cash flow. With the industry all grown up, a heads-down, keep-quiet mentality has taken root, workers say... Tech workers are still well-paid compared with other sectors, but currently there's a split in the industry. Those working in AI — and especially those with Ph.D.s — are seeing their compensation packages soar. But those without AI experience are finding they're better off staying where they are, because companies aren't paying what they were a few years ago.

Other excepts from the Wall Street Journal's article:

"I'm hearing of people having 30 direct reports," says David Markley, who spent seven years at Amazon and is now an executive coach for workers at large tech companies. "It's not because the companies don't have the money. In a lot of ways, it's because of AI and the narratives out there about how collapsing the organization is better...."
In some cases, companies post record revenue while still trimming head count.
Google co-founder Sergey Brin told a group of employees in February that 60 hours a week was the sweet spot of productivity, in comments reported earlier by the New York Times.
One recruiter at Meta who had been laid off by the company was rehired into her old role last year, but with a catch: She's now classified as a "short-term employee." Her contract is eligible for renewal, but she doesn't get merit pay increases, promotions or stock. The recruiter says she's responsible for a volume of work that used to be spread among several people. The company refers to being loaded with such additional responsibilities as "agility." More than 50,000 tech workers from over 100 companies have been laid off in 2025, according to Layoffs.fyi, a website that tracks job cuts and crowdsources lists of laid off workers...
Even before those 50,000 layoffs in 2025,
Silicon Valley's Mercury News was citing some interesting statistics from economic research/consulting firm Beacon Economics. In 2020, 2021 and 2022, the San Francisco Bay Area added 74,700 tech jobs But then in 2023 and 2024 the industry had slashed even more tech jobs -- 80,200 -- for a net loss (over five years) of 5,500.

So is there really a cutback in perks and a fear of layoffs that's casting a pall over the industry? share your own thoughts and experiences in the comments. Do you agree with the picture that's being painted by the Wall Street Journal?

They told their readers that tech workers are now "just like the rest of us: miserable at work."

[ Read more of this story ]( https://it.slashdot.org/story/25/04/27/088238/wsj-tech-industry-workers-now-miserable-fearing-layoffs-working-longer-hours?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

"Google's DeepMind UK team reportedly seeks to unionize," reports TechCrunch:

Around 300 London-based members of Google's AI-focused DeepMind team are seeking to unionize with the Communication Workers Union, according to a Financial Times report that cites three people involved with the unionization effort.

These DeepMind employees are reportedly unhappy about Google's decision to remove a pledge not to use AI for weapons or surveillance from its website. They're also concerned about the company's work with the Israeli military, including a $1.2 billion cloud computing contract that has prompted protests elsewhere at Google.
At least five DeepMind employees quit, according to the report (out of a 2,000 total U.K. staff members).

"A small group of around 200 employees of Google and its parent company Alphabet previously announced that they were unionizing," the article adds, "though as a union representing just a tiny slice of the total Google workforce, it lacked the ability to collectively bargain."

[ Read more of this story ]( https://tech.slashdot.org/story/25/04/27/1830241/googles-deepmind-uk-team-reportedly-seeks-to-unionize?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

Microsoft Copilot "isn't doing as well as the company would like," reports XDA-Developers.com (citing a report from startup/VC industry site Newcomer).

The Redmond giant has invested billions of dollars and a lot of manpower into making it happen, but as a recent report claims, people just don't care. In fact, if the report is to be believed, Microsoft's rise in the AI scene has already come to a screeching halt:

At Microsoft's annual executive huddle last month, the company's chief financial officer, Amy Hood, put up a slide that charted the number of users for its Copilot consumer AI tool over the past year. It was essentially a flat line, showing around 20 million weekly users. On the same slide was another line showing ChatGPT's growth over the same period, arching ever upward toward 400 million weekly users. OpenAI's iconic chatbot was soaring, while Microsoft's best hope for a mass-adoption AI tool was idling. It was a sobering chart for Microsoft's consumer AI team...
That's right; Microsoft Copilot's weekly user base is only 5% of the number of people who use ChatGPT, and it's not increasing. It's also worth noting that there are approximately 1.5 billion Windows users worldwide, which means just over 1% of them are using Copilot, a tool that's now a Windows default app....
It's not a huge surprise that Copilot is faltering. Despite Microsoft's CEO claiming that Copilot will become "the next Start button", the company has had to backtrack on the Copilot key and allow people to customise it to do something else, including giving back its original feature of the Menu key.
They also note earlier reports that Intel's AI PC chips aren't selling well.

