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Politics Unplugged (Full Episode) April 5, 2026
This week on Politics Unplugged, State Rep. Alexander Kolodin explains why he is running for the Republican nomination for Secretary of State. Then, consultants Marcus Dell’Artino and Adam Kinsey break down the latest Presidential approval polls and the candidates for governor debating whether to eat a taco on camera.
Gemma 4 and what makes an open model succeed
Having written a lot of model release blog posts, there’s something much harder about reviewing open models when they drop relative to closed models, especially in 2026. In recent years, there were so few open models, so when Llama 3 was released most people were still doing research on Llama 2 and super happy to get an update. When Qwen 3 was released, the Llama 4 fiasco had just gone down, and a whole research community was emerging to study RL on Qwen 2.5 — it was a no brainer to upgrade. Today, when an open model releases, it’s competing with Qwen 3.5, Kimi K2.5, GLM 5, MiniMax M2.5, GPT-OSS, Arcee Large, Nemotron 3, Olmo 3, and others. The space is populated, but still feels full of hidden opportunity. The potential of open models feels like a dark matter, a potential we know is huge, but few clear recipes and examples for how to unlock it are out there. Agentic AI, OpenClaw, and everything brewing in that space is going to spur mass experimentation in open models to complement the likes of Claude and Codex, not replace them. Especially with open models, the benchmarks at release are an extremely incomplete story. In some ways this is exciting, as new open models have a much higher variance and ability to surprise, but it also points at some structural reasons that make building businesses and great AI experiences around open models harder than the closed alternatives. When a new Claude Opus or GPT drops, spending a few hours with them in my agentic workflows is genuinely a good vibe test. For open models, putting them through this test is a category error. Something else to be said about open models in the era of agents is that they get out of the debate of integration, harnesses, and tools and let us see close to the ground on what exactly is the ability of just a model. Of course, we can’t test some things like search abilities without some tool, but being able to measure exactly the pace of progress of the model alone is a welcome simplification to a systematically opaque AI space. Share The list of factors I’d use to assess a new open-weight model I’m considering investing in includes: Model performance (and size) — how this model performs on benchmarks I care about and how it compares to other models of a similar size. Country of origin — some businesses care deeply about provenance, and if a model was built in China or not. Model license — if a model needs legal approval for use, uptake will be slower at mid-sized and large companies. Tooling at release — many models release with half-broken, or at least substantially slower, implementations in popular software like vLLM, Transformers, SGLANG, etc due to pushing the envelope of architectures or tools. Model fine-tunability — how easy or hard it is to modify the given model to your use-case when you actually try and use it. The core problem is that some of these are immediately available at release, e.g. general performance, license, origin, etc. but others such as tooling take day(s) to week(s) to stabilize, and others are open research questions — with no group systematically monitoring fine-tunability. In the early era of open models, the days of Llama 2 or 3 and Qwen pre v3.5, the architectures were fairly simple and the models tended to work out of the box. Some of this was due to the extremely hard work of the Llama, Qwen, Mistral, etc. developer teams. Some is due to the new models being genuinely harder to work with. When it comes to something like Qwen 3.5 or Nemotron 3, with hybrid models (either gated delta net or mamba layers), the tooling is very rough at release. Things you would expect to “just work” often don’t. I’ve been following this area closely since we released Olmo Hybrid with a similar architecture, and Qwen 3.5 is just starting to work well in the various open-source tools that need to all play nice together for RL research. That’s 1.5 months after the release date! This is just to start really investing more into understanding the behavior of the models. Of course, others started working on these models sooner by investing more engineering resources or relying on partially closed software. The fully open and distributed ecosystem takes a long time to get going on some new models. All of this is lead-in for the most important question for open models — how easy is it to adapt to specific use-cases? This is a different problem for different model sizes. Large MoE open-weight models may be used by entities like Cursor who need complex capabilities in their domain, e.g. Composer 2 trained on Kimi K2.5. Other applications can be built on much smaller models, such as Chroma’s Context-1 model for agentic search, built on GPT-OSS 20B. The question of “which models are fine-tunable” is largely background knowledge known by engineers across the industry. There should be a thriving research area here to support the open ecosystem model. The first step is to understand characteristics of different base and post-trained models to understand what they look like. The second step is to tune pretraining recipes for open models so they’re more flexible. Interconnects AI is a reader-supported publication. Consider becoming a subscriber. Subscribe For The ATOM Project and other Interconnects endeavors, we’ve put in substantial effort to measuring adoption trends in the open ecosystem. Everything takes a long time to unfold after a model