{"gname":"Stockholm University","grp_id":"14","rels":[{"rel_title":"Genetic architecture of lipoma susceptibility implicates telomere biology","rel_doi":"10.64898\/2026.09.08.26362503","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26362503","rel_abs":"Lipomas are common benign adipocytic neoplasms with well-characterized somatic cytogenetic alterations, but the inherited genetic architecture predisposing to their formation remains poorly understood. Recent phenome-wide evidence identified lipoma as strongly associated with genetic predisposition toward longer telomeres. Here, I examined this relationship from the complementary perspective of lipoma genetics. FinnGen R13 genome-wide association and native fine-mapping data resolved nine independent lipoma susceptibility signals across seven genomic regions. Unbiased annotation of these signals implicated telomere-maintenance and genome-stability genes, including telomerase reverse transcriptase (TERT), regulator of telomere elongation helicase 1 (RTEL1), and STN1 subunit of CST complex (STN1), with proximity-expanded mapping additionally encompassing telomerase RNA component (TERC). Using 198 leukocyte telomere length (LTL)-associated genetic variants from All of Us, multiplicative-random-effects inverse-variance-weighted Mendelian randomization showed a strong positive association between genetically proxied LTL and lipoma susceptibility (beta=0.445, 95% CI 0.355-0.535; P=2.49 x 10^-22). The association replicated using independent UK Biobank LTL effects (beta=0.587, 95% CI 0.459-0.715; P=3.09 x 10^-19), remained positive across alternative estimators and sensitivity analyses, persisted after exclusion of 15 variants assigned to canonical telomere\/DNA-damage-response genes, and extended across lipomas of the limbs, trunk, and head\/face\/neck. Regional analyses showed strong evidence for a shared LTL-lipoma association component at TERC (PP.H4=0.989), strong but unresolved regional overlap at TERT (PP.H4=0.924), and distinct association components at STN1 (formerly OBFC1; PP.H3=0.9995), demonstrating heterogeneous local architectures. The study used a human-supervised agentic research workflow in which ChatGPT contributed to analytical planning, interpretation, quality control, and synthesis, while Codex performed substantial computational execution and reproducibility auditing. Together, these findings connect the independently derived genetic architecture of lipoma susceptibility with a broader trade-off between maintenance of cellular replicative capacity and suppression of neoplastic growth.","rel_num_authors":1,"rel_authors":[{"author_name":"David Bryant Lowry","author_inst":"Michigan State University"}],"rel_date":"2026-09-09","rel_site":"medrxiv"},{"rel_title":"Empirically calibrated allele frequency thresholds for ACMG BA1, BS1 and PM2 evidence criteria","rel_doi":"10.64898\/2026.09.07.26362456","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.07.26362456","rel_abs":"Allele frequency (AF) is among the most frequently applied lines of evidence in variant classification, yet the ACMG\/AMP criteria that use it (BA1, BS1, PM2) are still applied at fixed defaults while computational predictors have been systematically recalibrated. Population frequencies are shaped by selection, ascertainment, and gene-level demography at once, and few genes carry enough classified variants to set a threshold directly. Extending the calibration approach applied to computational predictors, we used inheritance mode and gene-level missense constraint as stratification axes and pooled variants within each stratum. ClinVar missense variants annotated against gnomAD v4.1.1 were stratified along both, and gene-normalized kernel density estimates were fit to pathogenic and benign variants within a sliding window along the constraint axis. Thresholds were placed where the likelihood ratio crossed ACMG\/AMP evidence strengths at a prior of 0.0441. Derived thresholds varied systematically with constraint and differed between inheritance modes, departing from the fixed defaults in both directions. On held-out genes, stratified cutoffs reached 96.7% accuracy against 90.1% unstratified. Restricted to the 73 ClinGen expert panel genes with autosomal dominant or recessive inheritance, the derived cutoffs reached 91.0% accuracy at 69.5% variant coverage, against 88.8% accuracy at 86.2% coverage for the panel-specified cutoffs. AF thresholds for these criteria are not constant across genes, and inheritance mode and missense constraint capture much of that variation. The resulting cutoffs are empirically derived, carry explicit uncertainty, and deploy as a lookup table across thousands of genes no expert panel currently covers.","rel_num_authors":2,"rel_authors":[{"author_name":"Viksar Dubey","author_inst":"Bitscopic"},{"author_name":"Christopher Edward Eisenhart","author_inst":"Bitscopic"}],"rel_date":"2026-09-09","rel_site":"medrxiv"},{"rel_title":"Effects of Walnut Supplementation on Short-Chain Fatty Acid Levels in Healthy Volunteers","rel_doi":"10.64898\/2026.09.08.26362468","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.08.26362468","rel_abs":"Gut dysbiosis poses a significant public health concern, and malnutrition plays a central role in its development. In our recent clinical trial, we explored the effects of regulated walnut intake on the levels of 11 fecal metabolites to determine whether (I) walnut consumption promotes changes in metabolite profiles consistent with reduced gut dysbiosis, and (II) whether these changes are associated with the levels of urolithin A, a bioactive metabolite produced by colonic microbes following walnut consumption. DNA was extracted from fecal samples using a DNeasy 96 PowerSoil Pro QIAcube HT for 16S rRNA sequencing, and fecal short-chain fatty acids (SCFAs) and p-cresol were extracted fecal specimens by liquid chromatography\/mass spectrometry (LC\/MS-MS). At baseline, obese individuals (BMI > 30) had lower alpha diversity, higher p-cresol and valeric acid levels, and a higher trending Firmicutes to Bacteroidetes (F\/B) ratio compared to non-obese (BMI < 30) participants, indicating a level of inherent gut dysbiosis. Walnut intake was associated with an overall 2.8% increase in alpha diversity, a 17.6% reduction in estimated marginal mean F\/B ratio, and an overall reduction in three luminal proteolytic metabolites associated with gut dysbiosis: isobutyric acid, valeric acid, and isovaleric acid. Interestingly, the effects on the gut metabolome were more pronounced in obese individuals, with significant decreases observed in the same three SCFAs, as well as p-cresol. Given the known associations between these luminal proteolytic metabolites and gut dysbiosis, these results suggest that walnut intake may help to attenuate overall gut dysbiosis, particularly in obese populations.","rel_num_authors":10,"rel_authors":[{"author_name":"Thomas Petrillo","author_inst":"UConn Health"},{"author_name":"Raad Gharaibeh","author_inst":"University of Florida"},{"author_name":"James J Grady","author_inst":"UConn Health"},{"author_name":"Alexey Melnik","author_inst":"Arome Science"},{"author_name":"Alexander A Aksenov","author_inst":"University of Connecticut"},{"author_name":"John Birk","author_inst":"UConn Health"},{"author_name":"Haleh Vaziri","author_inst":"UConn Health"},{"author_name":"Huijia Liu","author_inst":"University of Florida"},{"author_name":"Christian Jobin","author_inst":"University of Florida"},{"author_name":"Daniel Rosenberg","author_inst":"UConn Health"}],"rel_date":"2026-09-09","rel_site":"medrxiv"},{"rel_title":"Heterogeneous Associations of Latency Duration with Neonatal Outcomes After Preterm Prelabor Rupture of Membranes: A Nationwide Cohort Study","rel_doi":"10.64898\/2026.09.07.26361886","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.07.26361886","rel_abs":"Importance: Expectant management for preterm prelabor rupture of membranes (PPROM) is guided primarily by gestational age (GA), yet whether the association between latency duration and neonatal outcomes varies among pregnancies remains uncertain. Objective: To characterize heterogeneous associations between latency duration and neonatal outcomes after PPROM and identify maternal and fetal characteristics associated with the largest estimated benefit. Design: Nationwide registry-based retrospective cohort study using restricted cubic spline regression and causal forest analysis. Data were analyzed from July 2025 to July 2026. Setting: The Korean Neonatal Network (KNN), a nationwide registry of infants born before 32 weeks' gestation or with a birth weight less than 1,500g, from 2013 to 2023. Participants: A total of 7,057 neonates born after PPROM were included. Exposures: Latency duration, defined as the number of days from PPROM diagnosis to delivery (0-118 days). Main Outcomes and Measures: Neonatal Health Index (NHI), an ordinal composite from 0 (death) to 8 (survival free of 7 major neonatal morbidities: intraventricular hemorrhage grades 3-4, periventricular leukomalacia, retinopathy of prematurity stage [&ge;]3, bronchopulmonary dysplasia, pulmonary hypertension, necrotizing enterocolitis stage [&ge;]2, and sepsis). Results: Among 7,057 neonates (median [IQR] maternal age, 34.0 [31.0-36.0] years; GA at PPROM, 27.0 [24.0-29.0] weeks; latency duration, 2.0 [0.0-8.0] days), longer latency was associated with better neonatal health, reflected by higher NHI (n = 6,872), in a non-linear, GA-dependent pattern (overall P < .001; nonlinearity P < .001). Causal forest analysis estimated an average partial effect of a 0.078-point increase in NHI per additional day of latency (P < .001), with significant heterogeneity across individuals (P < .001). GA at PPROM, oligohydramnios, and maternal age were the strongest modifiers; neonates with GA at PPROM of 26 weeks or less, no oligohydramnios, and maternal age younger than 30 years had an estimated treatment effect 28.0% greater than the rest of the cohort (0.121 vs 0.094 NHI points per latency-day). Conclusions and Relevance: Associations between neonatal outcomes and prolonged latency after PPROM were positive overall but heterogeneous in magnitude, varying by GA at PPROM, oligohydramnios status, and maternal age. These findings support tailoring expectant management after PPROM according to individual patient characteristics rather than a uniform, GA-based strategy.","rel_num_authors":4,"rel_authors":[{"author_name":"Chaeyoon Shin","author_inst":"Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University"},{"author_name":"Jinyun Kim","author_inst":"Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University"},{"author_name":"Se In Sung","author_inst":"Samsung Medical Center, Sungkyunkwan University"},{"author_name":"Yoonjung Yoonie Joo","author_inst":"Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center"}],"rel_date":"2026-09-09","rel_site":"medrxiv"},{"rel_title":"CypA is a molecular barrier to HIV emergence from Eastern chimpanzees","rel_doi":"10.64898\/2026.09.08.747897","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.747897","rel_abs":"Of the two lineages of lentivirus that endemically infect chimpanzees, only one has served as a source of infections in hu-mans. Using HIV-CRISPR screening, we identify factors that limit the replication of lentivirus from Eastern chimpanzees. We find that CypA restricts nonzoonotic Eastern chimpanzee lentivirus due to a unique feature encoded in capsid. The ability of CypA to restrict lentivirus replication is surprising given that CypA is a host factor exploited by HIV to promote its replica-tion. The selective ability of CypA to restrict this virus provides a molecular explanation as to why lentivirus from Eastern Chimpanzees has never been observed to infect humans. Our work has important implications for understanding the origins of HIV-1 and the potential for novel zoonosis of primate lentiviruses.","rel_num_authors":13,"rel_authors":[{"author_name":"Michael J Young","author_inst":"UC Berkeley"},{"author_name":"Fabricio Cotera","author_inst":"UC Berkeley"},{"author_name":"Clare C. C. Gill","author_inst":"UC Berkeley"},{"author_name":"Jacob A. Lewis","author_inst":"University of Utah"},{"author_name":"Frank G. Whitby","author_inst":"University of Utah"},{"author_name":"Alaa Abdellatif","author_inst":"University of California, San Francisco"},{"author_name":"Joana L. Rocha","author_inst":"New York University"},{"author_name":"Michael Singer","author_inst":"UC Berkeley"},{"author_name":"Mike A Nalls","author_inst":"Data Tecnica Int'l"},{"author_name":"Faraz Faghri","author_inst":"Data Tecnica Int'l"},{"author_name":"Peter H Sudmant","author_inst":"University of California Berkeley"},{"author_name":"Owen Pornillos","author_inst":"University of Utah"},{"author_name":"Molly Ohainle","author_inst":"UC Berkeley"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"CypA is a molecular barrier to HIV emergence from Eastern chimpanzees","rel_doi":"10.64898\/2026.09.08.747897","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.747897","rel_abs":"Of the two lineages of lentivirus that endemically infect chimpanzees, only one has served as a source of infections in hu-mans. Using HIV-CRISPR screening, we identify factors that limit the replication of lentivirus from Eastern chimpanzees. We find that CypA restricts nonzoonotic Eastern chimpanzee lentivirus due to a unique feature encoded in capsid. The ability of CypA to restrict lentivirus replication is surprising given that CypA is a host factor exploited by HIV to promote its replica-tion. The selective ability of CypA to restrict this virus provides a molecular explanation as to why lentivirus from Eastern Chimpanzees has never been observed to infect humans. Our work has important implications for understanding the origins of HIV-1 and the potential for novel zoonosis of primate lentiviruses.","rel_num_authors":13,"rel_authors":[{"author_name":"Michael J Young","author_inst":"UC Berkeley"},{"author_name":"Fabricio Cotera","author_inst":"UC Berkeley"},{"author_name":"Clare C. C. Gill","author_inst":"UC Berkeley"},{"author_name":"Jacob A. Lewis","author_inst":"University of Utah"},{"author_name":"Frank G. Whitby","author_inst":"University of Utah"},{"author_name":"Alaa Abdellatif","author_inst":"University of California, San Francisco"},{"author_name":"Joana L. Rocha","author_inst":"New York University"},{"author_name":"Michael Singer","author_inst":"UC Berkeley"},{"author_name":"Mike A Nalls","author_inst":"Data Tecnica Int'l"},{"author_name":"Faraz Faghri","author_inst":"Data Tecnica Int'l"},{"author_name":"Peter H Sudmant","author_inst":"University of California Berkeley"},{"author_name":"Owen Pornillos","author_inst":"University of Utah"},{"author_name":"Molly Ohainle","author_inst":"UC Berkeley"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging","rel_doi":"10.64898\/2026.09.04.749519","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749519","rel_abs":"Elevated sulfur-containing amino acids (SAA; methionine and cystine) are linked to human mortality. While methionine restriction (MR) extends lifespan in animals, it is often ignored that traditional longevity-promoting MR diets also lack cystine. When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via cystathionine {gamma}-lyase (CTH) in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged Cth-\/- mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.","rel_num_authors":15,"rel_authors":[{"author_name":"Lucie Orliaguet","author_inst":"Yale University School of Medicine"},{"author_name":"Hee-Hoon Kim","author_inst":"Yale University School of Medicine"},{"author_name":"Piyush Gupta","author_inst":"University and University Hospital of Cologne"},{"author_name":"Aileen Lee","author_inst":"Yale University School of Medicine"},{"author_name":"Yuanjiu Lei","author_inst":"Yale University School of Medicine"},{"author_name":"Ruiqi Li","author_inst":"Yale University School of Medicine"},{"author_name":"Carisa Zeng","author_inst":"Washington University School of Medicine, St. Louis"},{"author_name":"Yun-Hee Youm","author_inst":"Yale University School of Medicine"},{"author_name":"Tamara Dlugos","author_inst":"Yale University School of Medicine"},{"author_name":"Chenyang Guan","author_inst":"Yale University School of Medicine"},{"author_name":"Andrew Wang","author_inst":"Yale University School of Medicine"},{"author_name":"Maxim Artyomov","author_inst":"Washington University School of Medicine, St. Louis"},{"author_name":"Yuval Kluger","author_inst":"Yale University School of Medicine"},{"author_name":"Bjorn Schumacher","author_inst":"University and University Hospital of Cologne"},{"author_name":"Vishwa Deep Dixit","author_inst":"Yale University School of Medicine"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging","rel_doi":"10.64898\/2026.09.04.749519","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749519","rel_abs":"Elevated sulfur-containing amino acids (SAA; methionine and cystine) are linked to human mortality. While methionine restriction (MR) extends lifespan in animals, it is often ignored that traditional longevity-promoting MR diets also lack cystine. When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via cystathionine {gamma}-lyase (CTH) in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged Cth-\/- mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.","rel_num_authors":15,"rel_authors":[{"author_name":"Lucie Orliaguet","author_inst":"Yale University School of Medicine"},{"author_name":"Hee-Hoon Kim","author_inst":"Yale University School of Medicine"},{"author_name":"Piyush Gupta","author_inst":"University and University Hospital of Cologne"},{"author_name":"Aileen Lee","author_inst":"Yale University School of Medicine"},{"author_name":"Yuanjiu Lei","author_inst":"Yale University School of Medicine"},{"author_name":"Ruiqi Li","author_inst":"Yale University School of Medicine"},{"author_name":"Carisa Zeng","author_inst":"Washington University School of Medicine, St. Louis"},{"author_name":"Yun-Hee Youm","author_inst":"Yale University School of Medicine"},{"author_name":"Tamara Dlugos","author_inst":"Yale University School of Medicine"},{"author_name":"Chenyang Guan","author_inst":"Yale University School of Medicine"},{"author_name":"Andrew Wang","author_inst":"Yale University School of Medicine"},{"author_name":"Maxim Artyomov","author_inst":"Washington University School of Medicine, St. Louis"},{"author_name":"Yuval Kluger","author_inst":"Yale University School of Medicine"},{"author_name":"Bjorn Schumacher","author_inst":"University and University Hospital of Cologne"},{"author_name":"Vishwa Deep Dixit","author_inst":"Yale University School of Medicine"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"PhenoMapR: scalable mapping of sample phenotypes to single-cell, spatial, and bulk transcriptomics data","rel_doi":"10.64898\/2026.09.08.749933","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.749933","rel_abs":"Single-cell and spatial transcriptomic studies often lack sufficient sample size to compute robust statistical associations between a sample-level phenotype and cell types or spatial locations. In contrast, lower resolution methods such as bulk gene expression profiling have been applied at scale in large, annotated datasets, providing reliable signatures for phenotype associations. We introduce PhenoMapR, a semi-supervised method designed to integrate the phenotypic rigor of large-scale bulk expression studies with the cellular and spatial granularity of single-cell and spatial transcriptomics. PhenoMapR achieves this by deriving and mapping bulk gene expression signatures onto cells and spatial locations in a computationally efficient and scalable manner. The framework is broadly applicable across biological contexts, supporting the mapping of binary, continuous, and survival phenotypes derived from bulk expression studies across transcriptomic data modalities. This enables the identification of biologically-relevant cellular populations and spatial niches for experimental validation and therapeutic intervention.","rel_num_authors":4,"rel_authors":[{"author_name":"Brooks A Benard","author_inst":"Stanford University"},{"author_name":"Chinmay K Lalgudi","author_inst":"Stanford University"},{"author_name":"Armon Azizi","author_inst":"University of California San Diego"},{"author_name":"Andrew J Gentles","author_inst":"Stanford University"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Oral Actinobacteria sense and defend against parasitic epibionts","rel_doi":"10.64898\/2026.09.08.750141","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750141","rel_abs":"Bacteria contend with a wide range of antagonistic interactions from neighboring microbes. One widespread but poorly understood threat is posed by Patescibacteria, which proliferate by colonizing host bacteria surfaces and extracting cellular resources. Despite the ubiquity of Patescibacteria in the environment, how hosts defend against these epibionts remains unknown. Here we show that Actinomycetota fend off Patescibacteria using the Esx secretion system. We identify a secreted effector protein that mediates this defensive behavior and demonstrate that Esx induction is part of a multifaceted, epibiont-specific response that includes multiple predicted cell surface modifications. Finally, we show that this response occurs at the transcriptional level and is mediated by a previously undescribed threat sensing pathway whose activation leads to threonine phosphorylation of an FHA domain-containing output protein. Together with bioinformatic evidence linking this threat sensing pathway to Esx across Actinomycetales, our experimental findings establish a functional role for the elusive and broadly distributed Esx pathway in defense against epibionts. Furthermore, they help resolve the ecological relationship between Patescibacteria and their hosts as one of antagonism, not mutualism.","rel_num_authors":12,"rel_authors":[{"author_name":"Yaxi Wang","author_inst":"Yale University"},{"author_name":"Jake Colautti","author_inst":"Yale University"},{"author_name":"Larry A. Gallagher","author_inst":"University of Washington"},{"author_name":"Jaehoon Lee","author_inst":"Yale University"},{"author_name":"Yongjun Tan","author_inst":"Saint Louis University"},{"author_name":"Savannah Farrell","author_inst":"University of Washington"},{"author_name":"Conor Farrell","author_inst":"Yale University"},{"author_name":"Batbileg Bor","author_inst":"Forsyth Institute"},{"author_name":"John C. Whitney","author_inst":"McMaster University"},{"author_name":"Dapeng Zhang","author_inst":"Saint Louis University"},{"author_name":"S. Brook Peterson","author_inst":"Yale University"},{"author_name":"Joseph D. Mougous","author_inst":"Yale University \/ HHMI"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Proteoform plasticity modulates the temperature response in circadian timekeeping","rel_doi":"10.64898\/2026.09.05.749499","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.05.749499","rel_abs":"The molecular circadian clock optimally coordinates an organism's physiology with the light\/dark cycle. One commonality among circadian molecular clock proteins is that they undergo alternative splicing, yielding multiple proteoforms. The isoform-specific sequences spliced into clock proteins contain intrinsically disordered regions (IDRs), suggesting that these regions might be intricately involved in cellular regulation. However, the functions of these isoform-specific IDRs in the clock remain poorly defined. Here, we use the core clock repressor FREQUENCY (FRQ) from the fungal circadian model system Neurospora crassa to test the hypothesis that alternative splicing of core clock IDRs yields multiple proteoforms that expand the functional regulatory capacity of FRQ. To do so, we biophysically characterized an IDR specific to the long isoform of the core clock repressor FRQ and identified motifs and molecular behaviors that regulate clock robustness in a temperature-dependent manner. We further compared the interactomes of two FRQ isoforms, identifying distinct functions and interacting proteins that could contribute to temperature regulation. Taken together, our data highlight that isoform-specific IDRs in clock-repressor proteins enhance and expand clock function in a context-dependent manner.","rel_num_authors":13,"rel_authors":[{"author_name":"Jacqueline F Pelham","author_inst":"Department of Biology, Smith College, Northampton, MA, USA"},{"author_name":"Alex T Keeley","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Emery T Usher","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Jacob H Martinsen","author_inst":"REPIN, University of Copenhagen, Copenhagen, DK"},{"author_name":"Meaghan S Jankowski","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"},{"author_name":"David Moses","author_inst":"Department of Chemistry and Biochemistry, University of California, Merced, CA, USA"},{"author_name":"Alexander E Mosier","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"},{"author_name":"Joshua Thomas","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"},{"author_name":"Nathan D Buckley","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"},{"author_name":"Birthe B Kragelund","author_inst":"REPIN, University of Copenhagen, Copenhagen, DK"},{"author_name":"Shahar Sukenik","author_inst":"Department of Chemistry, Syracuse University, Syracuse, NY, USA"},{"author_name":"Alex S Holehouse","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Jennifer M Hurley","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Proteoform plasticity modulates the temperature response in circadian timekeeping","rel_doi":"10.64898\/2026.09.05.749499","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.05.749499","rel_abs":"The molecular circadian clock optimally coordinates an organism's physiology with the light\/dark cycle. One commonality among circadian molecular clock proteins is that they undergo alternative splicing, yielding multiple proteoforms. The isoform-specific sequences spliced into clock proteins contain intrinsically disordered regions (IDRs), suggesting that these regions might be intricately involved in cellular regulation. However, the functions of these isoform-specific IDRs in the clock remain poorly defined. Here, we use the core clock repressor FREQUENCY (FRQ) from the fungal circadian model system Neurospora crassa to test the hypothesis that alternative splicing of core clock IDRs yields multiple proteoforms that expand the functional regulatory capacity of FRQ. To do so, we biophysically characterized an IDR specific to the long isoform of the core clock repressor FRQ and identified motifs and molecular behaviors that regulate clock robustness in a temperature-dependent manner. We further compared the interactomes of two FRQ isoforms, identifying distinct functions and interacting proteins that could contribute to temperature regulation. Taken together, our data highlight that isoform-specific IDRs in clock-repressor proteins enhance and expand clock function in a context-dependent manner.","rel_num_authors":13,"rel_authors":[{"author_name":"Jacqueline F Pelham","author_inst":"Department of Biology, Smith College, Northampton, MA, USA"},{"author_name":"Alex T Keeley","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Emery T Usher","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Jacob H Martinsen","author_inst":"REPIN, University of Copenhagen, Copenhagen, DK"},{"author_name":"Meaghan S Jankowski","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"},{"author_name":"David Moses","author_inst":"Department of Chemistry and Biochemistry, University of California, Merced, CA, USA"},{"author_name":"Alexander E Mosier","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"},{"author_name":"Joshua Thomas","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"},{"author_name":"Nathan D Buckley","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"},{"author_name":"Birthe B Kragelund","author_inst":"REPIN, University of Copenhagen, Copenhagen, DK"},{"author_name":"Shahar Sukenik","author_inst":"Department of Chemistry, Syracuse University, Syracuse, NY, USA"},{"author_name":"Alex S Holehouse","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Jennifer M Hurley","author_inst":"Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Temporal niche partitioning through olfactory cell type evolution","rel_doi":"10.64898\/2026.09.04.749392","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749392","rel_abs":"Temporal niche partitioning enables species to use the same resource at different times, but the underlying mechanisms are unknown. We show that Drosophila sechellia, a specialist on Morinda citrifolia noni, exhibits narrow temporal preference for the most toxic, ripe fruit, reducing exposure to competition, parasitization and microbial infection that can occur on other stages. Chemical analysis highlighted ketones as signature odors of ripe noni. Comparative single-cell transcriptomic atlases revealed that D. sechellia has co-opted expression of a larval ketone receptor, Or45a, in an adult olfactory neuron population. The novel expression of Or45a can be ascribed solely to cis-regulatory changes and is sufficient to confer physiological sensitivity to ripe noni. Importantly, Or45a is required for D. sechellia's ripe noni preference, acting redundantly with a second ketone receptor, Or85c\/b, whose neuron population has expanded in D. sechellia. Our results provide an unprecedented link between cell type evolution and ecologically-advantageous, temporal niche partitioning.","rel_num_authors":10,"rel_authors":[{"author_name":"Ambra Masuzzo","author_inst":"University of Lausanne"},{"author_name":"Asfa S. Borbora","author_inst":"University of Lausanne"},{"author_name":"Rolando D. Moreira Soto","author_inst":"Max Planck Institute for Chemical Ecology"},{"author_name":"Liliane Abuin","author_inst":"University of Lausanne"},{"author_name":"Michael Reichelt","author_inst":"Max Planck Institute for Chemical Ecology"},{"author_name":"Michele Marconcini","author_inst":"University of Lausanne"},{"author_name":"Steeve Cruchet","author_inst":"University of Lausanne"},{"author_name":"Markus Knaden","author_inst":"Max Planck Institute for Chemical Ecology"},{"author_name":"Daehan Lee","author_inst":"Sungkyunkwan University"},{"author_name":"Richard Benton","author_inst":"University of Lausanne"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Metabolic Heterogeneity of Muscle Stem Cells is Controlled by the Myofiber Niche","rel_doi":"10.64898\/2026.09.04.749367","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749367","rel_abs":"Metabolic pathways support biomass synthesis and provide substrates for epigenetic modifications of histones and DNA. These findings are particularly relevant for adult stem cells, where metabolic changes significantly impact functional behavior. However, assessing the metabolism of these cells in their native microenvironment is challenging as this typically necessitates dissociation prior to metabolic analysis. In this study, we focus on muscle stem cells (MuSCs) and show that removing these cells from the niche significantly alters their metabolic profile. To overcome this issue, we developed a novel enzymatic staining method for in situ metabolic profiling at a single-cell resolution. This approach reveals unexpected metabolic heterogeneity of MuSCs, identifying oxidative and glycolytic subsets, and demonstrates that their metabolism is directly modulated by adjacent myofibers. Accordingly, perturbing myofiber metabolism remodels the MuSC niche and drives metabolic adaptation in MuSCs. Finally, we define the kinetics by which myofiber-dependent metabolic regulation of MuSCs is re-established during muscle regeneration, thereby revealing how niche-imposed metabolic cues shape stem cell identity in vivo.","rel_num_authors":9,"rel_authors":[{"author_name":"Clovis Chabert","author_inst":"Univ. Grenoble Alpes, Inserm U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA)"},{"author_name":"Marie Quetin","author_inst":"Universite Paris-Est Creteil Val de Marne"},{"author_name":"Laurence Neff","author_inst":"INSERM U1055 - University Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics"},{"author_name":"Alessandro Bonavoglia","author_inst":"University of Geneva"},{"author_name":"Olivier Marie Dorchies","author_inst":"INSERM U1055 - University Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics"},{"author_name":"Philippos Mourikis","author_inst":"Institut Necker Enfants Malades - INEM"},{"author_name":"Frederic Relaix","author_inst":"Univ Paris-Est Creteil, INSERM, U955 IMRB, \"Biology of the Neuromuscular System\" Team, Ecole Nationale Veterinaire d'Alfort"},{"author_name":"Marianne Gervais","author_inst":"Mondor Institute of Biomedical Research"},{"author_name":"Alexandre Prola","author_inst":"INSERM U1055 - University Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Proteomic and Kinetic Analyses Reveal Discordant Apolipoprotein Turnover and Support a Revised Model of Human Lipoprotein(a) Metabolism","rel_doi":"10.64898\/2026.09.04.749550","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749550","rel_abs":"Objective: Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease composed of apolipoprotein(a) [APO(a)] covalently linked to apolipoprotein B100 (APOB). Although plasma Lp(a) concentrations are largely genetically determined, the mechanisms governing Lp(a) metabolism after particle assembly remain poorly understood. We sought to define the Lp(a) proteome and determine the metabolic behavior of APO(a) and APOB within circulating Lp(a) particles using integrated proteomic, kinetic, and imaging approaches. Approach and Results: Sixteen healthy adults underwent stable isotope tracer studies with 2H3-L-leucine and 2H5-glycerol. Lp(a) particles were isolated by APO(a)-specific immunoprecipitation for high-resolution liquid chromatography-mass spectrometry and kinetic analyses, and extracellular vesicles (EVs) were characterized by imaging flow cytometry and super-resolution microscopy. Proteomic analysis identified 92 proteins associated with immuno-isolated Lp(a), enriched in pathways related to immunity, coagulation, and atherogenesis. Lp(a)-APO(a) exhibited a mean fractional clearance rate of 0.04 pools\/day, whereas Lp(a)-APOB cleared approximately sevenfold faster (0.25 pools\/day), independent of plasma Lp(a) concentration or APO(a) isoform size. Both APO(a) and APOB were detected on circulating EVs, suggesting that EVs may contribute to post-secretory Lp(a) particle remodeling. Conclusion: These integrated human studies demonstrate marked discordance between APO(a) and APOB turnover within circulating Lp(a) particles, challenging the prevailing assumption that both apolipoproteins behave as a single metabolic unit after Lp(a) assembly and supporting a revised model of human Lp(a) metabolism.","rel_num_authors":12,"rel_authors":[{"author_name":"Tiffany Thomas","author_inst":"Columbia University"},{"author_name":"Anastasiya Matveyenko","author_inst":"Columbia University Medical Center"},{"author_name":"Nelsa Matienzo","author_inst":"Columbia University"},{"author_name":"Michael Kissner","author_inst":"Columbia University"},{"author_name":"Santica M Marcovina","author_inst":"Medpace Reference Laboratories"},{"author_name":"Yihao Li","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Haotian Wu","author_inst":"Columbia University Mailman School of Public Health"},{"author_name":"Stacia M Nicholson","author_inst":"Columbia University"},{"author_name":"Shiori Kuraoka","author_inst":"Brigham and Women's Hospital"},{"author_name":"Masanori Aikawa","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Sasha A Singh","author_inst":"Brigham and Women's Hospital\/Harvard Medical School"},{"author_name":"Gissette Reyes-Soffer","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Proteomic and Kinetic Analyses Reveal Discordant Apolipoprotein Turnover and Support a Revised Model of Human Lipoprotein(a) Metabolism","rel_doi":"10.64898\/2026.09.04.749550","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749550","rel_abs":"Objective: Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease composed of apolipoprotein(a) [APO(a)] covalently linked to apolipoprotein B100 (APOB). Although plasma Lp(a) concentrations are largely genetically determined, the mechanisms governing Lp(a) metabolism after particle assembly remain poorly understood. We sought to define the Lp(a) proteome and determine the metabolic behavior of APO(a) and APOB within circulating Lp(a) particles using integrated proteomic, kinetic, and imaging approaches. Approach and Results: Sixteen healthy adults underwent stable isotope tracer studies with 2H3-L-leucine and 2H5-glycerol. Lp(a) particles were isolated by APO(a)-specific immunoprecipitation for high-resolution liquid chromatography-mass spectrometry and kinetic analyses, and extracellular vesicles (EVs) were characterized by imaging flow cytometry and super-resolution microscopy. Proteomic analysis identified 92 proteins associated with immuno-isolated Lp(a), enriched in pathways related to immunity, coagulation, and atherogenesis. Lp(a)-APO(a) exhibited a mean fractional clearance rate of 0.04 pools\/day, whereas Lp(a)-APOB cleared approximately sevenfold faster (0.25 pools\/day), independent of plasma Lp(a) concentration or APO(a) isoform size. Both APO(a) and APOB were detected on circulating EVs, suggesting that EVs may contribute to post-secretory Lp(a) particle remodeling. Conclusion: These integrated human studies demonstrate marked discordance between APO(a) and APOB turnover within circulating Lp(a) particles, challenging the prevailing assumption that both apolipoproteins behave as a single metabolic unit after Lp(a) assembly and supporting a revised model of human Lp(a) metabolism.","rel_num_authors":12,"rel_authors":[{"author_name":"Tiffany Thomas","author_inst":"Columbia University"},{"author_name":"Anastasiya Matveyenko","author_inst":"Columbia University Medical Center"},{"author_name":"Nelsa Matienzo","author_inst":"Columbia University"},{"author_name":"Michael Kissner","author_inst":"Columbia University"},{"author_name":"Santica M Marcovina","author_inst":"Medpace Reference Laboratories"},{"author_name":"Yihao Li","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Haotian Wu","author_inst":"Columbia University Mailman School of Public Health"},{"author_name":"Stacia M Nicholson","author_inst":"Columbia University"},{"author_name":"Shiori Kuraoka","author_inst":"Brigham and Women's Hospital"},{"author_name":"Masanori Aikawa","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Sasha A Singh","author_inst":"Brigham and Women's Hospital\/Harvard Medical School"},{"author_name":"Gissette Reyes-Soffer","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Over-the-counter fiber supplementation associates with metabolic and microbial shifts in rectal mucosa","rel_doi":"10.64898\/2026.09.08.750137","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.750137","rel_abs":"Fiber supplements are the first line of treatment for all patients with benign anorectal disease. In addition, fiber has been found to support gut microbiota and reduce inflammation; however, their integrated effect on the colonic mucosal environment is incompletely defined. We evaluated how mixed-fiber formulations may collectively shape the rectal mucosal environment through coordinated effects on microbiota composition, short-chain fatty acid (SCFA) handling, and host transcription. We evaluated multi-compartment responses to a 28-day mixed-fiber intervention in 37 participants with benign anorectal disease (~15 g\/day; 7.5g psyllium husk, 8g wheat dextrin) and assessed the microbiota (16S rRNA), the metabolome (GC-MS and LC-MS), and transcriptome (subset n=10) before (PRE) and after (POST) supplementation. Changes in KEGG pathways were tested with gene set enrichment analysis (GSEA). Associations were tested by Spearman correlation, and microbiota-based prediction of SCFA responses by random-forest regression. Microbiota diversity was stable after the fiber intervention, however, 10 mucosal ASVs were differentially abundant including Parabacteroides and Lachnospiraceae NK4A136 group while SCFAs, propionate and isobutyrate, both decreased in rectal tissue and butyrate decreased in serum. To understand these shifts in the metabolome, we proceeded with the transcriptome where we identified 130 differentially expressed genes and enrichment of metabolic and SCFA-related pathways. Random forest regression captured a modest signal for serum butyrate. Taken together, short-term mixed-fiber supplementation produced selective rectal mucosal taxonomic shifts and enriched mucosal metabolic and SCFA-metabolism program despite reduced SCFA pools, suggesting that even brief over-the-counter fiber supplementation may reshape the mucosal metabolic environment.","rel_num_authors":7,"rel_authors":[{"author_name":"David Alvarado","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Lydia Okyere","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Amber O'Connor","author_inst":"Oregon Health & Science University"},{"author_name":"Maura Walsh","author_inst":"Oregon Health & Science University"},{"author_name":"Siting Chen","author_inst":"Oregon Health & Science University"},{"author_name":"Liana Tsikitis","author_inst":"Oregon Health & Science University"},{"author_name":"Christopher A Gaulke","author_inst":"University of Illinois Urbana-Champaign College of Veterinary Medicine"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Quantitative reanalysis of classic pigeon homing experiments rejects a liver-based magnetic compass based on superparamagnetism","rel_doi":"10.64898\/2026.09.07.749779","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749779","rel_abs":"Lisowski et al. [1] recently proposed that the pigeon's magnetic compass resides in the liver and depends upon ferritin-containing macrophages operating through a superparamagnetic mechanism. Here we evaluate this hypothesis using behavioral, neurobiological, evolutionary, and biophysical evidence together with three original analyses. First, we present a quantitative reanalysis of the classic pigeon homing experiments of Walcott and Green [2], calculating for the first time the magnetic fringe-field distribution produced by the head-mounted coil apparatus. These calculations demonstrate that the liver would have experienced a maximum shift of about 1.4% of the ambient geomagnetic field, far too small to account for the observed orientation effects, thereby localizing the relevant magnetoreceptive structures to the region of the head and excluding the liver. Second, we quantify the magnetic alignment expected for ferritin cores under geomagnetic conditions and show that ferrihydrite nanoparticles are approximately five orders of magnitude too weak to resist thermal noise, while their superparamagnetic moments fluctuate on timescales roughly eleven orders of magnitude faster than those relevant to navigation. Third, we analyze the neurobiological requirements of magnetic navigation and show that mobile macrophages are unlikely to provide stable directional information because compass signals must be continuously cross-calibrated against vestibular and visual inputs within a body-centered reference frame. Comparative evidence from fish, birds, and turtles further associates magnetically responsive structures with craniofacial tissues and trigeminal sensory pathways. We suggest the disruption of the magnetic response is due to induced anemia from clodronate treatment that triggers dissolution and absorption of iron in the magnetite-containing cells involved in magnetoreception. Together these findings indicate that a liver-based ferritin compass is inconsistent with behavioral, neurobiological, and physical evidence and instead support cephalized magnetite-based receptor systems as the basis of avian magnetoreception.","rel_num_authors":2,"rel_authors":[{"author_name":"Joseph L. Kirschvink","author_inst":"California Institute of Technology"},{"author_name":"Charles Walcott","author_inst":"Cornell University"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Human single-neuron recordings reveal population coding of attentional dynamics during naturalistic movie viewing","rel_doi":"10.64898\/2026.09.08.748346","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.08.748346","rel_abs":"Our eyes move constantly. Where they land is shaped by internal cognitive state, making eye movements a rare, non-invasive window onto that state. However, how moment-to-moment eye-movements map onto human neural population activity during naturalistic viewing remains poorly characterized. We analyzed a public intracranial dataset in which 14 neurosurgical patients watched an eight-minute movie during simultaneous eye-tracking and neuronal activity recording. Single-neuron activity from 814 neurons across anterior cingulate cortex, pre-supplementary motor area, amygdala, hippocampus, and ventromedial prefrontal cortex was pooled into a single distributed population and related to a joint eye-movement state comprising pupil size, saccade rate and fixation duration. Using a cross-validated, multivariate analysis of population activity we found group-level coupling between the neural population and the joint eye-movement state (mean held-out canonical r = 0.145; one-sample t-test p = 0.0003; 9 of 14 subjects individually significant). The coupling was carried principally by saccade dynamics (r = 0.141) and pupil size (r = 0.094), with fixation duration contributing only marginally (r = 0.041). At the single-neuron level the picture differed: more neurons were eye-coupled than expected by chance, yet so weakly that almost none survived correction for multiple comparisons. Read out jointly, the same weakly coupled cells cohered into one reliable population dimension, and no single region's removal significantly reduced it. This pattern is more consistent with a distributed, redundant organization than with a small set of strongly coupled cells. In summary, eye-tracking offers a non-invasive window onto population-level neural states in humans.","rel_num_authors":2,"rel_authors":[{"author_name":"Carlo Cerquetella","author_inst":"Rutgers University"},{"author_name":"Salman Ehtesham Qasim","author_inst":"Rutgers University"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Tumor-derived SAA1-TLR4 signaling drives tumor-to-muscle communication in pancreatic cancer cachexia","rel_doi":"10.64898\/2026.09.04.748998","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.748998","rel_abs":"Cancer cachexia limits treatment tolerance and survival in pancreatic ductal adenocarcinoma (PDAC), yet the tumor-derived signals driving tissue dysfunction remain poorly understood. Here, we identify serum amyloid A1 (SAA1) as a mediator of tumor-to-host communication acting through Toll-like receptor 4 (TLR4). Tumor-derived SAA1 was elevated in human PDAC and in a mouse PDAC model and disrupted both myofiber and muscle stem cell (MuSC) homeostasis. Genetic reduction of tumor-derived SAA1 uncoupled tumor progression from host wasting, preserving muscle mass and function and prolonging survival without affecting primary tumor growth. Mechanistically, SAA1-TLR4 signaling drove multicellular remodeling of the skeletal muscle microenvironment. Therapeutic TLR4 inhibition after cachexia onset restored muscle mass, function and MuSC abundance and prolonged survival independently of tumor growth. Conservation of SAA1-TLR4 signaling in human skeletal muscle identifies a therapeutically actionable tumor-host pathway and demonstrates that host deterioration can be targeted independently of tumor progression.","rel_num_authors":27,"rel_authors":[{"author_name":"Gabriele Guarnaccia","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Jimmy Massenet","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Alessandra Cecchini","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Elena Guarnaccia","author_inst":"University of Rome Tor Vergata, Rome, Italy"},{"author_name":"Beatrice Silvestri","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Chiara Nicoletti","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Jesus R Barajas","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"David Sala","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Marcos Garcia Teneche","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Brightany Li","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Luca Caputo","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Cedomir Stamenkovic","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Tatiana M Moreno","author_inst":"Sanford Burnham Prebys Meidcal Discovery Institute"},{"author_name":"Rabi Murad","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Shawn Delaware","author_inst":"University of California San Diego"},{"author_name":"Daphne Mayer","author_inst":"Rice University"},{"author_name":"Yijuan Zhang","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Priyanka Gupta","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Alexandre R Colas","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Alessandro Vasciaveo","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Caroline Kumsta","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Peter D Adams","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Yu Xin Wang","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Cesare Gargioli","author_inst":"Tor Vergata Rome University"},{"author_name":"Cosimo Commisso","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Pier Lorenzo Puri","author_inst":"Sanford BurnhamPrebys Medical Discovery Institute"},{"author_name":"Alessandra Sacco","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Spatial Logic and Evolutionary Innovation in Human Placentation","rel_doi":"10.64898\/2026.09.04.749511","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749511","rel_abs":"Human pregnancy unfolds in a unique mosaic tissue context. Embryonic\/fetal placental and maternal uterine cells (decidua basalis) coalesce, forming the basal plate where immune tolerance is coordinated and the utero-placental circulation is initiated. The remaining approximately 70% of the maternal-fetal interface is comprised of the chorionic membranes, an epithelial-like layer of placental cells that lies adjacent to but does not coalesce with the overlying decidua capsularis and parietalis. It is unknown how these two regions of the maternal-fetal interface, which are comprised of seemingly similar cell types, diverge anatomically and functionally. Likewise, it is unknown whether the molecular characteristics of the maternal-fetal interface vary across human populations, potentially contributing to population disparities in pregnancy complications. Here, we generated large-scale paired single-nucleus RNA-seq and chromatin-accessibility profiles of the basal plate and chorionic membranes-associated decidual compartments from diverse-ancestry pregnancies, integrated with spatial transcriptomics and multiplexed protein imaging. We show that the two interfaces share a conserved cytotrophoblast differentiation hierarchy, which is deployed differently resulting in the observed distinct architectures. In the chorionic membranes, progenitor, early, and mature extravillous cytotrophoblast (EVT) states form an epithelial-like laminar shell. In the basal plate, this hierarchy is elaborated upon to enable deep placentation: EVTs that arise early in pregnancy invade the farthest into the uterus, while mature EVTs accumulate superficially to sculpt the local maternal immune microenvironment. Comparative analysis identified DSC4, a decidual stromal cell subtype, as an anti-invasive barrier that is densely enriched adjacent to the chorionic membranes but substantially reduced at the basal plate. Population-resolved analysis further identified the DSC4 marker NID2, which encodes the basement-membrane glycoprotein nidogen-2, as an ancestry-associated rheostat of EVT invasion. A specific NID2 promoter haplotype arose on the modern-human lineage, is absent from available archaic-human genomes, and shows evidence of positive selection in Eurasian populations. This haplotype is associated with reduced local chromatin accessibility and lower NID2 expression in DSC4 cells. Consistent with this genetic association, extracellular NID2 directly suppressed the invasion of primary human cytotrophoblasts in vitro. Together, these findings reveal how a shared developmental program is spatially reconfigured across distinct regions of the maternal-fetal interface and identify a recent modern-human regulatory innovation that modulates maternal decidual restraint of fetal trophoblast invasion across populations.","rel_num_authors":16,"rel_authors":[{"author_name":"Zhida Luo","author_inst":"University of California San Francisco"},{"author_name":"Cheng Wang","author_inst":"Deparment of Neurology, School of Medicine, University of California, San Francisco, CA, USA"},{"author_name":"Yan Zhou","author_inst":"Deparments of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California, San Francisco, CA, USA"},{"author_name":"Tuhin Kumar Guha","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Purnima Narasimhan Lyer","author_inst":"Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Selina Lao Mason","author_inst":"UCSF California Preterm Birth Initiative, University of California San Francisco, CA, USA"},{"author_name":"Areca Smit","author_inst":"UCSF California Preterm Birth Initiative, University of California San Francisco, CA, USA"},{"author_name":"Xiaofei Sun","author_inst":"Center of Reproductive Sciences, Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH, USA"},{"author_name":"Michael Paul Snyder","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Gary M. Shaw","author_inst":"Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"David K. Stevenson","author_inst":"Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Antonina Frolova","author_inst":"Division of Maternal-Fetal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Sarah England","author_inst":"Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Virginia D. Winn","author_inst":"Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Susan J. Fisher","author_inst":"Deparments of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California, San Francisco, CA, USA"},{"author_name":"Jingjing Li","author_inst":"Deparment of Neurology, School of Medicine, University of California, San Francisco, CA, USA"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Spatial Logic and Evolutionary Innovation in Human Placentation","rel_doi":"10.64898\/2026.09.04.749511","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749511","rel_abs":"Human pregnancy unfolds in a unique mosaic tissue context. Embryonic\/fetal placental and maternal uterine cells (decidua basalis) coalesce, forming the basal plate where immune tolerance is coordinated and the utero-placental circulation is initiated. The remaining approximately 70% of the maternal-fetal interface is comprised of the chorionic membranes, an epithelial-like layer of placental cells that lies adjacent to but does not coalesce with the overlying decidua capsularis and parietalis. It is unknown how these two regions of the maternal-fetal interface, which are comprised of seemingly similar cell types, diverge anatomically and functionally. Likewise, it is unknown whether the molecular characteristics of the maternal-fetal interface vary across human populations, potentially contributing to population disparities in pregnancy complications. Here, we generated large-scale paired single-nucleus RNA-seq and chromatin-accessibility profiles of the basal plate and chorionic membranes-associated decidual compartments from diverse-ancestry pregnancies, integrated with spatial transcriptomics and multiplexed protein imaging. We show that the two interfaces share a conserved cytotrophoblast differentiation hierarchy, which is deployed differently resulting in the observed distinct architectures. In the chorionic membranes, progenitor, early, and mature extravillous cytotrophoblast (EVT) states form an epithelial-like laminar shell. In the basal plate, this hierarchy is elaborated upon to enable deep placentation: EVTs that arise early in pregnancy invade the farthest into the uterus, while mature EVTs accumulate superficially to sculpt the local maternal immune microenvironment. Comparative analysis identified DSC4, a decidual stromal cell subtype, as an anti-invasive barrier that is densely enriched adjacent to the chorionic membranes but substantially reduced at the basal plate. Population-resolved analysis further identified the DSC4 marker NID2, which encodes the basement-membrane glycoprotein nidogen-2, as an ancestry-associated rheostat of EVT invasion. A specific NID2 promoter haplotype arose on the modern-human lineage, is absent from available archaic-human genomes, and shows evidence of positive selection in Eurasian populations. This haplotype is associated with reduced local chromatin accessibility and lower NID2 expression in DSC4 cells. Consistent with this genetic association, extracellular NID2 directly suppressed the invasion of primary human cytotrophoblasts in vitro. Together, these findings reveal how a shared developmental program is spatially reconfigured across distinct regions of the maternal-fetal interface and identify a recent modern-human regulatory innovation that modulates maternal decidual restraint of fetal trophoblast invasion across populations.","rel_num_authors":16,"rel_authors":[{"author_name":"Zhida Luo","author_inst":"University of California San Francisco"},{"author_name":"Cheng Wang","author_inst":"Deparment of Neurology, School of Medicine, University of California, San Francisco, CA, USA"},{"author_name":"Yan Zhou","author_inst":"Deparments of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California, San Francisco, CA, USA"},{"author_name":"Tuhin Kumar Guha","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Purnima Narasimhan Lyer","author_inst":"Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Selina Lao Mason","author_inst":"UCSF California Preterm Birth Initiative, University of California San Francisco, CA, USA"},{"author_name":"Areca Smit","author_inst":"UCSF California Preterm Birth Initiative, University of California San Francisco, CA, USA"},{"author_name":"Xiaofei Sun","author_inst":"Center of Reproductive Sciences, Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH, USA"},{"author_name":"Michael Paul Snyder","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Gary M. Shaw","author_inst":"Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"David K. Stevenson","author_inst":"Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Antonina Frolova","author_inst":"Division of Maternal-Fetal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Sarah England","author_inst":"Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA"},{"author_name":"Virginia D. Winn","author_inst":"Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Susan J. Fisher","author_inst":"Deparments of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, University of California, San Francisco, CA, USA"},{"author_name":"Jingjing Li","author_inst":"Deparment of Neurology, School of Medicine, University of California, San Francisco, CA, USA"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"mRNA editing of the Alzheimer's risk gene APOE","rel_doi":"10.64898\/2026.09.03.749263","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749263","rel_abs":"Variants in the human APOE gene govern the risk of Alzheimer's disease and other disorders. Three major APOE variants in humans reflect C to T replacements at two positions in a single exon: an upstream variant (AE4 site) that differs between the ancestral APOE epsilon 4 allele (APOE4) (C) and human-specific APOE2\/E3 (T), and a downstream variant (AE2 site) that differentiates APOE3\/E4 (C) from APOE2 (T). It has long been assumed that APOE allelotypes are genomically encoded, but here we report that multiple individuals express brain APOE C or U\/T variant transcripts that differ from genomically templated versions. We demonstrate up to 10% C to U, or U to C nucleotide replacement at AE4 and AE2, but not at other sites, and with no corresponding changes in genomic DNA. Single-cell transcriptomic datasets from brain microglia revealed sporadic (up to ~8%) C to U replacement at AE2. We found 0.4 to 1.6% of brain transcripts in human APOE knock-in mice harbor selective C to U changes at either AE4 or AE2 sites. Transfection of HepG2 or Huh7 cells with either mouse or human APOBEC1 led to efficient (>90%) C to U editing of APOE4 mRNA at the AE4 but not AE2 site, with lower (<10%) C to T editing of genomic DNA at the AE4 site by mouse, but not human, APOBEC1. Furthermore, interrogation of proteomic datasets revealed up to 4% of non-genomically encoded APOE peptides in human plasma, indicating that the edited APOE transcripts are functional in vivo. These data suggest that APOE mRNA is subject to RNA editing that interconverts the different allelic forms of APOE.","rel_num_authors":5,"rel_authors":[{"author_name":"Valerie Blanc","author_inst":"Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"author_name":"Samantha J. Griffiths","author_inst":"Division of Infection Medicine, University of Edinburgh Medical School, Little France, Edinburgh, UK"},{"author_name":"Jurgen Haas","author_inst":"University of Edinburgh"},{"author_name":"Nicholas Davidson","author_inst":"Washington University School of Medicine - St. Louis, MO"},{"author_name":"Richard Lathe","author_inst":"University of Edinburgh"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Spatial multi-omics resolve epithelium-fibroblast gradients and highlight NESTIN-NOTCH1-expressing subepithelial fibroblasts during human pancreatic tumorigenesis","rel_doi":"10.64898\/2026.09.04.749182","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749182","rel_abs":"Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursors of pancreatic ductal adenocarcinoma undergoing dynamic epithelial and stromal remodeling during progression. In this study, we integrated computational pathology, cyclic immunofluorescence, and Xenium spatial transcriptomics to define the spatial organization of the IPMN microenvironment. We queried cell-based histopathological features and identified stromal patterns strongly associated with epithelium proximity. Cyclic immunofluorescence and Xenium revealed a subepithelial gradient extending from myofibroblasts to inflammatory fibroblasts. Xenium further identified a distinct subepithelial NOTCH1-NESTIN-expressing fibroblast subset in myofibroblasts that expands with tumor progression. By recapitulating the spatial remodeling event using human pancreatic tumor cells and primary myofibroblast co-culture models, we demonstrated the capacity of pancreatic tumor cells to induce a NESTIN-expressing state in neighboring myofibroblasts. These findings reveal new dynamic epithelial-stromal interactions through subepithelial NESTIN+ fibroblasts associated with pancreatic tumorigenesis and immediate microenvironment remodeling by active tumor cells, highlighting the power of computational pathology integrated with spatial transcriptomics.","rel_num_authors":28,"rel_authors":[{"author_name":"Ma\u00eblle Batardiere","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada."},{"author_name":"Myriam Iliana Ibanez-Rios","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada."},{"author_name":"Abdelhakim Khellaf","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Elham Dianati","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Sarah-Slim Diwan","author_inst":"Research Institute of the McGill University Health Center, McGill University, Montreal, Canada."},{"author_name":"Maxence Pelloux","author_inst":"Institut de biologie et pathologies, CHU Grenoble-Alpes, Grenoble, France."},{"author_name":"Alexandre Archambault-Marsan","author_inst":"Centre de recherche du Centre Hospitalier de l Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada."},{"author_name":"Camille Beaussier","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Jade Diwan","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Sasha Sapon-Cousineau","author_inst":"Centre de recherche du Centre Hospitalier de l Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada."},{"author_name":"Jumanah Baig","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Ayman Shoukari","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Zean Ghanmeh","author_inst":"Department of Computer Science and Software Engineering, Concordia University, Montreal, Canada."},{"author_name":"Zhiyuan Yang","author_inst":"Department of Computer Science and Software Engineering, Concordia University, Montreal, Canada."},{"author_name":"Melisa Farias Gonzalez","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Jia-Lin Li","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Ali Kassab","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Leonardo Lando","author_inst":"Boston Image Reading Center, Boston, Massachusetts, United States."},{"author_name":"Philippe Lefrancois","author_inst":"Lady Davis Institute, Jewish General Hospital, Montreal, Canada."},{"author_name":"Simon Turcotte","author_inst":"Centre de recherche du Centre Hospitalier de l Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada."},{"author_name":"Youngmin A Lee","author_inst":"Department of Surgery, Vanderbilt University Medical Center, Nashville, United States."},{"author_name":"Simon F Roy","author_inst":"Rosalind and Morris Goodman Cancer Institute, McGill University, Montr\u00e9al, QC, Canada."},{"author_name":"Mahdi S Hosseini","author_inst":"Department of Computer Science and Software Engineering, Concordia University, Montreal, Canada."},{"author_name":"Basile Tessier-Cloutier","author_inst":"Research Institute of the McGill University Health Center, McGill University, Montreal, Canada."},{"author_name":"Marcus CB Tan","author_inst":"Department of Surgery, Vanderbilt University Medical Center, Nashville, United States."},{"author_name":"Kathleen E DelGiorno","author_inst":"Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States."},{"author_name":"David JHF Knapp","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Vincent Q Trinh","author_inst":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Arrayed hydrogels pair whole-cell imaging with single-cell mass spectrometry proteomics","rel_doi":"10.64898\/2026.09.04.749469","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749469","rel_abs":"Multimodal single-cell analysis aims to elucidate cellular-level phenotype within heterogeneous cell populations. Advancements in single-cell proteomics (SCP) seek to deepen quantitative depth, coverage, and reproducibility for a robust view of functional cell state. However, broadly accessible multimodal approaches are poised to benefit from sample-preparation advancements upstream of the mass spectrometer. Here, we introduce ProteoParcel, a multimodal SCP platform for indexing upstream widefield single-cell images to downstream label-free, bottom-up proteomics. Parcels are spatially arrayed planar polyacrylamide gels patterned with microwells. Each parcel, containing one microwell and an abutting gel region, is designed to integrate the single-cell imaging and SCP analysis modes. First, for whole-cell imaging, each microwell isolates an intact, individual breast cancer cell (MCF-7). After imaging, cells are subjected to in-microwell chemical cell lysis, electro-injection of whole-cell lysate from the microwell into the abutting gel region, in-gel chemical fixation, and finally in-gel tryptic digestion prior to peptide extraction for SCP. Location-indexed parcels are independently releasable to confer single-cell resolution to downstream mass spectrometry. To ensure SCP-suitable proteome solubilization and trypsin\/Lys-C digestion, we optimize cell lysis, electrophoresis, and gel pre-equilibration conditions within the gel. Using ProteoParcel, we identify over 1,400 protein species from single, imaged MCF-7 cells. Scrutiny of the gel preparation conditions confirms that hydrogel-lysate interactions introduce predictable, physicochemically interpretable (cell membrane, hydrophobicity) detection biases, while broad functional-class composition and subcellular compartment coverage are preserved when benchmarked to in-solution digestion. ProteoParcel makes facile same-cell multimodal SCP and live-cell imaging.","rel_num_authors":7,"rel_authors":[{"author_name":"Maya Overton","author_inst":"University of California, Berkeley"},{"author_name":"Cyril Deroy","author_inst":"University of California, Berkeley"},{"author_name":"Eileen Wang","author_inst":"Biohub San Francisco"},{"author_name":"Amber Lennon","author_inst":"Biohub Chicago"},{"author_name":"Joshua E. Elias","author_inst":"Biohub San Francisco"},{"author_name":"Ryan McClure","author_inst":"Biohub Chicago"},{"author_name":"Amy E. Herr","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"De novo Rubisco design with protein language models","rel_doi":"10.64898\/2026.09.04.749267","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749267","rel_abs":"Ribulose-1,5-bisphosphate carboxylase\/oxygenase (Rubisco) fixes the majority of carbon dioxide globally but is challenged with low specificity for CO2 versus O2 and low catalytic efficiencies. Traditional engineering efforts have remained difficult because folding, assembly, specificity, and catalysis are tightly coupled, hampering efforts to explore sequence space. Therefore, we leveraged recent advances in protein large language models (PLMs) to generate sequences beyond those observed in nature, using both ProGen-2 that was fine-tuned on a limited dataset of non-Form I Rubiscos and an ESM-2 discriminator. With this approach, we generated 5.6 million novel Rubisco-like sequences and identified 21 highly diverse candidates predicted to be active that occupy regions of Rubisco phylogenetic space not previously observed in nature. Six designs were soluble in Escherichia coli, and five were shown to produce quantifiable 3PGA. One design produced an apparent CO2\/O2 specificity estimate beyond the range of the natural representative Rubiscos assayed. We also solved the crystal structure of one de novo design that reproduced the predicted dimer and active-site geometry with sub-angstrom C agreement. Sequence-only generation followed by independent structural filtering therefore recovered soluble, active Rubiscos from regions of sequence space that are not represented in genomic databases. Together, these results establish a scalable strategy for accessing previously unexplored Rubisco sequence space, providing a broadly accessible path toward generating de novo Rubiscos that may have activity and specificity parameters needed to address longstanding limitations in biological carbon fixation.","rel_num_authors":9,"rel_authors":[{"author_name":"Alexander J. Kehl","author_inst":"Biophysics Graduate Group, University of California, Davis, Davis, CA, USA, Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Labo"},{"author_name":"Simon K. S. Chu Chu","author_inst":"NVIDIA, Santa Clara, CA, USA"},{"author_name":"Jose Henrique Pereira","author_inst":"Feedstocks Division, Joint BioEnergy Institute, Emeryville, CA, USA. Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laborat"},{"author_name":"Jennifer Lee","author_inst":"Genome Center, University of California Davis, Davis, CA, USA"},{"author_name":"Renee Z. Wang","author_inst":"Department of Earth and Planetary Science, University of California, Berkeley, Berkeley, CA, USA, Department of Plant and Microbial Biology, University of Calif"},{"author_name":"Michael Gigl","author_inst":"Food Processing and Health, ZIEL - Institute for Food and Health, Technical University of Munich, Freising 85354, Germany"},{"author_name":"Paul D. Adams","author_inst":"Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA, Department of Bioengineering, University of C"},{"author_name":"Patrick M. Shih","author_inst":"Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA, Feedstocks Division, Joint BioEnergy Instit"},{"author_name":"Justin B. Siegel","author_inst":"Genome Center, University of California Davis, Davis, CA, USA, Department of Chemistry, University of California-Davis, Davis, California 95616, USA, Department"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Nup98 regulates the G1\/S transition","rel_doi":"10.64898\/2026.09.04.749412","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749412","rel_abs":"Nuclear pore complexes (NPCs) are embedded throughout the nuclear envelope of all eukaryotic cells and are composed of 30 unique proteins called nucleoporins (Nups). While Nups primarily function at NPCs, multiple Nups function in the nucleoplasm independent of the NPC. We previously found that Nup98-96 is necessary for entry into S phase in Drosophila cells, however, the mechanism is unknown. Here, we demonstrate that Nup98-96 is one of only a subset of Nup genes that can promote entry into S phase. We identify that transcripts dependent on Nup98-96 in Drosophila cells are enriched in cell cycle processes and that many of these transcripts are also dependent on the cell cycle regulator, E2f1. Importantly, we find that entry into S phase can be rescued by co-depleting the CycE\/CDK2 inhibitor, dacapo, in Nup98-96-depleted cells. Furthermore, Nup96-98 promotes S phase entry across multiple cell and tissue types and cell cycle contexts. Critically, overexpression of Nup98 has a dominant-negative effect on entry into S phase in larval salivary glands, suggesting that Nup98, not Nup96, promotes entry into S phase. Our work identifies Nup98 as a key regulator of the G1\/S transition in metazoans.","rel_num_authors":4,"rel_authors":[{"author_name":"Evi M Malagise","author_inst":"Vanderbilt University"},{"author_name":"Anna Sherman","author_inst":"Vanderbilt University"},{"author_name":"Maya Capelson","author_inst":"San Diego State University"},{"author_name":"Jared T. Nordman","author_inst":"Vanderbilt University"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Sequential assembly in vivo of the bacteriophage P22 genome translocation channel","rel_doi":"10.64898\/2026.09.03.749273","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749273","rel_abs":"Bacteriophage P22 ejects four internal proteins into infected cells to assemble a channel for genome translocation across the cell envelope. However, how these proteins cooperate to build the trans-envelope channel remains enigmatic. Using in situ single-particle cryogenic electron microscopy, we determined near-atomic in vivo structures of P22 infection intermediates, revealing how the tail hub protein gp10 templates the sequential assembly of three internal proteins gp7*, gp20 and gp16 into a ~50-nm trans-envelope channel that extends from the virion into the host cytoplasm. Functional analyses explain why phage DNA can be detected in supernatant fluids during infection by channel-defective mutants. Our structures also provide a mechanistic basis for the long-standing observation that a P22 virion lacking gp16 can be complemented, extra-cytoplasmically, by a co-infecting virion lacking gp20, thereby allowing the genome in the gp16-deficient particle to enter the host cytoplasm.","rel_num_authors":7,"rel_authors":[{"author_name":"Huaxin Yu","author_inst":"Yale University"},{"author_name":"Jian Yue","author_inst":"Yale university"},{"author_name":"Taehyun Park","author_inst":"University of Texas at Austin"},{"author_name":"chunyan wang","author_inst":"Yale University"},{"author_name":"Muyuan Chen","author_inst":"SLAC, Stanford University"},{"author_name":"Jun Liu","author_inst":"Yale University"},{"author_name":"Ian J Molineux","author_inst":"University of Texas at Austin"}],"rel_date":"2026-09-09","rel_site":"biorxiv"},{"rel_title":"Clinical Phenotypes of Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection: A Longitudinal Cohort Study from Karachi, Pakistan","rel_doi":"10.64898\/2026.09.04.26361413","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26361413","rel_abs":"Post Acute Sequelae of SARS CoV 2 infection, or PASC, is an emerging public health concern. Longitudinal data from South Asia remain limited and the burden of persistent symptoms in Pakistan is not well characterized. This study examined the long term clinical course of PASC and its relationship with fecal viral shedding and serotonin levels over a 12 month follow up period. We conducted a prospective longitudinal study of individuals with PASC. Participants underwent serial assessments of clinical symptoms, stool SARS CoV 2 RNA detection, and serum serotonin measurements. A symptom score was developed using 22 symptoms reported by more than 30 percent of participants. Participants were predominantly female with 60 percent female participation and a mean age of 42.1 years. Overall, 66 percent were overweight or obese and 23 percent reported multiple SARS CoV 2 reinfections. Symptom burden decreased significantly at 9 months and 12 months compared with baseline. Despite overall improvement, several symptoms persisted. Myalgia remained common, increasing slightly from 60 percent at baseline to 63 percent at 12 months. Musculoskeletal symptoms remained stable at approximately 60 percent. Neurocognitive symptoms declined from 40 percent to 31.3 percent, whereas psychological symptoms increased slightly from 40 percent to 45.8 percent. Fecal viral shedding was detected in 50 percent of participants and demonstrated intermittent or persistent patterns. Significant associations between fecal shedding and symptoms emerged at 6 months, particularly breathlessness, fatigue, weakness, and joint pain. Serotonin levels were comparable to those reported during acute COVID 19 infection. PASC symptoms including myalgia, joint pain, weakness, and fatigue persisted for up to one year after infection. The association between ongoing fecal viral shedding and persistent symptoms suggests that viral persistence and sustained physiological disturbances may contribute to Long COVID pathogenesis in a subset of individuals.","rel_num_authors":12,"rel_authors":[{"author_name":"Iffat Khanum","author_inst":"Aga Khan University"},{"author_name":"Kumail Ahmed","author_inst":"Aga Khan University"},{"author_name":"Tahir Munir","author_inst":"Aga Khan University"},{"author_name":"Haniya Zia","author_inst":"Aga Khan University"},{"author_name":"Wajiha Saif","author_inst":"Aga Khan University"},{"author_name":"Haleema Sadia","author_inst":"Aga Khan University"},{"author_name":"Syed Faisal Mahmood","author_inst":"Aga Khan University Hospital"},{"author_name":"Nosheen Nasir","author_inst":"Aga Khan University"},{"author_name":"Kulsoom Ghias","author_inst":"Aga Khan University"},{"author_name":"Peter Rabinowitz","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"Wes Van Voorhis","author_inst":"University of Washington"},{"author_name":"Najeeha Talat T Iqbal","author_inst":"Aga Khan University"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Towards Democratizing CNS Tumor Classification: 10-fold reduction in methylation sequencing cost with the Flongle Flow Cell","rel_doi":"10.64898\/2026.09.03.26361431","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.03.26361431","rel_abs":"Oxford Nanopore Technologies-based methylation profiling enables rapid, accurate CNS tumor classification but is currently mostly performed with MinION flow cells (~$1,000 USD). We benchmarked the low-cost Flongle flow cell (~$100, 10-fold reduction) for methylation-based tumor classification. Across 12 pediatric CNS tumor samples with highly variable sequencing yields (17-330 Mbp), both Sturgeon and nanoDx classifiers achieved perfect diagnostic accuracy when operating above significance thresholds, despite extreme data sparsity. Bootstrap analysis determined empirically defined minimum data thresholds. These results demonstrate that Flongle flow cells enable cost-effective deployment of rapid, accurate nanopore-based CNS diagnostics while maintaining clinical reliability.","rel_num_authors":6,"rel_authors":[{"author_name":"Assaf Grunwald","author_inst":"Tel-Aviv university"},{"author_name":"Gala Feinberg-Gorenshtein","author_inst":"Schneider Childrens Medical Center of Israel"},{"author_name":"Helen Toledano","author_inst":"Schneider Childrens Medical Center of Israel"},{"author_name":"Yehudit Birger","author_inst":"Tel-Aviv university"},{"author_name":"Shai Izraeli","author_inst":"Tel Aviv University"},{"author_name":"Yuval Ebenstein","author_inst":"Tel Aviv University"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"A survey and review of eye-tracking in clinical practice","rel_doi":"10.64898\/2026.09.07.26361936","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.07.26361936","rel_abs":"Purpose. The aim of this study was to evaluate how eye-trackers are currently used in clinical settings and to explore whether guidelines are perceived to be needed to support their use in a clinical context. Methods. A survey was developed and distributed to clinical eye-tracker users, manufacturers, professional bodies and other key stakeholders. The survey explored current practices, perceived barriers to clinical eye-tracking, guideline availability, and the perceived need for guidelines to support clinical practice. Results. Eighty responses to at least one of the survey questions were received. Of these, three were excluded from some analyses due to having no clinical involvement in eye-tracking (their involvement was in research only). Eye-tracking was performed by ophthalmologists, orthoptists, neurologists, optometrists, allied scientists and audiologists. Whilst most respondents were assessing eye movements daily, eye-tracking was mostly performed either rarely (less than 10%) or moderately often (10-60%) in their practice. Most clinical respondents (76%) reported they both performed eye-tracking and interpreted the results. The most commonly identified barriers to clinical eye-tracking were eye-trackers being considered primarily research tools, considered unsuitable for performing the assessments, and lack of access to an eye-tracker. Most respondents (71%) were unaware of any existing guidelines for clinical eye-tracking. Where guidelines were reported to exist, they were described as somewhat sufficient to completely insufficient. Most respondents (93%) supported the development of guidelines for clinical eye-tracking. A small number of respondents (7%) reported concerns about introducing clinical eye-tracking guidelines. Conclusion. A broad range of clinicians, professionals and other stakeholders involved in clinical eye-tracking responded to this survey. Their responses suggest a general consensus of a need for clinical eye-tracking guidelines. Whilst guidelines may address some of the reported barriers to eye-tracking clinically, and support benchmarking and standardisation across a broad range of clinical disciplines, concerns around a perceived threat to autonomous clinical practice should also be considered.","rel_num_authors":10,"rel_authors":[{"author_name":"Fiona Brid Mulvey","author_inst":"Dept. of Health Technology, Technical University of Denmark, Copenhagen, Denmark"},{"author_name":"Onyekachukwu Mary-Anne Amiebenomo","author_inst":"School of Health and Social Wellbeing, University of the West of England, Bristol, UK"},{"author_name":"Denize Atan","author_inst":"Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK; School of Psychology and Neuroscience, University of B"},{"author_name":"Siyuan Chen","author_inst":"School of Electrical Engineering and Telecommunications, University of New South Wales, Sydney, Australia"},{"author_name":"Amanda Douglass","author_inst":"Department of Optometry and Vision Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia"},{"author_name":"Matt J. Dunn","author_inst":"School of Optometry and Vision Sciences, Cardiff University, Wales, UK"},{"author_name":"Daniel Goldstone","author_inst":"Bristol Medical School, School of Health Sciences, University of Bristol, Bristol, UK"},{"author_name":"Rasha Sameer Moustafa","author_inst":"Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Faculty of Science, Forestry and Technology, University of Eastern Finland, Joe"},{"author_name":"Frederic Shic","author_inst":"Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, USA; Department of Pediatrics, University of Washington School of Medicine, Sea"},{"author_name":"Gemma Arblaster","author_inst":"School of AHPNM, University of Sheffield, Sheffield, England, UK; Sheffield Teaching Hospitals NHS FT, Sheffield, England, UK"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Analysis of east Asian Parkinson's disease Genomes Identifies Novel Susceptibility Loci and Functional Regulatory Variation","rel_doi":"10.64898\/2026.09.03.26362212","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.03.26362212","rel_abs":"Background: Parkinson disease (PD) is a genetically complex neurodegenerative disorder, but most genetic discoveries have been derived from populations of European ancestry, limiting the understanding of ancestry-specific genetic risk. Methods: This GWAS included 5,825 East Asian participants (3,043 patients with PD and 2,782 controls). We then combined these results with data from two additional East Asian cohorts through meta-analysis, resulting in a total of 74,716 participants (15,603 patients with PD and 59,113 controls). To our knowledge, this represents the largest genetic study of PD in East Asian populations to date. Findings: We identified two novel loci that were associated with PD in East Asian cohorts and reached genome-wide significance in the cross-ancestry meta-analysis (>1.9 million subjects): TLE4 (lead variant rs10780320, Pmeta_combined = 2.853 x 10^-10) and HLA-V\/HLA-G (lead variant rs11751333, Pmeta_combined = 1.031 x 10^-9). Integration of brain eQTL data identified an East Asian-specific intergenic variant at the LRRK2 locus (rs1388594) that was significantly associated with LRRK2 expression in the basal ganglia. This association was replicated across three independent East Asian cohorts (Pgp2_EAS = 8.71 x 10^-4, Psg_EAS = 1.13 x 10^-5, PTPMI_EAS = 4.86 x 10^-4) and reached genome-wide significance in the East Asian meta-analysis (Pmeta_EAS = 5.85 x 10^-10; OR = 1.10, 95% CI: 1.07-1.13). The variant was not associated with PD in populations of European ancestry (P = 0.08). Interpretation: These findings improve our understanding of the genetics of PD across ancestry groups and highlight the importance of including diverse populations in genetic studies to identify ancestry-specific risk variants.","rel_num_authors":30,"rel_authors":[{"author_name":"Qiaoyang Sun","author_inst":"National Neuroscience Institute of Singapore"},{"author_name":"Ebonne Yulin Ng","author_inst":"National Neuroscience Institute"},{"author_name":"Tzi Shin Toh","author_inst":"Universiti Malaya"},{"author_name":"Kai Shi Lim","author_inst":"Universiti Malaya"},{"author_name":"James Jia Dong Wang","author_inst":"Nanyang Technological University"},{"author_name":"Thomas Welton","author_inst":"National Neuroscience Institute"},{"author_name":"Louis Chew Seng Tan","author_inst":"National Neuroscience Institute"},{"author_name":"Kumar Manharlal Prakash","author_inst":"National Neuroscience Institute"},{"author_name":"Ling-Ling Chan","author_inst":"Singapore General Hospital"},{"author_name":"Jia Nee Foo","author_inst":"Nanyang Technological University Singapore"},{"author_name":"Andrew Singleton","author_inst":"The Global Parkinson Genetics Program"},{"author_name":"Laurel Screven","author_inst":"The Global Parkinson Genetics Program"},{"author_name":"Hampton Leonard","author_inst":"The Global Parkinson Genetics Program"},{"author_name":"Mike A Nalls","author_inst":"Data Tecnica Int'l"},{"author_name":"Azlina Ahmad-Annuar","author_inst":"Universiti Malaya"},{"author_name":"Yi Wen Tay","author_inst":"UNIVERSITY OF MALAYA"},{"author_name":"Han-Joon Kim","author_inst":"Seoul National University Hospital"},{"author_name":"Jung Hwan Shin","author_inst":"Seoul National University"},{"author_name":"Manabu Funayama","author_inst":"Juntendo University"},{"author_name":"Nobutaka Hattori","author_inst":"Juntendo University School of Medicine"},{"author_name":"Taku Hatano","author_inst":"Juntendo University"},{"author_name":"Jee-Young Lee","author_inst":"Seoul National University Hospital"},{"author_name":"Beomseok Jeon","author_inst":"Seoul National University Hospital"},{"author_name":"Cheng-Hsuan Li","author_inst":"National Taiwan University Hospital"},{"author_name":"Sung-Pin Fan","author_inst":"National Taiwan University Hospital"},{"author_name":"Pin-Shiuan Chen","author_inst":"National Taiwan University Hospital Bei-Hu Branch"},{"author_name":"Chin-Hsien Lin","author_inst":"National Taiwan University Hospital"},{"author_name":"Shen-Yang Lim","author_inst":"Universiti Malaya"},{"author_name":"Ai-Huey Tan","author_inst":"Universiti Malaya"},{"author_name":"Eng-King Tan","author_inst":"National Neuroscience Institute"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Ensemble SHAP Aggregation and Attribution Variability in Clinical Machine Learning: A COVID-19 Mortality Study","rel_doi":"10.64898\/2026.09.07.26362459","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.07.26362459","rel_abs":"ObjectiveTo combine performance-weighted ensemble SHAP aggregation with resampling-based assessment of feature-importance variability and patient-level attribution alignment for interpreting COVID-19 mortality predictions.\n\nMethodsWe analyzed a prospective cohort of 1,857 patients hospitalized with COVID-19 at two hospitals in Peru. Ten predictive algorithms were evaluated using five-fold cross-validation, and their mean AUROC values determined their attribution-aggregation weights. Within each model and training trial, signed SHAP values were normalized by the mean total absolute attribution across evaluation patients before performance-weighted aggregation. Feature importance was summarized across 30 resampled training trials using means and normal-approximation 95% confidence intervals. Patient-level attribution alignment was assessed using cosine similarity between signed feature-attribution vectors for corresponding patients, with whole-trial patient-correspondence randomization and Benjamini-Hochberg correction. Subgroup observations were reweighted toward the evaluated populations feature distributions for secondary comparisons of existing absolute SHAP values.\n\nResultsAmong the 1,857 included patients, 982 (52.9%) died during hospitalization. Random forest achieved the highest mean AUROC (0.925 {+\/-} 0.010), followed by AdaBoost (0.919 {+\/-} 0.017) and logistic regression (0.918 {+\/-} 0.007), with variability reported as the SEM. Attribution profiles were more similar across repeated training trials of the same algorithm (mean Pearson r = 0.783; SEM, 0.004) than across algorithms within the same trial (mean Pearson r = 0.369; SEM, 0.006). The largest normalized attribution magnitudes were observed for dexamethasone use at home without oxygen support (6.186%; 95% CI, 5.795-6.577), PaO2\/FiO2 ratio (3.014%; 95% CI, 2.787-3.242), shortness of breath (2.774%; 95% CI, 2.592-2.956), and FiO2 (2.560%; 95% CI, 2.284-2.836). Features differed in patient-level attribution alignment, indicating that importance magnitude and robustness provided complementary information. Among 1,763 eligible subgroup-feature comparisons, 64 had nominal one-sided p < 0.05, although none remained below 0.05 after Benjamini-Hochberg adjustment.\n\nConclusionsAlgorithms with similar predictive performance produced substantially different feature-attribution profiles. Normalized performance-weighted SHAP aggregation provided a representative relative-importance summary across algorithms, while resampling-based alignment assessment qualified the consistency of individual feature contributions. The resulting attribution patterns describe fitted-model behavior and should not be interpreted as causal clinical effects.","rel_num_authors":7,"rel_authors":[{"author_name":"Na Dai","author_inst":"Independent Researcher"},{"author_name":"Ruben K Briceno","author_inst":"Global Health Institute, Michigan State University, MI, USA"},{"author_name":"Alex N Castaneda","author_inst":"Universidad Cesar Vallejo, Trujillo, Peru"},{"author_name":"Miguel A Tresierra","author_inst":"Hospital Victor Lazarte Echegaray, Trujillo, Peru"},{"author_name":"Maribel L Esteban","author_inst":"Hospital de Alta Complejidad Virgen de la Puerta"},{"author_name":"Moises E Rosas","author_inst":"Universidad Cesar Vallejo, Trujillo, Peru"},{"author_name":"Rene C Hinojosa","author_inst":"Global Health Institute, Michigan State University, MI, USA"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Generalised anxiety as a mediator linking ADHD symptoms and autistic traits to digital addictions in Australian emerging adults","rel_doi":"10.64898\/2026.09.06.26362218","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.06.26362218","rel_abs":"Background and aimsDigital addiction is highly prevalent among emerging adults and is associated with significant detrimental health outcomes. Through the lens of the Interaction of Person-Affect-Cognition-Execution model, attention-deficit\/hyperactivity disorder (ADHD) symptoms and autistic traits may increase vulnerability to digital addictions both directly through executive functioning deficits and indirectly through affective-cognitive processes such as anxiety. This study estimated whether internet, mobile phone, and video game addictions were represented by a common latent construct, estimated the associations of ADHD symptoms, autistic traits, generalised anxiety, and participant sex with these addictions, and estimated the extent to which anxiety mediated associations of ADHD symptoms and autistic traits with these addictions.\n\nDesignCross-sectional observational study.\n\nSettingOnline survey conducted at Queensland University of Technology, Brisbane, Australia.\n\nParticipantsThe analyses included 222 emerging adults aged 17-29 years (77.0% female) recruited between July and October 2015.\n\nMeasurementsThe primary outcomes were the Internet Addiction Test (IAT), Mobile Phone Problem Use Scale (MPPUS), and Video Game Addiction Test (VAT). Predictors included the Autism Spectrum Quotient-10 (AQ-10), Adult ADHD Self-Report Scale v1.1 screener (ASRS-S), Generalised Anxiety Disorder-7 (GAD-7), and participant sex.\n\nFindingsInternet, mobile phone, and video game addictions were not well represented by a single latent construct. GAD-7 was positively associated with AQ-10 (B = 0.20, 95% confidence interval [CI] [0.04, 0.37], p = .020) and ASRS-S (B = 0.54, CI [0.38, 0.70], p < .001). GAD-7 was positively associated with VAT (B = 0.63, CI [0.23, 1.00], p = .003), but neither IAT nor MPPUS. ASRS-S showed positive direct effects across IAT (B = 0.56, CI [0.08, 0.99], p = .024), MPPUS (B = 2.63, CI [1.06, 4.08], p < .001), and VAT (B = 0.41, CI [0.06, 0.78], p = .024), and a small-to-moderate positive indirect effect on VAT through GAD-7 (B = 0.35, CI [0.12, 0.60], p = .013). Sex did not moderate the associations between GAD-7 and digital addictions. Females reported higher MPPUS (B = 13.16, CI [6.17, 19.69], p < .001) and lower VAT (B = -5.22, CI [-7.00, -3.48], p < .001) scores than males.\n\nConclusionsAttention-deficit\/hyperactivity disorder symptoms were associated with all three forms of digital addiction and showed an indirect association with video game addiction through generalised anxiety, consistent with the proposed mechanisms in the Interaction of Person-Affect-Cognition-Execution model.","rel_num_authors":4,"rel_authors":[{"author_name":"Matthew J. Giblett","author_inst":"School of Psychology, The University of Queensland"},{"author_name":"Cara Jaklich","author_inst":"School of Psychology and Counselling, Queensland University of Technology"},{"author_name":"Brooke Andrew","author_inst":"School of Psychology and Counselling, Queensland University of Technology"},{"author_name":"Penelope A. Lind","author_inst":"Psychiatric Genetics, Brain and Mental Health Research Program, QIMR Berghofer"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Self-weaning versus dose-adjusted caffeine regimens in preterm infants discharged home: a prospective cohort study","rel_doi":"10.64898\/2026.09.07.26361207","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.07.26361207","rel_abs":"Objective: To compare self-weaning and dose-adjusted caffeine regimens in preterm infants discharged home on caffeine for apnea of prematurity (AOP). Design: A prospective cohort study. Setting: Tertiary neonatal unit and outpatient clinics, Karachi, Pakistan, April 2023 to July 2025. Patients: 204 preterm infants (<37 weeks' gestation) discharged home on caffeine for AOP; 94 self-weaning, 110 dose adjusted. Interventions: Self-weaning (absolute dose fixed, so mg\/kg\/day exposure declined with weight gain) versus dose-adjusted weaning (dose recalculated to current weight at each visit). Both were followed to 36 weeks postmenstrual age (PMA). Main outcome measures: Proportion continuing caffeine beyond 36 weeks PMA and caregiver-reported apnea after discontinuation. Results: Caffeine was continued beyond 36 weeks PMA in 68\/94 self-weaning infants (72.3%) and 84\/110 dose-adjusted infants (76.4%). No apnea was reported after discontinuation in either group, and all 204 infants survived to 36 weeks PMA. Apnea-related readmission on caffeine occurred in 1\/94 (1.1%) versus 2\/110 (1.8%). Weight at discontinuation was lower with self-weaning (1917 vs 2157g); the dose-adjusted group was more premature (mean 30.0 vs 30.7 weeks). After adjustment for gestational age and birth weight, regimen was not associated with continuation beyond 36 weeks (adjusted OR 0.82, 95% CI 0.43 to 1.57) or time to discontinuation (adjusted HR 1.21, 95% CI 0.91 to 1.60). Conclusions: Within a structured outpatient follow-up program, no post-discontinuation apnea was reported with either regimen,and apnea-related readmissions were infrequent. Self-weaning avoids repeated dose recalculation. A multicenter randomized trial with objective home monitoring is needed to determine the optimal timing of discontinuation.","rel_num_authors":7,"rel_authors":[{"author_name":"Shabina Ariff","author_inst":"The Aga Khan University"},{"author_name":"Uzma Khan","author_inst":"The Aga Khan University"},{"author_name":"Khubaib M Abdullah","author_inst":"The Aga Khan University"},{"author_name":"Syed ALI ALI RIZWI","author_inst":"The Aga Khan University"},{"author_name":"Saima Fayyaz","author_inst":"The Aga Khan University"},{"author_name":"Ijaz Hussain","author_inst":"The Aga Khan University"},{"author_name":"Siddiqa Ghani","author_inst":"The Aga Khan University"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Using large language models to facilitate literature review and data extraction for infectious disease models: COVID-19 as a test case","rel_doi":"10.64898\/2026.09.06.26362399","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.06.26362399","rel_abs":"Infectious disease transmission models are governed by parameters informed by systematic review of epidemiological literature. Large language models (LLMs) could facilitate this, but the reliability of the results to inform models has not been tested. We built an open-source, end-to-end pipeline to simulate LLM performance in a hypothetical scenario where they were available to inform COVID-19 models developed during the first four months of 2020. It screened articles and extracted the reproduction number, serial interval, and incubation period from full-text PDFs. We applied it to 2,067 PubMed\/medRxiv records published 31 December 2019-30 April 2020 using four models (GPT-5-mini, GPT-5.4, Claude Opus 4.8 and Gemini 2.5 Pro) and evaluated it against full-corpus human screening and 50-article extraction gold standards. We combined models post hoc, pooled the extracted values into an infectious disease (SEIR) model, and ran sensitivity analyses to test approaches to improve extraction accuracy. Screening sensitivity was 0.72-0.95 and specificity 0.92-0.99. For articles reporting few values, extraction F1 was 0.90-0.96 with precision 0.91-1.00; across all articles, including those with dozens of stratified estimates, recall fell to 0.38-0.78. No fabricated values observed; errors were misassignments of values filed under the wrong parameter, or borrowed values treated as the study's own. Incomplete extraction from dense articles was mainly due to prompting and output format, not model capability. Ensembling allowed recall-precision trade-offs, and correctness increased with model agreement, from about 30% at one vote to 92-95% at four. The pipeline processed the corpus in hours versus an estimated 130-265 person-hours of manual effort. Our results show that current models can extract transmission parameters from unstructured literature accurately enough to inform outbreak modelling. The bottleneck lies in task specification, and careful prompt and output schema design are key to reducing misassignment errors. Human effort is best directed at workflow development and provenance validation.","rel_num_authors":6,"rel_authors":[{"author_name":"Xiyu Yang","author_inst":"Ann S. Bowers College of Computing and Information Science, Cornell University"},{"author_name":"Chui Yee Lee","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Billy J Quilty","author_inst":"Charite - Universitatsmedizin Berlin"},{"author_name":"Linxi Zhang","author_inst":"School of Basic Medical Sciences, Capital Medical University"},{"author_name":"Yao Mu","author_inst":"College of Agriculture and Life Sciences, Cornell University"},{"author_name":"Mark Jit","author_inst":"Department of Global and Environmental Health, School of Global Public Health, New York University"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"External validation of dynamic clinical states in acute stroke: transportability and independent rediscovery across 176 hospitals","rel_doi":"10.64898\/2026.09.07.26362407","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.07.26362407","rel_abs":"Objective: Four dynamic clinical states were identified in the first 72 h of stroke intensive care in one centre. We tested whether this representation transports to an independent multicentre cohort, predicts the next state, and is independently recovered. Materials and Methods: 8279 adults in 176 hospitals (eICU CRD v2.0) contributed 70 630 six hour windows. Phenotype, dictionaries and eligibility rules were frozen before any state was assigned; the model was applied unchanged and judged against five prespecified criteria. Generalised estimating equations related state to subsequent organ support and ICU death; prediction was assessed against a persistence null at 6, 12 and 24 h; a model was fitted de novo in the strictest scope. Results: All five transportability criteria were met in all four scopes. All nine state outcome comparisons reproduced the direction of association, with exact rank order for invasive ventilation and ICU death; between hospital intraclass correlations were 0.012 to 0.027. States persisted across 90.7% of pairs, so prediction was scored on change: AUROC (95% CI) 0.730 (0.723 to 0.736) externally, 0.735 (0.721to 0.749) internally. Fitted de novo, eICU favoured four by BIC but three by restart reproducibility; neither recovered neurological impairment low support, the other three matched closely in both (r = 0.962 to 0.991). Discussion: The representation transports and carries forward-looking information but is not fully rediscoverable. The unrecovered state is defined by a combination, not a feature: eICU places its windows consistently but never pairs impairment with absent organ support. Conclusion: Three of four states are strongly supported. Transportability and independent rediscovery are distinct and should be reported separately.","rel_num_authors":3,"rel_authors":[{"author_name":"Ping LEI","author_inst":"Institute of Global Health, Geneva University, Geneva, Switzerland; Department of Overseas Liaison, School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Yanyi XU","author_inst":"Department of Environmental Health, School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Yuxia ZHANG","author_inst":"Department of Nursing, Zhongshan Hospital, Fudan University, Shanghai,China"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Impulse Control Disorders Are Independent of Parkinson Disease Motor Subtypes","rel_doi":"10.64898\/2026.09.04.26362266","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362266","rel_abs":"Objective: Impulse control disorders (ICDs) are clinically important nonmotor features of Parkinson's disease (PD). Tremor-dominant PD (TD-PD) has been associated with greater cerebello-thalamo-cortical involvement, whereas postural instability\/gait difficulty-dominant PD (PIGD-PD) has been linked to more prominent basal ganglia and frontostriatal dysfunction. We therefore examined whether ICD symptoms differ by motor phenotypes. Methods: This cross-sectional study analyzed baseline data from the Parkinson's Precision Medicine Initiative (PPMI). Motor subtype classification was based on Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) criteria. ICD symptoms were assessed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Current Short Form (QUIP-CS) and evaluated across multiple levels of analysis using the standard screening definition and normalized QUIP-CS scores analyzed categorically and continuously. Temporal-alignment, subgroup, multivariable, and Bayesian analyses were performed to assess the robustness of the primary findings. Results: We analyzed 305 participants (173 TD-PD, 132 PIGD-PD). Screening-defined ICD positivity was similar between subtypes (21.4% vs 21.2%, OR = 1.01, 95% CI 0.58-1.76, p = 0.970). Continuous and categorical normalized QUIP-CS scores likewise did not differ between groups (continuous score: 0.0338 vs 0.0384, p = 0.674; categorical score: 3.5% vs 4.5%, p = 0.632). Temporally aligned, subgroup, and multivariable sensitivity analyses consistently supported the primary finding, and Bayesian analysis provided moderate evidence supporting the null hypothesis (BF01 = 7.21). Conclusions: ICD symptoms do not differ between TD-PD and PIGD-PD motor subtypes in early PD. These findings suggest that motor subtype-associated differences in cerebellar involvement do not substantially influence ICD symptoms in early PD.","rel_num_authors":7,"rel_authors":[{"author_name":"M. Eymaz Chhotani","author_inst":"Baylor College of Medicine"},{"author_name":"William Saban","author_inst":"Tel Aviv University"},{"author_name":"Malco Rossi","author_inst":"Instituto Fleni-CONICET (INEU)"},{"author_name":"Sheng-Han Kuo","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Leila Montaser-Kouhsari","author_inst":"Brigham and Womens Hospital, Harvard University"},{"author_name":"Chi-Ying R Lin","author_inst":"Baylor College of Medicine"},{"author_name":"- Parkinsons Precision Medicine Initiative","author_inst":""}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Impulse Control Disorders Are Independent of Parkinson Disease Motor Subtypes","rel_doi":"10.64898\/2026.09.04.26362266","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362266","rel_abs":"Objective: Impulse control disorders (ICDs) are clinically important nonmotor features of Parkinson's disease (PD). Tremor-dominant PD (TD-PD) has been associated with greater cerebello-thalamo-cortical involvement, whereas postural instability\/gait difficulty-dominant PD (PIGD-PD) has been linked to more prominent basal ganglia and frontostriatal dysfunction. We therefore examined whether ICD symptoms differ by motor phenotypes. Methods: This cross-sectional study analyzed baseline data from the Parkinson's Precision Medicine Initiative (PPMI). Motor subtype classification was based on Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) criteria. ICD symptoms were assessed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Current Short Form (QUIP-CS) and evaluated across multiple levels of analysis using the standard screening definition and normalized QUIP-CS scores analyzed categorically and continuously. Temporal-alignment, subgroup, multivariable, and Bayesian analyses were performed to assess the robustness of the primary findings. Results: We analyzed 305 participants (173 TD-PD, 132 PIGD-PD). Screening-defined ICD positivity was similar between subtypes (21.4% vs 21.2%, OR = 1.01, 95% CI 0.58-1.76, p = 0.970). Continuous and categorical normalized QUIP-CS scores likewise did not differ between groups (continuous score: 0.0338 vs 0.0384, p = 0.674; categorical score: 3.5% vs 4.5%, p = 0.632). Temporally aligned, subgroup, and multivariable sensitivity analyses consistently supported the primary finding, and Bayesian analysis provided moderate evidence supporting the null hypothesis (BF01 = 7.21). Conclusions: ICD symptoms do not differ between TD-PD and PIGD-PD motor subtypes in early PD. These findings suggest that motor subtype-associated differences in cerebellar involvement do not substantially influence ICD symptoms in early PD.","rel_num_authors":7,"rel_authors":[{"author_name":"M. Eymaz Chhotani","author_inst":"Baylor College of Medicine"},{"author_name":"William Saban","author_inst":"Tel Aviv University"},{"author_name":"Malco Rossi","author_inst":"Instituto Fleni-CONICET (INEU)"},{"author_name":"Sheng-Han Kuo","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Leila Montaser-Kouhsari","author_inst":"Brigham and Womens Hospital, Harvard University"},{"author_name":"Chi-Ying R Lin","author_inst":"Baylor College of Medicine"},{"author_name":"- Parkinsons Precision Medicine Initiative","author_inst":""}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Applying a multiplex electrochemiluminescence NS1 assay to detect and differentiate Zika and dengue virus exposures in long-term community cohorts in Brazil and Thailand","rel_doi":"10.64898\/2026.09.04.26362297","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362297","rel_abs":"Background: Distinguishing Zika virus (ZIKV) from dengue virus (DENV) infection remains a major diagnostic challenge in co-endemic regions due to antigenic cross-reactivity. We evaluated a multiplex electrochemiluminescence Meso Scale Discovery System (MSD) NS1 assay to define ZIKV infection with high specificity across diverse immune backgrounds. Methods: We analyzed longitudinal samples from PCR-confirmed ZIKV and DENV infections across multiple cohorts, assessed correlations between MSD NS1 signal intensities and PRNT50 titres, and performed ROC analyses to derive seroconversion thresholds. We then applied these criteria to identify ZIKV seroconversions in Brazil (2015-2024) and Thailand (2015-2025). Findings: ZIKV infections produced sustained NS1 responses, whereas primary DENV infections showed minimal ZIKV cross-reactivity and secondary DENV infections exhibited only transient, low-level increases. MSD NS1 signal intensities correlated with PRNT50 titres for ZIKV and all four DENV serotypes (rho = 0.54-0.84). ROC analyses identified a fold-change of at least 10.96 as the optimal ZIKV seroconversion cutoff, with an AUC of 100% among DENV-naive and 90.7% among DENV-exposed participants. Adding a second criterion - ZIKV\/DENV fold-change ratio > 1 - further increased specificity. Application of this dual-threshold framework revealed high ZIKV incidence during the 2015-2016 epidemic in Brazil and very low incidence in the post-epidemic period. In the Thailand cohort, synchronous seroconversion among household members suggested potential intra-household transmission. Interpretation: The MSD NS1 multiplex assay provides a scalable, quantitative, and highly specific approach for identifying ZIKV infection and estimating seroincidence in co-endemic settings. The dual-threshold framework (fold-change of at least 10.96 and ZIKV\/DENV ratio > 1) enhances diagnostic precision, offering a robust tool for surveillance and transmission studies in flavivirus-endemic regions.","rel_num_authors":25,"rel_authors":[{"author_name":"Nivison Nery Jr.","author_inst":"Institute of Collective Health, Federal University of Bahia, Salvador, Brazil"},{"author_name":"Marco Hamins-Puertolas","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Lauren Bahr","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Jaqueline