{"gname":"Michigan State University","grp_id":"7","rels":[{"rel_title":"Sex and generation shape the genetic architecture of smoking initiation","rel_doi":"10.64898\/2026.11.11.26367842","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367842","rel_abs":"The rapidly changing cultural contexts over the past century modified the genetic factors that influence smoking initiation (SI). Using data from nearly seven million respondents, we conducted genome-wide associations study (GWAS) meta-analyses stratified by sex and generation across European, East Asian, African American, and Latino genetic ancestry populations. Sex and generation, but not genetic ancestry, moderate both the SNP-based heritability estimates and associations with individual loci. Specifically, SI is more heritable in females and younger generations. Furthermore, the impact of both discrete policy changes that target smoking and the gradual cultural redefinition of smoking norms across sex and generation are captured within the patterns of cross-trait genetic correlations between SI and extant smoking-relevant phenotypes. Robust cross-ancestry genetic correlations allowed us to meta-analyze the results across subsamples, identifying 1,717 loci associated with SI, including both main and moderated associations for either moderator. Genome-wide heterogeneity analyses identified 45 sex-specific loci and 7 generation-specific loci with distinct associations with SI. Finemapping analyses highlighted 389 and 304 loci with distinct patterns of potential causal variants by sex and generation. Accordingly, sex- and generation-specific macrosocial contexts dynamically influence the genetic architecture of SI, underscoring the need to consider gene-environment interplay for health behaviors as societal norms evolve.","rel_num_authors":22,"rel_authors":[{"author_name":"Yeongmi Jeong","author_inst":"Purdue University"},{"author_name":"Saranya Arirangan","author_inst":"Purdue University"},{"author_name":"Evelina Akimova","author_inst":"Purdue University"},{"author_name":"Katherine N. Thompson","author_inst":"University College London"},{"author_name":"Rafael Geurgas","author_inst":"Purdue University"},{"author_name":"Jiachen Liu","author_inst":"Purdue University"},{"author_name":"Aahan Bajpai","author_inst":"Purdue University"},{"author_name":"Kathryn Fiuza Malerbi","author_inst":"Purdue University"},{"author_name":"Katelyn Kukar Bond","author_inst":"23andMe Research Institute"},{"author_name":"Julie M. Granka","author_inst":"23andMe Research Institute"},{"author_name":"Barry Hicks","author_inst":"23andMe Research Institute"},{"author_name":"David A. Hinds","author_inst":"23andMe Research Institute"},{"author_name":"Robert K. Bell","author_inst":"23andMe Research Institute"},{"author_name":"- 23andMe Research Team","author_inst":"-"},{"author_name":"Geyu Zhou","author_inst":"Purdue University"},{"author_name":"Boran Gao","author_inst":"Purdue University"},{"author_name":"Meghan Zacher","author_inst":"Brown University"},{"author_name":"Andrew D. Grotzinger","author_inst":"Memorial University"},{"author_name":"Andrea Ganna","author_inst":"University of Helsinki"},{"author_name":"Michel G. Nivard","author_inst":"University of Bristol"},{"author_name":"Brad Verhulst","author_inst":"Texas A and M University"},{"author_name":"Robbee Wedow","author_inst":"Purdue University"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Sex and generation shape the genetic architecture of smoking initiation","rel_doi":"10.64898\/2026.11.11.26367842","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367842","rel_abs":"The rapidly changing cultural contexts over the past century modified the genetic factors that influence smoking initiation (SI). Using data from nearly seven million respondents, we conducted genome-wide associations study (GWAS) meta-analyses stratified by sex and generation across European, East Asian, African American, and Latino genetic ancestry populations. Sex and generation, but not genetic ancestry, moderate both the SNP-based heritability estimates and associations with individual loci. Specifically, SI is more heritable in females and younger generations. Furthermore, the impact of both discrete policy changes that target smoking and the gradual cultural redefinition of smoking norms across sex and generation are captured within the patterns of cross-trait genetic correlations between SI and extant smoking-relevant phenotypes. Robust cross-ancestry genetic correlations allowed us to meta-analyze the results across subsamples, identifying 1,717 loci associated with