is first publicly available — and adaptability is why. What we know for sure now, when Qwen has been going from strength to strength with its releases, is that technical staff across the industry has gotten comfortable working with Qwen models. Countless research methods and datasets were made to work with Qwen. It’ll take patience for any other model family to get to this point — a patience I’m not sure many open model builders have. This takes us to Gemma 4, Google’s latest open models. Gemma 3 was released more than a year ago, in March of 2025, and is a bit underrated. Gemma 4 comes in 4 sizes for now, with a bigger, MoE model of over 100B total parameters rumored but not released yet. The models we have today come in sizes of ~5B dense, 8B dense, 26B total 4B active MoE, and 31B dense. I’m most excited that they’re finally adopting a standard Apache 2.0 open source license. This’ll massively boost adoption. The standard of better licenses for strong open-weight LLMs was set by mostly Chinese open model labs in the last 1-2 years, and now U.S. companies are following suit. I will personally be so happy if the horrible Llama licenses and Gemma terms of service were an ~18-month transient dynamic of the industry being nervous about releasing strong open models. The Gemma 4 scores look very solid, the small models have incredible benchmark scores (especially in general domains like LMArena) and the 31B model rivals the recent Qwen 3.5 27B, which is the leading member of that class. The ~30B size range is an important one, as it’s accessible both to researchers and to enterprises looking to deploy the model in real use-cases. Where the 7B model scale is the default for tinkering and research, a 30B model is the default for seeing if an open model can unlock substantial value in your specific workflow — a good mix of intelligence, low price, tractability for downstream training, etc. This takes us back to the above adoption criteria I mentioned for open models and the bigger question — do I think Gemma 4 will be an overwhelming success? Previous Gemma models have been plagued by tooling issues and poorer performance when being finetuned. Gemma 4’s success is going to be entirely determined by ease of use, to a point where a 5-10% swing on benchmarks wouldn’t matter at all. It’s strong enough, small enough, with the right license, and from the U.S., so many companies are going to slot it in. I’m cautiously optimistic that Gemma 4 is going to work better here. Winds are shifting for open models built in America. We saw GPT-OSS go through a bumpy launch to become an overwhelming success. There’s a collective energy around the likes of Reflection, Arcee, Nemotron, Gemma, Olmo, and peers that show substantial demand for building new stacks around open models. There’s capital to be spent on AI stacks across the economy by those who want more ownership of everything, including the model. After launching The ATOM Project 240 days ago, the conversation is shifting into the next stage. Summer of 2025 was a crisis moment where the U.S. AI scene realized it can’t wait and figure out open models after building AGI. The two markets will capture different areas and proceed in parallel. Now that more companies in the U.S. are releasing strong models, we need to improve the ecosystem so that these models are easy to use, understand, and build value around. It’s the hard work to build another inflection point in these adoption plots I’ve been updating consistently, but that’s the work to be done. Join me in it. More data coming soon! Here’s a sneak peek:
FY2027 Budget Request Slashes Billions in Science Funding
The Trump administration is requesting the cancellation of billions of dollars in funds for space science, renewable energy, carbon removal, and climate change education in its FY 2027 budget.
Slay the Spire 2 nerfs card removal, buffs shivs, and adds a new reward system
New Slay the Spire 2 patch notes include a rework for Borrowed Time, a replacement for the Gloom Ascension, and a system called Badges.
Trump pushed the Iran war in prime time. The public wasn’t sold.
The president is in a precarious political moment seven months before the midterm elections, facing some of his lowest approval ratings and presiding over an unpopular war.
Trump ballroom gets approval from agency after judge halts work on it
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Coinbase clears key regulatory hurdle in bid to bolster its stablecoin business
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‘Good riddance’: Mass. politicians react to Pam Bondi’s removal as attorney general
The move ends the contentious tenure of a loyalist who upended the Justice Department’s culture of independence from the White House.
Donald Trump’s Approval Rating Is Tanking. Unfortunately, That Doesn’t Mean What You Think It Does.
This isn't good news for Trump—but it's terrible news for others.
Fairfax launches pilot to help small business owners obtain permits for store renovations
A new Fairfax County government pilot program aims to make life easier for small business owners seeking to make minor alterations before they open their stores. The Tenant Support Services (TSS) initiative is designed to move applicants through the permit approval process more efficiently by providing "early guidance, clear expectations and coordinated review support," county
Congress is in no rush to authorize Trump’s ballroom after judge’s ruling
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CNN Poll: Trump’s approval rating on the economy hits a new low
President Donald Trump’s approval rating for handling the economy has fallen to a new career low of 31%, according to a new CNN poll conducted by SSRS, reflecting growing pessimism among Americans over the issue they consistently describe as the most important.
