Muller Lab @Muller_Lab

On the front page of The Free Press now.

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Reasonable Democrats are going to have to get off their couches, roll up their sleeves and start organizing real voters on the ground. We can no longer rely only on TV ads, digital spend and endorsements. Just donating from afar and complaining about the DSA won’t cut it. The DSA (Democratic Socialists of America) can beat moderates in a growing number of blue strongholds. Why? Because the DSA has patiently built an army of on-the-ground organizers — who go to meetings, help each other, study together and THEN work to turn out voters on Election Day. That army grows every day — election or no election. Their investment in real people grows (and compounds) with each election cycle. The DSA has a bigger army, every time, win or lose. But at the end of any election, all moderate Dems have for their efforts is a bunch of ads that nobody will ever see again. That’s not going to work anymore. If you are a Democrat who believes in opportunity, dignity and democracy for all — but you don’t hate rich people, cops, free enterprise, the West, Israel and the United States of America — I’m talking to you!

Twenty-five years ago, Larry Sanger co-founded Wikipedia, arguably the most important encyclopedia in human history. This week, he was banned from the site. The story of how and why is an emblem of our time. Read @lsanger in @TheFP: thefp.com/p/larry-sanger…

In the Appendix to my book, The Code as Witness, I assemble 166 facts, observations, evidence, and analyses that are inconsistent with SARS-CoV-2 having arisen from a market in December 2019. Challenge each one if you want but you need to negate all of them to support a market origin. Items 1-166: No Huanan Seafood Market case is universally accepted to have had disease onset before December 2019. A Bayesian analysis of sixteen independent pre-December-2019 observations gives a posterior probability of less than 0.0000001 for the hypothesis that SARS-CoV-2 began at the Huanan Seafood Market in December 2019. Multiple tMRCA estimates place the first human SARS-CoV-2 infections between May and October 2019, before the market outbreak. A tMRCA protocol based on 3.14 million genomes estimated two early viral variants with common ancestors on May 1, 2019, and October 17, 2019. An analysis of 86,582 high-quality genomes estimated a SARS-CoV-2 tMRCA of August 16, 2019. An analysis of ten cat-derived SARS-CoV-2 genomes estimated a tMRCA of July 30, 2019, with an R² of 0.98. An analysis of 970,777 high-quality full-length genomes estimated a tMRCA range of June 12 to July 7, 2019. A random-genome analysis using five tMRCA methods estimated a July 13–24, 2019, origin range. Ralph Baric testified that the molecular clock indicated SARS-CoV-2 emergence in mid-to-late October 2019, with five or six transmission cycles before the market cases. Antarctic tundra sequencing data contained SARS-CoV-2-like sequences with ancestral mutations C8782T, C18060T, and T28144C not found in the market genomes. Antarctic sequencing data contained host signatures most consistent with human, green monkey, and Chinese hamster biological material. The Antarctic dataset contained laboratory cell-culture signatures involving VERO cells, Chinese hamster ovary cells, and possible VERO–CHO hybrid material. The Antarctic sequencing evidence was linked to Sangon Biotech, a Shanghai sequencing company named in the DEFUSE-related WIV budget line for conventional DNA sequencing. A Monte Carlo analysis of Antarctic sequencing metadata estimated a mean sequencing date of May 9, 2019, with a 95 percent confidence interval from January 20 to September 10, 2019. A second model using Sangon HiSeq 4000 flow-cell identifiers refined the Antarctic sequencing window toward October 2019, still before reported COVID-19 cases. The probability that the Antarctic sequencing occurred after January 2020 was less than 0.005 percent. The Antarctic variant contained a rare 27-nucleotide spike deletion and eight SNVs not known to co-occur in any natural circulating lineage. The Antarctic mutational pattern was more consistent with a lab-restricted or engineered construct than with a natural spillover lineage. SNV comparisons between countries that did and did not attend the Wuhan Military Games provided strong pre-December evidence against the market-origin hypothesis. The Wuhan Military Games outbreak and antibody evidence provided pre-December-2019 