S. Cruz","author_inst":"Goncalo Moniz Institute, Oswaldo Cruz Foundation, Brazilian Ministry of Health, Salvador, Brazil"},{"author_name":"Joseph Lu","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"M. Catherine Muenker","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Juan P. Aguilar Ticona","author_inst":"Institute of Collective Health, Federal University of Bahia, Salvador, Brazil"},{"author_name":"Ruchira Khosavanna","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Mariam O. Fofana","author_inst":"Department of Emergency Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Daiana de Oliveira","author_inst":"Institute of Collective Health, Federal University of Bahia, Salvador, Brazil"},{"author_name":"Darunee Buddhari","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"Taweewun Hunsawong","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"Aaron Farmer","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"Kathryn A. McGuckin","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"John S. Brooks","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"Sopon Iamsirithaworn","author_inst":"Ministry of Public Health, Tiwanond, Nonthaburi, Thailand"},{"author_name":"Matthew H. Collins","author_inst":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Guilherme S. Ribeiro","author_inst":"Goncalo Moniz Institute, Oswaldo Cruz Foundation, Brazilian Ministry of Health, Salvador, Brazil"},{"author_name":"Stephen J. Thomas","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Federico Costa","author_inst":"Institute of Collective Health, Federal University of Bahia, Salvador, Brazil"},{"author_name":"Mitermayer G. Reis","author_inst":"Goncalo Moniz Institute, Oswaldo Cruz Foundation, Brazilian Ministry of Health, Salvador, Brazil"},{"author_name":"Derek A.T. Cummings","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Kathryn Anderson","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Albert I. Ko","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Adam Waickman","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Applying a multiplex electrochemiluminescence NS1 assay to detect and differentiate Zika and dengue virus exposures in long-term community cohorts in Brazil and Thailand","rel_doi":"10.64898\/2026.09.04.26362297","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362297","rel_abs":"Background: Distinguishing Zika virus (ZIKV) from dengue virus (DENV) infection remains a major diagnostic challenge in co-endemic regions due to antigenic cross-reactivity. We evaluated a multiplex electrochemiluminescence Meso Scale Discovery System (MSD) NS1 assay to define ZIKV infection with high specificity across diverse immune backgrounds. Methods: We analyzed longitudinal samples from PCR-confirmed ZIKV and DENV infections across multiple cohorts, assessed correlations between MSD NS1 signal intensities and PRNT50 titres, and performed ROC analyses to derive seroconversion thresholds. We then applied these criteria to identify ZIKV seroconversions in Brazil (2015-2024) and Thailand (2015-2025). Findings: ZIKV infections produced sustained NS1 responses, whereas primary DENV infections showed minimal ZIKV cross-reactivity and secondary DENV infections exhibited only transient, low-level increases. MSD NS1 signal intensities correlated with PRNT50 titres for ZIKV and all four DENV serotypes (rho = 0.54-0.84). ROC analyses identified a fold-change of at least 10.96 as the optimal ZIKV seroconversion cutoff, with an AUC of 100% among DENV-naive and 90.7% among DENV-exposed participants. Adding a second criterion - ZIKV\/DENV fold-change ratio > 1 - further increased specificity. Application of this dual-threshold framework revealed high ZIKV incidence during the 2015-2016 epidemic in Brazil and very low incidence in the post-epidemic period. In the Thailand cohort, synchronous seroconversion among household members suggested potential intra-household transmission. Interpretation: The MSD NS1 multiplex assay provides a scalable, quantitative, and highly specific approach for identifying ZIKV infection and estimating seroincidence in co-endemic settings. The dual-threshold framework (fold-change of at least 10.96 and ZIKV\/DENV ratio > 1) enhances diagnostic precision, offering a robust tool for surveillance and transmission studies in flavivirus-endemic regions.","rel_num_authors":25,"rel_authors":[{"author_name":"Nivison Nery Jr.","author_inst":"Institute of Collective Health, Federal University of Bahia, Salvador, Brazil"},{"author_name":"Marco Hamins-Puertolas","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Lauren Bahr","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Jaqueline S. Cruz","author_inst":"Goncalo Moniz Institute, Oswaldo Cruz Foundation, Brazilian Ministry of Health, Salvador, Brazil"},{"author_name":"Joseph Lu","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"M. Catherine Muenker","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Juan P. Aguilar Ticona","author_inst":"Institute of Collective Health, Federal University of Bahia, Salvador, Brazil"},{"author_name":"Ruchira Khosavanna","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Mariam O. Fofana","author_inst":"Department of Emergency Medicine, Emory University, Atlanta, GA, USA"},{"author_name":"Daiana de Oliveira","author_inst":"Institute of Collective Health, Federal University of Bahia, Salvador, Brazil"},{"author_name":"Darunee Buddhari","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"Taweewun Hunsawong","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"Aaron Farmer","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"Kathryn A. McGuckin","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"John S. Brooks","author_inst":"Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"},{"author_name":"Sopon Iamsirithaworn","author_inst":"Ministry of Public Health, Tiwanond, Nonthaburi, Thailand"},{"author_name":"Matthew H. Collins","author_inst":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Guilherme S. Ribeiro","author_inst":"Goncalo Moniz Institute, Oswaldo Cruz Foundation, Brazilian Ministry of Health, Salvador, Brazil"},{"author_name":"Stephen J. Thomas","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Federico Costa","author_inst":"Institute of Collective Health, Federal University of Bahia, Salvador, Brazil"},{"author_name":"Mitermayer G. Reis","author_inst":"Goncalo Moniz Institute, Oswaldo Cruz Foundation, Brazilian Ministry of Health, Salvador, Brazil"},{"author_name":"Derek A.T. Cummings","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Kathryn Anderson","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"},{"author_name":"Albert I. Ko","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Adam Waickman","author_inst":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Posttraumatic Stress Disorder Epigenome-Wide Association Studies in the Million Veteran Program","rel_doi":"10.64898\/2026.09.04.26362177","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362177","rel_abs":"Genomic studies have improved our understanding of posttraumatic stress disorder (PTSD) biology. Epigenetic differences in DNA methylation can reflect environmental influences, which are critical in PTSD etiology, and may additionally differentiate between PTSD cases and controls or distinguish severity of PTSD symptoms. We conducted PTSD epigenome-wide association studies (EWAS) in a large cohort, n = 22,141 subjects from the United States V.A. Million Veteran Program (MVP), with the PTSD Checklist (PCL-17), including 17,674 European ancestry (EUR), 3,430 African ancestry (AFR), and 1,037 admixed American descent (AMR). We evaluated the 17-item PCL-Total as well as symptom subdomains (re-experiencing, avoidance, and hyperarousal), and used lasso regression on electronic health records to define lifetime PTSD diagnoses. There were 9,413 total cases of Lifetime PTSD and 27,257 controls, with 5,184 cases and 19,382 controls in EUR, 3,095 cases and 6,240 controls in AFR, and 1,134 cases and 1,635 controls in AMR. We identified a total of 241 epigenome-wide-significant associated CpG sites across all PTSD traits. We replicated 5 out of 11 CpG sites reported in a prior (Psychiatric Genomics Consortium) PTSD EWAS. Overlap with differentially methylated CpG sites in subregions of the amygdala and hippocampus of human postmortem brains of individuals with PTSD vs. controls was evaluated at the CpG and gene levels. Ten genes of the 195 identified in the brain study overlapped with the 192 identified in our EWAS. There was significant enrichment of genes downregulated in somatostatin interneurons and brain endothelial cells. Regression analyses showed that PTSD case status was significantly associated with accelerated DNA methylation aging. Contrary to previous PTSD EWAS findings, smoking status stratification suggested that the association between PTSD and methylation of the AHRR gene may be confounded by smoking status. Our findings showcase the largest-scale PTSD EWAS in multiple ancestries and the first large PTSD EWAS on symptom severity. We replicated several findings from previous EWAS and greatly extended current knowledge of the relationship between epigenetics and PTSD.","rel_num_authors":16,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Marco Galimberti","author_inst":"Yale University"},{"author_name":"Cassie Overstreet","author_inst":"Yale University"},{"author_name":"Jiarui Chen","author_inst":"Yale University"},{"author_name":"Priya Gupta","author_inst":"BRIC-National Institute of Immunology"},{"author_name":"Cecilia Dao","author_inst":"Yale University"},{"author_name":"Bluma J. Lesch","author_inst":"Yale University"},{"author_name":"Janitza L. Montalvo-Ortiz","author_inst":"Yale University"},{"author_name":"- The V.A. Million Veteran Program","author_inst":"-"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"John H. Krystal","author_inst":"Yale University"},{"author_name":"Renato Polimanti","author_inst":"Yale University"},{"author_name":"Matthew J. Girgenti","author_inst":"Yale School of Medicine"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Posttraumatic Stress Disorder Epigenome-Wide Association Studies in the Million Veteran Program","rel_doi":"10.64898\/2026.09.04.26362177","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362177","rel_abs":"Genomic studies have improved our understanding of posttraumatic stress disorder (PTSD) biology. Epigenetic differences in DNA methylation can reflect environmental influences, which are critical in PTSD etiology, and may additionally differentiate between PTSD cases and controls or distinguish severity of PTSD symptoms. We conducted PTSD epigenome-wide association studies (EWAS) in a large cohort, n = 22,141 subjects from the United States V.A. Million Veteran Program (MVP), with the PTSD Checklist (PCL-17), including 17,674 European ancestry (EUR), 3,430 African ancestry (AFR), and 1,037 admixed American descent (AMR). We evaluated the 17-item PCL-Total as well as symptom subdomains (re-experiencing, avoidance, and hyperarousal), and used lasso regression on electronic health records to define lifetime PTSD diagnoses. There were 9,413 total cases of Lifetime PTSD and 27,257 controls, with 5,184 cases and 19,382 controls in EUR, 3,095 cases and 6,240 controls in AFR, and 1,134 cases and 1,635 controls in AMR. We identified a total of 241 epigenome-wide-significant associated CpG sites across all PTSD traits. We replicated 5 out of 11 CpG sites reported in a prior (Psychiatric Genomics Consortium) PTSD EWAS. Overlap with differentially methylated CpG sites in subregions of the amygdala and hippocampus of human postmortem brains of individuals with PTSD vs. controls was evaluated at the CpG and gene levels. Ten genes of the 195 identified in the brain study overlapped with the 192 identified in our EWAS. There was significant enrichment of genes downregulated in somatostatin interneurons and brain endothelial cells. Regression analyses showed that PTSD case status was significantly associated with accelerated DNA methylation aging. Contrary to previous PTSD EWAS findings, smoking status stratification suggested that the association between PTSD and methylation of the AHRR gene may be confounded by smoking status. Our findings showcase the largest-scale PTSD EWAS in multiple ancestries and the first large PTSD EWAS on symptom severity. We replicated several findings from previous EWAS and greatly extended current knowledge of the relationship between epigenetics and PTSD.","rel_num_authors":16,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Marco Galimberti","author_inst":"Yale University"},{"author_name":"Cassie Overstreet","author_inst":"Yale University"},{"author_name":"Jiarui Chen","author_inst":"Yale University"},{"author_name":"Priya Gupta","author_inst":"BRIC-National Institute of Immunology"},{"author_name":"Cecilia Dao","author_inst":"Yale University"},{"author_name":"Bluma J. Lesch","author_inst":"Yale University"},{"author_name":"Janitza L. Montalvo-Ortiz","author_inst":"Yale University"},{"author_name":"- The V.A. Million Veteran Program","author_inst":"-"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"John H. Krystal","author_inst":"Yale University"},{"author_name":"Renato Polimanti","author_inst":"Yale University"},{"author_name":"Matthew J. Girgenti","author_inst":"Yale School of Medicine"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Genetic predictors of clonal contraction and hematologic response in IDH mutant myeloid malignancies","rel_doi":"10.64898\/2026.09.03.26361825","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.03.26361825","rel_abs":"IDH inhibitors promote differentiation and hematological improvement in myeloid malignancies by reversing epigenetic dysregulation. However, molecular predictors of response remain poorly defined. We retrospectively analyzed 79 patients with IDH-mutated myeloid malignancies treated with either ivosidenib (IDH1; n=36) or enasidenib (IDH2; n=43). Hematologic benefit was assessed using a composite complete hematologic response (CHR), defined by neutrophil and platelet recovery, and transfusion independence. Targeted sequencing was performed at baseline and at best hematologic response. Associations between co-mutations, hematologic response, and treatment duration were evaluated using multivariable models. Overall, 43% of patients achieved CHR, with similar rates between inhibitors. Ivosidenib-treated patients achieving CHR demonstrated a significant reduction in IDH1 VAF (p=0.010), which was not observed in enasidenib-treated CHR patients. Within the CHR cohort, ivosidenib patients had a greater reduction in IDH VAF relative to enasidenib patients (mean VAF change -16.74% vs - 0.05%, p=0.034). Ivosidenib responders demonstrated a trend toward more durable treatment duration compared with enasidenib responders (p = 0.0908). RUNX1 and BCOR mutations were significantly enriched among patients with incomplete hematologic response and were independently associated with shorter treatment duration after adjustment for clinical factors (RUNX1: HR 2.53, p=0.0024; BCOR: HR 2.31, p=0.0058). IDH1 inhibition was associated with clonal contraction and durable hematologic benefit, a pattern not observed with IDH2 inhibition. Co-mutations in RUNX1 and BCOR identified patients unlikely to achieve sustained hematologic improvement, suggesting a secondary block to differentiation. These findings support the integration of mutational and molecular profiling to refine patient selection and guide combinatorial strategies in IDH-mutated myeloid malignancies.\n\nKey Points* Distinct molecular response patterns accompany hematologic benefit following IDH1 versus IDH2 inhibition.\n\n* RUNX1 and BCOR mutations predict inferior hematologic response and shorter duration of IDH inhibitor therapy.","rel_num_authors":21,"rel_authors":[{"author_name":"Amy Song","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Yi Chen","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Sunil Iyer","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Sebastian Fernando","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Varun S Sudunagunta","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Edna Stewart","author_inst":"Columbia University, Department of Biomedical Engineering"},{"author_name":"Rong Deng","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Viviana Scoca","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Jane J Xu","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Benjamin May","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Alina Varabyeva","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Susan J Hsiao","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Christopher Freeman","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Mahesh Mansukhani","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Andrew H Lipsky","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Nicole Lamanna","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Todd L Rosenblat","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Monica Kasbekar","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Joseph G Jurcic","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Brian Chernak","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Aaron D Viny","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"A cyclooxygenase-2 associated pro-tumorigenic inflammatory signature predicts outcome after surgery in lung cancer","rel_doi":"10.64898\/2026.09.04.26362237","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362237","rel_abs":"With increased lung cancer screening, early-stage diagnoses and recurrences are expected to rise. Identifying the [~]20% of patients with early-stage non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), who relapse after curative-intent surgery remains a major clinical challenge. Here, we identify a COX-2-associated pro-tumorigenic inflammatory signature (PTI) in resected tumors as an independent predictor of disease relapse in both LUAD and LUSC, with particular utility within one year after surgery in stage I NSCLC. We developed a clinically compatible workflow for PTI scoring in tumor resections and validated its predictive performance in real-world samples from routine care and screening programs. Spatial immune profiling revealed that PTIhigh tumors, which swiftly recur, exhibit markedly reduced tumor cell content alongside expanded neutrophil-rich immune-stromal compartments. These findings link COX-2-driven inflammation to early post-surgical recurrence in NSCLC and indicate that PTI may serve as a biomarker for risk stratification to guide imaging surveillance and adjuvant therapy decisions.\n\nOne sentence summaryA COX-2-linked pro-tumorigenic inflammatory signature measurable in real-world surgical samples predicts relapse in early-stage lung cancer.","rel_num_authors":27,"rel_authors":[{"author_name":"Victoria Fife","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Christian P. Bromley","author_inst":"Cancer Inflammation & Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK"},{"author_name":"Matthew Roberts","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Ian C. H. Lee","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Daisy Grainger","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Anshuman Chaturvedi","author_inst":"Department of Pathology, Christie NHS Foundation Trust, Manchester, UK"},{"author_name":"Cong Zhou","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Christopher M. Fife","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Karen Morris","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Ariadna Fuertes Gassio","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Sophie Atkinson","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Shamilene Sivagnanam","author_inst":"Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Konjit Betre","author_inst":"Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Antonn J. Cheeseman","author_inst":"Cancer Inflammation & Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK"},{"author_name":"Matthew Crowther","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Jonathan C. M. Wan","author_inst":"Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK"},{"author_name":"Takahiro Karasaki","author_inst":"Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK"},{"author_name":"David Millrine","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Elaine Kilgour","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Nicholas McGranahan","author_inst":"Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK"},{"author_name":"Mariam Jamal-Hanjani","author_inst":"Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK"},{"author_name":"Charles Swanton","author_inst":"Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK"},{"author_name":"- TRACERx consortium","author_inst":""},{"author_name":"Lisa M. Coussens","author_inst":"Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA"},{"author_name":"Philip A. J. Crosbie","author_inst":"Lung Cancer and Thoracic Surgery Directorate, Manchester University NHS Foundation Trust, Manchester, UK"},{"author_name":"Caroline Dive","author_inst":"Cancer Research UK National Biomarker Centre, The University of Manchester, Manchester, UK"},{"author_name":"Santiago Zelenay","author_inst":"Cancer Inflammation & Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Education and Alzheimer Disease Genetic Risk in Associations of GLP-1 Receptor Agonists With Dementia Among Adults With Type 2 Diabetes","rel_doi":"10.64898\/2026.09.04.26362304","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362304","rel_abs":"Objective: To evaluate whether educational attainment and Alzheimer disease genetic risk were associated with GLP-1 receptor agonist initiation and dementia incidence and whether adjustment for these measured factors materially changed the estimated association between GLP-1 receptor agonist initiation and incident dementia among adults with type 2 diabetes. Research Design and Methods: We conducted an observational cohort study using linked electronic health record, survey, and genetic data from 14,364 All of Us Research Program participants with type 2 diabetes. We estimated associations of educational attainment and Alzheimer disease genetic risk with treatment initiation and incident dementia and compared GLP-1 receptor agonist initiators with initiators of non-sodium-glucose cotransporter 2 inhibitor second-line therapies, with a separate sodium-glucose cotransporter 2 inhibitor comparison. Models were estimated before and after additional adjustment for educational attainment, APOE {varepsilon}4, and non-APOE genetic risk. Results: Among 14,364 participants (mean age, 60.2 years; 54.2% female), the mean follow-up duration was 4.3 years. The estimated hazard ratio for dementia comparing GLP-1 receptor agonist initiation with non-SGLT2 inhibitor second-line therapy was 0.85 (95% CI 0.64-1.12) before adjustment for education or Alzheimer disease genetic risk and 0.84 (95% CI 0.64-1.12) after adjustment for educational attainment, APOE {varepsilon}4, and non-APOE genetic risk. Conclusions: Among adults with type 2 diabetes, adjustment for measured educational attainment and Alzheimer disease genetic susceptibility produced little change in the estimated association between GLP-1 receptor agonist initiation and incident dementia. These findings do not exclude confounding by these factors in other populations or residual confounding from socioeconomic, clinical, behavioral, and health-care-related factors.","rel_num_authors":14,"rel_authors":[{"author_name":"Jingxuan Wang","author_inst":"Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02"},{"author_name":"Anna M. Pederson","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158"},{"author_name":"Michael D. Flanders","author_inst":"Department of Epidemiology, Brown University, Providence, RI 02903"},{"author_name":"Minhyuk Choi","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158"},{"author_name":"Peter Buto","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118"},{"author_name":"Kendra D. Sims","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118"},{"author_name":"Ruijia Chen","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118"},{"author_name":"Elyse Couch","author_inst":"Department of Health Services, Policy, & Practice, Brown University, Providence, RI 02903"},{"author_name":"Paola Gilsanz","author_inst":"Division of Research, Kaiser Permanente Northern California, Pleasanton, CA 94588"},{"author_name":"Kaleen N. Hayes","author_inst":"Department of Health Services, Policy, & Practice, Brown University, Providence, RI 02903"},{"author_name":"Andrew R. Zullo","author_inst":"Department of Epidemiology, Brown University, Providence, RI 02903"},{"author_name":"Andrew Stokes","author_inst":"Division of Research, Kaiser Permanente Northern California, Pleasanton, CA 94588"},{"author_name":"Maria M. Glymour","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118"},{"author_name":"Sarah F. Ackley","author_inst":"Department of Epidemiology, Brown University, Providence, RI 02903"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Education and Alzheimer Disease Genetic Risk in Associations of GLP-1 Receptor Agonists With Dementia Among Adults With Type 2 Diabetes","rel_doi":"10.64898\/2026.09.04.26362304","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362304","rel_abs":"Objective: To evaluate whether educational attainment and Alzheimer disease genetic risk were associated with GLP-1 receptor agonist initiation and dementia incidence and whether adjustment for these measured factors materially changed the estimated association between GLP-1 receptor agonist initiation and incident dementia among adults with type 2 diabetes. Research Design and Methods: We conducted an observational cohort study using linked electronic health record, survey, and genetic data from 14,364 All of Us Research Program participants with type 2 diabetes. We estimated associations of educational attainment and Alzheimer disease genetic risk with treatment initiation and incident dementia and compared GLP-1 receptor agonist initiators with initiators of non-sodium-glucose cotransporter 2 inhibitor second-line therapies, with a separate sodium-glucose cotransporter 2 inhibitor comparison. Models were estimated before and after additional adjustment for educational attainment, APOE {varepsilon}4, and non-APOE genetic risk. Results: Among 14,364 participants (mean age, 60.2 years; 54.2% female), the mean follow-up duration was 4.3 years. The estimated hazard ratio for dementia comparing GLP-1 receptor agonist initiation with non-SGLT2 inhibitor second-line therapy was 0.85 (95% CI 0.64-1.12) before adjustment for education or Alzheimer disease genetic risk and 0.84 (95% CI 0.64-1.12) after adjustment for educational attainment, APOE {varepsilon}4, and non-APOE genetic risk. Conclusions: Among adults with type 2 diabetes, adjustment for measured educational attainment and Alzheimer disease genetic susceptibility produced little change in the estimated association between GLP-1 receptor agonist initiation and incident dementia. These findings do not exclude confounding by these factors in other populations or residual confounding from socioeconomic, clinical, behavioral, and health-care-related factors.","rel_num_authors":14,"rel_authors":[{"author_name":"Jingxuan Wang","author_inst":"Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02"},{"author_name":"Anna M. Pederson","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158"},{"author_name":"Michael D. Flanders","author_inst":"Department of Epidemiology, Brown University, Providence, RI 02903"},{"author_name":"Minhyuk Choi","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158"},{"author_name":"Peter Buto","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118"},{"author_name":"Kendra D. Sims","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118"},{"author_name":"Ruijia Chen","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118"},{"author_name":"Elyse Couch","author_inst":"Department of Health Services, Policy, & Practice, Brown University, Providence, RI 02903"},{"author_name":"Paola Gilsanz","author_inst":"Division of Research, Kaiser Permanente Northern California, Pleasanton, CA 94588"},{"author_name":"Kaleen N. Hayes","author_inst":"Department of Health Services, Policy, & Practice, Brown University, Providence, RI 02903"},{"author_name":"Andrew R. Zullo","author_inst":"Department of Epidemiology, Brown University, Providence, RI 02903"},{"author_name":"Andrew Stokes","author_inst":"Division of Research, Kaiser Permanente Northern California, Pleasanton, CA 94588"},{"author_name":"Maria M. Glymour","author_inst":"Department of Epidemiology, Boston University, Boston, MA 02118"},{"author_name":"Sarah F. Ackley","author_inst":"Department of Epidemiology, Brown University, Providence, RI 02903"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Longitudinal intergenerational patterns of psychopathology in a population-based dataset: an ABCD study","rel_doi":"10.64898\/2026.09.04.26362261","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362261","rel_abs":"Objective: To identify longitudinal trajectories of clinically relevant psychopathology from middle childhood to early adolescence and to examine the extent to which parental psychopathology influences child psychopathology trajectories. Method: Participants were children and biological parents enrolled in the Adolescent Brain Cognitive Development (ABCD) Study (N=11,142) with up to five annual assessments of psychopathology using the Child Behavior Checklist and the Adult Self Report. Sequential latent class analysis identified longitudinal trajectories based on clinically elevated subscale scores (T-score[&ge;]65). Cross-lagged panel models examined bidirectional associations between parent and child internalizing and externalizing symptoms across development, including separate analyses of mother-child and father-child dyads. Results: The majority of the sample (76.1%) showed stable psychopathology trajectories (67.9% low, 6.8% moderate, 1.3% high) of clinically elevated symptom endorsement. Nearly one-quarter of participants (21.9%) transitioned between trajectory classes over time (9.9% improved, 8.1% worsened, 5.9% fluctuating). Greater parental psychopathology was associated with increased odds of membership in the moderate- and high-symptom trajectory classes (ORs=1.28-2.61, p<0.001). Among 10,633 biological parent-child dyads, maternal internalizing symptoms demonstrated the strongest longitudinal associations with child internalizing symptoms 2-years later (standardized cross-lagged path {beta} = 0.128, 95% CI = 0.094-0.161, p<0.001). Findings remained robust across sensitivity analyses. Conclusion: These findings provide novel insight into population-level trends of psychopathology trajectories and the importance of understanding how parental psychopathology influences child psychopathology over the course of development. This study highlights the importance of maternal psychopathology as a risk factor for child psychopathology elevations across development.","rel_num_authors":7,"rel_authors":[{"author_name":"Hajer Nakua","author_inst":"Children's Hospital of Eastern Ontario Research Institute \/ University of Ottawa"},{"author_name":"Jingxi Wang","author_inst":"Department of Biostatistics, Mailman School of Public Health, Columbia University"},{"author_name":"Jennifer Warmingham","author_inst":"University of Rochester"},{"author_name":"Nicole Racine","author_inst":"School of Psychology, University of Ottawa"},{"author_name":"Marco Solmi","author_inst":"Ottawa Hospital Research Institute \/ University of Ottawa"},{"author_name":"Rachel Marsh","author_inst":"Department of Psychiatry, Columbia University Irving Medical Center"},{"author_name":"Seonjoo Lee","author_inst":"Columbia University"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Longitudinal intergenerational patterns of psychopathology in a population-based dataset: an ABCD study","rel_doi":"10.64898\/2026.09.04.26362261","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362261","rel_abs":"Objective: To identify longitudinal trajectories of clinically relevant psychopathology from middle childhood to early adolescence and to examine the extent to which parental psychopathology influences child psychopathology trajectories. Method: Participants were children and biological parents enrolled in the Adolescent Brain Cognitive Development (ABCD) Study (N=11,142) with up to five annual assessments of psychopathology using the Child Behavior Checklist and the Adult Self Report. Sequential latent class analysis identified longitudinal trajectories based on clinically elevated subscale scores (T-score[&ge;]65). Cross-lagged panel models examined bidirectional associations between parent and child internalizing and externalizing symptoms across development, including separate analyses of mother-child and father-child dyads. Results: The majority of the sample (76.1%) showed stable psychopathology trajectories (67.9% low, 6.8% moderate, 1.3% high) of clinically elevated symptom endorsement. Nearly one-quarter of participants (21.9%) transitioned between trajectory classes over time (9.9% improved, 8.1% worsened, 5.9% fluctuating). Greater parental psychopathology was associated with increased odds of membership in the moderate- and high-symptom trajectory classes (ORs=1.28-2.61, p<0.001). Among 10,633 biological parent-child dyads, maternal internalizing symptoms demonstrated the strongest longitudinal associations with child internalizing symptoms 2-years later (standardized cross-lagged path {beta} = 0.128, 95% CI = 0.094-0.161, p<0.001). Findings remained robust across sensitivity analyses. Conclusion: These findings provide novel insight into population-level trends of psychopathology trajectories and the importance of understanding how parental psychopathology influences child psychopathology over the course of development. This study highlights the importance of maternal psychopathology as a risk factor for child psychopathology elevations across development.","rel_num_authors":7,"rel_authors":[{"author_name":"Hajer Nakua","author_inst":"Children's Hospital of Eastern Ontario Research Institute \/ University of Ottawa"},{"author_name":"Jingxi Wang","author_inst":"Department of Biostatistics, Mailman School of Public Health, Columbia University"},{"author_name":"Jennifer Warmingham","author_inst":"University of Rochester"},{"author_name":"Nicole Racine","author_inst":"School of Psychology, University of Ottawa"},{"author_name":"Marco Solmi","author_inst":"Ottawa Hospital Research Institute \/ University of Ottawa"},{"author_name":"Rachel Marsh","author_inst":"Department of Psychiatry, Columbia University Irving Medical Center"},{"author_name":"Seonjoo Lee","author_inst":"Columbia University"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Longitudinal intergenerational patterns of psychopathology in a population-based dataset: an ABCD study","rel_doi":"10.64898\/2026.09.04.26362261","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362261","rel_abs":"Objective: To identify longitudinal trajectories of clinically relevant psychopathology from middle childhood to early adolescence and to examine the extent to which parental psychopathology influences child psychopathology trajectories. Method: Participants were children and biological parents enrolled in the Adolescent Brain Cognitive Development (ABCD) Study (N=11,142) with up to five annual assessments of psychopathology using the Child Behavior Checklist and the Adult Self Report. Sequential latent class analysis identified longitudinal trajectories based on clinically elevated subscale scores (T-score[&ge;]65). Cross-lagged panel models examined bidirectional associations between parent and child internalizing and externalizing symptoms across development, including separate analyses of mother-child and father-child dyads. Results: The majority of the sample (76.1%) showed stable psychopathology trajectories (67.9% low, 6.8% moderate, 1.3% high) of clinically elevated symptom endorsement. Nearly one-quarter of participants (21.9%) transitioned between trajectory classes over time (9.9% improved, 8.1% worsened, 5.9% fluctuating). Greater parental psychopathology was associated with increased odds of membership in the moderate- and high-symptom trajectory classes (ORs=1.28-2.61, p<0.001). Among 10,633 biological parent-child dyads, maternal internalizing symptoms demonstrated the strongest longitudinal associations with child internalizing symptoms 2-years later (standardized cross-lagged path {beta} = 0.128, 95% CI = 0.094-0.161, p<0.001). Findings remained robust across sensitivity analyses. Conclusion: These findings provide novel insight into population-level trends of psychopathology trajectories and the importance of understanding how parental psychopathology influences child psychopathology over the course of development. This study highlights the importance of maternal psychopathology as a risk factor for child psychopathology elevations across development.","rel_num_authors":7,"rel_authors":[{"author_name":"Hajer Nakua","author_inst":"Children's Hospital of Eastern Ontario Research Institute \/ University of Ottawa"},{"author_name":"Jingxi Wang","author_inst":"Department of Biostatistics, Mailman School of Public Health, Columbia University"},{"author_name":"Jennifer Warmingham","author_inst":"University