Trump to address the nation with 'important' Iran war update
The address, scheduled for Wednesday at 9 p.m. ET, comes after Trump said he expects the U.S. to leave Iran "soon."
Trans athletes find space in Brooklyn sports leagues
All programs are inclusive, though the center says some ensure trans people are centered.
Will $4 Gas Hurt Trump’s Approval Ratings? Here’s What History Shows.
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The Bull Case For PENN Entertainment (PENN) Could Change Following Aurora Casino Relocation And Expansion
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Blakeman accuses Hochul of planning to raise taxes
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Apple Intelligence Accidentally Goes Live in China Before Regulatory Approval
Apple accidentally started rolling out Apple Intelligence features in China before receiving regulatory approval, reports Bloomberg's Mark Gurman. Some Chinese users began seeing Apple Intelligence features listed as available and active in the Settings app on their iPhones, but Apple made no formal announcement. Gurman says that Apple is not planning to launch the feature imminently, and that its availability was a mistake. Apple has since removed the Apple Intelligence features.
Whole Hog Politics: A top-down crisis in democratic legitimacy
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Novant Health to build new hospital in Leland
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Axcelis Announces SBTi Approval of Science-Based Greenhouse Gas Emissions Reduction Targets
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Vext Science Announces Strategic Optimization of Arizona Operations and Plans for Ohio Cultivation Expansion
Strategic closure and planned sale of Eloy cultivation facility expected to improve Arizona profitability and enhance free cash flow.Proceeds from the sale to facilitate debt reduction, with key equipment redeployed to the Ohio market, saving approximately $2 million in capital expenditures to support Vext's build-out in the State. Plans to seek approval to expand Jackson cultivation to support a growing retail footprint as Ohio adult-use sales surpass $1 billion in the first full year1.Vext to.
Developers warn flood of vibe-coded apps could slow Apple approvals
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Trump’s approval ratings just hit a new low. A Latino voter shift could reshape the midterms
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It's Your Business | Taking care of business
In addition to dog waste removal at residential and commercial properties, Poo Squad Champaign also offers a sanitation treatment that deodorizes the yard and kills bacteria, said owner Avian Gerdes.
Here’s the starting grid for F1’s 2026 Japanese Grand Prix
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Cottage Grove board advances sports complex project with permit approvals
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Ganim reelection, DECD study, nursing home spending: CT politics news
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New dean of the College of Health Sciences announced
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Business owner faces April 24 move-out as I-26 Connector project advances
After receiving federal approval, the North Carolina Department of Transportation (NCDOT) will move forward with its newest plans for the I-26 Connector project
Three charts that are warning signs flashing for Trump on Iran war
As gas prices rise, Trump's approval rating is heading into politically dangerous territory.
Lukaku faces consequences after infuriating Napoli and Conte
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Pokémon Champions' removal of IVs led to a "heated discussion" with one of the franchise's original devs
Settle it...with a Pokémon battle!
Photos: Pro Football Cares Sports Emergency Response Training at Raiders HQ
A Pro Football Cares Sports Emergency Response Training was held at Raiders HQ where athletic trainers and coaches were able to participate in a series of simulations on football equipment removal, cardiac arrest and exertional heat stroke.
‘Congress needs to have a greater say’: GOP Rep. Mace shifts position on Trump needing Congressional approval for Iran War
EPA approves sale of higher ethanol fuel to try to lower gas prices
The higher ethanol blend is usually limited to use in winter months
Precigen Reports Full Year 2025 Financial Results and Business Updates
Precigen transitioned to a commercial stage company with the US approval of PAPZIMEOS™ (zopapogene imadenovec-drba), the first-and-only FDA-approved treatment...
Fox News Poll: Voters oppose action in Iran but give US military positive marks
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Corus Entertainment Secures Court Approval For $363 Million Debt Plan
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Startups juice carbon removal with power generation
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The brain's cleaning system can be boosted to rid Alzheimer's proteins
A duo of drugs that boosts our glympathic system, which clears waste from our brain, also improves the removal of proteins associated with the onset of Alzheimer's disease
Gen Z brothers bought a $4,000 pickup truck to start their business—now it brings in $3 million a year
Kirk and Jacob McKinney found entrepreneurial inspiration at a local dump, launching junk removal and reselling business Junk Teens while still in high school.
Colby Covington plans to step away from politics after President Trump leaves office
Colby Covington plans to step away from politics after Trump’s second term Colby Covington says he plans to step away from politics once Donald Trump’s second term comes to an end. The former interim UFC welterweight champion has built much of his persona around his support for Trump, even bringing a belt to the Oval Office back in 2018.
Pharma bribery corrupts health care, puts patients at risk, new review warns
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Trump sinks to record low approval rating due to Iran war in new poll
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We disagreed on politics. We agreed on wine. That was enough.