evidence against a December market origin. The Wuhan CDC identified forty early cases before December 2019. A U.S. deputy consul reported a flu-like outbreak in Wuhan in October 2019. Satellite imagery showed increased Wuhan hospital activity in September–October 2019. WIV researchers were reportedly sick in fall 2019. U.S. intelligence issued warnings in November 2019. ThermoGenesis, a California company, claimed awareness of the outbreak in November 2019. A Milan skin biopsy from November 2019 contained SARS-CoV-2 RNA and nucleocapsid signal. Connor Reed was a PCR-confirmed November 2019 Wuhan COVID-19 case excluded from official Chinese records. Jesse Bloom’s recovery of deleted early Chinese SARS-CoV-2 sequences showed ancestral mutations making those viruses closer to bat relatives than the market sequences. The first U.S. case, WA1, came from a traveler who had been in Wuhan but had not visited the Huanan Market and carried a genotype ancestral to market-associated viruses. Pneumonia-and-influenza mortality anomalies and smell-loss Google Trends in California indicated SARS-CoV-2 spread in the United States by late December 2019. The WIV’s reported 21-day completion of sequencing, isolation, receptor-binding studies, serology, antigenic characterization, and manuscript submission was statistically improbable under ordinary research timelines. A Monte Carlo analysis of the WIV Nature-paper timeline produced a mean completion time of 31.12 days and a less-than-2.5-percent likelihood of completion within 21 days. The WIV’s rapid early characterization was most plausibly explained by prior access to SARS-CoV-2 before its reported first sequencing. The first hospitalized COVID-19 patient described in the January 2020 Lancet report had onset on December 1, 2019, and neither he nor his family had any market connection. Three of the first four patients infected by December 10, 2019, had no Huanan Seafood Market exposure. The WHO’s first identified patient had onset on December 8, 2019, no Huanan exposure, and a link instead to an RT-Mart supermarket more than twelve miles away that did not sell live wildlife. Only ten of 678 Huanan Market stalls sold wildlife, and none of those ten wildlife vendors had COVID-19. Unlike SARS-1, where early human cases included wildlife-trade workers, no Huanan wildlife vendor was among the first COVID-19 cases. All eleven human genomes associated with the Huanan Market were Lineage B, not the more ancestral Lineage A. A single Lineage A environmental market specimen was verified as post-collection laboratory contamination. A spatiotemporal analysis by market-origin proponents found early human cases beginning in the northeastern portion of the western market section and moving toward the wildlife stalls, not away from them. Another market analysis found early cases dispersed 66–131 feet apart and better explained by shared indoor spaces such as toilets, Mahjong rooms, and canteens than by animal stalls. A total of 457 animal-related samples from 188 individuals across eighteen species in or around the market all tested negative for SARS-CoV-2 by RT-PCR. A total of 616 specimens from market suppliers all tested negative for SARS-CoV-2 by PCR. In SARS-1, 91 of 91 civet cats and 15 of 15 raccoon dogs tested positive, whereas the Huanan Market animal samples for SARS-CoV-2 were negative. Of 923 environmental specimens from the market and surrounding areas, 73 were SARS-CoV-2-positive, but the positive samples were most strongly correlated with human genetic material. Six of seven market environmental sequences were Lineage B and three to six SNVs from the inferred ancestral genome, implying six to twelve weeks of prior evolution. SARS-CoV-2 environmental reads in the market did not reliably co-occur with susceptible animal mitochondrial DNA. Market metagenomic data placed humans at the top of SARS-CoV-2 association and raccoon dogs at the bottom. A total of 96,359 animal specimens tested negative for SARS-CoV-2. Raccoon dogs and bats in Hubei tested negative in January 2020. SARS-CoV-2 binds primate ACE2 best, not bat or pangolin ACE2. Hubei bats were an unlikely source for ecological and genetic reasons, including the local absence of appropriate SARS-CoV-2-like viruses. Hubei sarbecoviruses had spike deletions that prevent human ACE2 binding. Pangolin-origin evidence appeared synthetic or contaminated because pangolin datasets contained SARS-CoV-2-like material alongside multiple other mammalian species and laboratory-cloning