[ Read more of this story ]( https://slashdot.org/story/25/04/27/1925219/consumers-arent-flocking-to-microsofts-ai-tool-copilot?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

What can you build with a 3D printer? Starbucks just printed itself a new store — a drive-through location in the southern tip of Texas.

Fast Company says it's a store that "looks more like the future of construction than your average café."

Built with layers of concrete piped out by a giant robotic printer, the 1,400-square-foot structure is part of the company's ongoing effort to modernize operations and trim costs... Peri-3D, a German company, used a giant 3D printer to pump out layers of concrete mixture to create the structure. According to the Texas Department of Licensing and Regulation, the cost for building the small scale coffee shop was about $1.2 million...

Of course, the new method is a first for the brand. And builders say, the more they use the technology, the more efficient they are at it. In Georgetown, Texas, an entire community of 100 homes was recently built using 3D-printing. The company who built the community, Lennar, says they're seeing costs drop with each build. Stuart Miller, chairman and co-CEO of Lennar, told CNBC earlier this year that the construction company says their costs and cycle time go down "by half" by adopting 3D-printing. "This is significant improvement in evolving a housing market that has the ability to change over time and being more adaptable and more functional in providing affordable and attainable housing for a broader swath of the market," said Miller...

3D-printing is also much faster, meaning that projects can be completed in a fraction of the time, potentially drastically cutting labor costs. According to the World Economic Forum, 3D-printing can cost just 30% of what building structures the old-fashioned way costs.

The article offers more examples of 3D-printed buildings. ("in Japan, a 3D-printed train station was just erected. And Peri-3D, itself, has completed at least 15 construction projects, including residential buildings in Europe and Germany.")
3D-printing has even been incorporated into some restaurants for customizing food, the article notes, "but building restaurants with the technology is a brand-new development."

Although not everyone seems convinced. Instagram comments on a picture of Starbucks' new 3D-printed drive-through characterized its aesthetic as "dirty", "fugly", "violently hideous", and "like hot garbage".

[ Read more of this story ]( https://hardware.slashdot.org/story/25/04/27/2041226/starbucks-opens-its-first-3d-printed-store?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

An anonymous reader shared this report from Reuters:

The secretive Russian satellite in space that U.S. officials believe is connected to a nuclear anti-satellite weapon program has appeared to be spinning uncontrollably, suggesting it may no longer be functioning in what could be a setback for Moscow's space weapon efforts, according to U.S. analysts... [The Cosmos 2553 satellite launched in 2022] has had various bouts of what appears to be errant spinning over the past year, according to Doppler radar data from space-tracking firm LeoLabs and optical data from Slingshot Aerospace shared with Reuters.

Believed to be a radar satellite for Russian intelligence as well as a radiation testing platform, the satellite last year became the center of U.S. allegations that Russia for years has been developing a nuclear weapon capable of destroying entire satellite networks, such as SpaceX's vast Starlink internet system that Ukrainian troops have been using. U.S. officials assess Cosmos 2553's purpose, though not itself a weapon, is to aid Russia's development of a nuclear anti-satellite weapon. Russia has denied it is developing such a weapon and says Cosmos 2553 is for research purposes....

"This observation strongly suggests the satellite is no longer operational," the Center for Strategic and International Studies, a Washington-based think tank, said of LeoLabs' analysis in its annual Space Threat Assessment published on Friday.

[ Read more of this story ]( https://science.slashdot.org/story/25/04/27/2158224/russian-satellite-linked-to-its-nuclear-anti-satellite-weapon-program-appears-out-of-control-analyst-says?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

Its goal was to "support workers to reclaim the power of future-making". A 2022 pilot project saw over 25 Amazon workers meeting online "to discuss how science fiction shed light on their working conditions and futures." 13 of them then continued meeting regularly in 2023 with the "Worker as Futurist" project (funded by Canada's Social Sciences and Humanities Research Council, according to an article by the project's leaders in the socialist magazine Jacobin). "Our team of scholars, teachers, writers, and activists has been able to pay Amazon workers (warehouse workers, drivers, copy editors, MTurk workers, and more) to participate in a series of skill-building writing workshops and information sessions...."
And when it was over, "the participants were supported to draft the stories they wanted to tell about The World After Amazon...."