of Rochester"},{"author_name":"Nicole Racine","author_inst":"School of Psychology, University of Ottawa"},{"author_name":"Marco Solmi","author_inst":"Ottawa Hospital Research Institute \/ University of Ottawa"},{"author_name":"Rachel Marsh","author_inst":"Department of Psychiatry, Columbia University Irving Medical Center"},{"author_name":"Seonjoo Lee","author_inst":"Columbia University"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"Abdominal Adiposity and Lacunar Stroke: A Mendelian Randomization Mediation Study","rel_doi":"10.64898\/2026.09.02.26362110","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26362110","rel_abs":"Background: Lacunar stroke accounts for approximately 25% of ischaemic strokes and is linked to metabolic and vascular risk factors. Abdominal adiposity, measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI), is a heritable predictor of cerebrovascular disease independent of overall adiposity, but its biological mediators remain unclear. We performed a two-sample Mendelian randomization (MR) mediation analysis of 16 candidate biomarkers. Methods: Summary-level GWAS data were obtained from the IEU Open GWAS and EBI GWAS Catalog for WHRadjBMI (exposure), 16 mediators, and lacunar stroke (outcome). Instruments met genome-wide significance (P < 5 x 10), LD clumping (r2 < 0.001, 10,000 kb; 1000 Genomes European panel), and F-statistic 10. Inverse variance weighted regression was the primary analysis, with MR-Egger, weighted median, and MR-PRESSO sensitivity analyses. Mediation was quantified using the product-of-coefficients method with delta-method standard errors. Results: Systolic blood pressure showed the largest mediation proportion (29.6%; 95% CI, 12.7%-46.5%), followed by diastolic blood pressure (29.2%; 12.1%-46.3%) and glycated hemoglobin (23.0%; 11.2% to 57.2%). Other mediators included triglycerides (10.8%), fasting insulin (9.9%), blood glucose (7.0%), HDL cholesterol (3.2%), and LDL cholesterol (1.1%). Sensitivity analyses were generally consistent, though MR-Egger intercepts suggested directional pleiotropy for glycoprotein acetyls and CRP (Path A only). Because mediators are intercorrelated, proportions cannot be summed; multivariable MR is needed for joint effects. The HbA1c estimate was imprecise and requires cautious interpretation. Conclusions: Blood pressure, and possibly glycemic control, are the leading mediators linking abdominal adiposity to lacunar stroke. These findings support prioritizing blood pressure management-and potentially glycemic control-to reduce small vessel cerebrovascular disease in individuals with elevated WHRadjBMI.","rel_num_authors":3,"rel_authors":[{"author_name":"Mengmeng Guo","author_inst":"Peking University People's Hospital"},{"author_name":"Lu Cong","author_inst":"Peking University People's Hospital"},{"author_name":"Zunjing Liu","author_inst":"Peking University People's Hospital"}],"rel_date":"2026-09-08","rel_site":"medrxiv"},{"rel_title":"A passive protein environment offsets RNA folding energetics in cells","rel_doi":"10.64898\/2026.09.07.749977","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749977","rel_abs":"RNA structure can be predicted from sequence in dilute solution, but these predictions often fail in cells. Many cellular RNAs keep their in vitro folds, whereas others are substantially less structured. We combined single-molecule FRET with Xenopus oocyte extract to measure RNA folding and duplex formation under cell-like conditions. Extract proteins passively suppressed base pairing: they slowed apparent strand association while leaving duplex dissociation largely unchanged, without sequence specificity or ATP consumption. A competitive binding model captured this activity as an effective folding penalty of ~0.45 kcal\/mol per nucleotide. Similar activity occurred in HeLa lysate. Applied to in-cell chemical probing data, this correction stratified reactivity across ~42,000 stem-loops, whereas predictive models established in dilute solution classified nearly all as stably folded. Our results identify a passive protein-mediated mechanism as a key contributor to cellular RNA folding, shifting the balance between paired and unpaired states without changing the underlying base-pairing rules.","rel_num_authors":3,"rel_authors":[{"author_name":"Marco Todisco","author_inst":"Whitehead Institute"},{"author_name":"Filip Boskovic","author_inst":"HHMI-University of Chicago"},{"author_name":"Ankur Jain","author_inst":"Whitehead Institute for Biomedical Research"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Interface-mediated secondary phase separation","rel_doi":"10.64898\/2026.09.04.749388","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749388","rel_abs":"Inside living cells, many types of biomolecular condensates coexist and interact. Recent experiments have shown that new phases often form at the surface of preexisting condensates. However, the mechanisms for this interface-mediated phase transition remain elusive despite its importance to numerous biological processes. Here, we show that interface-mediated secondary phase separation is a universal pathway for forming a new phase in multicomponent solutions. Using Cahn-Hilliard simulations, we successfully generate puncta of client protein on the surface of scaffold condensates. Based on a quasistatic protocol, we theoretically demonstrate that an interfacial instability triggers new-phase formation and predict the amount of client protein needed for the instability to occur. Remarkably, our quasistatic theory successfully predicts the onset of secondary phase separation even if the client is rapidly added or both the client and scaffold are rapidly added. In the latter case, coarsening of the primary condensates drives secondary phase separation. Our work reveals that cells can exploit existing condensates to lower nucleation barriers of new phases, with important implications for protein aggregation.","rel_num_authors":2,"rel_authors":[{"author_name":"Kaifeng Weng","author_inst":"Peking University"},{"author_name":"Jie Lin","author_inst":"Peking University"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Universal modulation of liquid-liquid phase separation by macromolecules","rel_doi":"10.64898\/2026.09.03.749048","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749048","rel_abs":"Liquid-liquid phase separation (LLPS) widely organizes the cellular interior, yet how third-party macromolecules modulate LLPS remains a puzzle. While one would expect that macromolecules can either promote or suppress phase separation, empirical observations show that a small dosage of macromolecules virtually always promotes phase separation. To resolve this paradox, we study the linear response of phase separation to macromolecule addition. We prove that for macromolecules significantly larger than the solvent molecule, their addition essentially always promotes phase separation, regardless of how they interact with the scaffold protein. Crucially, in the biologically relevant scenario of dilute condensates, the linear responses, including the saturation volume fraction, scale proportionally to [1-v2(1+{chi}12)2], where v2 is the macromolecule size and {chi}12 is the scaffold-macromolecule interaction parameter. Importantly, this universal behavior extends to multicomponent solutions in which the effective interaction parameter is composition-dependent. Our work shifts macromolecular modulation of LLPS from empirical observation to predictable design.","rel_num_authors":2,"rel_authors":[{"author_name":"Yunxiao Kan","author_inst":"Peking University"},{"author_name":"Jie Lin","author_inst":"Peking University"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"EukaUTR: a foundation model for functional modelling and design of eukaryotic 3' UTRs","rel_doi":"10.64898\/2026.09.07.749809","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.07.749809","rel_abs":"Eukaryotic mRNA 3' UTRs encode regulatory information that shapes post-transcriptional control, RNA fate and gene expression. However, a 3' UTR-specific foundation model that spans broad eukaryotic sequence diversity while supporting both functional prediction and sequence design is lacking. Here we present EukaUTR, a 3' UTR-specific foundation model trained on a large-scale eukaryotic 3' UTR sequence corpus spanning diverse evolutionary lineages. Across 13 prediction tasks spanning post-transcriptional regulation, RNA fate and expression output, EukaUTR models matched or exceeded the strongest external baselines on nearly all tasks, with relative improvements of up to 27.45%. EukaUTR also generated de novo 3' UTRs with natural-like sequence and regulatory properties. EukaUTR-Guide further derived stability-associated signals from small sequence sets to guide editing towards enhanced predicted stability. Together, EukaUTR provides a sequence-to-function-to-design framework for transferable 3' UTR modelling and design.","rel_num_authors":9,"rel_authors":[{"author_name":"Mei lang","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences"},{"author_name":"Xingyu Fang","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China"},{"author_name":"Mingxuan Chen","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China"},{"author_name":"Zhen Wang","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences"},{"author_name":"Zhaowen Cheng","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China"},{"author_name":"Xiagu Zhu","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China"},{"author_name":"Kin Yip Tam","author_inst":"Faculty of Health Sciences, University of Macau, Avenida da  Universidade, Taipa, 999078, China"},{"author_name":"Junwei Zhang","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China"},{"author_name":"Xiaolin Li","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Transcription-Coupled Chromatin Reinforcement Maintains the Mature Cardiomyocyte State","rel_doi":"10.64898\/2026.09.04.749300","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749300","rel_abs":"Chromatin homeostasis is fundamental to maintaining transcriptional programs that stabilize cell states while permitting plasticity for timely state transitions. However, mechanisms that actively sustain mature cell states after their establishment remain poorly defined despite being essential for lifelong maintenance of specialized cellular functions. Here we demonstrate that the transcription-coupled chromatin regulator RNF20 is crucial for maintaining chromatin accessibility at identity-associated promoters that support mature cardiomyocyte transcriptional programs in adult murine cardiomyocytes. Depletion of RNF20 progressively erodes the transcriptional, structural, and functional integrity of adult cardiomyocytes and activates AP-1-associated stress-responsive enhancer elements without cell-cycle re-entry. Spatial transcriptomics further revealed a subendocardial localization of this stress-responsive state. Together, these findings support a model in which transcription-coupled chromatin reinforcement continuously stabilizes the mature cardiomyocyte attractor state while constraining transitions toward pathological cell states.","rel_num_authors":4,"rel_authors":[{"author_name":"Han-Hsuan Tang","author_inst":"Academia Sinica"},{"author_name":"Hsin-Yi Tseng","author_inst":"Academia Sinica"},{"author_name":"Chia-Yeh Lin","author_inst":"Academia Sinica"},{"author_name":"Cheng-Fu Kao","author_inst":"Academia Sinica"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Transcription-Coupled Chromatin Reinforcement Maintains the Mature Cardiomyocyte State","rel_doi":"10.64898\/2026.09.04.749300","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749300","rel_abs":"Chromatin homeostasis is fundamental to maintaining transcriptional programs that stabilize cell states while permitting plasticity for timely state transitions. However, mechanisms that actively sustain mature cell states after their establishment remain poorly defined despite being essential for lifelong maintenance of specialized cellular functions. Here we demonstrate that the transcription-coupled chromatin regulator RNF20 is crucial for maintaining chromatin accessibility at identity-associated promoters that support mature cardiomyocyte transcriptional programs in adult murine cardiomyocytes. Depletion of RNF20 progressively erodes the transcriptional, structural, and functional integrity of adult cardiomyocytes and activates AP-1-associated stress-responsive enhancer elements without cell-cycle re-entry. Spatial transcriptomics further revealed a subendocardial localization of this stress-responsive state. Together, these findings support a model in which transcription-coupled chromatin reinforcement continuously stabilizes the mature cardiomyocyte attractor state while constraining transitions toward pathological cell states.","rel_num_authors":4,"rel_authors":[{"author_name":"Han-Hsuan Tang","author_inst":"Academia Sinica"},{"author_name":"Hsin-Yi Tseng","author_inst":"Academia Sinica"},{"author_name":"Chia-Yeh Lin","author_inst":"Academia Sinica"},{"author_name":"Cheng-Fu Kao","author_inst":"Academia Sinica"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Ebola virus mRNAs contain RNA structures that are critical for viral infection and targetable by antisense oligonucleotides","rel_doi":"10.64898\/2026.09.04.749507","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749507","rel_abs":"Filoviruses, such as Ebola virus (EBOV), are highly pathogenic non-segmented negative-sense RNA viruses (nsNSVs) with limited therapeutic options. Filovirus RNA structures remain largely untapped due to the enhanced biosafety requirements for handling infectious virus. Here, we present the first in-cell secondary structure maps of four EBOV mRNAs (VP35, VP40, VP30, and VP24) using two orthogonal chemical probing approaches: SHAPE-MaP and fbDMS-MaP. We find that EBOV mRNA coding sequences (CDS) are highly structured, much like +ssRNA viruses, whereas untranslated regions (UTRs) are significantly less structured. This suggests that high CDS structure contents are general features of viral translation templates, and that nsNSVs have evolved separate regulatory function at the RNA structure level that extends beyond using distinct mRNAs and genomes. These structure maps are consistent with formation of mRNA 5' hairpin structures during infection and reveal numerous additional RNA structures within the CDS, 3' UTRs, and at CDS-UTR junctions. To assess functionality, we disrupted these structures with locked nucleic acid (LNA) antisense oligonucleotides. Disrupting the TSS hairpins in VP35, VP30, and VP24 decreased infection by >60%, indicating these mRNA structures are critical for infection. LNA targeting of the newly identified structures reduced EBOV infection by 31% to 88%, thereby linking RNA structural integrity to viral function. Synonymous mutation rates and covariation analysis provided evolutionary support across mammalian filoviruses for the functional RNA elements observed. Collectively, these results demonstrate EBOV mRNAs contain numerous conserved RNA motifs contributing to viral infection, and that these elements represent promising targets for development of pan-filoviral therapeutics.","rel_num_authors":6,"rel_authors":[{"author_name":"Michelle Luo","author_inst":"Yale University"},{"author_name":"Judith Olejnik","author_inst":"Boston University School of Medicine"},{"author_name":"Kristina Meier","author_inst":"Boston University"},{"author_name":"Tanja Hann","author_inst":"Yale University"},{"author_name":"Elke Muhlberger","author_inst":"Boston University School of Medicine"},{"author_name":"Anna Marie Pyle","author_inst":"Yale University"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Increased receptor binding capability of the SARS-CoV-2 saltational variant PJ.2.1","rel_doi":"10.64898\/2026.09.03.749172","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749172","rel_abs":"The recently identified SARS-CoV-2 saltational variant PJ.2.1, a highly mutated descendant of MC.10.1, has achieved rapid intercontinental spread since its detection in May 2026. Here, we show that PJ.2.1 exhibits exceptionally high human ACE2-binding capability, significantly outperforming contemporary variants such as NB.1.8.1, XFG, and BA.3.2.2. However, despite acquiring over 25 spike mutations, PJ.2.1 remains antigenically similar to the circulating JN.1 family and does not display strong humoral immune evasion. Neutralization profiling indicates that PJ.2.1 possesses heightened neutralization sensitivity to human plasma and RBD-targeting antibodies, especially against cryptic-site-targeting class 4 and class 5 antibodies. This distinct sensitivity profile strongly suggests an altered spike structural dynamic that favors a receptor-accessible \"up\" conformation. While PJ.2.1 currently lacks the extreme immune evasion capabilities of other contemporary strains, its robust baseline receptor binding strength mirrors the early evolutionary trajectory of BA.2.86 to JN.1. This high receptor binding affinity provides a structural buffer that could facilitate the rapid acquisition of potent immune-evasive mutations, necessitating continued genomic, epidemiological, and virological surveillance of PJ.2.1.","rel_num_authors":8,"rel_authors":[{"author_name":"Peizhuo He","author_inst":"Changping Laboratory"},{"author_name":"Bingkun Li","author_inst":"Changping Laboratory"},{"author_name":"Caiwan Guo","author_inst":"Peking University"},{"author_name":"Lingling Yu","author_inst":"Changping Laboratory"},{"author_name":"Yuanling Yu","author_inst":"Changping Laboratory"},{"author_name":"Fanchong Jian","author_inst":"Peking University"},{"author_name":"Fei Shao","author_inst":"Changping Laboratory"},{"author_name":"Yunlong Cao","author_inst":"Peking University"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Terminal selector and subtype selector function across 200 million years of nematode evolution","rel_doi":"10.64898\/2026.09.04.749377","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749377","rel_abs":"The evolution of brains is subject to investigation in many different animal groups, each offering unique advantages to advance our understanding of the cellular, molecular and regulatory substrates of evolutionary change. Here, we use two nematode species, C. elegans and P. pacificus, separated by more than 200 million years of evolution to explore how neuronal cell types and the regulatory programs instructing the identity of these cell types have evolved over time. Using gene expression pattern analysis, we compare the differentiation programs of over half of all nematode neuron classes. To explore how the gene regulatory architecture of neuronal differentiation programs evolves, we apply our deep understanding of neuronal differentiation programs, controlled by terminal selectors and subtype selectors in C. elegans. Through mutant analysis of orthologous P. pacificus regulatory factors, we elucidate patterns of conservation and novelties over such substantial evolutionary distance. We discovered striking similarities in terminal selector expression and activities throughout the nervous system but also observed that terminal selectors can acquire novel sites of expression and distinct regulatory capabilities, manifested by changes in effector gene expression and, hence, neuronal phenotypes. Our mutant analysis argues for a buffering of terminal selector function and for an evolutionary lability of differences in closely related neuronal subtypes. Taken together, our analysis reveals molecular substrates of evolutionary change in nervous systems.","rel_num_authors":11,"rel_authors":[{"author_name":"Yasmin Ramadan","author_inst":"Columbia University"},{"author_name":"Curtis Loer","author_inst":"University of San Diego"},{"author_name":"Hyunsoo Yim","author_inst":"Columbia University"},{"author_name":"Luke T Geiger","author_inst":"Columbia University"},{"author_name":"Daniel M Merritt","author_inst":"Columbia University"},{"author_name":"Itai Antoine Toker","author_inst":"Columbia University"},{"author_name":"Joke Evenblij","author_inst":"Columbia University"},{"author_name":"Hanh Witte","author_inst":"Max Planck Institut"},{"author_name":"Steven J Cook","author_inst":"Columbia University"},{"author_name":"Ralf J Sommer","author_inst":"Max Planck Institut"},{"author_name":"Oliver Hobert","author_inst":"Columbia University"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"SPP1+ Microglia Are Associated with Neuroimmune Rewiring and Glutamatergic Neuronal Injury in ART-Suppressed People Living with HIV","rel_doi":"10.64898\/2026.09.04.749241","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749241","rel_abs":"Abstract Antiretroviral therapy (ART) effectively suppresses systemic HIV replication but does not eradicate viral reservoirs in the brain, where their identity and contribution to neurological injury remain poorly defined. Using bulk, single-cell, and single-nucleus transcriptomics of postmortem human brain tissue, we identify an activated SPP1 microglial population that expands 5.8-fold during ART and serves as the primary central nervous system (CNS) reservoir, preferentially harboring HIV transcripts. These reservoir microglia adopt a distinct, immune-evasive reprogramming state marked by chronic type I interferon signaling and inflammasome activation, which we recapitulate in primary human microglia via prolonged interferon-{beta} exposure. We show that viral transcription in ART-suppressed brains is dominated by nef, which may sustain the viral reservoir by disrupting host HLA-A and HLA-E presentation machinery. This persistent, immune-evasive state is associated with TREM2-C1QC complement-mediated synaptic pruning and severe DNA damage response dysregulation, culminating in a profound loss of VGLUT1 and GAD67 glutamatergic neurons that persists despite viral suppression. Our findings establish SPP1 microglia as an active, pathogenic CNS reservoir, identifying the SPP1, MHC-I, and complement pathways as therapeutic targets to eliminate viral persistence and reverse HIV-associated neurocognitive dysfunction.","rel_num_authors":11,"rel_authors":[{"author_name":"Ciniso S Shabangu","author_inst":"The University of North Carolina at Chapel Hill"},{"author_name":"Hongjie Chen","author_inst":"The University of North Carolina at Chapel Hill"},{"author_name":"Manickam Ashokkumar","author_inst":"UNC-Chapel Hill: The University of North Carolina at Chapel Hill"},{"author_name":"Nikesh Katuwal","author_inst":"The University of North Carolina at Chapel Hill"},{"author_name":"Jacob B Lovins","author_inst":"UNC-Chapel Hill: The University of North Carolina at Chapel Hill"},{"author_name":"Edward P Browne","author_inst":"UNC-CH"},{"author_name":"Sara Gianella","author_inst":"University of California at San Diego, La Jolla, CA, USA"},{"author_name":"Antoine Chaillon","author_inst":"University of California San Diego"},{"author_name":"David M. Margolis","author_inst":"The University of North Carolina at Chapel Hill School of Medicine"},{"author_name":"Yuyang Tang","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Guochun Jiang","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Why woodiness repeatedly evolves--and disappears","rel_doi":"10.64898\/2026.09.04.749323","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749323","rel_abs":"Derived woodiness--the evolution of woody growth from herbaceous ancestors--has arisen hundreds of times across flowering plants, yet the environmental conditions associated with its repeated evolution remain poorly understood. Here, we analyse woodiness evolution in the mustard family (Brassicaceae; ~4,150 species) using a time-calibrated phylogeny of 2,927 species, including 374 of the 385 known woody species, together with global growth-form and climatic niche data. We infer 231 independent origins of woodiness alongside 176 reversals to herbaceousness, indicating that woodiness evolves repeatedly but remains evolutionarily unstable. Although woody species are enriched on islands, most occur on the mainland, where woodiness is consistently associated with drought and reduced frost. Correlated-evolution analyses reveal that drought is associated primarily with the persistence of woodiness, whereas reduced frost is associated with gains of woodiness and increased frost with its loss. These findings identify distinct climatic associations with the gain, persistence, and loss of woody growth forms.","rel_num_authors":53,"rel_authors":[{"author_name":"Kasper P. Hendriks","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Ihsan A. Al-Shehbaz","author_inst":"Missouri Botanical Garden"},{"author_name":"Dmitry A. German","author_inst":"Altai State University"},{"author_name":"Marcus A. Koch","author_inst":"Heidelberg University"},{"author_name":"Lydia van Slooten","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Carlijn Kusse","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Lisa J.M.A. Dominicus","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Marit Kuijt","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Lila E. Trepp","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Sander van Zon","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Elena Castillo-Lorenzo","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"Baris Ozudogru","author_inst":"Hacettepe University"},{"author_name":"Andreas Berger","author_inst":"Natural History Museum Vienna"},{"author_name":"Michael D. Windham","author_inst":"Duke University"},{"author_name":"Leopoldo Medina Domingo","author_inst":"Real Jardin Botanico (CSIC)"},{"author_name":"Nora Walden","author_inst":"Heidelberg University"},{"author_name":"Christiane Kiefer","author_inst":"Heidelberg University"},{"author_name":"David S. Aukes","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Dario Javier Schiavinato","author_inst":"University of Buenos Aires"},{"author_name":"Edie Burns","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"C. Donovan Bailey","author_inst":"New Mexico State University"},{"author_name":"Raquel Negrao","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"Stanislav _paniel","author_inst":"Slovak Academy of Sciences"},{"author_name":"Alexey P. Seregin","author_inst":"M. V. Lomonosov Moscow State University"},{"author_name":"Hamid Moazzeni","author_inst":"Ferdowsi University of Mashhad"},{"author_name":"Oscar Toro-Nunez","author_inst":"Universidad de Concepcion"},{"author_name":"Vanessa R. Invernon","author_inst":"Museum national dHistoire naturelle"},{"author_name":"Atena Eslami-Farouji","author_inst":"Shiraz University"},{"author_name":"Peter Heenan","author_inst":"Bioeconomy Science Institute"},{"author_name":"Terezie Mandakova","author_inst":"Masaryk University"},{"author_name":"Hongliang Chen","author_inst":"Zhejiang Chinese Medical University"},{"author_name":"Martin A. Lysak","author_inst":"Masaryk University"},{"author_name":"Natalia M. Shiyan","author_inst":"M.G. Kholodny Institute of Botany"},{"author_name":"Nikolai M. Hay","author_inst":"Duke University"},{"author_name":"Mats Thulin","author_inst":"Uppsala University"},{"author_name":"Robert Vogt","author_inst":"Freie Universitat Berlin"},{"author_name":"Mathieu Chambouleyron","author_inst":"Reneco North Africa"},{"author_name":"Steven B. Janssens","author_inst":"Meise Botanic Garden"},{"author_name":"Marie Briggs","author_inst":"Royal Botanic Garden Edinburgh"},{"author_name":"Michaela Schmull","author_inst":"Harvard University"},{"author_name":"Alan Forrest","author_inst":"Royal Botanic Garden Edinburgh"},{"author_name":"Hang Sun","author_inst":"Chinese Academy of Sciences"},{"author_name":"Alessia Guggisberg","author_inst":"ETH Zurich"},{"author_name":"Fred W. Stauffer","author_inst":"Botanic Garden of Geneva"},{"author_name":"Pieter J.D. Winter","author_inst":"South African National Biodiversity Institute, Kirstenbosch"},{"author_name":"M. Eric Schranz","author_inst":"Wageningen University & Research"},{"author_name":"Lachezar A. Nikolov","author_inst":"Indiana University"},{"author_name":"Alexandre R. Zuntini","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"William J. Baker","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"Felix Forest","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"Olivier Maurin","author_inst":"Meise Botanic Garden"},{"author_name":"Klaus Mummenhoff","author_inst":"University of Osnabruck"},{"author_name":"Frederic Lens","author_inst":"Naturalis Biodiversity Center"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Why woodiness repeatedly evolves--and disappears","rel_doi":"10.64898\/2026.09.04.749323","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.04.749323","rel_abs":"Derived woodiness--the evolution of woody growth from herbaceous ancestors--has arisen hundreds of times across flowering plants, yet the environmental conditions associated with its repeated evolution remain poorly understood. Here, we analyse woodiness evolution in the mustard family (Brassicaceae; ~4,150 species) using a time-calibrated phylogeny of 2,927 species, including 374 of the 385 known woody species, together with global growth-form and climatic niche data. We infer 231 independent origins of woodiness alongside 176 reversals to herbaceousness, indicating that woodiness evolves repeatedly but remains evolutionarily unstable. Although woody species are enriched on islands, most occur on the mainland, where woodiness is consistently associated with drought and reduced frost. Correlated-evolution analyses reveal that drought is associated primarily with the persistence of woodiness, whereas reduced frost is associated with gains of woodiness and increased frost with its loss. These findings identify distinct climatic associations with the gain, persistence, and loss of woody growth forms.","rel_num_authors":53,"rel_authors":[{"author_name":"Kasper P. Hendriks","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Ihsan A. Al-Shehbaz","author_inst":"Missouri Botanical Garden"},{"author_name":"Dmitry A. German","author_inst":"Altai State University"},{"author_name":"Marcus A. Koch","author_inst":"Heidelberg University"},{"author_name":"Lydia van Slooten","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Carlijn Kusse","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Lisa J.M.A. Dominicus","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Marit Kuijt","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Lila E. Trepp","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Sander van Zon","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Elena Castillo-Lorenzo","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"Baris Ozudogru","author_inst":"Hacettepe University"},{"author_name":"Andreas Berger","author_inst":"Natural History Museum Vienna"},{"author_name":"Michael D. Windham","author_inst":"Duke University"},{"author_name":"Leopoldo Medina Domingo","author_inst":"Real Jardin Botanico (CSIC)"},{"author_name":"Nora Walden","author_inst":"Heidelberg University"},{"author_name":"Christiane Kiefer","author_inst":"Heidelberg University"},{"author_name":"David S. Aukes","author_inst":"Naturalis Biodiversity Center"},{"author_name":"Dario Javier Schiavinato","author_inst":"University of Buenos Aires"},{"author_name":"Edie Burns","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"C. Donovan Bailey","author_inst":"New Mexico State University"},{"author_name":"Raquel Negrao","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"Stanislav _paniel","author_inst":"Slovak Academy of Sciences"},{"author_name":"Alexey P. Seregin","author_inst":"M. V. Lomonosov Moscow State University"},{"author_name":"Hamid Moazzeni","author_inst":"Ferdowsi University of Mashhad"},{"author_name":"Oscar Toro-Nunez","author_inst":"Universidad de Concepcion"},{"author_name":"Vanessa R. Invernon","author_inst":"Museum national dHistoire naturelle"},{"author_name":"Atena Eslami-Farouji","author_inst":"Shiraz University"},{"author_name":"Peter Heenan","author_inst":"Bioeconomy Science Institute"},{"author_name":"Terezie Mandakova","author_inst":"Masaryk University"},{"author_name":"Hongliang Chen","author_inst":"Zhejiang Chinese Medical University"},{"author_name":"Martin A. Lysak","author_inst":"Masaryk University"},{"author_name":"Natalia M. Shiyan","author_inst":"M.G. Kholodny Institute of Botany"},{"author_name":"Nikolai M. Hay","author_inst":"Duke University"},{"author_name":"Mats Thulin","author_inst":"Uppsala University"},{"author_name":"Robert Vogt","author_inst":"Freie Universitat Berlin"},{"author_name":"Mathieu Chambouleyron","author_inst":"Reneco North Africa"},{"author_name":"Steven B. Janssens","author_inst":"Meise Botanic Garden"},{"author_name":"Marie Briggs","author_inst":"Royal Botanic Garden Edinburgh"},{"author_name":"Michaela Schmull","author_inst":"Harvard University"},{"author_name":"Alan Forrest","author_inst":"Royal Botanic Garden Edinburgh"},{"author_name":"Hang Sun","author_inst":"Chinese Academy of Sciences"},{"author_name":"Alessia Guggisberg","author_inst":"ETH Zurich"},{"author_name":"Fred W. Stauffer","author_inst":"Botanic Garden of Geneva"},{"author_name":"Pieter J.D. Winter","author_inst":"South African National Biodiversity Institute, Kirstenbosch"},{"author_name":"M. Eric Schranz","author_inst":"Wageningen University & Research"},{"author_name":"Lachezar A. Nikolov","author_inst":"Indiana University"},{"author_name":"Alexandre R. Zuntini","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"William J. Baker","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"Felix Forest","author_inst":"Royal Botanic Gardens, Kew"},{"author_name":"Olivier Maurin","author_inst":"Meise Botanic Garden"},{"author_name":"Klaus Mummenhoff","author_inst":"University of Osnabruck"},{"author_name":"Frederic Lens","author_inst":"Naturalis Biodiversity Center"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Acute lysergic acid diethylamide induces a time-dependent shift toward hippocampal control of default mode network reorganization","rel_doi":"10.64898\/2026.09.03.748807","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.748807","rel_abs":"Background Classical psychedelics induce profound changes in brain function, yet the temporal organization of these effects remains incompletely understood. Methods We investigated the effects of acute lysergic acid diethylamide (LSD) on large-scale brain connectivity in nine male Long-Evans rats using resting-state functional magnetic resonance imaging. Following a 15-min baseline acquisition, rats received LSD (500 g\/kg, i.p.), and imaging continued during two consecutive 15-min post-injection periods. Network reorganization was assessed using independent component analysis (ICA), seed-to-voxel mapping, stationary seed-to-seed connectivity, dynamic graph-based metrics, and dynamic causal modeling. Results LSD produced widespread but regionally heterogeneous changes across default mode network related, cortical, striatal, thalamic, sensory, and limbic systems. During the early post-injection window, ICA revealed a predominance of increased functional coupling, while dynamic analyses showed prominent fluctuations in hippocampal coupling strength and medial frontal network centrality. Dynamic causal modeling identified a false discovery rate-corrected reduction in retrosplenial-to-infralimbic influence, accompanied by a broader descriptive pattern of reduced posterior- and hippocampal-to-frontal coupling. During the later window, ICA showed a relative shift toward connectivity decreases, while complementary analyses revealed more selective hippocampal and parahippocampal involvement. Conclusions Across complementary analyses, acute LSD induced a temporally structured reorganization of brain hierarchy, characterized by an early weakening of directed cortical interactions followed by a later shift toward hippocampal-centered network control. These findings identify a dynamic shift in effective network organization and provide a mechanistic framework for psychedelic-induced default mode network reconfiguration.","rel_num_authors":11,"rel_authors":[{"author_name":"Fahd Fran\u00e7ois Hilal","author_inst":"University of Picardie Jules Verne (UPJV)"},{"author_name":"Rayane Benkeddada","author_inst":"Universit\u00e9 de Picardie Jules Verne"},{"author_name":"Jeanblanc J\u00e9r\u00f4me","author_inst":"Universit\u00e9 de Picardie Jules Verne"},{"author_name":"Marion Sourty","author_inst":"University of Strasbourg"},{"author_name":"Fall Sidy","author_inst":"Universit\u00e9 de Picardie Jules Verne"},{"author_name":"Rachel Utama","author_inst":"Northeastern University"},{"author_name":"Sima Soltanpour","author_inst":"Ontario Tech University"},{"author_name":"Praveen Kulkarni","author_inst":"Northeastern University"},{"author_name":"Micka\u00ebl Naassila","author_inst":"Universit\u00e9 de Picardie Jules Verne"},{"author_name":"Sami Ben Hamida","author_inst":"Universit\u00e9 de Picardie Jules Verne"},{"author_name":"Md Taufiq Nasseef","author_inst":"Prince Sattam Bin Abdulaziz University"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Social-Cognitive Dysregulation Model of Misophonia: Perspective from a Behavioural Study","rel_doi":"10.64898\/2026.09.03.749152","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749152","rel_abs":"Misophonia is increasingly conceptualized as more than a disorder of sound tolerance, with trigger over-reactivity shaped by the social meaning of sounds, inferred intentions, and representations of others actions. We tested a social-cognitive dysregulation model of misophonia in (N = 