signals. Raccoon dogs remained a speculative host because field surveillance failed to detect natural infections and market samples showed no co-occurrence of SARS-CoV-2 RNA with raccoon-dog mitochondrial DNA. 43,586 Wuhan blood-donor samples from September–December 2019 contained no SARS-CoV-2 antibodies, despite an expected roughly 260 positives if a SARS-1/MERS-like pre-epidemic zoonotic phase had occurred. SARS-CoV-2 lacked the seroconversion pattern characteristic of natural zoonosis. SARS-CoV-2 began without posterior genetic diversity, unlike SARS-1 and MERS. All SARS-CoV-2 cases trace back to Lineage A, rather than to multiple animal-to-human jumps. In SARS-1 and MERS, about 54 percent of early sequenced human infections were independent animal-to-human events, whereas SARS-CoV-2 showed no comparable pattern. Ralph Baric acknowledged that early Wuhan strains had limited genetic diversity consistent with a single source. A Bayesian analysis of eleven WIV-related events gave a posterior probability of less than 0.001 for the hypothesis that no WIV laboratory-acquired infection occurred. On March 31, 2019, deadly pathogens including Ebola, Hendra, and Nipah strains were shipped from Canada’s National Microbiology Laboratory to the WIV on a commercial Air Canada flight. In July 2019, China’s Ministry of Science and Technology ordered review of a grant that funded coronavirus and bat-sample collection in Yunnan caves. On July 16, 2019, the WIV issued a tender for hazardous-waste-system renovation at the Wuhan National Biosafety Laboratory. In August 2019, Eddie Holmes privately relayed that someone claimed a contact at the WIV had a human “SARS-like sample” from August 2019. On September 12, 2019, the WIV viral sequence and sample database was taken offline between 2:00 and 3:00 a.m. The offline WIV database contained about 22,000 sample records, including 15,000 bat samples, more than 1,400 viral strains, about 1,000 coronaviruses, and at least 500 recently discovered bat coronaviruses. The WIV database had 603,793 page downloads from April to September 2019, with 99 percent in June and 99 percent from Beijing computers. On September 12, 2019, the WIV also issued a security-services tender covering gatekeepers, guards, surveillance, patrols, and foreign-personnel registration. On November 15, 2019, the WIV filed a patent for a device to treat bleeding finger injuries from animal bites in a pathogenic-virus laboratory. In December 2019, a PLA bioweapons expert was installed as head of the WIV BSL-4 laboratory. On December 30, 2019, Shi Zhengli’s stated first thought on hearing of a Wuhan coronavirus outbreak was whether it had come from her lab. On December 30, 2019, Shi changed WIV database search terms in a way that obscured wildlife-sampling references. Raw sequencing data from the first WIV-processed clinical specimens contained numerous laboratory contaminants inconsistent with ordinary human lung specimens. A synthetic Nipah-virus infectious-clone signature appeared in WIV raw RNA-seq reads from early COVID-19 patient samples. The Nipah signal involved the highly pathogenic Bangladesh strain, the same strain shipped from Canada to the WIV in March 2019. Xi Jinping’s February 14, 2020, call for national biosecurity laws was more consistent with a laboratory-safety problem than a market spillover. China’s new biosecurity law addressed escaped laboratory animals and biotechnology endangering public health, issues unrelated to a simple market spillover. Prior SARS-CoV-1 laboratory-acquired infections occurred in Singapore, Taiwan, and Beijing. A 2021 SARS-CoV-2 lab accident in Taiwan showed that SARS-CoV-2 laboratory infections can occur even under containment. A 2025 study identified eight likely occult SARS-CoV-2 lab-acquired infections at UNC between June 2020 and January 2021. Reanalysis of WIV early COVID-19 patient sequencing data found vectorized H7N9 hemagglutinin segments in all five SARS-CoV-2-positive early patient samples. One early WIV patient sample contained six times more H7N9 DNA-vaccine-related reads than SARS-CoV-2 reads. The H7N9 segments were embedded in pVAX1 vectors, consistent with DNA-vaccine work. Vectorized Nipah sequences suggested use of a full-length infectious clone despite no public record of such WIV research. Wuhan agricultural-rice sequencing datasets contained DNA clones of an HKU4-related Merbecovirus close to MERS-CoV. The HKU4-related Merbecovirus data included bacterial artificial chromosome insertion and