At the Virginia Governor’s Cup Gala in Richmond earlier this month, a very dapper gentleman approached me and introduced himself. In his light-colored suit and bowtie, he looked very Southern in a classical sense, the sort of Virginia Gentleman you used to see south of the Rappahannock as recently as my college days. “I’m a longtime reader and fan of your writing, if not your politics,” he said. His comment was the proverbial iron fist in a velvet glove, simultaneously conveying praise and disapproval while establishing boundaries. Man, I wish we still discoursed like this instead of shouting bromides and insults to try and “own” our opponents with a funny meme and a furrowed brow. Subscribe “Well, we’ll always have wine to share together,” I said, and thanked him for his kind words. We clinked glasses, exchanged pleasantries about the delicious gold medal-winning wines being poured that evening, and went our separate ways. Our exchange reminded me that more unites us than divides us. Wine brings people together to share a meal and a few hours of joy despite our differences.1 That’s why I refer to the wine community — including readers and consumers — rather than the wine industry. Together, we are so much more than production, distribution and sales statistics. A few minutes later the evening’s awards ceremony began. Applause grew as the 12 winemakers who made the top-scoring wines for the Governor’s Case took the stage, including a loud cheer for Jonathan Wheeler of Trump Winery and his 2018 Blanc de Noir sparkling wine. All the winemakers on stage had reason to be proud, Wheeler perhaps more so. Trump Winery was the only winery to win six gold medals in the competition this year. (Wineries are limited to six entries.) Two of Wheeler’s ciders also won gold medals in a separate competition. When you cover the labels and take the sour taste of politics off your palate, the wines are pretty darn good.2 Then Gov. Abigail Spanberger, newly elected Democrat and Virginia’s first female governor, was introduced to great applause to announce which of the 12 wines had won the Governor’s Cup. She spoke for a few minutes about the importance of wine to Virginia’s economy and tourism and the international acclaim Virginia wine has received. Just two weeks earlier, she gave the Democrats’ response to Trump’s State of the Union speech, but this night wasn’t about politics. That didn’t stop several people in the crowd from speculating on the irony should she have to present the trophy to Trump Winery. In the end, Valley Road Vineyards was displayed on the screen behind Spanberger as the winning winery. Blue Bee Cidery in Richmond took top honors for that category. The crowd cheered a female governor presenting the state’s highest trophy to a female winemaker and then resumed the evening’s festivities, united by their mutual love of wine. A whiff of politics couldn’t dim the cheer of celebration and a community united by its love of wine. In Memoriam: Michel Rolland The global wine community lost a giant March 20, with the passing of Michel Rolland. He was 78. Rolland was the original “flying winemaker,” a globe-trotting consultant who helped Bordeaux regain its mojo in the 1970s and then shaped the rise of Napa Valley cult Cabernet as consultant to Simi, Harlan, Newton, Screaming Eagle, Araujo, Dalle Valle and other wineries. He was instrumental in Argentina’s rise to prominence and even had his own winery, Clos de los Siete, in a partnership with other wine families. Rolland’s career arc paralleled that of Robert Parker, the world’s most influential critic. Parker championed many of the wines Rolland consulted on, helping build his reputation and demand for his services. It also made him a target for Parker’s critics. As W. Blake Gray wrote on Wine-Searcher in his excellent tribute to Rolland: Rolland created the type of wines Parker loved: rich body, plenty of fruit, soft tannins. He sometimes faced the accusation of creating a generic international style of red wine, where the great wines he made in Argentina were indistinguishable from the great wines he made in France. Rolland chafed at that critique, as did many of his fans. He was credited with championing green harvesting and leaf pulling, as well as careful selection of grapes in the winery, practices we nearly universally think of today for high-quality winemaking. “Michel was an incredible innovator who changed how wine was made and how grapes were grown,” Napa Valley winemaker Aaron Pott wrote on Facebook. “His work has transformed the