SI, including both main and moderated associations for either moderator. Genome-wide heterogeneity analyses identified 45 sex-specific loci and 7 generation-specific loci with distinct associations with SI. Finemapping analyses highlighted 389 and 304 loci with distinct patterns of potential causal variants by sex and generation. Accordingly, sex- and generation-specific macrosocial contexts dynamically influence the genetic architecture of SI, underscoring the need to consider gene-environment interplay for health behaviors as societal norms evolve.","rel_num_authors":22,"rel_authors":[{"author_name":"Yeongmi Jeong","author_inst":"Purdue University"},{"author_name":"Saranya Arirangan","author_inst":"Purdue University"},{"author_name":"Evelina Akimova","author_inst":"Purdue University"},{"author_name":"Katherine N. Thompson","author_inst":"University College London"},{"author_name":"Rafael Geurgas","author_inst":"Purdue University"},{"author_name":"Jiachen Liu","author_inst":"Purdue University"},{"author_name":"Aahan Bajpai","author_inst":"Purdue University"},{"author_name":"Kathryn Fiuza Malerbi","author_inst":"Purdue University"},{"author_name":"Katelyn Kukar Bond","author_inst":"23andMe Research Institute"},{"author_name":"Julie M. Granka","author_inst":"23andMe Research Institute"},{"author_name":"Barry Hicks","author_inst":"23andMe Research Institute"},{"author_name":"David A. Hinds","author_inst":"23andMe Research Institute"},{"author_name":"Robert K. Bell","author_inst":"23andMe Research Institute"},{"author_name":"- 23andMe Research Team","author_inst":"-"},{"author_name":"Geyu Zhou","author_inst":"Purdue University"},{"author_name":"Boran Gao","author_inst":"Purdue University"},{"author_name":"Meghan Zacher","author_inst":"Brown University"},{"author_name":"Andrew D. Grotzinger","author_inst":"Memorial University"},{"author_name":"Andrea Ganna","author_inst":"University of Helsinki"},{"author_name":"Michel G. Nivard","author_inst":"University of Bristol"},{"author_name":"Brad Verhulst","author_inst":"Texas A and M University"},{"author_name":"Robbee Wedow","author_inst":"Purdue University"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"A multinational pharmacoepidemiology atlas of prescription medication associations with all-cause mortality across six population cohorts","rel_doi":"10.64898\/2026.11.12.26367024","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.12.26367024","rel_abs":"Observational studies sometimes report that individual medications are associated with lower mortality, but such signals are rarely compared across drugs and health systems. We screened prescription medications for associations with all-cause mortality using time-dependent Cox models in six cohorts from the UK, US, Finland, Hong Kong and Japan (8.93 million individuals aged 40 years or older; 1.49 billion prescriptions). Most medications were associated with higher mortality, reflecting confounding by indication. A few medications showed inverse associations with mortality, notably the varicella-zoster virus (VZV) vaccine, the antimalarials atovaquone-proguanil (Malarone) and mefloquine, and the hormone replacement therapy estradiol. These associations were only modestly attenuated by adjustment for comorbidity, lifestyle and socio-economic factors, and persisted within strata defined by pre-existing disease. While adjustment for self-reported health abolished the Malarone association, probably reflecting a healthy traveler profile, the VZV association was maintained. In FinnGen, deaths from external causes, which vaccination cannot prevent, were lower among VZV vaccine users, but much less so than all-cause mortality. In a target trial emulation in All of Us, the VZV association was maintained against matched unvaccinated individuals (HR 0.61, 95% CI 0.53-0.70) and pneumococcal vaccine recipients (HR 0.64, 0.55-0.74), but was attenuated against recipients of tetanus-diphtheria vaccines, a group that also has low mortality (HR 0.85, 0.70-1.03). Healthy-user selection contributes to these signals but does not appear to fully explain the VZV vaccine association, which warrants confirmation in randomized trials. This multinational atlas provides a resource for prioritizing drug-repurposing candidates in ageing research.","rel_num_authors":8,"rel_authors":[{"author_name":"Kevin Perez","author_inst":"Institute of Oncology Research (IOR), Bellinzona, Switzerland"},{"author_name":"Jonathan K. L. Mak","author_inst":"Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"author_name":"Kathryn