Six months ago they held the big launch event for the book's print edition, while also promising that "you can read the workers' stories online, or download the book as a PDF or an ebook, all for free." The Amazon-worker stories have tempting titles like "The Museum of Prime", "The Dark Side of Convenience", and even "The Iron Uprising." ("In a dystopian future of corporate power, humans and robots come together in resistance and in love.")
And the project also created a 13-episode podcast offering "interviews with experts on Amazon, activists and organizers, science fiction writers and others dedicated to reclaiming the future from corporate control." As they wrote in Jacbon:

This isn't finding individual commercial or literary success, but dignity, imagination, and common struggle... Our "Worker as Futurist" project returns the power of the speculative to workers, in the name of discovering something new about capitalism and the struggle for something different...

We must envision the futures we want in order to mobilize and fight for them together, rather than cede that future to those who would turn the stars into their own private sandbox... The rank-and-file worker — the target of daily exploitation, forced to build their boss's utopia — may have encrypted within them the key to destroying his world and building a new one.

[ Read more of this story ]( https://news.slashdot.org/story/25/04/27/2336243/to-reclaim-future-making-amazon-workers-published-a-collection-of-science-fiction-stories?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

Remember First Light Fusion? Founded in 2011, it was a pioneering British startup that in 2022 "successfully combined atomic nuclei, which U.K. regulators called a milestone in the decades-long push for fusion energy.

It's now "pulled the plug on plans to build its first reactor," reports the Telegraph, abandoning its push for a prototype power plant based on its "projectile fusion" technology due to a lack of funding.
The technology involves a 5p-sized projectile being fired at a fuel cell at extreme speeds using electromagnets to generate a powerful reaction and simulate collisions at extremely high speeds, such as those in space. Instead of building its own plant, First Light plans to supply other nuclear power companies with one of its inventions, called an "amplifier", which houses a nuclear fuel capsule and boosts the power of fusion reactions.

The group has burned through tens of millions of pounds trying to bring its technology to fruition... The decision to ditch its original plan will allow First Light Fusion to be more "capital light", the nuclear group said in March, while licensing its inventions would generate more revenues. The company said it had recently secured the first tranche of a new funding round. Mark Thomas, First Light Fusion's chief executive, said: "We have been very pleased with the response to our strategy pivot, moving to an enabler of inertial fusion while rapidly accelerating revenues...
First Light Fusion's other investors include Chinese technology giant Tencent.

[ Read more of this story ]( https://hardware.slashdot.org/story/25/04/28/013206/nuclear-fusion-pioneer-abandons-plan-for-prototype-reactor-will-license-reaction-boosting-nuclear-fuel-capsule?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

A new DARPA project called expMath "aims to jumpstart math innovation with the help of AI," writes The Register. America's "Defense Advanced Research Projects Agency" believes mathematics isn't advancing fast enough, according to their article...

So to accelerate — or "exponentiate" — the rate of mathematical research, DARPA this week held a Proposers Day event to engage with the technical community in the hope that attendees will prepare proposals to submit once the actual Broad Agency Announcement solicitation goes out...

[T]he problem is that AI just isn't very smart. It can do high school-level math but not high-level math. [One slide from DARPA program manager Patrick Shafto noted that OpenAI o1 "continues to abjectly fail at basic math despite claims of reasoning capabilities."] Nonetheless, expMath's goal is to make AI models capable of:

- auto decomposition — automatically decompose natural language statements into reusable natural language lemmas (a proven statement used to prove other statements); and
auto(in)formalization — translate the natural language lemma into a formal proof and then translate the proof back to natural language.
"How must faster with technology advance with AI agents solving new mathematical proofs?" asks former DARPA research scientist Robin Rowe (also long-time Slashdot reader robinsrowe):

DARPA says that "The goal of Exponentiating Mathematics is to radically accelerate the rate of progress in pure mathematics by developing an AI co-author capable of proposing and proving useful abstractions."
Rowe is cited in the article as the founder/CEO of an AI research institute named "Fountain Adobe". (He tells The Register that "It's an indication of DARPA's concern about how tough this may be that it's a three-year program. That's not normal for DARPA.")
Rowe is optimistic. "I think we're going to kill it, honestly. I think it's not going to take three years. But I think it might take three years to do it with LLMs. So then the question becomes, how radical is everybody willing to be?"
"We will robustly engage with the math and AI communities toward fundamentally reshaping the practice of mathematics by mathematicians," explains the project's home page. They've already uploaded an hour-long video of their Proposers Day event.