wine trade. He created new ways of looking at wine, tasting wine, evaluating ripeness and quality. … This was not just a man with a ‘style’ that he imposed on vineyards but a man that understood how to make great wine from great sites.” Rolland started his consulting company in 1973 in Libourne, in Bordeaux, with his wife, Dany. Both had graduated the year before from Bordeaux’s Institute d’Oenologie. The couple sold their majority share in the business in 2020, according to Wine Spectator. Over his career, Rolland reportedly worked with more than 100 wineries in 20 countries. He even made it to Virginia, where he consulted for Kluge Estate in the mid-2000s. (Kluge Estate is now Trump Winery.) Reader feedback, please! Last week, I did my first WineLine Live! with Dr. Laura Catena of Catena Zapata winery in Argentina. We enjoyed a fascinating discussion about her efforts to preserve the genetic heritage of old vineyards in Mendoza. I conceived of WineLine Live! for paid subscribers, as a thank you for your financial support. And while only a few people joined live, the video now has more views than I have paid subscribers, so I guess that’s pretty good. Even so, I’m considering opening future installments to anyone on Substack to reach a broader audience. So my questions to you: Should these be public? And what format do you prefer? Live gives a chat feature with the potential for viewers to interact with me and the guest, while a video post would just be that. Another alternative is a podcast, which would just be audio, without video of my chins. Please let me know in the comments. Leave a comment In the Glass A few wines I’ve enjoyed recently: Bonny Doon Vineyard Take Me to Your Liter, Le Cigare Volant, Red Wine of the Earth. 2023, Central Coast, CA. Blend of Grenache, Syrah Cinsaut and Petite Sirah. Delightful wine with expressive red fruit flavors, casual drinking. Doon lovers of a certain age will remember Randall Grahm’s Big House Red; this is more in that style than his original Le Cigare Volant, modeled after Chateauneuf du Pape. The liter bottle makes it an even better value. I see this online at about $15. Great value. Albert Bichot Bourgogne Pinot Noir Origines 2023. 13% - Textbook pinot noir and an excellent, affordable entry (regional) Burgundy. Wine Enthusiast Top 100 Wines of 2025. $24 at Total Wine & More. Loma Larga Pinot Noir 2021 “Coastal Cool Climate Wine”, Valle de Casablanca, Chile. An older sample, showing beautifully. Spicy and fruit forward. I’m seeing widely varied pricing online, from $18-$32. At the lower end, it’s a terrific value. 13.5% Dr. Loosen Riesling Dry 2016, Mosel, Germany. Found this “in the stack.” And it stacked up well, shedding some of its youthful acidity for opulent Riesling character, including a hint of the mineral oil older Riesling often features. A great value, as I’m seeing it as low as $14 online. 12% abv. Red Tail Ridge Blau Franc Blend 2024, Sans Oak, Finger Lakes. 13.4% abv. The name is a neat portmanteau of Blaufrankisch and Cabernet Franc, thus Blau Franc. The blend is 50-50, no oak involved. The Blau dominates on the palate, with the spicy caraway seed (think New York deli rye bread). The Franc adds body. The result is juicy, energetic and joyful. Sokol Blosser Estate Rosé of Pinot Noir 2025, Dundee Hills, Willamette Valley, Oregon. This first rosé of 2025 was a welcome respite to our cold, snowy winter here in the Mid-Atlantic. Oh man, I needed this! Bright and energetic, exuberant even, it perks up the mood and goes down fast. 13%. Certified B Corp. Ingredient and nutrition labeling, and in a modest way that doesn’t occupy a lot of label space. (Since it’s not required, presumably there are no minimum font size requirements.) More wineries should follow this example. Dave McIntyre's WineLine is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Subscribe Thanks for reading Dave McIntyre's WineLine! This post is public so feel free to share it. Share 1 Some restraint may be required. 2 Especially the bubblies.
Ambani's Reliance Jio: businesses and investors of the IPO-bound firm
Indian billionaire Mukesh Ambani's Reliance Jio Platforms is gearing up to file papers seeking regulatory approvals for a Mumbai listing, in what is likely to be the biggest-ever stock offering in the country.
Executive Council seeks greater role in half-billion-dollar rural health initiative
New Hampshire executive councilors are seeking a greater role in a $640 million rural health initiative after initially delaying approval and securing more oversight.