341) adults using behavioural measures of Theory of Mind and emotion recognition, alongside measures of reflective functioning, empathy, alexithymia, and mimicry. Dimensional associations with misophonia severity and its five different dimensions were examined while accounting for age, sex, sound sensitivity, and anxiety\/depressive symptoms. Increased misophonia severity was associated with less accurate and slower mental-state inference and emotion recognition. ToM accuracy effects were evident for more complex, cognitive, and affective mentalizing, but not for simpler mentalizing or physical control judgments, while emotion-recognition accuracy differences emerged for positive but not negative stimuli. Greater severity was also characterized by reduced certainty and greater uncertainty about mental states, greater difficulty identifying one s own feelings, and elevated alexithymia, whereas global self-reported empathy was largely preserved. Misophonia severity further predicted a greater propensity to mimic trigger-producing actions or sounds; 41% of participants exceeding the S-Five clinical cutoff (> 87) endorsed mimicry, which was particularly associated with a subjective restoration of control. Findings remained robust following influential-case sensitivity analyses. These results reveal a selective disturbance in self-other representation spanning mentalizing, emotion decoding, emotional self-representation, and embodied regulatory processes. They position misophonia within a broader social-cognitive framework in which auditory-affective reactivity may intersect with altered inferential and sensorimotor processing, while stopping short of causal inference.","rel_num_authors":2,"rel_authors":[{"author_name":"Mercede Erfanian","author_inst":"ESSCA, School of Management, OMDS"},{"author_name":"Sukhbinder Kumar","author_inst":"Department of Neurosurgery, University of Iowa"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Ups and downs of liquid-liquid transitions in GUV membranes from osmolarity and aspiration tensions","rel_doi":"10.64898\/2026.09.03.748981","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.748981","rel_abs":"Lipid membranes undergo liquid-liquid phase separation to form micron-scale domains. Several physical parameters affect this phase transition. For example, a decrease in temperature causes membranes to demix, as does an increase in hydrostatic pressure. However, measurements to determine how tension affects membrane phase separation have yielded conflicting results. Experiments that have applied osmotic pressure differences to a population of vesicles have reported an increase in the membrane's miscibility transition temperature. Conversely, experiments that have applied micropipette aspiration or substrate stretching to single membranes have reported a decrease. Here, we find that both osmotic pressure and micropipette aspiration can increase transition temperatures. We discuss how membrane pores and hidden areas in membranes present challenges to researchers seeking to quantitatively convert experimentally measured osmolarity differences into membrane tensions. We show that challenges of comparing data from different osmotic pressure experiments can be mitigated by renormalizing osmolarity differences, specifically by dividing by the exterior osmolarity. We discuss our results in the context of existing theoretical predictions and in light of four known effects of increasing tension on vesicle membranes: 1) a reduction in hidden area of tubes and aggregates, 2) a reduction in out-of-plane thermal fluctuations, 3) an increase in the area per lipid, and 4) the formation of pores. First, hidden area can explain why vesicles can sustain high osmolarity differences. Next, suppression of thermal fluctuations and increases in the area per lipid may account for shifts in miscibility transition temperatures. Finally, pores can explain time dependences. Overall, our results highlight the need for new theory and simulation that unify predictions of how transition temperatures vary over all four regimes of membrane tension.","rel_num_authors":6,"rel_authors":[{"author_name":"Takashi Kuroyanagi","author_inst":"University of Washington"},{"author_name":"Kent J Wilson","author_inst":"University of Washington"},{"author_name":"Aymeric Chorlay","author_inst":"University of California, Berkeley"},{"author_name":"Caitlin E Cornell","author_inst":"University of California, Berkeley"},{"author_name":"Daniel A Fletcher","author_inst":"University of California, Berkeley"},{"author_name":"Sarah L Keller","author_inst":"University of Washington"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Native Hydrogen\/Deuterium Exchange Ion Mobility Mass Spectrometry of Structured DNA Oligonucleotides","rel_doi":"10.64898\/2026.09.03.749223","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749223","rel_abs":"Hydrogen\/deuterium exchange coupled to mass spectrometry (HDX\/MS) is a powerful technique to probe nucleic acid secondary structures and dynamics, but its ability to resolve conformers with identical masses remains limited. To overcome this challenge, we integrated ion mobility spectrometry (IMS) into our native HDX\/MS workflow, and tested the approach on a variety of model DNA G-quadruplex structures. We show several examples of human telomeric sequence oligonucleotides where complexes of the same mass differ in their collision cross section, and each gas-phase conformational ensembles corresponds to unique solution exchange behaviors, allowing kinetic analysis beyond what is possible with HDX\/native MS alone. But we also found examples where several gas-phase populations separated in ion mobility have exactly the same solution exchange behavior, suggesting that conformational rearrangements occur either during electrospray or at later stages in the gas phase. Finally, we show how IMS filtering can be leveraged to distinguish groups of non-specific cation binding on a given conformational ensemble, as indicated by populations with different masses and same exchange rates. These findings establish IMS as an essential tool for complementing HDX\/MS in the characterization of structural polymorphism and conformational ensembles in DNA oligonucleotides.","rel_num_authors":4,"rel_authors":[{"author_name":"Matthieu Ranz","author_inst":"Univ. Bordeaux, Inserm U1212, CNRS UMR 5320, ARNA, F-33000 Bordeaux, France"},{"author_name":"Romane Guisiano","author_inst":"Univ. Bordeaux, Inserm U1212, CNRS UMR 5320, ARNA, F-33000 Bordeaux, France"},{"author_name":"Eric Largy","author_inst":"Univ. Bordeaux, Inserm U1212, CNRS UMR 5320, ARNA, F-33000 Bordeaux, France"},{"author_name":"Val\u00e9rie Gabelica","author_inst":"University of Geneva"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Mice use predictive environmental cues to adapt predatory behavior in hunting tasks of variable difficulty","rel_doi":"10.64898\/2026.09.03.749200","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749200","rel_abs":"Prey capture has long served as a model of complex, multimodal behavior with ethological relevance. In this context, the ability of laboratory animals to capture fleeing prey has been investigated in terms of the sensory systems and neuroanatomical regions required for successful capture. While the ability to hunt is experience-dependent, prey capture is often assumed to be a reflexive behavior, governed by innate neural circuits and a basic drive to obtain food. Whether hunting performance depends on complex learning and cognitive strategy remains largely untested, in part because it is difficult to systematically manipulate the difficulty of predator-prey interactions. To address this, we varied ambient temperature across thousands of trials in which laboratory mice pursued cold-blooded cockroaches, whose movement speed was directly determined by body temperature. As expected, capture difficulty increased as a function of temperature. To test whether mice rely on external cues to adjust their predatory behavior, we then mismatched the ambient temperature and that of the prey, finding that mice learn to use relevant environmental information to inform their hunting strategy. Our results suggest that animals can extract and apply meaningful information from predictive environmental cues to adapt their learned behavior.","rel_num_authors":7,"rel_authors":[{"author_name":"Jacob L Amme","author_inst":"Washington University in St Louis"},{"author_name":"John M. Grady","author_inst":"University of Maine"},{"author_name":"Kiran Bhaskaran-Nair","author_inst":"Washington University in Saint Louis"},{"author_name":"Varun Sinha","author_inst":"Washington University in Saint Louis"},{"author_name":"Samuel J Brunwasser","author_inst":"Washington University in Saint Louis"},{"author_name":"Anthony I Dell","author_inst":"National Great Rivers Research and Education Center"},{"author_name":"Keith B Hengen","author_inst":"Washington University In St. Louis"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Mice use predictive environmental cues to adapt predatory behavior in hunting tasks of variable difficulty","rel_doi":"10.64898\/2026.09.03.749200","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749200","rel_abs":"Prey capture has long served as a model of complex, multimodal behavior with ethological relevance. In this context, the ability of laboratory animals to capture fleeing prey has been investigated in terms of the sensory systems and neuroanatomical regions required for successful capture. While the ability to hunt is experience-dependent, prey capture is often assumed to be a reflexive behavior, governed by innate neural circuits and a basic drive to obtain food. Whether hunting performance depends on complex learning and cognitive strategy remains largely untested, in part because it is difficult to systematically manipulate the difficulty of predator-prey interactions. To address this, we varied ambient temperature across thousands of trials in which laboratory mice pursued cold-blooded cockroaches, whose movement speed was directly determined by body temperature. As expected, capture difficulty increased as a function of temperature. To test whether mice rely on external cues to adjust their predatory behavior, we then mismatched the ambient temperature and that of the prey, finding that mice learn to use relevant environmental information to inform their hunting strategy. Our results suggest that animals can extract and apply meaningful information from predictive environmental cues to adapt their learned behavior.","rel_num_authors":7,"rel_authors":[{"author_name":"Jacob L Amme","author_inst":"Washington University in St Louis"},{"author_name":"John M. Grady","author_inst":"University of Maine"},{"author_name":"Kiran Bhaskaran-Nair","author_inst":"Washington University in Saint Louis"},{"author_name":"Varun Sinha","author_inst":"Washington University in Saint Louis"},{"author_name":"Samuel J Brunwasser","author_inst":"Washington University in Saint Louis"},{"author_name":"Anthony I Dell","author_inst":"National Great Rivers Research and Education Center"},{"author_name":"Keith B Hengen","author_inst":"Washington University In St. Louis"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Lipid Activation of a Thalamic GPCR Extends Working Memory Time-scales","rel_doi":"10.64898\/2026.09.03.749183","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749183","rel_abs":"Working memory capacity is poorly understood. The ability to control and extend working memory time-scales provides the potential to alleviate cognitive decline in disease and aging. Through an unbiased genetic search, we previously identified a thalamic orphan receptor Gpr12 as a potent enhancer of working memory, however its activation mechanism remains poorly understood. Here, we describe the CryoEM structure of Gpr12, revealing a lipidic regulatory site enabling an activated signaling state. By surveying the native lipidic environment in mouse thalamus we identified a class of 20 carbon:4 double bond fatty acid eicosanoids as potential ligands. Cell-based assays confirmed that the endogenous cannabinoid anandamide (AEA), but not other closely related family members or derivatives, robustly activates Gpr12. In vivo imaging during behavior revealed that Gpr12 activation produces a striking molecular state - the persistent suppression of cAMP in thalamus that tracks the duration of memory maintenance. Notably, genetic or pharmacological manipulations that enhance the AEA-Gpr12 signaling axis are sufficient to prolong cAMP suppression and extend the temporal window of memory maintenance. Furthermore, AEA-mediated cAMP suppressions in thalamus support sustained neural activity in PFC, specifically during memory maintenance. Thus, while cannabinoids often impair memory, here we identify an AEA-Gpr12 signaling axis in thalamus that enhances memory, including in primates. These findings identify a lipidic signaling mechanism in thalamus that is sufficient to control and extend working memory duration.","rel_num_authors":12,"rel_authors":[{"author_name":"James Newton Brandt","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Alessandra Bonito-Oliva","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Navid Paknejad","author_inst":"Laboratory of Neurophysiology and Behavior, The Rockefeller University, New York, NY, 10065, USA"},{"author_name":"Celine Chen","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"John J Fak","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Andrew Luskin","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Genelle Rankin","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Miriam Kirylo","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Leslie J Sibener","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Amy Arnsten","author_inst":"Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510 USA"},{"author_name":"Vanessa Ruta","author_inst":"Laboratory of Neurophysiology and Behavior, The Rockefeller University, New York, NY, 10065, USA"},{"author_name":"Priya Rajasethupathy","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Lipid Activation of a Thalamic GPCR Extends Working Memory Time-scales","rel_doi":"10.64898\/2026.09.03.749183","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749183","rel_abs":"Working memory capacity is poorly understood. The ability to control and extend working memory time-scales provides the potential to alleviate cognitive decline in disease and aging. Through an unbiased genetic search, we previously identified a thalamic orphan receptor Gpr12 as a potent enhancer of working memory, however its activation mechanism remains poorly understood. Here, we describe the CryoEM structure of Gpr12, revealing a lipidic regulatory site enabling an activated signaling state. By surveying the native lipidic environment in mouse thalamus we identified a class of 20 carbon:4 double bond fatty acid eicosanoids as potential ligands. Cell-based assays confirmed that the endogenous cannabinoid anandamide (AEA), but not other closely related family members or derivatives, robustly activates Gpr12. In vivo imaging during behavior revealed that Gpr12 activation produces a striking molecular state - the persistent suppression of cAMP in thalamus that tracks the duration of memory maintenance. Notably, genetic or pharmacological manipulations that enhance the AEA-Gpr12 signaling axis are sufficient to prolong cAMP suppression and extend the temporal window of memory maintenance. Furthermore, AEA-mediated cAMP suppressions in thalamus support sustained neural activity in PFC, specifically during memory maintenance. Thus, while cannabinoids often impair memory, here we identify an AEA-Gpr12 signaling axis in thalamus that enhances memory, including in primates. These findings identify a lipidic signaling mechanism in thalamus that is sufficient to control and extend working memory duration.","rel_num_authors":12,"rel_authors":[{"author_name":"James Newton Brandt","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Alessandra Bonito-Oliva","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Navid Paknejad","author_inst":"Laboratory of Neurophysiology and Behavior, The Rockefeller University, New York, NY, 10065, USA"},{"author_name":"Celine Chen","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"John J Fak","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Andrew Luskin","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Genelle Rankin","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Miriam Kirylo","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Leslie J Sibener","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"},{"author_name":"Amy Arnsten","author_inst":"Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510 USA"},{"author_name":"Vanessa Ruta","author_inst":"Laboratory of Neurophysiology and Behavior, The Rockefeller University, New York, NY, 10065, USA"},{"author_name":"Priya Rajasethupathy","author_inst":"Laboratory of Neural Dynamics & Cognition, The Rockefeller University, New York, NY 10065, USA"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Mnemonic Demand Reconfigures the Neural Architecture of Memory Encoding","rel_doi":"10.64898\/2026.09.03.749199","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749199","rel_abs":"Memory encoding must accommodate increasingly demanding loads, yet it remains unclear whether the underlying brain state is preserved or adaptively reconfigured as load increases. Here, we recorded EEG from 111 participants performing a visual memory task in which they encoded lists of real images ranging from 1 to 128 items, spanning low to high mnemonic demands, followed by a recognition test. We measured the similarity of set-size-specific interelectrode correlation patterns to a low-load reference. Similarity decreased monotonically as list length increased: patterns at set sizes below 4 remained close to the low-load configuration, whereas set sizes of 8 and above progressively shifted toward a distinct high-load configuration. This transition was captured by a single rotating eigenvector, revealing a low-dimensional trajectory from low- to high-load neural geometry. Smaller rotation angles from the low-load template predicted better memory performance at high loads. Together, these findings provide evidence for adaptive reconfiguration and reveal a structured, low-dimensional neural trajectory through which encoding architecture changes as mnemonic demands increase.","rel_num_authors":3,"rel_authors":[{"author_name":"Chong Zhao","author_inst":"University of Chicago"},{"author_name":"Edward  K. Vogel","author_inst":"University of Chicago Department of Psychology"},{"author_name":"Monica D. Rosenberg","author_inst":"University of Chicago"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Gonadal remodelling in socially driven sex change is associated with novel and known sex genes, epigenetic reprogramming, and inflammation-mediated apoptosis.","rel_doi":"10.64898\/2026.09.03.749291","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749291","rel_abs":"Many fish undergo dramatic, socially cued female-to-male sex change, yet the events that initiate and then regulate gonadal reprogramming and reorganisation during this phenomenal metamorphosis are broadly unknown. The New Zealand spotted wrasse, Notolabrus celidotus, is a temperate fish species that displays the extraordinary ability to undergo protogynous sex change. Removal of a terminal-phase male from a social group triggers the most dominant female to change sex and become a male. To characterise the molecular changes associated with gonadal metamorphosis in spotty, we used genomic and transcriptomic approaches, generating a high-quality genome and a transcriptomic time-series that captures the sex change process from start to finish. These data, together with paired histological data, reveal distinct transcriptional profiles that characterise the process of sex change. As expected, the expression of masculinising genes steadily increases, while feminising genes steadily decrease, throughout the transition. We further identify novel candidate genes, including genes involved in immune signalling and tissue remodelling through inflammation-mediated apoptosis, whose expression strongly correlates with key events in sex change, while also confirming the roles of known sex determination and differentiation genes in this process. Collectively these data give us new insights into how a normally committed developmental process remains plastic and is reversed to completely alter organ structures, and also sheds light on the evolution of sex determination in other animals. This work furthers the development of the spotty as a new tractable model for sex change research.","rel_num_authors":12,"rel_authors":[{"author_name":"Chlo\u00e9 A van der Burg","author_inst":"Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand"},{"author_name":"Alexander A Goikoetxea","author_inst":"Catalan Department of Education (Departament d'Educaci\u00f3 i Formaci\u00f3 Professional), Barcelona, Spain"},{"author_name":"Simon Muncaster","author_inst":"School of Science, University of Waikato, Tauranga, New Zealand"},{"author_name":"Oscar Ortega-Recalde","author_inst":"Departamento de Morfolog\u00eda, Facultad de Medicina e Instituto de Gen\u00e9tica, Universidad Nacional de Colombia, Bogot\u00e1, D.C, Colombia"},{"author_name":"Tim Hore","author_inst":"Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand."},{"author_name":"Kaj Kamstra","author_inst":"Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand"},{"author_name":"Olivier Fedrigo","author_inst":"Colossal BioScience, Dallas, TX, USA"},{"author_name":"Erich D Jarvis","author_inst":"The Vertebrate Genome Lab, The Rockefeller University, New York, NY, USA"},{"author_name":"Alan Tracey","author_inst":"Tree of Life, Wellcome Sanger Institute"},{"author_name":"Kerstin Howe","author_inst":"Tree of Life, Wellcome Sanger Institute"},{"author_name":"Erica V Todd","author_inst":"Deakin Marine Research and Innovation Centre, School of Life and Environmental Sciences, Deakin University, Geelong, VIC, Australia"},{"author_name":"Neil Gemmell","author_inst":"Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Lamin A\/C depletion from myofibers and satellite cells in mice reveals selective muscle pathology","rel_doi":"10.64898\/2026.09.03.749246","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749246","rel_abs":"Mutations in the laminA\/C gene (LMNA), which encodes the nuclear lamina proteins lamin A and lamin C (lamin A\/C), have been linked to different human diseases affecting different tissues. Most LMNA mutations cause cardiomyopathy and muscular dystrophy, such as autosomal dominant Emery-Dreifuss muscular dystrophy. Recent studies to understand striated muscle laminopathies have taken advantage of Lmna conditional knockout mice to examine the effects of lamin A\/C depletion in cardiomyocytes and cardiac fibroblasts. However, the role of lamin A\/C in skeletal muscle has largely been uncharacterized using conditional knockout mice. We used different mouse lines to deplete lamin A\/C from specific cell types in striated muscle. Lamin A\/C depletion from fetal myofibers and cardiomyocytes led to no observable phenotype in the skeletal muscles despite leading to dramatic heart dilation and early lethality. Depletion of lamin A\/C from both skeletal myofibers and satellite cells was lethal, with the most dramatic myopathic abnormalities observed in the intrinsic muscles of the tongue. The presence of lamin A\/C in skeletal muscle satellite cells prevented the development of lethal myopathy when the proteins were deleted only from differentiated myofibers. Overall, our results provide a foundation for understanding the roles of lamin A\/C in muscle maintenance and development, including the variable skeletal muscle involvement and much more invariant cardiomyopathy in patients with LMNA mutations.","rel_num_authors":5,"rel_authors":[{"author_name":"Qi Jin","author_inst":"Columbia University"},{"author_name":"Kurenai Tanji","author_inst":"Columbia University"},{"author_name":"Leroy C Joseph","author_inst":"Columbia University"},{"author_name":"Ji-Yeon Shin","author_inst":"Hackensack Meridian Health Center for Discovery and Innovation"},{"author_name":"Howard J Worman","author_inst":"Columbia University"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma","rel_doi":"10.64898\/2026.09.03.749206","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749206","rel_abs":"Acquired resistance to mitogen-activated protein kinase (MAPK) pathway inhibitors remains a major barrier to durable control of BRAF-mutant melanoma. Although resistance mechanisms are heterogeneous, they converge on adaptive programs that support survival, phenotypic plasticity, and metabolic fitness. We asked whether eukaryotic translation initiation factor 4A (eIF4A)-dependent mRNA translation represents a shared vulnerability of kinase inhibitor-resistant melanoma. Using matched BRAFV600E A375 and BRAF inhibitor-resistant A375R cells together with additional melanoma models, we integrated pharmacological and functional assays with polysome-associated RNA sequencing, quantitative proteomics, bioenergetic profiling, metabolomics, [U-13C5]glutamine tracing, and xenograft studies. Melanoma cells remained sensitive to multiple eIF4A inhibitors regardless of their responsiveness to BRAF inhibition. The eIF4A inhibitor CR-1-31-B rapidly reduced nascent protein synthesis when used alone in A375 cells and when added to the BRAF inhibitor PLX4032 in A375R cells; it also reduced BCL-2, CDK4, and cyclin D3 abundance, suppressed clonogenic growth, and induced apoptosis. Integrated analysis showed that acquired resistance involved broad RNA-abundance remodeling with superimposed changes in translational efficiency and buffering, affecting survival, extracellular-matrix and plasticity programs, and mitochondrial and metabolic functions. In resistant cells, CR-1-31-B induced early transcript-selective translational changes, accompanied at later time points by RNA-abundance and proteome remodeling. Publicly annotated 5' untranslated regions (5'UTRs) of CR-1-31-B-sensitive transcripts were enriched for purine-rich sequence architecture and local structural complexity. eIF4A inhibition preferentially attenuated the expression of proteins acquired during resistance and imposed a lower-output metabolic state in sensitive and resistant cells, reducing tricarboxylic-acid-cycle and pentose-phosphate-pathway metabolite pools and restricting intracellular glutamine-carbon transfer downstream of uptake. In A375 xenografts, CR-1-31-B delayed tumor growth, while its combination with PLX4720 produced deeper and more sustained tumor control and prolonged tumor endpoint-free survival compared with PLX4720 alone. These findings show that multiple resistance-associated programs spanning signaling, cell survival, and metabolism share a dependency on eIF4A-dependent translation and provide a preclinical rationale to test whether adding eIF4A inhibition can prolong responses to MAPK-targeted therapy in melanoma.","rel_num_authors":15,"rel_authors":[{"author_name":"Alejandro Schcolnik-Cabrera","author_inst":"Universite de Montreal"},{"author_name":"Meriem Takdenti","author_inst":"Universite de Montreal"},{"author_name":"Anavasadat Sadr Hashemi Nejad","author_inst":"Universite de Montreal"},{"author_name":"Zaynab Nouhi","author_inst":"Maisonneuve-Rosemont Hospital Research Centre"},{"author_name":"Sarah St-Amand","author_inst":"Universite de Montreal"},{"author_name":"Caroline Capdevielle","author_inst":"Universite de Montreal"},{"author_name":"Donia Issa","author_inst":"Universite de Montreal"},{"author_name":"Melody Riaud","author_inst":"McGill University"},{"author_name":"April A. N. Rose","author_inst":"McGill University"},{"author_name":"Mireille Khacho","author_inst":"University of Ottawa"},{"author_name":"Frederick A. Mallette","author_inst":"Universite de Montreal"},{"author_name":"Martin Roffe","author_inst":"Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Tommy Alain","author_inst":"Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Ivan Topisirovic","author_inst":"McGill University"},{"author_name":"Laura Hulea","author_inst":"University of Montreal"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"eIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma","rel_doi":"10.64898\/2026.09.03.749206","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.03.749206","rel_abs":"Acquired resistance to mitogen-activated protein kinase (MAPK) pathway inhibitors remains a major barrier to durable control of BRAF-mutant melanoma. Although resistance mechanisms are heterogeneous, they converge on adaptive programs that support survival, phenotypic plasticity, and metabolic fitness. We asked whether eukaryotic translation initiation factor 4A (eIF4A)-dependent mRNA translation represents a shared vulnerability of kinase inhibitor-resistant melanoma. Using matched BRAFV600E A375 and BRAF inhibitor-resistant A375R cells together with additional melanoma models, we integrated pharmacological and functional assays with polysome-associated RNA sequencing, quantitative proteomics, bioenergetic profiling, metabolomics, [U-13C5]glutamine tracing, and xenograft studies. Melanoma cells remained sensitive to multiple eIF4A inhibitors regardless of their responsiveness to BRAF inhibition. The eIF4A inhibitor CR-1-31-B rapidly reduced nascent protein synthesis when used alone in A375 cells and when added to the BRAF inhibitor PLX4032 in A375R cells; it also reduced BCL-2, CDK4, and cyclin D3 abundance, suppressed clonogenic growth, and induced apoptosis. Integrated analysis showed that acquired resistance involved broad RNA-abundance remodeling with superimposed changes in translational efficiency and buffering, affecting survival, extracellular-matrix and plasticity programs, and mitochondrial and metabolic functions. In resistant cells, CR-1-31-B induced early transcript-selective translational changes, accompanied at later time points by RNA-abundance and proteome remodeling. Publicly annotated 5' untranslated regions (5'UTRs) of CR-1-31-B-sensitive transcripts were enriched for purine-rich sequence architecture and local structural complexity. eIF4A inhibition preferentially attenuated the expression of proteins acquired during resistance and imposed a lower-output metabolic state in sensitive and resistant cells, reducing tricarboxylic-acid-cycle and pentose-phosphate-pathway metabolite pools and restricting intracellular glutamine-carbon transfer downstream of uptake. In A375 xenografts, CR-1-31-B delayed tumor growth, while its combination with PLX4720 produced deeper and more sustained tumor control and prolonged tumor endpoint-free survival compared with PLX4720 alone. These findings show that multiple resistance-associated programs spanning signaling, cell survival, and metabolism share a dependency on eIF4A-dependent translation and provide a preclinical rationale to test whether adding eIF4A inhibition can prolong responses to MAPK-targeted therapy in melanoma.","rel_num_authors":15,"rel_authors":[{"author_name":"Alejandro Schcolnik-Cabrera","author_inst":"Universite de Montreal"},{"author_name":"Meriem Takdenti","author_inst":"Universite de Montreal"},{"author_name":"Anavasadat Sadr Hashemi Nejad","author_inst":"Universite de Montreal"},{"author_name":"Zaynab Nouhi","author_inst":"Maisonneuve-Rosemont Hospital Research Centre"},{"author_name":"Sarah St-Amand","author_inst":"Universite de Montreal"},{"author_name":"Caroline Capdevielle","author_inst":"Universite de Montreal"},{"author_name":"Donia Issa","author_inst":"Universite de Montreal"},{"author_name":"Melody Riaud","author_inst":"McGill University"},{"author_name":"April A. N. Rose","author_inst":"McGill University"},{"author_name":"Mireille Khacho","author_inst":"University of Ottawa"},{"author_name":"Frederick A. Mallette","author_inst":"Universite de Montreal"},{"author_name":"Martin Roffe","author_inst":"Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Tommy Alain","author_inst":"Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Ivan Topisirovic","author_inst":"McGill University"},{"author_name":"Laura Hulea","author_inst":"University of Montreal"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Xylazine Reshapes the Sleep and Respiratory Consequences of Chronic Fentanyl Exposure in a Sex-Dependent Manner","rel_doi":"10.64898\/2026.09.02.748951","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.02.748951","rel_abs":"Recent shifts in the illicit fentanyl supply have led to widespread exposure to xylazine, yet the biological consequences of chronic fentanyl-xylazine co-exposure remain poorly understood. Here, we compared the behavioral and molecular effects of chronic exposures to fentanyl and xylazine both alone and in combination in male and female mice. Combined fentanyl-xylazine produced distinct, sex-dependent alterations in sleep architecture, including changes in NREMS recovery, REMS dynamics, and reduced sleep bout duration compared with fentanyl alone. The 2-adrenergic receptor antagonist yohimbine partially reversed these sleep alterations in a sex-dependent manner. Fentanyl-xylazine also exacerbated respiratory depression relative to fentanyl alone, particularly in males. In contrast, despite its prevalence in humans no skin lesions were observed. Molecular analyses revealed that fentanyl-xylazine co-administration leads to increased peripheral Fibroblast growth factor 21, a hepatokine linked to reduced opioid preference and alcohol consumption. Together, these findings demonstrate that xylazine substantially alters the physiological and neurobiological consequences of chronic fentanyl exposure in a sex-dependent manner, providing a preclinical framework for understanding the growing public health impact of fentanyl-xylazine co-use.","rel_num_authors":6,"rel_authors":[{"author_name":"Mackenzie C. Gamble","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Samara J Vilca","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Benjamin Williams","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Grace Guindon","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Vivian Dang","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Ryan W Logan","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-09-08","rel_site":"biorxiv"},{"rel_title":"Markers of environmental enteric dysfunction are associated with changes in pharmacokinetics of praziquantel in preschool age children with Schistosoma mansoni infection in Albertine region of Uganda","rel_doi":"10.64898\/2026.09.02.26362031","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26362031","rel_abs":"IntroductionPraziquantel (PZQ) is the only widely available chemotherapy that is effective against all species of schistosomes. Environmental enteric dysfunction (EED) is an acquired intestinal disorder of altered gut function whose effect on drug pharmacokinetics has not been directly explored.\n\nMethodsPreschool-age children infected with S. mansoni were randomized to receive 40mg\/kg or 80mg\/kg of crushed PZQ tablets. Plasma PZQ concentrations were quantified using ultra-high performance liquid chromatography mass spectrometry. Maximum concentration (Cmax), time to Cmax (Tmax) and area under the curve (AUC) of PZQ were calculated. Biomarkers of intestinal inflammation (stool calprotectin), epithelial damage (plasma Intestinal Fatty Acid Binding Protein (IFABP)), permeability (urine lactulose:mannitol (LM) ratio and alpha-1 antitrypsin (AAT)), microbial translocation (plasma Endotoxin core antibodies (EndoCAb), systemic inflammation (plasma C-reactive protein (CRP)), and presence of faecal occult blood (FOB) were measured. Using linear regression, we assessed association of AUC, Cmax, Tmax and R- to S-PZQ exposure with each biomarker, adjusting for dose, age, and sex.\n\nResultsOf the 184 participants included in the final analysis, 91 received 40mg\/kg and 93 received 80mg\/kg of PZQ. The Tmax was associated with LM ratio ({beta}=0.06, 95% CI 0.02 - 0.11, p=0.003) and calprotectin ({beta}=0.001, 0.0002 - 0.002, p=0.013). CRP was associated with AUC ({beta}=0.13, 95% CI 0.06 - 0.21, p=0.001) and Cmax ({beta}=0.12, 95% CI 0.05 - 0.21, p=0.002). Calprotectin ({beta}=0.12, 95% CI 0.04 - 0.20, p=0.003) and AAT ({beta}=0.09, 95% CI 0.02 - 0.15, p=0.008) were associated with a higher R-PZQ\/S-PZQ AUC ratio, while CRP was not (p=0.38).\n\nConclusionElevated intestinal inflammatory markers were associated with increased Tmax, indicating reduced rate of absorption and relative increase in exposure to the active R-enantiomer. Systemic inflammation was associated with higher Cmax and AUC, implying increased exposure to PZQ. This is the first report linking alterations in praziquantel pharmacokinetics to EED markers and systemic inflammation.