engineered spike proteins likely capable of binding human DPP4. BtSY2, a SARS-CoV-2-like bat coronavirus, had large portions of its genome, especially spike, lacking raw-read support. The SARS-CoV-2 backbone was not from Hubei viruses but from southern China or northern Laos, the regions where EcoHealth Alliance and WIV had repeatedly sampled. The SARS-CoV-2 receptor-binding domain was 99.5 percent optimized for human ACE2 binding from the beginning. SARS-1 began with only about 15 percent of its optimized human-binding amino acids and initially bound civet ACE2 better than human ACE2. SARS-CoV-2 was so human-adapted from the start that it could no longer infect bat cells easily. No furin cleavage site has ever been found in a natural SARS-related virus. Sampling of 13,064 bats failed to find any SARS-CoV-2-related virus with or without a furin cleavage site. GenBank contained 736 bat sarbecoviruses, none of which had a furin cleavage site. A 2024 recombination analysis found that 183 of 199 validated betacoronavirus recombination events were intraspecies, making distant recombination into SARS-CoV-2 unlikely. The closest coronavirus with a furin cleavage site was only 56 percent homologous to SARS-CoV-2, a distance at which recombination has not been observed. No known mechanism explains how a sarbecovirus without a furin site could acquire one from another coronavirus family, genus, or subgenus. SARS-related viruses and furin-site-containing betacoronaviruses are hosted by different bat groups, reducing the likelihood of coinfection needed for recombination. Since at least 1992, virologists have understood that furin cleavage sites can increase pathogenicity and infectivity. Laboratory insertion of furin cleavage sites into viruses has been done repeatedly, including in cytomegalovirus, RSV, and coronaviruses. In 2015, Baric and Shi engineered a bat coronavirus spike protein to create a furin-like S1/S2 cleavage site that enabled human-cell infection without external proteases. The SARS-CoV-2 furin cleavage site sits at the same S1/S2 junction and is absent from close bat relatives. Robert Garry privately said he could not see a plausible natural scenario for the perfect 12-nucleotide insertion creating the furin site. Eddie Holmes privately said the market could not have generated the selective pressure needed for an optimal furin cleavage site because mammal density was too low. The SARS-CoV-2 RRAR-SVAS furin-cleavage motif is identical to the human ENaC-alpha furin-cleavage site. The probability of a natural pathway producing the observed eight-mer ENaC-identical motif was less than 0.001 percent. A Bayesian analysis of the ENaC-motif overlap gave a laboratory-associated posterior probability exceeding 99.999 percent. The SARS-CoV-2 S1/S2 polyfunctional motif combines a furin cleavage site, pat7 nuclear-localization signal, and flanking O-glycosylation sites. This polyfunctional motif was absent from 10,666 naturally occurring betacoronaviruses. The only non-SARS-CoV-2 match to the polyfunctional motif was MERS-MA30, a synthetic mouse-adapted virus engineered by serial passage in Baric’s laboratory. A Bayesian comparison of the polyfunctional motif gave a 99.99 percent posterior probability favoring laboratory origin. The SARS-CoV-2 furin cleavage site contains the CGG-CGG arginine codon pair. CGG is the sixty-second least-used codon in coronaviruses. CGG-CGG would be expected in only one of four hundred arginine dimers in nature. Thirteen conserved arginine dimers in SARS-related viruses contain no natural CGG-CGG pair. CGG is the most common synthetic arginine codon used in laboratories. The CGG-CGG pair was selectively lost in later SARS-CoV-2 variants, consistent with pressure against a maladaptive synthetic inclusion. CGG-CGG forms a recognizable restriction-enzyme site, consistent with cloning or molecular tracking. A Bayesian analysis calculated a 99.95 percent probability that the CGG-CGG motif is synthetic. SARS-CoV-2 has an atypical BsaI/BsmBI restriction-site architecture associated with reverse-genetics assembly. Natural sarbecoviruses show randomly distributed restriction sites, whereas SARS-CoV-2 shows segregated placement and depletion. The probability that the SARS-CoV-2 restriction-site pattern arose naturally was reported as less than one in a billion. Seven synonymous mutations separate SARS-CoV-2 from RaTG13 at restriction sites, consistent with deliberate genome modification. The WIV had previously published methods using