"It's very unclear that current AI systems can succeed at this task..." program manager Shafto says in a short video introducing the project. But...

"There's a lot of enthusiasm in the math community for the possibility of changes in the way mathematics is practiced. It opens up fundamentally new things for mathematicians. But of course, they're not AI researchers. One of the motivations for this program is to bring together two different communities — the people who are working on AI for mathematics, and the people who are doing mathematics — so that we're solving the same problem.
At its core, it's a very hard and rather technical problem. And this is DARPA's bread-and-butter, is to sort of try to change the world. And I think this has the potential to do that.

[ Read more of this story ]( https://science.slashdot.org/story/25/04/28/0255248/could-a-math-genius-ai-co-author-proofs-within-three-years?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.

"A new study found that a gene recently recognized as a biomarker for Alzheimer's disease is actually a cause of it," announced the University of California, San Diego, "due to its previously unknown secondary function."

"Researchers at the University of California San Diego used artificial intelligence to help both unravel this mystery of Alzheimer's disease and discover a potential treatment that obstructs the gene's moonlighting role."

A team led by Sheng Zhong, a professor in the university's bioengineering department, had previously discovered a potential blood biomarker for early detection of Alzheimer's disease (called PHGDH). But now they've discovered a correlation: the more protein and RNA that it produces, the more advanced the disease. And after more research they ended up with "a therapeutic candidate with demonstrated efficacy that has the potential of being further developed into clinical tests..."

That correlation has since been verified in multiple cohorts from different medical centers, according to Zhong... [T]he researchers established that PHGDH is indeed a causal gene to spontaneous Alzheimer's disease. In further support of that finding, the researchers determined — with the help of AI — that PHGDH plays a previously undiscovered role: it triggers a pathway that disrupts how cells in the brain turn genes on and off. And such a disturbance can cause issues, like the development of Alzheimer's disease....

With AI, they could visualize the three-dimensional structure of the PHGDH protein. Within that structure, they discovered that the protein has a substructure... Zhong said, "It really demanded modern AI to formulate the three-dimensional structure very precisely to make this discovery." After discovering the substructure, the team then demonstrated that with it, the protein can activate two critical target genes. That throws off the delicate balance, leading to several problems and eventually the early stages of Alzheimer's disease. In other words, PHGDH has a previously unknown role, independent of its enzymatic function, that through a novel pathway leads to spontaneous Alzheimer's disease...

Now that the researchers uncovered the mechanism, they wanted to figure out how to intervene and thus possibly identify a therapeutic candidate, which could help target the disease.... Given that PHGDH is such an important enzyme, there are past studies on its possible inhibitors. One small molecule, known as NCT-503, stood out to the researchers because it is not quite effective at impeding PHGDH's enzymatic activity (the production of serine), which they did not want to change. NCT-503 is also able to penetrate the blood-brain-barrier, which is a desirable characteristic. They turned to AI again for three-dimensional visualization and modeling. They found that NCT-503 can access that DNA-binding substructure of PHGDH, thanks to a binding pocket. With more testing, they saw that NCT-503 does indeed inhibit PHGDH's regulatory role.

When the researchers tested NCT-503 in two mouse models of Alzheimer's disease, they saw that it significantly alleviated Alzheimer's progression. The treated mice demonstrated substantial improvement in their memory and anxiety tests...

The next steps will be to optimize the compound and subject it to FDA IND-enabling studies.

The research team published their results on April 23 in the journal Cell.

[ Read more of this story ]( https://science.slashdot.org/story/25/04/28/0610254/ai-helps-unravel-a-cause-of-alzheimers-disease-and-identify-a-therapeutic-candidate?utm_source=atom1.0moreanon&utm_medium=feed ) at Slashdot.