\n\nAuthor summarySchistosomiasis, also known as bilharzia, affects approximately 240 million people in 79 countries with children in Africa bearing almost 50% of the burden. Praziquantel (PZQ), an oral drug, is the only widely available treatment for the disease. However, some studies have reported differences in pharmacokinetics and efficacy of PZQ across geographical locations suggesting environmental factors to affect drug response. We hypothesized that environmental enteric dysfunction, a disorder of altered intestinal function, may affect absorption and metabolism of PZQ because of the damage it inflicts on the intestinal mucosa, and subsequent systemic inflammation due to leakage of intestinal contents, a process referred to as \"microbial translocation\". Our findings indicate that markers of intestinal inflammation were associated with reduced rate of absorption while systemic inflammation was associated with increased plasma concentrations and overall exposure to PZQ. The reduced rate of absorption may result from destruction of the intestinal absorptive surface while increased plasma concentration and exposure may be due to reduced activity of PZQ-metabolizing enzymes in the liver. These observations could inform approaches for optimizing the effectiveness of PZQ by accounting for inflammation. This has implications for the use of PZQ as an effective control strategy and subsequent elimination of schistosomiasis by 2030, in line with World Health Organization targets.","rel_num_authors":16,"rel_authors":[{"author_name":"Andrew Edielu","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Bonniface Obura","author_inst":"University of Liverpool"},{"author_name":"Patrice  A. Mawa","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Martin  J. Holland","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Emily  L. Webb","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Alison  M. Elliott","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Gloria  Kakoba Ayebazibwe","author_inst":"MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Hannah  Wei Wu","author_inst":"Rhode Island Hospital"},{"author_name":"Nicholas Mancini","author_inst":"University of Rhode Island"},{"author_name":"Fabian  C. Fischer","author_inst":"University of Rhode Island"},{"author_name":"Susannah Colt","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"Meagan  A. Barry","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"William Hope","author_inst":"University of Liverpool"},{"author_name":"Catriona Waitt","author_inst":"University of Liverpool"},{"author_name":"Jennifer  F. Friedman","author_inst":"Rhode Island Hospital"},{"author_name":"Amaya  L. Bustinduy","author_inst":"London School of Hygiene & Tropical Medicine"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Revision Behavior and Explainability in Adaptive LLM Swarms for ICU Mortality Risk Prediction: A Two-Dataset Evaluation","rel_doi":"10.64898\/2026.09.01.26361960","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.01.26361960","rel_abs":"PurposeTo evaluate how adaptive LLM swarm revision changes ICU mortality-risk outputs and to characterize evidence use, explanation indicators, auditability, and computational burden in final adaptive outputs relative to an independently executed fixed-voting (FV) architecture.\n\nMethodsWe retrospectively analyzed 1,607 eICU encounters (1,500 stays) and 1,607 ICU-2012 encounters. Initial (ASI) and final (ASF) adaptive outputs were compared within runs for revision engagement and risk-score drift; final ASF and separately generated FV outputs were compared for evidence use, explanation indicators, auditability, and computation. Paired differences and 95% confidence intervals used 10,000 hospital-stay-clustered bootstrap replicates.\n\nResultsAt least one specialist revision trace occurred in 84.32% of eICU and 56.44% of ICU-2012 encounters. Mean ASF-minus-ASI risk-score changes were +0.0810 and +0.0539; 757 of 761 0.50-threshold crossings moved toward mortality, without clear AUROC or AUPRC improvement. In the independent benchmark, ASF explanations contained 1.26 and 0.55 more supporting-evidence items than FV, but counterevidence acknowledgement was 21.59 and 7.47 percentage points lower and unsupported-claim flags were 1.43 and 0.68 points higher. All final records met the reconstruction-completeness criterion, although ASF generated more warnings and required 1.97 and 1.52 times the FV runtime.\n\nConclusionAdaptive revision materially changed swarm operating behaviour. Independently, final ASF outputs showed greater supporting-evidence use but less balanced evidence engagement, more process warnings, and greater computational burden than FV. These automated artifact-level findings do not establish superior explanation quality or isolate revision as their cause.","rel_num_authors":1,"rel_authors":[{"author_name":"Callum Anderson","author_inst":"University of Ottawa"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Revision Behavior and Explainability in Adaptive LLM Swarms for ICU Mortality Risk Prediction: A Two-Dataset Evaluation","rel_doi":"10.64898\/2026.09.01.26361960","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.01.26361960","rel_abs":"PurposeTo evaluate how adaptive LLM swarm revision changes ICU mortality-risk outputs and to characterize evidence use, explanation indicators, auditability, and computational burden in final adaptive outputs relative to an independently executed fixed-voting (FV) architecture.\n\nMethodsWe retrospectively analyzed 1,607 eICU encounters (1,500 stays) and 1,607 ICU-2012 encounters. Initial (ASI) and final (ASF) adaptive outputs were compared within runs for revision engagement and risk-score drift; final ASF and separately generated FV outputs were compared for evidence use, explanation indicators, auditability, and computation. Paired differences and 95% confidence intervals used 10,000 hospital-stay-clustered bootstrap replicates.\n\nResultsAt least one specialist revision trace occurred in 84.32% of eICU and 56.44% of ICU-2012 encounters. Mean ASF-minus-ASI risk-score changes were +0.0810 and +0.0539; 757 of 761 0.50-threshold crossings moved toward mortality, without clear AUROC or AUPRC improvement. In the independent benchmark, ASF explanations contained 1.26 and 0.55 more supporting-evidence items than FV, but counterevidence acknowledgement was 21.59 and 7.47 percentage points lower and unsupported-claim flags were 1.43 and 0.68 points higher. All final records met the reconstruction-completeness criterion, although ASF generated more warnings and required 1.97 and 1.52 times the FV runtime.\n\nConclusionAdaptive revision materially changed swarm operating behaviour. Independently, final ASF outputs showed greater supporting-evidence use but less balanced evidence engagement, more process warnings, and greater computational burden than FV. These automated artifact-level findings do not establish superior explanation quality or isolate revision as their cause.","rel_num_authors":1,"rel_authors":[{"author_name":"Callum Anderson","author_inst":"University of Ottawa"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Evaluating synthetic-data fidelity in two-group biomedical studies: a multidimensional validation framework","rel_doi":"10.64898\/2026.08.31.26361878","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.31.26361878","rel_abs":"Synthetic data increasingly support model development and privacy-conscious sharing in biomedicine. Two-group studies require synthetic data to reproduce within-group structure and between-group differences, yet marginal agreement or predictive performance may obscure multivariate and conditional-dependence changes. We present a multidimensional validation framework for class-conditional synthetic data and apply it to three datasets spanning sample-size and dimensionality regimes. Two controls and four generators spanning mixture, interpolation, hybrid, and latent-variable architectures (GMM, SMOTE, GMM-SMOTE, and CVAE, respectively) were assessed using predictive utility, real-synthetic distinguishability, marginal agreement, PCA and t-SNE geometry, pairwise dependence, and Graphical LASSO networks. Noise perturbation, within-class permutation, and reverse ablation probed the sources of real-synthetic distinguishability. Across 18 dataset-method comparisons, discriminator AUC ranged from 0.55 to 1.00, while mean feature-level KS statistics ranged from 0.027 to 0.282. Thus, strong performance under individual criteria coexisted with detectable differences and lost or synthetic-only dependencies. Rather than assigning a single fidelity score, the framework supports multidimensional fidelity reporting as a minimum standard for shared synthetic biomedical data.","rel_num_authors":3,"rel_authors":[{"author_name":"Tony Tran","author_inst":"University of Guelph"},{"author_name":"Mohammad Sajjad Ghaemi","author_inst":"National Research Council Canada"},{"author_name":"Chapin Stephen Korosec","author_inst":"University of Guelph"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Ejection fraction on a budget: mapping the accuracy-compute trade space for video-based ejection fraction estimation","rel_doi":"10.64898\/2026.09.02.26362055","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26362055","rel_abs":"Deep video networks estimate left ventricular ejection fraction (EF) from echocardiograms with expert-level accuracy, but the compute cost of running them is rarely reported, which leaves anyone building a handheld or bedside tool without guidance on what to deploy. We measured the accuracy versus compute trade space for EF estimation on EchoNet-Dynamic by training 22 configurations that vary clip length (8 to 64 frames), frame sampling period (1 to 4), and backbone (R(2+1)D-18, R3D-18, MC3-18, X3D-S, X3D-M, and a 2D ResNet-18 with temporal pooling), under one fixed training recipe. Every configuration was scored on accuracy (mean absolute error, R2, Bland-Altman agreement), on clinical utility (sensitivity and specificity at the EF 40% and 50% treatment thresholds, error stratified by EF band), and on cost (floating point operations, parameters, GPU and CPU latency, peak memory) under a single frozen measurement protocol. Headline claims were stress tested with replicate training seeds. Sparse temporal sampling consistently beat dense sampling: at a fixed frame count, period 4 improved mean absolute error by about one full point over period 1 across all nine cross-seed pairings while also cutting per-video cost. A plain R3D-18 achieved the best point accuracy in the study (mean absolute error 3.99), statistically tied with the reference, at 19% less CPU latency, and a 16-frame, period-4 R(2+1)D-18 halved the reference cost with no statistically confirmed accuracy loss, though with a small seed-consistent disadvantage that no single seed reveals. Removing temporal modeling entirely collapsed accuracy (mean absolute error 5.65), placing a floor under how cheap this task can get. We release the code, the cost protocol, and all per-configuration results.","rel_num_authors":3,"rel_authors":[{"author_name":"Aryan Pandey","author_inst":"Vanderbilt University"},{"author_name":"Kushaan Sharma","author_inst":"The University of Texas at Austin"},{"author_name":"Aryan Shah","author_inst":"Texas A and M University"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Metabolomic profiling in treated mucopolysaccharidosis IH reveals candidate biomarkers and adjunctive therapeutic pathways","rel_doi":"10.64898\/2026.09.04.26362233","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362233","rel_abs":"Both severe (Hurler syndrome; MPS IH) and attenuated (Hurler-Scheie or Scheie syndrome; MPS IA) forms of mucopolysaccharidosis I (MPS I) arise from the same underlying enzyme deficiency; however, they differ in the onset, persistence, and severity of key clinical features. These include skeletal abnormalities, joint contractures, cardiac disease, and neurocognitive and neurobehavioral impairment, which is not fully alleviated with either enzyme replacement (ERT) or hematopoietic cell transplantation (HCT). The objective of this study was to identify metabolic differences between MPS IH and MPS IA that could result in meaningful biomarkers and targeted adjunctive therapies to address unmet clinical needs in MPS IH treated with HCT. We performed plasma metabolomics in patients with MPS IH treated with HCT (N=17) or MPS IA treated with ERT (N=8). Welchs two-sample t-test was used to identify metabolites that differed significantly between groups. Statistical significance was evaluated based on p<0.05. After controlling for multiple testing, we used a false discovery rate of q<0.05. We identified 125 compounds that were significantly different between MPS IH and MPS IA. Of those metabolites, 14 had a q<0.05. Individuals with MPS IH had increased metabolites in the sphingolipid, beta-oxidation, amino acid catabolism, and glycosaminoglycan pathways compared to MPS IA. Persistent metabolic differences were observed in MPS IH treated with HCT compared to MPS IA treated with ERT, pointing towards additional biological processes that may contribute to disease progression in MPS IH after HCT. Although these results require further confirmation, they provide a foundation to guide future investigations towards potential biomarkers or targeted adjunctive therapies.","rel_num_authors":11,"rel_authors":[{"author_name":"Troy  C. Lund","author_inst":"University of Minnesota"},{"author_name":"Ryan  H. Peretz","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"Patricia  I. Dickson","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"Jennifer  K. Yee","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"Michelina Iacovino","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"Kent  D. Taylor","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"David Elashoff","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"Ellen Fung","author_inst":"UCSF Benioff Children's Hospital"},{"author_name":"Bradley  S. Miller","author_inst":"University of Minnesota"},{"author_name":"Paul  J. Orchard","author_inst":"University of Minnesota"},{"author_name":"Lynda  E Polgreen","author_inst":"The Lundquist Institute for Biomedical Innovation: The Lundquist Institute"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Metabolomic profiling in treated mucopolysaccharidosis IH reveals candidate biomarkers and adjunctive therapeutic pathways","rel_doi":"10.64898\/2026.09.04.26362233","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.04.26362233","rel_abs":"Both severe (Hurler syndrome; MPS IH) and attenuated (Hurler-Scheie or Scheie syndrome; MPS IA) forms of mucopolysaccharidosis I (MPS I) arise from the same underlying enzyme deficiency; however, they differ in the onset, persistence, and severity of key clinical features. These include skeletal abnormalities, joint contractures, cardiac disease, and neurocognitive and neurobehavioral impairment, which is not fully alleviated with either enzyme replacement (ERT) or hematopoietic cell transplantation (HCT). The objective of this study was to identify metabolic differences between MPS IH and MPS IA that could result in meaningful biomarkers and targeted adjunctive therapies to address unmet clinical needs in MPS IH treated with HCT. We performed plasma metabolomics in patients with MPS IH treated with HCT (N=17) or MPS IA treated with ERT (N=8). Welchs two-sample t-test was used to identify metabolites that differed significantly between groups. Statistical significance was evaluated based on p<0.05. After controlling for multiple testing, we used a false discovery rate of q<0.05. We identified 125 compounds that were significantly different between MPS IH and MPS IA. Of those metabolites, 14 had a q<0.05. Individuals with MPS IH had increased metabolites in the sphingolipid, beta-oxidation, amino acid catabolism, and glycosaminoglycan pathways compared to MPS IA. Persistent metabolic differences were observed in MPS IH treated with HCT compared to MPS IA treated with ERT, pointing towards additional biological processes that may contribute to disease progression in MPS IH after HCT. Although these results require further confirmation, they provide a foundation to guide future investigations towards potential biomarkers or targeted adjunctive therapies.","rel_num_authors":11,"rel_authors":[{"author_name":"Troy  C. Lund","author_inst":"University of Minnesota"},{"author_name":"Ryan  H. Peretz","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"Patricia  I. Dickson","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"Jennifer  K. Yee","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"Michelina Iacovino","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"Kent  D. Taylor","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"David Elashoff","author_inst":"University of California Los Angeles David Geffen School of Medicine"},{"author_name":"Ellen Fung","author_inst":"UCSF Benioff Children's Hospital"},{"author_name":"Bradley  S. Miller","author_inst":"University of Minnesota"},{"author_name":"Paul  J. Orchard","author_inst":"University of Minnesota"},{"author_name":"Lynda  E Polgreen","author_inst":"The Lundquist Institute for Biomedical Innovation: The Lundquist Institute"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"When to return genomic newborn screening results: health care professional perspectives","rel_doi":"10.64898\/2026.09.02.26362059","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26362059","rel_abs":"Background and ObjectivesDozens of projects around the world are sequencing the genomes of healthy babies near birth. Genomic information becomes actionable across infancy, childhood and adulthood, making timing of return a design choice for programs. We report the first study of health care professionals views on timing.\n\nMethodsWe conducted a qualitative interview study of US-based clinical geneticists, genetic counselors, laboratory personnel, pediatric primary care clinicians and genomic screening implementers. Participants responded to three strategies: staged throughout childhood when information becomes actionable, all at birth with adult-actionable results deferred, and all at birth. Transcripts were analyzed using framework analysis.\n\nResultsWe interviewed 52 individuals; 39 were asked directly about timing. Giving parents a choice, raised by participants rather than presented, was the most endorsed position (18), ahead of staging across childhood (12). Many viewed staging as preferable in theory, but feasibility concerns weighed against it, including that \"actionability\" was not a robust enough concept. A further concern was that parents would not grasp the distinction between data generated and data examined, on which staging depends. Where information is staged, participants saw a role for adolescent assent; where it is not, disclosure to the developing child becomes important, and participants identified a lack of support for parents.\n\nConclusionsTying the return of information to the age of actionability is intuitive but hard to operationalize. Parental choice was the most endorsed position but will only be viable with decision support and guidance for disclosure to children.","rel_num_authors":7,"rel_authors":[{"author_name":"Anna C F Lewis","author_inst":"Mass General Brigham; Harvard Medical School; Broad Institute"},{"author_name":"Adam H Buchanan","author_inst":"Geisinger"},{"author_name":"Aaron J Goldenberg","author_inst":"Case Western Reserve University"},{"author_name":"Bartha M Knoppers","author_inst":"McGill University"},{"author_name":"Amy L McGuire","author_inst":"Baylor College of Medicine"},{"author_name":"Robert C Green","author_inst":"Brigham and Women's Hospital, Broad Institute, Harvard Medical School"},{"author_name":"Ingrid A Holm","author_inst":"Harvard Medical School; Boston Children's Hospital"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Venetoclax-based Therapy Improves Outcomes across the Evolving Biology of t(11;14) Multiple Myeloma","rel_doi":"10.64898\/2026.09.02.26361956","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26361956","rel_abs":"BackgroundTranslocation t(11;14) defines a biologically distinct subset of multiple myeloma (MM) enriched for BCL2 dependency. Treatment with venetoclax, selective BCL2 inhibitor, has shown varied responses in clinical trials and retrospective cohorts. Efficacy of venetoclax-based combination therapies and optimal timing of treatment in t(11;14) MM patients remain incompletely characterized.\n\nMethodsWe have compared the overall survival of t(11;14) MM patients who received Venetoclax (N = 97) at any moment in time, to those who never did (N =284), in the largest retrospective cohort (N = 381) reported to date. We used longitudinal fluorescence in situ hybridization (FISH) to assess cytogenetic evolution and genomic complexity. We performed transcriptomic profiling of CD138-enriched tumors using RNA sequencing in a subset of samples and gene-expression signatures (UAMS\/HALLMARKS) were used to define molecular subtypes. Ex vivo drug sensitivity assays integrated with paired RNA sequencing were used to identify subtype-specific therapeutic vulnerabilities and rational venetoclax-based combination strategies.\n\nResultsVenetoclax exposure was associated with an improvement of median overall survival by nearly four years compared to non-VEN-exposed patients (p = 0.0003). Longitudinal cytogenetic analysis demonstrated stability of the primary t(11;14) translocation over time, while secondary abnormalities tend to accumulate, including those harboring high-risk secondary cytogenetic abnormalities such as del13q, amp\/gain1q21, del17p, and del1p, resulting in increasing genomic complexity with disease progression. Transcriptomic analyses identified selective enrichment of CD1\/CD2 signature (associated with t(11;14) NDMM) by single-sample gene set enrichment analysis as a marker of prolonged progression-free survival. However, patients with more than five prior lines of therapy were enriched for transcriptionally complex biology characterized by CD1\/CD2 with either proliferative\/hypermetabolic or inflammatory transcriptional programming which were associated with inferior outcomes with VEN-based treatment. Ex vivo drug sensitivity profiling revealed subtype-specific vulnerabilities, identifying daratumumab, lenalidomide, ixazomib, and panobinostat as rational partners for venetoclax depending on transcriptional context.\n\nConclusionVenetoclax-based therapy significantly improved overall survival in t(11;14) MM. Clinical benefit, defined by improved progression free survival, was greatest when venetoclax was administered earlier, preceding the emergence of transcriptomic reprogramming that reduces BCL2 dependency. These findings support transcriptomic biomarker-guided, subtype-specific venetoclax-based treatment strategies to optimize outcomes in patients with t(11;14) MM.","rel_num_authors":16,"rel_authors":[{"author_name":"Praneeth Reddy Sudalagunta","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Filip Ionescu","author_inst":"Mon Health Cancer Center"},{"author_name":"Rafael Renatino Canevarolo","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Maria Coehlo Siqueira Silva","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Daniel DeAvila","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Mark B. Meads","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Xiaohong Zhao","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Angel Perez","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Dimitrios Drekolias","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Ruxandra Irimia","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Shrinjaya Thapa","author_inst":"Swedish Cancer Institute"},{"author_name":"Parth Patel","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rachid Baz","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Kenneth H. Shain","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Ariosto Siqueira Silva","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Ariel Grajales-Cruz","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Socioeconomic disparities in substance use disorder prevalence and severity across the life course","rel_doi":"10.64898\/2026.09.03.26362182","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.03.26362182","rel_abs":"Gradients across socioeconomic status (SES) exist across most health conditions. While there has been significant attention devoted to the relationship between SES and physical and mental health, less research has examined how these relate to substance use disorders (SUD). In the current study, we use data from the prospective study within the Collaborative Study on the Genetics of Alcoholism (COGA) to explore the relationship between SES (in early life and adulthood) with multiple substance use disorders (alcohol, tobacco, cannabis, opioid, cocaine, and other substances). We find that early life SES (parental education and income) are associated with lower odds of lifetime diagnoses and lower severity for tobacco (TUD) and cannabis (CUD) use disorders. Associations with TUD remain after adjusting for demographic and familial risk, but associations with CUD were null after including familial risk factors. In participants aged 25+, adult education was associated with lower odds of diagnosis and severity for each of the SUD considered, conditional on early life SES, adult income, sociodemographic characteristics, and familial risk for SUD. Exploratory analyses of changes in SES revealed that those who were upwardly or downwardly mobile were at the lowest or greatest risk for more severe SUD across multiple substances, respectively. Our results demonstrate the relevance of both early life and adult SES in SUD risk. Early life conditions seem particularly relevant for specific substances while greater adult education was associated with reduced risk across all forms of SUDs.","rel_num_authors":11,"rel_authors":[{"author_name":"Peter B. Barr","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Sally I-Chun Kuo","author_inst":"Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ"},{"author_name":"Megan E. Cooke","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Henri M. Garrison-Desany","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Gayathri Pandey","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Kathleen K. Bucholz","author_inst":"Department of Psychiatry, School of Medicine, Washington University in St. Louis, St Louis, MO"},{"author_name":"Howard J. Edenberg","author_inst":"Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN Department of Biochemistry and Molecular Biology, School "},{"author_name":"Sivan Kinreich","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Bernice Porjesz","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Jessica E. Salvatore","author_inst":"Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ"},{"author_name":"Jacquelyn L. Meyers","author_inst":"VA New York Harbor Healthcare System, Brooklyn, NY Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Ins"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Socioeconomic disparities in substance use disorder prevalence and severity across the life course","rel_doi":"10.64898\/2026.09.03.26362182","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.03.26362182","rel_abs":"Gradients across socioeconomic status (SES) exist across most health conditions. While there has been significant attention devoted to the relationship between SES and physical and mental health, less research has examined how these relate to substance use disorders (SUD). In the current study, we use data from the prospective study within the Collaborative Study on the Genetics of Alcoholism (COGA) to explore the relationship between SES (in early life and adulthood) with multiple substance use disorders (alcohol, tobacco, cannabis, opioid, cocaine, and other substances). We find that early life SES (parental education and income) are associated with lower odds of lifetime diagnoses and lower severity for tobacco (TUD) and cannabis (CUD) use disorders. Associations with TUD remain after adjusting for demographic and familial risk, but associations with CUD were null after including familial risk factors. In participants aged 25+, adult education was associated with lower odds of diagnosis and severity for each of the SUD considered, conditional on early life SES, adult income, sociodemographic characteristics, and familial risk for SUD. Exploratory analyses of changes in SES revealed that those who were upwardly or downwardly mobile were at the lowest or greatest risk for more severe SUD across multiple substances, respectively. Our results demonstrate the relevance of both early life and adult SES in SUD risk. Early life conditions seem particularly relevant for specific substances while greater adult education was associated with reduced risk across all forms of SUDs.","rel_num_authors":11,"rel_authors":[{"author_name":"Peter B. Barr","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Sally I-Chun Kuo","author_inst":"Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ"},{"author_name":"Megan E. Cooke","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Henri M. Garrison-Desany","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Gayathri Pandey","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Kathleen K. Bucholz","author_inst":"Department of Psychiatry, School of Medicine, Washington University in St. Louis, St Louis, MO"},{"author_name":"Howard J. Edenberg","author_inst":"Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN Department of Biochemistry and Molecular Biology, School "},{"author_name":"Sivan Kinreich","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Bernice Porjesz","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Jessica E. Salvatore","author_inst":"Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ"},{"author_name":"Jacquelyn L. Meyers","author_inst":"VA New York Harbor Healthcare System, Brooklyn, NY Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Ins"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Cumulative Burden of Prediabetes, Subclinical Myocardial Injury, and Myocardial Stress and Risk of Incident Atrial Fibrillation in Adults With Hypertension","rel_doi":"10.64898\/2026.09.02.26362108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26362108","rel_abs":"AbstractO_ST_ABSBackgroundC_ST_ABSMetabolic dysfunction, subclinical myocardial injury, and myocardial stress may contribute to atrial fibrillation (AF), but ther independent and cumulative associations with incident AF are unclear.\n\nMethodsWe analyzed 7,261 Systolic Blood Pressure Intervention Trial (SPRINT) participants without prevalent AF, who had baseline fasting glucose, high-sensitivity cardiac troponin I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements. By trial design, SPRINT excluded individuals with diabetes, prior stroke or recent symptomatic heart failure or left ventricular ejection fraction <35%. Prediabetes represented metabolic dysfunction, elevated hs-cTnI myocardial injury, and elevated NT-proBNP myocardial stress. Cox models assessed associations of individual domains and the number of abnormal domains (0-3) with incident AF. Secondary analyses examined the 8 mutually exclusive domain combinations.\n\nResultsDuring a median 3.76-year follow-up, 174 participants developed AF. In multivariable adjusted model, prediabetes, elevated hs-cTnI, and elevated NT-proBNP were associated with incident AF (HR, 1.48 [95% CI, 1.07-2.05], 1.84 [95% CI, 1.30-2.60], and 2.35 [95% CI, 1.56-3.55], respectively). AF risk increased progressively with increasing domain burden (P for trend <0.001); each additional abnormal domain was associated with an 82% higher AF risk (HR, 1.82 [95% CI, 1.50-2.22]). Participants with abnormalities in all 3 domains had the highest risk (HR, 6.11 [95% CI, 2.82-13.24]).\n\nConclusionsPrediabetes, subclinical myocardial injury, and myocardial stress were independently associated with incident AF, with progressively greater risk as abnormalities accumulated. These findings support a multidomain framework in which complementary metabolic and cardiac abnormalities collectively characterize susceptibility to AF.","rel_num_authors":8,"rel_authors":[{"author_name":"Moustafa Elnewishy","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Asem M. Mohsen","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Tarek Zaho","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Richard Kazibwe","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Takeki Suzuki","author_inst":"Wake Forest University"},{"author_name":"M. Benjamin Shoemaker","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Prashant Bhave","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Elsayed Z. Soliman","author_inst":"Wake Forest University School of Medicine"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"Who Is Reached by Supervised Psilocybin Services? Oregon Services Versus National Psilocybin Use","rel_doi":"10.64898\/2026.09.03.26362170","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.03.26362170","rel_abs":"Supervised psilocybin services are expanding across the United States, yet how individuals accessing these programs compare with those using psilocybin in the general population is unknown. We conducted a cross-sectional descriptive comparison of Oregon Psilocybin Services (OPS) data from licensed service centers in 2025 (5,935 encounters) and the 2024 National Survey on Drug Use and Health (NSDUH) public-use file (1,822 of 47,299 adults reporting past-year psilocybin use), examining demographics, reasons for use, self-reported disability, and past-year psychiatric conditions and treatment. OPS clients were predominantly female (58.2%) and aged 35 or older (82.1%), whereas adults reporting psilocybin use nationally were predominantly male (64.0%) and younger than 35 (56.7%). Racial and ethnic minority representation was narrower in Oregon (0.9% Black, 2.5% Hispanic vs. 5.4% and 14.3% nationally). OPS clients reported higher incomes (58.5% earning >$95,000) and primarily cited wellness; self-reported disability was uncommon. Adults using psilocybin nationally had high past-year rates of major depressive episode (22.7%), serious psychological distress (36.8%), substance use disorder (61.7%), and mental health treatment receipt (42.9%). Oregons open-access model selects higher-income, clinically stable, wellness-oriented adults, while millions with psychiatric and substance-use burden use psilocybin outside supervised channels; its safety and utilization data should not be generalized.","rel_num_authors":4,"rel_authors":[{"author_name":"Gabriel P. A. Costa","author_inst":"Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Christina Riggione","author_inst":"Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Christopher Pittenger","author_inst":"Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA"},{"author_name":"Joao P. De Aquino","author_inst":"Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-09-07","rel_site":"medrxiv"},{"rel_title":"MAP3K7 Loss of Function Causes Dilated Cardiomyopathy","rel_doi":"10.64898\/2026.09.02.26361780","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26361780","rel_abs":"Background and AimsDilated cardiomyopathy (DCM) is a genetically heterogeneous cause of heart failure and sudden cardiac death. Many patients remain without a molecular diagnosis. MAP3K7 encodes TAK1, a serine\/threonine kinase important for cardiac homeostasis. MAP3K7 variants are an established cause of syndromic disease, including cardiospondylocarpofacial syndrome (CSCF), in which DCM has been occasionally reported. Here, we demonstrate that MAP3K7 variants can cause apparently isolated DCM, expanding the phenotypic spectrum of MAP3K7-related disorders.\n\nMethodsWe compiled four orthogonal lines of human genetic evidence: de novo variation in paediatric cardiomyopathy; common variant association with adult DCM; familial segregation; and rare variant enrichment in DCM cases, together with functional categorisation of rare variants.\n\nResultsIn 117 paediatric cardiomyopathy trios from the 100,000 Genomes Project, two probands harboured rare de novo MAP3K7 missense variants, significantly more than expected (Bonferroni-adjusted p=0.036). Independent GWAS implicated MAP3K7 as a susceptibility locus for adult DCM. Across global DCM cohorts, we identified families harbouring rare MAP3K7 variants, including one with segregation in nine affected relatives. Rare damaging non-truncating variants were enriched in DCM cases, while truncating variants were associated with DCM in the Genomics England cohort and increased left ventricular volumes in UK Biobank. DCM-associated variants reduced TAK1 kinase activity, supporting a loss-of-function mechanism consistent with CSCF-associated alleles.\n\nConclusionMultiple independent lines of evidence establish an association between MAP3K7 loss of function variants and DCM. Several affected individuals lacked overt syndromic features, demonstrating that MAP3K7-related disease may present as apparently isolated DCM across the lifespan and supporting inclusion of MAP3K7 in DCM diagnostic pipelines.\n\nGRAPHICAL ABSTRACTO_ST_ABSKey Question: Do MAP3K7 variants cause isolated dilated cardiomyopathy?C_ST_ABSMAP3K7 variants are known to cause rare syndromic disease, including cardiospondylocarpofacial syndrome (CSCF). Some patients with CSCF develop dilated cardiomyopathy (DCM), however we do not know whether MAP3K7 variants cause primary or isolated DCM without overt syndromic disease.\n\nKey FindingWe present multiple orthogonal data sources supporting an association between MAP3K7 loss-of-function variants and DCM. The collective evidence for this gene-disease association encompasses paediatric trio de novo discovery, GWAS, familial segregation, rare variant case-control analysis and variant categorisation in vitro. Strong segregation evidence was obtained for p.(Tyr125Cys), with 9 clinically affected genotype-positive individuals in one pedigree (estimated LOD score 2.7).