BsaI/BsmBI-like restriction enzymes for synthetic virus assembly. RaTG13, the closest published relative used to support zoonosis, itself showed evidence of laboratory engineering. RaTG13 was labeled as bat feces, but its source sample was more than 67 percent eukaryotic rather than predominantly bacterial. The RaTG13 sample contained primate genetic material consistent with VERO-cell contamination. The RaTG13 genome was assembled from low-coverage RNA sequencing with gaps and discrepancies. RaTG13’s genome diverged by nearly 5 percent from amplicon sequencing data, an error rate fifty times higher than standard. RaTG13 showed more than 220 synonymous silent mutations concentrated in spike and pp1ab with almost no amino-acid-changing mutations. The RaTG13 silent-mutation pattern was consistent with codon optimization rather than natural evolution. RaTG13 reporting inconsistencies included mismatched sequencing dates, missing raw files, and retroactive renaming from BtCoV/4991 to RaTG13. RaTG13 mutations near functional regions could falsely inflate its evolutionary distance from SARS-CoV-2 and obscure laboratory origin. SARS-CoV-2’s furin-cleavage-site/D614 combination is inherently unstable in animals or humans. The D614/FCS combination is rapidly outcompeted by D614G, which stabilizes spike and improves infection and transmission. The D614 lineage tMRCA was estimated as November 13, 2019, and the G614 lineage tMRCA as January 18, 2020. Working backward from the D614-to-G614 interval yielded a likely first human infection with the D614/FCS virus between August 6 and October 8, 2019. In ferrets, cats, hamsters, primates, and mice, the D614 variant rapidly converts to D614G within one to four passages. No known intermediate host can maintain the metastable D614/FCS form long enough for a market-origin chain. The 2018 DEFUSE grant proposed constructing chimeric bat coronaviruses with enhanced human infectivity. DEFUSE proposed inserting human-specific proteolytic cleavage sites, including furin sites, into SARS-related coronaviruses. DEFUSE proposed use of hACE2 transgenic mice and “batified” animal models. DEFUSE proposed screening more than 180 unpublished bat SARS-related coronavirus sequences. Many DEFUSE-proposed features later appeared in SARS-CoV-2. A Bayesian DEFUSE analysis raised the posterior probability of DEFUSE-style research contributing to SARS-CoV-2 from 10 percent to about 68 percent. The genetic evidence showed that SARS-CoV-2 began as a wild-region virus from southern China or northern Laos and was modified for bat-to-human host switching and enhanced infectivity. SARS-CoV-2 ORF8 was structurally novel, functionally potent, and evolutionarily discontinuous. ORF8 suppresses host immune responses through MHC-I downregulation and interferon antagonism. ORF8 was linked to SARS-CoV-2’s unusually high 40–50 percent asymptomatic infection rate. No other new human respiratory virus is known to have such a high asymptomatic incidence. No homologs of SARS-CoV-2 ORF8 are found in more than two dozen closely related sarbecoviruses. No evolutionary intermediates for ORF8 have been identified. A Bayesian ORF8 analysis gave an engineering-hypothesis posterior range of 32.1 percent to 89.6 percent depending on priors. RmYN02’s conflicting descriptions as either a single-bat isolate or pooled sample weakened its value as a natural ORF8 intermediate. SARS-CoV-2 shows central-nervous-system tropism and compartment-specific lung-versus-brain viral evolution. Brain-adapted SARS-CoV-2 populations in hACE2 mice repeatedly deleted the furin cleavage site, while pulmonary reintroduction favored FCS reversion. The FCS functioned as a molecular switch for tissue targeting between lung/gut TMPRSS2 entry and brain cathepsin-dependent entry. A PLA-affiliated 2024 study of a SARS-CoV-2-related pangolin coronavirus clone caused uniform lethality in hACE2 mice through brain invasion rather than respiratory failure. SARS-CoV-2 CNS tropism converged with contemporaneous WIV synthetic-biology work on Nipah virus, a classic neurotropic virus. Chinese military-affiliated research linked SARS-CoV-2 to acute and long-term neurological damage. A 2017 Chinese thesis discussed coronavirus neuroinvasion and the SARS spike protein’s ability to reach CNS targets through olfactory and trigeminal routes. The convergence of neurological damage, immune evasion, asymptomatic spread, and neurotropic-virus research created a dual-use pattern inconsistent with a simple market spillover.