Your Thymus and Your Healthspan
Our thymus gland plays a central role in the development or our immune system, specifically for supporting T cell development (how these cells got their name, maturation and differentiation in the thymus) and discriminating between self and foreign, non-self antigen proteins with production of dendritic cells. As we age, our thymus gland shrinks—the process known as involution—with progressive change from spongy to fatty tissue, with loss of functionality. But this process, with respect to timeline and extent, markedly varies from one person to the next. And to make things even more complicated, our thymus gland anatomy and precise location in the chest also is highly variable. So the famous Frank Netter diagrams from the 1960s (such as at left below) don’t capture the remarkable heterogeneity that a random set of 12 chest CT scans (below at right). What I consider as 2 landmark papers in Nature this week (here and here) used AI to quantify health of the thymus in 2 large cohorts, and then correlate the metric to a broad array of health outcomes. In this edition of Ground Truths, I’m going to cover three questions: (1) How was thymus health determined by AI?; (2) How is thymus health linked to key clinical outcomes? and (3) Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years? Subscribe 1. How was thymus health determined by AI? This was accomplished by extensive work developing and validating an AI pipeline for 2 stages, the first for localization and segmentation of the thymus bed, and the second to quantify a digital marker, termed the thymic health score. There’s a lot to this algorithmic development, so I won’t go into all the details, but just provide a rudimentary outline of what was done. The 1st stage used supervised learning with 2 radiologists reviewing 2,461 chest CT scans. That work trained a 3D U-Net model to automatically identify the thymic bed’s 3D cropped region using center of mass coordinates, which reached 99.8% accuracy. The 2nd stage used a foundation model that was pre-trained with SwAV (which stands for Swapping Assignment between multiple Views), a self-supervised model, that generated a high-dimensional thymus representation of 4,096 features. That compares to the radiology reductionist and subjective scoring of 0 to 3 where 0 means the thymus is fully degenerated and fatty, and 3 is considered dense, intact glandular soft tissue. Notably, the self-supervised learning (SSL) performance was superior to supervised (AUC ~0.75 vs 0.55, respectively) reflecting the shallowness of the 0-3 classifier vs SSL’s holistic, self-taught AI. The thymic health score ranged from 0 to 100, with the highest number indexed to fully preserved thymic health. The algorithmic work extended to explainability with both Shapely value distribution, meaning the model was holistic not relying on any “magic” pixel, and occlusion sensitivity, demonstrating the model’s performance was not affected by ribs, sternum, lung tissue, but rather focused on the thymic bed directly. Below are a few saliency maps from the occlusion sensitivity that indicate the thymic bed focus, not affected by neighboring structures, using the jet color scale. Now the AI was ready for processing ~25,000 CT scans, each over 30 MB files, from the 2 large participant cohorts to provide a thymic health score, it did so in less than 14 hours, which is less than 2 seconds per scan! Share 2. How is thymus health linked to key clinical outcomes? The two cohorts were the National Lung Screening Trial, NLST (N=25,031) and the Framingham Heart Study, FHS (N=2,581) each with baseline demographics and long term follow up of >12 years for health outcomes. From the NSLT, you can see below that increased age and body-mass index were correlated to reduced thymic health. And, overall, men had reduced thymic health scores compared with women. There are a lot of graphs in the paper for outcomes, for both the NLST and FHS cohorts. To simplify the major outcomes, below is a composite Figure with striking reduction of all-cause mortality and for the different causes of death. The results were consistent between the 2 cohorts. For example, the cardiovascular mortality hazard ratio average was 0.57 in NLST and 0.38 in FHS (weighted to be 0.53 for the aggregate). The reduction of mortality also extended to digestive diseases and pulmonary disease (data not shown below). Lung cancer incidence was reduced by 36% for high vs low thymic health (Figure below, with a panel -incidence and b panel-mortality, adjusted for age, sex, BMI, smoking status). Notably, there was a smoker’s paradox: lower incidence and improved survival for lung cancer in smokers who had a high thymus health score. Smoking was associated with lower thymic scores whereas alcohol was not. Higher thymic health was linked to higher HDL cholesterol, lower triglycerides, lower fasting blood glucose, and lower systolic and diastolic blood pressure. Inflammation biomarkers, such as C-reactive protein and interleukin-6, were elevated in the people with lower thymic health scores. In their second paper, the same team looked at the relationship between thymic score and outcomes for 3,476 patients receiving cancer immunotherapy. The non-small cell lung cancer progression-free survival was reduced in patients with low thymic health score. A parallel relationship for survival was seen for other types of cancer including melanoma, breast, and kidney with a 44% lower risk among high thymic scores (Figure). A similar pattern was seen with different immune checkpoint inhibitors. The thymus health score outperformed programmed death ligand-1 (PD-L1)and tumor mutation burden (TMB) assay of the tumor and was an independent prognostic marker of progression-free survival. In this dataset, a direct connect with thymus score and adaptive immune function was noted with a correlation before cancer treatment for both T-cell diversity and thymus T-cell production (a metric known as T cell receptor excision circles). Thymus Removal Study There is a highly relevant citation about thymus function before moving onto ways to rejuvenate it. In 2023, a very important study of thymus removal during cardiothoracic surgery was published, with 1146 patients undergoing thymus removal vs 1146 matched controls (mean age 55 years). The adverse outcomes for thymus removal were striking, with a 2.9 higher risk of all-cause mortality and doubling of cancer incidence, 1.5 fold increase in cancer mortality, and 1.5-fold increase in autoimmune diseases. The immune function showed marked compromise after thymus removal, as reflected by CD4+ and CD8+ T cells (Figure below) Share Ground Truths 3. Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years? In recent months we’ve learned a lot about the process of thymus involution and the pathways by which this may be modulated. Thymus involution is primarily due to loss to thymus epithelial cells (TECs) and there are 2 subtypes with different functions: the cortical, responsible for positive selection of T cells, and the medullary, for negative selection. When adipose tissue infiltrates the thymus, thymic adipocytes are pro-inflammatory, knocking out T-cell output. Likewise, systemic inflammation, or “inflammaging,” from smoking, obesity, and chronic stress promote thymic adipocytes. Now, from preclinical studies, we know about key pathways that account for these processes. Historically, back in 2014, FOXN1 was recognized as a single master transcription factor essential for TEC function, with studies in mice with forced FOXN1 upregulation leading to thymus regeneration. That laid the foundation for potential regrowth of quiescent thymus cells. It took awhile to find pathways to accomplish this goal and to even refute its role as the master regulator. The Liver-Thymus Axis Feng Zhang and his team recently showed that injection of an mRNA vaccine to the liver encoding DLL1, IL-7 and FLT3-L in combination, factors known to support thymopoiesis (Figure), successfully enhanced immune function in aged mice. However, the effect was transient. The FGF21 Story Two reports in 2025 addressed the thymus gland’s production of FGF21, a growth factor (fibroblast growth factor 21) and its control of thymus involution. This growth factor is also produced by the liver, but it doesn’t have impact on the thymus in aged rodent models. In contrast, The liver’s hepatocyte growth factor (HGF) has been shown to reverse senescent TEC structural changes. Growth hormone stimulates production of insulin growth factor-1 (IGF-1) in the liver and the thymus. Two small studies in human participants (TRIIM, for Thymus Regeneration, Immunorestoration, and Insulin Mitigation) of 6 and 50 people, respectively, treated with combined human growth hormone, metformin and DHEA, suggested the potential of slowing epigenetic aging and improving thymus mass and function. But the combination of drugs, small sample, and lack of controls make conclusions murky. Increased thymus FGF21 led to increased CD8 T cells in old mice and extended healthspan and improved physical performance. Building on the previous FOXN1 data, ablation of β-klotho, the obligatory co-receptor for FOXN1, accelerated thymic aging. The benefit to FGF21 was confirmed in a companion paper using an FGF21 knock-in mouse model showing thymus enlargement and increased TECs throughout the lifespan. (schematic Figure below). The accompanying editorial for these 2 papers speculated: “The proposed link between age-associated thymus involution and organismal aging is intriguing, and suggests we might seek to achieve systemic rejuvenation by counteracting thymic involution.” Other Factors Lessons from the Axolotl (Mexican Salamander) In an elegant set of experiments of the axolotl (Figure), known for its complete thymus regeneration after total surgical removal, mediators were identified. Surprisingly FOXN1 was dispensable. But midkine, a growth factor, appeared to be the driver, the initiator of thymus cell growth, survival, and repair. Other components that contributed were Postn+ (periostin-expressing mesenchymal niches) and Ccl19, a chemokine protein from the bloodstream. RANK and RANKL RANK (receptor activator of nuclear factor κB its ligand (RANKL) have been considered key regulators of medullary TECs. In a study of both aged mice and human thymus cell cultures, their key role was confirmed, with multiple benefits of resorting TEC function, recruitment of progenitor cells, and T cell development. Subscribe Summing Up This body of work strongly supports the health of the thymus gland as a critical regulator of human healthspan, not just a correlate or link. The new landmark studies are reinforced by the regenerative biology experimental models that have shown, via an array of mediators, that healthspan of aged mice is at least in part dependent on thymus gland function and its critical role for maintaining adaptive immunity. It sure seems that we’d be better off having an immune reservoir of naive T cells instead of a profile in older adults of exhausted, low quality, memory T cells, with a senescent phenotype. It is striking that we ignored the importance of the thymus gland for many decades. A wake-up call was the results of the thymectomy matched control study reviewed here, with the opposite of high thymic health score improved health outcomes. The convergence of AI and healthspan here is notable. The exceptional and laborious work for developing and validating (no less explaining) the AI to quantify thymus health set the foundation for probing the connect the major health outcomes in two cohorts with extensive follow-up. We’ve never had a way to meaningfully quantify the thymus gland before, so this represents important leverage of supervised, self-supervised, and transformer models. The