\n\nTake-Home MessageLoss-of-function variants in MAP3K7 are associated with DCM and several affected individuals lack overt syndromic features. MAP3K7-related disease may present as apparently isolated DCM across the lifespan. These findings support the incorporation of MAP3K7 testing into DCM diagnostic pipelines.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC=\"FIGDIR\/small\/26361780v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (29K):\norg.highwire.dtl.DTLVardef@1489e0eorg.highwire.dtl.DTLVardef@80b827org.highwire.dtl.DTLVardef@ba0dd4org.highwire.dtl.DTLVardef@e1ddc5_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":39,"rel_authors":[{"author_name":"Katherine S. Josephs","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Carlos C. Smith-Diaz","author_inst":"Garvan Institute of Medical Research and University of New South Wales, Sydney, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, Uni"},{"author_name":"Angela Woods","author_inst":"MRC Laboratory of Medical Sciences, Imperial College London, London, United Kingdom"},{"author_name":"Claire Prince","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"},{"author_name":"Sean L. Zheng","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC Laboratory of Medical Sciences, Imperial College London, London, United "},{"author_name":"Rachel Buchan","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Esme Cavanagh","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Shezan Elahi","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Emma Jennings","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Henry Procter","author_inst":"Leeds Clinical Genomics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom"},{"author_name":"James S. McTaggart","author_inst":"Leeds Clinical Genomics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom"},{"author_name":"Riyad Janan","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"},{"author_name":"Pantazis Theotokis","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"},{"author_name":"Amy Baker","author_inst":"Garvan Institute of Medical Research and University of New South Wales, Sydney, NSW, Australia"},{"author_name":"Natasha Henden","author_inst":"Garvan Institute of Medical Research and University of New South Wales, Sydney, NSW, Australia"},{"author_name":"Kathryn A. McGurk","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC Laboratory of Medical Sciences, Imperial College London, London, United "},{"author_name":"Katrina Prescott","author_inst":"Leeds Clinical Genomics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom"},{"author_name":"- Newcastle Clinical Genetics Team","author_inst":"Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom"},{"author_name":"Vaidehi Jobanputra","author_inst":"New York Genome Center, New York, NY, USA"},{"author_name":"Paul James","author_inst":"Department of Genomic Medicine, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia;"},{"author_name":"Tina Thompson","author_inst":"Department of Genomic Medicine, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia"},{"author_name":"Dominica Zentner","author_inst":"Department of Genomic Medicine, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia;"},{"author_name":"Upasana Tayal","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Brian P. Halliday","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Sanjay K. Prasad","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Declan P. O'Regan","author_inst":"MRC Laboratory of Medical Sciences, Imperial College London, London, United Kingdom"},{"author_name":"R. Thomas Lumbers","author_inst":"Institute of Health Informatics, University College London, London, United Kingdom"},{"author_name":"Paul J. R. Barton","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Kate Richardson","author_inst":"Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom"},{"author_name":"Sabine Klaassen","author_inst":"Charite-Universitatsmedizin Berlin and Max Delbruck Center for Molecular Medicine, Berlin, Germany; DZHK, Berlin, Germany"},{"author_name":"Andres Rico-Armada","author_inst":"Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom"},{"author_name":"Piers E. F. Daubeney","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"Verity L. Hartill","author_inst":"Leeds Clinical Genomics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom"},{"author_name":"Stephen P. Page","author_inst":"Leeds Clinical Genomics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom"},{"author_name":"Angharad M. Roberts","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom"},{"author_name":"David Carling","author_inst":"MRC Laboratory of Medical Sciences, Imperial College London, London, United Kingdom"},{"author_name":"Jodie Ingles","author_inst":"Garvan Institute of Medical Research and University of New South Wales, Sydney, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, Uni"},{"author_name":"James S. Ware","author_inst":"National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation "},{"author_name":"- GoDCM Consortium","author_inst":""}],"rel_date":"2026-09-06","rel_site":"medrxiv"},{"rel_title":"Performance of protein panels is inflated across many biomarker studies","rel_doi":"10.64898\/2026.09.02.26362037","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26362037","rel_abs":"Data leakage is a prevalent yet underappreciated flaw in biomarker discovery studies. Through simulation and real-world proteomic data, we demonstrate that typical pipelines are broadly susceptible to this issue, producing inflated performance estimates, poor generalization, and excess false positives. We further introduce two tools to detect data leakage at the code and manuscript level, providing a practical path toward more rigorous and reproducible biomarker reporting.","rel_num_authors":5,"rel_authors":[{"author_name":"Lijun An","author_inst":"Lund University"},{"author_name":"Caitlin A Finney","author_inst":"The University of Sydney"},{"author_name":"Artur Shvetcov","author_inst":"The University of Sydney"},{"author_name":"- The Global Neurodegeneration Proteomics Consortium","author_inst":"-"},{"author_name":"Jacob Vogel","author_inst":"Lund University"}],"rel_date":"2026-09-06","rel_site":"medrxiv"},{"rel_title":"A dual proteomics analysis of paired cerebrospinal fluid and plasma from patients with neurodegenerative diseases","rel_doi":"10.64898\/2026.09.02.26361977","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26361977","rel_abs":"INTRODUCTIONUnderstanding concordance across biofluids and platforms is critical for understanding neurodegenerative biomarkers results and translating them into clinical use; yet systematic comparisons remain limited. To address this gap, we performed large-scale proteomic profiling of patient-paired plasma and CSF to characterize cross-modal relationships.\n\nMETHODSWe profiled paired plasma and CSF from 67 individuals using SomaScan 11K and NULISAseq CNS panels. Disease severity was assessed with the CDR+NACC FTLD-M Global Score.\n\nRESULTSWe identified 269 SomaScan and 18 NULISA proteins with significant cross-biofluid correlation. Cross-platform concordance within biofluids was strong. NEFL, NPTX2, TREM2, and CHIT1 demonstrated consistent cross-platform agreement. Associations with disease severity were compartment-specific, with decreased NPTX2 in CSF, increased NEFL and GFAP in plasma, and decreased TREM2 across biofluids.\n\nDISCUSSIONCross-platform consistency supports biomarker robustness, while limited cross-biofluid concordance highlights compartmental biology. Given additional clinical correlations despite varying underlying pathology, these findings may point to shared neurodegenerative disorder pathways.","rel_num_authors":18,"rel_authors":[{"author_name":"Isabelle Kowal","author_inst":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institute"},{"author_name":"Sonja W Scholz","author_inst":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Jacob Epstein","author_inst":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institute"},{"author_name":"Bryan J Traynor","author_inst":"Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA"},{"author_name":"Laura E Danielian","author_inst":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Ying Hao","author_inst":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institute"},{"author_name":"Jody Crook","author_inst":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Ziyi Li","author_inst":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institute"},{"author_name":"Katelyn Porter","author_inst":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Brian Sellers","author_inst":"NIH Center for Human Immunology, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Thomas J Langowski","author_inst":"NIH Center for Human Immunology, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Marisa N Denkinger","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden"},{"author_name":"Nicholas J Ashton","author_inst":"Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"Kendall Van Keuron-Jensen","author_inst":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institute"},{"author_name":"Mark R Cookson","author_inst":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institute"},{"author_name":"Justin Y Kwan","author_inst":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Yue Andy A Qi","author_inst":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institute"},{"author_name":"Allison Snyder","author_inst":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"}],"rel_date":"2026-09-06","rel_site":"medrxiv"},{"rel_title":"Peer Facilitation as a Methodological Condition: What Participatory Photovoice Revealed About Transition to Adulthood Among Youth Living with HIV in India","rel_doi":"10.64898\/2026.09.02.26361557","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26361557","rel_abs":"Transition readiness instruments for youth living with HIV were developed in high-income settings and define readiness as clinical competence and individual autonomy. Few reflect youth in low- and middle-income settings, where family obligation and community stigma shape the passage to adulthood. In March 2026, sixteen youth living with HIV aged 13-22 years took part in a peer-facilitated photovoice study at two sites in Karnataka, India: Bengaluru and Belgaum. Participants photographed and collectively interpreted their experiences of growing up and their expectations of the future. Six returned in May 2026 for a reflective discussion of the method. Participants defined independence as the capacity to sustain others, located the principal risks of transition in relational and social rather than clinical domains, and recommended that transition preparation begin around age twelve. Reciprocal obligation was absent from the initial codebook and emerged through participants visual metaphors. Peer facilitation was a condition of the inquiry rather than an enhancement of it, and photovoice reporting should specify who exercised interpretive authority. Participatory photovoice can broaden prevailing definitions of transition readiness and inform more youth-responsive assessments.","rel_num_authors":8,"rel_authors":[{"author_name":"Anusha Sulladmath","author_inst":"University of Washington"},{"author_name":"Siddha Sannigrahi","author_inst":"John Hopkins University"},{"author_name":"Suhas Reddy","author_inst":"RISHI Foundation"},{"author_name":"Meghana Gowda","author_inst":"RISHI Foundation"},{"author_name":"Michael Babu Raj","author_inst":"Y.R. Gaitonde Centre for AIDS Research and Education (YRGCARE), Chennai, Tamil Nadu, India"},{"author_name":"Satish Kumar SK","author_inst":"Y.R. Gaitonde Centre for AIDS Research and Education (YRGCARE), Chennai, Tamil Nadu, India."},{"author_name":"Lakshmi Ganapathi","author_inst":"Massachusetts General Hospital"},{"author_name":"Anita Shet","author_inst":"John Hopkins University"}],"rel_date":"2026-09-06","rel_site":"medrxiv"},{"rel_title":"A Multidimensional Immune Signature Predicts Susceptibility to Omicron Infection in Vaccinated Individuals","rel_doi":"10.64898\/2026.08.31.26361844","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.31.26361844","rel_abs":"Substantial inter-individual variation in susceptibility to viral infection persists despite widespread vaccination, and its immunological basis remains poorly understood. We investigated how innate and adaptive immune responses contribute to susceptibility to SARS-CoV-2 infection during the early COVID-19 pandemic. We compared two groups of vaccinated individuals who either remained uninfected or became infected during the first Omicron wave. Blood samples were collected at baseline and 24 weeks later. Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were isolated and stimulated with the TLR7\/8 agonist R848 to assess innate responses. PBMCs were stimulated with SARS-CoV-2 peptide pools and highly purified inactivated viruses (ancestral and Omicron BA.1) to evaluate adaptive immunity. Prior to infection, individuals in the infected group exhibited reduced CD4 and CD8 T cells proliferative responses, alongside with increased TNF production across all stimulation conditions, despite largely comparable immune phenotypes, indicating a pre-existing functional immune deficit. Following infection, T-cell proliferation and IFN-{gamma} production were partially restored in response to viral antigens, although responses to Omicron BA.1 remained suboptimal. This functional deficit was accompanied by heightened inflammatory activity, including increased TNF and IFN-{gamma} production, elevated anti-nucleocapsid IgG3 levels, higher frequencies of B cells and myeloid cells, reduced circulating interferon-inducible T-cell Alpha Chemoattractant (I-TAC) concentrations, and a modest impairment in PMN IL-8 responses. Notably, these alterations were detectable prior to infection and persisted thereafter, indicating that they represent determinants rather than consequences of viral infection. Importantly, beyond differences in the magnitude of immune responses, protection was associated with the degree of functional coordination within the humoral compartment, as reflected by the relationship between Spike-binding antibodies and neutralizing activity. Together, these results demonstrate that susceptibility to Omicron infection is linked to a pre-existing and persistent functional immune imbalance affecting both innate and adaptive arms of immunity.\n\nHighlightsO_LIPre-existing impairment in CD4 and CD8 T cell proliferative capacity identifies individuals at higher risk of Omicron infection.\nC_LIO_LISusceptibility to Omicron infection is associated with a combined immune signature including altered cytokines (I-TAC, TNF), anti-N IgG3 antibodies, and cellular phenotypes.\nC_LIO_LIOmicron infected individuals displayed higher frequency of B cells and myeloid cells.\nC_LIO_LIOmicron infection partially restores T-cell function but fails to normalize responses to homologous viral stimulation.\nC_LIO_LIExtended 7-day proliferation assays using highly purified viral antigens enhance detection of functional immune deficits undetected by usual analysis alone such as ELISpot IFN-{gamma} AIM assay or phenotype analysis.\nC_LI","rel_num_authors":19,"rel_authors":[{"author_name":"Hend Jarras","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Wilfried Wenceslas Bazie","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Programme de Recherche sur les Maladies In"},{"author_name":"Isalie Blais","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Benjamin Goyer","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Julien Boucher","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Arielle Pakenham","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Kimberly Dancause-Caron","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Henintsoa Rabezanahary","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Mathieu Theriault","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Kim Santerre","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Marc-Andre Langlois","author_inst":"Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Philippe A Tessier","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Departement de Microbiologie-Infectiologie"},{"author_name":"Jean-Francois Masson","author_inst":"Department of Chemistry, Institut Courtois, Quebec Center for Advanced Materials, Regroupement quebecois sur les materiaux de pointe, and Centre interdisciplina"},{"author_name":"Joelle N Pelletier","author_inst":"Department of Chemistry, Department of Biochemistry, Universite de Montreal, Montreal, QC, Canada, PROTEO- The Quebec Network for Research on Protein Function, "},{"author_name":"Nicholas Brousseau","author_inst":"Direction des risques biologiques, Institut national de sante publique du Quebec, Quebec, QC, Canada"},{"author_name":"Denis Boudreau","author_inst":"Departement de chimie et Centre d optique, photonique et laser COPL, Universite Laval, Quebec, QC, Canada"},{"author_name":"Sylvie Trottier","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Centre de recherche en infectiologie de l "},{"author_name":"Mariana Baz","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Departement de Microbiologie-Infectiologie"},{"author_name":"Caroline Gilbert","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Departement de Microbiologie-Infectiologie"}],"rel_date":"2026-09-04","rel_site":"medrxiv"},{"rel_title":"A Multidimensional Immune Signature Predicts Susceptibility to Omicron Infection in Vaccinated Individuals","rel_doi":"10.64898\/2026.08.31.26361844","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.31.26361844","rel_abs":"Substantial inter-individual variation in susceptibility to viral infection persists despite widespread vaccination, and its immunological basis remains poorly understood. We investigated how innate and adaptive immune responses contribute to susceptibility to SARS-CoV-2 infection during the early COVID-19 pandemic. We compared two groups of vaccinated individuals who either remained uninfected or became infected during the first Omicron wave. Blood samples were collected at baseline and 24 weeks later. Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were isolated and stimulated with the TLR7\/8 agonist R848 to assess innate responses. PBMCs were stimulated with SARS-CoV-2 peptide pools and highly purified inactivated viruses (ancestral and Omicron BA.1) to evaluate adaptive immunity. Prior to infection, individuals in the infected group exhibited reduced CD4 and CD8 T cells proliferative responses, alongside with increased TNF production across all stimulation conditions, despite largely comparable immune phenotypes, indicating a pre-existing functional immune deficit. Following infection, T-cell proliferation and IFN-{gamma} production were partially restored in response to viral antigens, although responses to Omicron BA.1 remained suboptimal. This functional deficit was accompanied by heightened inflammatory activity, including increased TNF and IFN-{gamma} production, elevated anti-nucleocapsid IgG3 levels, higher frequencies of B cells and myeloid cells, reduced circulating interferon-inducible T-cell Alpha Chemoattractant (I-TAC) concentrations, and a modest impairment in PMN IL-8 responses. Notably, these alterations were detectable prior to infection and persisted thereafter, indicating that they represent determinants rather than consequences of viral infection. Importantly, beyond differences in the magnitude of immune responses, protection was associated with the degree of functional coordination within the humoral compartment, as reflected by the relationship between Spike-binding antibodies and neutralizing activity. Together, these results demonstrate that susceptibility to Omicron infection is linked to a pre-existing and persistent functional immune imbalance affecting both innate and adaptive arms of immunity.\n\nHighlightsO_LIPre-existing impairment in CD4 and CD8 T cell proliferative capacity identifies individuals at higher risk of Omicron infection.\nC_LIO_LISusceptibility to Omicron infection is associated with a combined immune signature including altered cytokines (I-TAC, TNF), anti-N IgG3 antibodies, and cellular phenotypes.\nC_LIO_LIOmicron infected individuals displayed higher frequency of B cells and myeloid cells.\nC_LIO_LIOmicron infection partially restores T-cell function but fails to normalize responses to homologous viral stimulation.\nC_LIO_LIExtended 7-day proliferation assays using highly purified viral antigens enhance detection of functional immune deficits undetected by usual analysis alone such as ELISpot IFN-{gamma} AIM assay or phenotype analysis.\nC_LI","rel_num_authors":19,"rel_authors":[{"author_name":"Hend Jarras","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Wilfried Wenceslas Bazie","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Programme de Recherche sur les Maladies In"},{"author_name":"Isalie Blais","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Benjamin Goyer","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Julien Boucher","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Arielle Pakenham","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Kimberly Dancause-Caron","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Henintsoa Rabezanahary","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Mathieu Theriault","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Kim Santerre","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada"},{"author_name":"Marc-Andre Langlois","author_inst":"Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Philippe A Tessier","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Departement de Microbiologie-Infectiologie"},{"author_name":"Jean-Francois Masson","author_inst":"Department of Chemistry, Institut Courtois, Quebec Center for Advanced Materials, Regroupement quebecois sur les materiaux de pointe, and Centre interdisciplina"},{"author_name":"Joelle N Pelletier","author_inst":"Department of Chemistry, Department of Biochemistry, Universite de Montreal, Montreal, QC, Canada, PROTEO- The Quebec Network for Research on Protein Function, "},{"author_name":"Nicholas Brousseau","author_inst":"Direction des risques biologiques, Institut national de sante publique du Quebec, Quebec, QC, Canada"},{"author_name":"Denis Boudreau","author_inst":"Departement de chimie et Centre d optique, photonique et laser COPL, Universite Laval, Quebec, QC, Canada"},{"author_name":"Sylvie Trottier","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Centre de recherche en infectiologie de l "},{"author_name":"Mariana Baz","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Departement de Microbiologie-Infectiologie"},{"author_name":"Caroline Gilbert","author_inst":"Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada, Departement de Microbiologie-Infectiologie"}],"rel_date":"2026-09-04","rel_site":"medrxiv"},{"rel_title":"Secondary causes among adult patients presenting with first-episode psychosis to acute medical settings in Hong Kong: A 10-Year retrospective study","rel_doi":"10.64898\/2026.09.02.26362044","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26362044","rel_abs":"BackgroundThe prevalence and pattern of secondary causes of first-onset psychosis (FEP) in Asian populations are understudied. Our objectives are to investigate the prevalence and pattern of secondary causes of FEP presenting in an acute medical setting in a metropolitan, Chinese-predominant population, and to investigate the prevalence and pattern of undiagnosed conditions presenting as psychosis.\n\nMethodThis is a retrospective observational study. We reviewed medical records of patients referred to the consultation psychiatry team at a tertiary acute teaching hospital in Hong Kong from January 2015 to Apr 2025. The inclusion criteria of the study are 1) age 18-64 at the time of the assessment, and 2) FEP confirmed by the consultation liaison team. Patients diagnosed with delirium were excluded.\n\nResultAmong the 384 patients included in the study (mean age = 40.0 {+\/-}13.7 years, 69% female), secondary causes of psychosis were found in 9.6% (n=37) of the cohort. Substance use is the most common secondary cause found (n=11, 2.9% of all FEPs) overall. Among those with secondary psychoses, patients underlying conditions were revealed only by the workup in relation to the FEP in 16 of them, of which definitive or probable autoimmune encephalitis (n=5) and early-onset dementia (n=4) were the most common conditions uncovered.\n\nConclusionThe prevalence of secondary psychoses in our FEP cohort is lower than published international figures. Clinicians need to be aware of the suspicious clinical features suggestive of autoimmune encephalitis and early-onset dementia in FEP patients with otherwise unremarkable past history and toxicology test.","rel_num_authors":6,"rel_authors":[{"author_name":"Steven Wai Ho Chau","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Lam KW Lam","author_inst":"Department of Psychiatry, Prince of Wales Hospital, Hong Kong"},{"author_name":"Matthew PM Yu","author_inst":"Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong, China"},{"author_name":"Yuen Cheuk Wong","author_inst":"Department of General Adult Psychiatry, Castle Peak Hospital, Hong Kong, China"},{"author_name":"Joseph CC Choi","author_inst":"Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China"},{"author_name":"Howan HW Leung","author_inst":"5.\tDivision of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China"}],"rel_date":"2026-09-04","rel_site":"medrxiv"},{"rel_title":"Socio-demographic and environmental factors amplify typhoon-related excess mortality in Japan","rel_doi":"10.64898\/2026.09.01.26362002","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.01.26362002","rel_abs":"Mechanisms shaping population vulnerability to typhoon-related mortality remain poorly understood. Constructing a Bayesian spatio-temporal model, we linked 12.9 million deaths across Japan from 2010 to 2019 to population-weighted typhoon wind exposure and assessed effect modification by income, natural hazard vulnerability and healthcare access. Typhoon exposure was associated with 2,426 cumulative excess deaths [95% credible interval (CrI): 139, 4,632] among adults [&ge;]70 years, with mortality increasing within 0-1 weeks of exposure and more strongly in areas with limited healthcare access and greater hazard vulnerability. Among individuals <70 years, cumulative excess mortality was uncertain [781 deaths; -309 to 1,900], but delayed mortality increases were concentrated in lower-income and landslide-prone areas. These distinct patterns suggest that typhoon mortality reflects an interaction between acute exposure, demographic ageing and geographically uneven adaptive capacity, highlighting the need to incorporate local vulnerability into climate-resilient health systems.","rel_num_authors":5,"rel_authors":[{"author_name":"Lisa Yamasaki","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Hiroaki Murayama","author_inst":"International University of Health and Welfare"},{"author_name":"Paul LC Chua","author_inst":"The University of Tokyo"},{"author_name":"Masahiro Hashizume","author_inst":"The University of Tokyo"},{"author_name":"Robbie M Parks","author_inst":"Columbia University"}],"rel_date":"2026-09-04","rel_site":"medrxiv"},{"rel_title":"Very low-calorie diet reduces hepatic steatosis and remodels circulating metabolite-microRNAs networks in metabolic dysfunction-associated steatotic liver disease: A pilot study","rel_doi":"10.64898\/2026.09.01.26361664","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.01.26361664","rel_abs":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease, with weight loss as the pivotal therapeutic strategy. However, the metabolic and molecular adaptations underlying rapid weight loss remain incompletely defined. In this pilot study, women with obesity and MASLD but without diabetes consumed a very low-calorie diet (VLCD) for 8 weeks. Clinical parameters, hepatic steatosis measured by controlled attenuation parameter (CAP), circulating metabolites, and microRNAs (miRs) were assessed before and after the dietary intervention. Integrated correlation and hierarchical clustering analyses were performed to identify molecular networks associated with clinical improvement. VLCD was well tolerated, resulting in significant weight loss ([~]11%) with [~]80% adherence. Significant improvements in metabolic parameters were observed, including fat mass, waist circumference, blood pressure, insulinemia, HOMA-IR, HbA1c, and triglycerides, with unchanged liver enzymes. Hepatic steatosis decreased markedly, as indicated by a reduction in CAP, while stiffness remained unchanged. Metabolomic profiling revealed elevated ketone bodies and broad reductions in amino acid levels, consistent with enhanced fatty acid oxidation and a catabolic metabolic state. Correlation analysis identified distinct metabolite signatures associated with hepatic steatosis, with changes in CAP positively associated with changes in amino acids and inversely associated with changes in ketone bodies and tricarboxylic acid cycle intermediates. Circulating miRs underwent selective rather than global remodeling, with only a limited subset showing strong associations with clinical parameters, including CAP and HOMA-IR. Specifically, VLCD altered the circulating levels of miR-148a-3p, miR-140-3p, miR-10b-5p, and miR-345-5p. Integration of metabolomic and miR datasets identified coordinated metabolitemiR modules involving glucose metabolism, branched-chain amino acid catabolism, mitochondrial metabolism, purine metabolism, microbial metabolites, and cellular redox pathways. These findings demonstrate that improvement in hepatic steatosis during VLCD-induced weight loss is accompanied by coordinated remodeling of circulating metabolite-miR networks. Integrated multi-omics analysis identifies candidate molecular signatures associated with metabolic adaptation and highlights circulating miR-metabolite modules as potential biomarkers of therapeutic response in MASLD.","rel_num_authors":13,"rel_authors":[{"author_name":"Paroma Deb","author_inst":"University of Iowa"},{"author_name":"Darin Bagar","author_inst":"University of Iowa"},{"author_name":"Prashant Kumar","author_inst":"University of Iowa"},{"author_name":"Leon Sun","author_inst":"University of Iowa"},{"author_name":"Ethan Chen","author_inst":"University of Iowa"},{"author_name":"Ravinder Reddy Gaddam","author_inst":"University of Iowa"},{"author_name":"Lorrana F Ferretto","author_inst":"University of Iowa"},{"author_name":"Constance R Shelsky","author_inst":"University of Iowa"},{"author_name":"Antonio J Sanchez","author_inst":"University of Iowa"},{"author_name":"Himani Thakkar","author_inst":"University of Iowa"},{"author_name":"Bhagirath Chaurasia","author_inst":"University of Iowa"},{"author_name":"Ajit Vikram","author_inst":"University of Iowa"},{"author_name":"Marcelo Lima DG Correia","author_inst":"University of Iowa"}],"rel_date":"2026-09-04","rel_site":"medrxiv"},{"rel_title":"Nanopore sequencing panel for saliva-based host pharmacogenomic screening in anti-tubercular therapy","rel_doi":"10.64898\/2026.09.02.26362034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.02.26362034","rel_abs":"RationaleHost genotypes can predict subtherapeutic anti-tubercular drug exposures and treatment-associated toxicities. Screening for these variants could enable personalized dosing, but scalable assays for second-line drugs are lacking.\n\nObjectivesWe developed a nanopore sequencing panel to detect host variants affecting anti-tuberculosis drug troughs and toxicities, and evaluated its performance as a saliva-based screening tool.\n\nMethodsWe designed a 16-plex panel targeting 23 variants (21 clinically validated, 2 predicted actionable) relevant to linezolid, bedaquiline, clofazimine, moxifloxacin, and ethambutol exposure. We first sequenced 50 Coriell DNA (1000 Genomes Project) to benchmark accuracy against Illumina, then sequenced saliva from 202 individuals treated for drug-resistant tuberculosis in India using MinION Mk1C (R10.4). Plasma trough concentrations and toxicity frequencies were stratified by genotype. Data were analyzed using in-house pipelines.\n\nMeasurements and Main ResultsThe panel showed high coverage in saliva (median 3,609X). Several suggestive genotype-phenotype trends reached nominal significance in distinct subsets. Among patients on high-dose moxifloxacin (800mg daily), UGT1A1 rs3755319 A>C was associated with higher troughs in heterozygotes (6\/14, p<0.01) and homozygous alternates (4\/14, p<0.05). Among patients with linezolid-associated toxicity dose-reduced to 300mg, ABCB1 rs2032582 A>C homozygous alternates (7\/98) had significantly lower Cmin versus wild-type (p<0.05) and heterozygotes (p<0.01); neither association held at standard dosing. Linezolid toxicity was more frequent among ABCB1 rs1128503 A>G heterozygotes versus homozygous reference (58.3% vs. 29.1%), and UGT1A1 rs4148323 G>A heterozygotes showed higher moxifloxacin toxicity rates than wild-type (42.9% vs. 14.3%).\n\nConclusionsPortable, saliva-based sequencing reliably detects pharmacogenetic variants and could inform pre-treatment screening for drug exposure or toxicity.\n\nAt a glance summaryO_ST_ABSScientific knowledge on the subjectC_ST_ABSInterindividual variability in anti-tuberculosis plasma drug concentrations may contribute to poor outcomes, relapse, and toxicity, particularly with second-line regimens. Variants in host pharmacogenes partly explain subtherapeutic exposure and adverse effects and can be leveraged to identify individuals at risk, enabling dose optimization. However, pharmacogenes for second-line drugs remain underexplored, often assessed using limited variants in small populations despite substantial ethnic diversity. Scalable assays evaluating multiple variants are needed to enable routine screening for pharmacogenomics-guided treatment in clinical practice.\n\nWhat this study adds to the fieldWe developed a custom Nanopore sequencing panel targeting pharmacogenes for five second-line anti-tuberculosis drugs, incorporating both validated and predicted pharmacogenomic variants. The panel showed 100% concordance with Illumina whole-genome data (n=50) and was clinically validated on saliva samples from 202 patients receiving guideline-concordant, susceptibility-guided multidrug therapy for rifampin-resistant tuberculosis. The panel generated high-quality data from low DNA input, supporting scalable and noninvasive screening. This allowed for 174 distinct assessments of the impact of genotype on drug concentration and 152 assessments of association between genotype and clinical toxicity, with 3 associations demonstrating significance in subpopulations of people treated for MDR-TB. Specifically, UGT1A1 and ABCB1 polymorphisms were associated with moxifloxacin and linezolid trough concentrations at the extremes of the doses prescribed (800mg and 300mg daily, respectively). Carriers of an ABCB1 variant suggested a higher frequency of high-grade linezolid-associated toxicity. Overall, the panel provides baseline evidence for further validation of these markers in large-scale pharmacokinetic studies, as well as first clinical data on predicted variants that warrant screening in larger cohorts, demonstrating suitability for use on low-cost, portable Nanopore sequencers with shorter turnaround times.","rel_num_authors":16,"rel_authors":[{"author_name":"Priyanka Yadav","author_inst":"Institute of Bioinformatics, International Tech Park, Bangalore, Karnataka, India"},{"author_name":"Swarup A. V. Shah","author_inst":"PD Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India"},{"author_name":"Aishwarya S. Babu","author_inst":"1. Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India 2. Institute of Bioinformatics, International Tech Park, Bangalore, Karnataka, India"},{"author_name":"Minal Paradkar","author_inst":"PD Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India"},{"author_name":"Shruthi Vasanthaiah","author_inst":"1. Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India 2. Institute of Bioinformatics, International Tech Park, Bangalore, Karnataka, India"},{"author_name":"Karthick Vasudevan","author_inst":"1. Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India 2. Institute of Bioinformatics, International Tech Park, Bangalore, Karnataka, India"},{"author_name":"Prerna R. Arora","author_inst":"PD Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India"},{"author_name":"Rohan V. Lokhande","author_inst":"PD Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India"},{"author_name":"Heeral U.B. Pandya","author_inst":"PD Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India"},{"author_name":"Paolo Denti","author_inst":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa"},{"author_name":"Camilla Rodrigues","author_inst":"PD Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India"},{"author_name":"Jason  R. Andrews","author_inst":"Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, California, USA"},{"author_name":"Akhilesh Pandey","author_inst":"Department of Laboratory Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Jeffrey A Tornheim","author_inst":"Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Tester F. Ashavaid","author_inst":"PD Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India"},{"author_name":"Renu Verma","author_inst":"Institute of bioinformatics"}],"rel_date":"2026-09-04","rel_site":"medrxiv"}]}