#OnlineFirst: TUB-040, a Homogenous and Hydrophilic NaPi2b-Targeting #ADC with Stably Linked #Exatecan, Exhibits Long-lasting Anti-tumor Activity and a Well-Tolerated Safety Profile. doi.org/10.1158/1535-7… #AntibodyDrugConjugate #FirstDisclosure #OpenAccess

The European Commission literally shut off air conditioning but only for floors 1-7, where people of lower rank work.

BREAKING: The US military just struck Iran near the Strait of Hormuz.

They say imitation is the most sincere form of flattery. An account with 1.7 million followers straight-up stealing my content.

Terrible Maps @TerribleMaps

a day ago

Only one group-stage match at this World Cup has both nations’ largest cities on the 41st parallel

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A rare variant of a gene called TP53 means Tracy Hutchinson has an extreme risk of developing cancer anywhere in her body, causing endless anxiety and requiring regular whole-body MRIs and other screening. newscientist.com/article/253207…

Vaccines work. Glyphosate doesn’t cause cancer. Evidence beats ideology every time.

14th C Depiction of Gain of Function Research

also, no improvements, more rats! you pretend to pay rent, and they pretend to house you

Mayor Zohran Kwame Mamdani @NYCMayor

2 days ago

It might be hot outside but the rent is freezing.

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Guess who Tucker Carlson's next guest is Notorious Russian arms dealer and Putin ally Viktor Bout If you can't see what's going on here there is no hope for you Its so blindingly obvious

1/ A St Petersburg doctor has been arrested for illegally selling human heads. The city's Alexandrovskaya Hospital is suspected of trafficking in body parts, selling them to organisations specialising in cosmetology, surgery, and dentistry. ⬇️

Wow, now Iran’s regime and Egypt have objected to Seattle’s Pride Match and urged FIFA to remove Pride-related symbols. This is exactly what I’ve been warning about: authoritarian Islamists never stop at asking for tolerance. First: “Respect our religious practices. Respect our customs. Respect our sensitivities.” Then: “Change your traditions. Silence your values. Adjust your society to our ideology.” These are the same “values” that sentence women to 74 lashes for singing, execute gay people, and shoot peaceful protesters in the streets. Free societies should never surrender their values to appease authoritarianism.

TRUMP IS RIGHT

Unexpected, but good news

NEXTA @nexta_tv

2 days ago

⚡️BREAKING: The United States has reinstated sanctions on Russian oil.

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Herculaneum fused scroll read in full. scrollprize.org/firstscroll

Let me take a guess. This person has never tried an experiment in living cells that involves performing biological replicates.

Zach Ocean @zachocean_

2 days ago

it's pretty wild that biology is still so hard when there's only like 25k protein coding genes

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Macron: Since 2022 Europeans adopted strategic autonomy themselves — Ukraine accelerated it and the last 18 months pushed us across another threshold. I support a strong European pillar within NATO. I don't favor distancing from the US. 2X