study wouldn’t have been possible without AI. And it begs the question as to whether there are ways we can maintain our thymus at a high health score. But it’s not so simple to rejuvenate our thymus. There are multiple risks including the induction of autoimmunity, increasing the risk of cancer, and inducing a pro-inflammatory state. For example, factors that increase TEC proliferation could compromise the medulllary negative selection process and leak out auto-reactive (self-attacking) T cells. Thymic cells could be induced to proliferate, but we know, for example, that growth hormone and IGF-1 are associated with an increase risk of cancer. If thymus rejuvenation doesn’t clear out the accumulated senescent cells in older adults, then inflammation within the gland could block the production of TECs. Keeping these risks in mind, we now have identified many ways to keep our thymus healthy as we age that undoubtedly will be tested in clinical trials going forward. Ultimately, the benefit-to-risk tradeoffs will be defined. In the meantime, we have desperately needed an immunome. As I’ve stressed in multiple prior Ground Truths, we have no test in the clinic to assess a patient’s immune status! It was very encouraging for me to get an email from Hugo Aerts, the senior author of the landmark papers in the days after they were published: “I also wanted to say that your Substack on “Why We Need an Immunome” was inspiring for this work. We found it a very compelling perspective and greatly enjoyed reading it.” Just having an assessment of a person’s immune status via a chest CT scan, with millions of these performed per year, might help in guiding the right immunotherapy for cancer (e.g. more intensive, combinations for those with low thymic health scores) and help define people who are increased risk for age-related diseases of cancer, cardiovascular, and neurodegenerative. The main theme of Super Agers is that we now have many layers of data (genetics, proteins, biomarkers, organ clocks that can be integrated via multimodal AI) for us to define a person’s specific risk decades before one of these age-related diseases leads to symptoms, enabling prevention. From the new studies this week, we can add thymus health score as yet another way to understand a person’s risk, a window into their adaptive immune system and healthspan. And perhaps someday we will be able to safely rejuvenate the thymus, or maintain its health through one’s life, and use the thymus health score to monitor. NB: I wrote this post (No A.I.) A Quick Poll Loading... ********************************************************************* Thanks to Ground Truths subscribers (now > 200,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Share Ground Truths Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Leave a comment Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.
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Downtown Chico business owner voices concerns over street closures for events
A DOWNTOWN CHICO MERCHANT IS EXPRESSING CONCERN OVER THE IMPACT OF STREET CLOSURES FOR EVENTS -- ON THEIR BUSINESS. ACTION NEWS NOW REPORTER BELLA BARBOSA REPORTS FROM DOWNTOWN CHICO { "@context": "https://schema.org", "@type": "VideoObject", "name": "Downtown Road Closure Dilemma", "description": "A DOWNTOWN CHICO MERCHANT IS EXPRESSING CONCERN OVER THE IMPACT OF STREET CLOSURES FOR EVENTS -- ON THEIR BUSINESS. ACTION NEWS NOW REPORTER BELLA BARBOSA REPORTS FROM DOWNTOWN CHICO", "thumbnailUrl": "https://bloximages.newyork1.vip.townnews.com/actionnewsnow.com/content/tncms/assets/v3/editorial/c/47/c47e26d6-03c3-5f35-bf49-37925ab603d7/69bdedc4eb57d.image.jpg", "uploadDate": "2026-03-20T17:45:00-07:00", "contentUrl": "https://cdn.field59.com/KHSL/1774053903-6e1ef36dd09fbebf020833aee86b60da3b3cca3f_fl9-720p.mp4" } CHICO, Calif. - A downtown Chico business owner is voicing concerns about the impact of street closures for events on local shops. Leann Powell, owner of The Peddler’s Closet, expressed concern about events closing down streets downtown and bringing in food trucks and other shops’ products that directly compete with the brick-and-mortar stores in downtown Chico.Powell said an upcoming event held on a Saturday has brought up concerns for her and other business owners downtown, due to it being a busy day for businesses. "We're already struggling, and then to bring in more businesses on top of our businesses and shut our streets down is absolutely devastating," said Powell.Powell noted a decline in business during events like the Thursday Night Market, where street closures allow outside vendors to set up shop. She shared that while organizers for these types of events often offer booths to local businesses, it does not alleviate the burden."I don't really feel like that's a solution because you're bringing in other businesses, you're shutting the streets down. Yes, we can go down and set up a space, but then you've gotta pay somebody to run that space, plus run your own business for the day, and it's really not, it's really not helpful for us," said Powell.Applying for a street closure permit in Chico involves approval from the Public Works Department, the Chief of Police, and the Fire Chief. Permits can be denied only under a handful of circumstances, such as interference with first responders, previously scheduled construction, or existing permits for the same space.Mayor Kasey Reynolds addressed the issue, saying the city council has tasked staff with reviewing the municipal code for street closure permits with the goal of finding ways to minimize negative impacts on local businesses during events.Reynolds mentioned that any recommended changes might require further direction from the city council, depending on the extent of any changes recommended. googletag.cmd.push(function() { googletag.display('ad-1514992'); });
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