C. B. Tan","author_inst":"Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"author_name":"Andrea Ganna","author_inst":"Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland"},{"author_name":"Alessandro Ceschi","author_inst":"Faculty of Biomedical Sciences, Universita della Svizzera italiana, Lugano, Switzerland"},{"author_name":"Juulia Jylhava","author_inst":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Ching-Lung Cheung","author_inst":"Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"author_name":"Andrea Alimonti","author_inst":"Institute of Oncology Research (IOR), Bellinzona, Switzerland"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"The contribution of Neanderthal ancestry to cancer risk","rel_doi":"10.64898\/2026.11.10.26367742","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367742","rel_abs":"Modern human genomes harbor DNA inherited from interbreeding with Neanderthals. Genetic variants inherited from Neanderthals associate with variation in many immune and metabolic phenotypes, two systems with direct relevance to cancer. However, the influence of Neanderthal variants on germline cancer risk has not been comprehensively evaluated. Here, we evaluated genome-wide association study (GWAS) hits for 17 cancer types for Neanderthal ancestry. Twelve cancers have multiple Neanderthal alleles significantly associated with variation in risk. Next, we fine-mapped these risk loci and identified 32 associations across seven cancers where Neanderthal variants are likely causal (>= posterior inclusion probability). Fine-mapped loci include Neanderthal alleles that both increase and decrease cancer risk. Nine of the 32 Neanderthal associations, including the high frequency BNC2 Neanderthal variants, have signatures of adaptive introgression, and several suggest evidence of both mediated and antagonistic pleiotropy. Finally, we tested for enrichment of cancer heritability in genomic regions with Neanderthal ancestry. As expected, Neanderthal variants are depleted of heritability for most cancers. However, Neanderthal variants were enriched for heritability in breast cancer GWAS in both East Asian and Europeans, and this enrichment replicated using individual-level UK Biobank data. These results suggest that Neanderthal alleles that influence germline cancer risk were largely selected against. However, introgressed Neanderthal variants implicated in many cancers persist, potentially due to adaptive pleiotropic effects. This evolutionary perspective provides new insights into the complex evolution and etiology of cancer risk among modern human populations.","rel_num_authors":3,"rel_authors":[{"author_name":"Colin M. Brand","author_inst":"University of California San Francisco"},{"author_name":"Yaen Chen","author_inst":"University of California San Francisco"},{"author_name":"John Anthony Capra","author_inst":"University of California, San Francisco"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"PSEN1 loss-of-function variants do not cause early-onset Alzheimer's disease","rel_doi":"10.64898\/2026.11.13.26367865","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.13.26367865","rel_abs":"PSEN1 variants are the most common cause of familial early-onset Alzheimer's disease (EOAD), but it is debated whether they act through a loss- or gain-of-function. Following a recent report of a duo with EOAD carrying a predicted loss-of-function (LoF) stop-gain variant (p.K109*) in PSEN1, we sought to determine whether PSEN1 LoF variants, as a class, cause EOAD. We identified 45 carriers of PSEN1 LoF variants predicted to trigger nonsense-mediated decay in the Alzheimer's Disease Sequencing Project, UK Biobank, and BioVU databases. None of these carriers had a recorded case of early-onset dementia, and 17 were older than 65 years at last follow-up with no dementia or AD reported. Re-analysis of the reported AD-associated variant p.K109* revealed a cryptic splice site predicted to produce an in-frame deletion of 5 amino acids (p.K109_L113del). These results suggest that PSEN1 variants must produce an altered PSEN1 protein product to cause EOAD, while true null LoF PSEN1 alleles do not cause EOAD.","rel_num_authors":7,"rel_authors":[{"author_name":"Amelia Farinas","author_inst":"Stanford University"},{"author_name":"Andr\u00e9s Pe\u00f1a-Tauber","author_inst":"Stanford University"},{"author_name":"Timothy J. Hohman","author_inst":"Vanderbilt University"},{"author_name":"Alex G. Contreras","author_inst":"Vanderbilt University"},{"author_name":"Tanner D. Jensen","author_inst":"Stanford University"},{"author_name":"Yann Le Guen","author_inst":"Stanford University"},{"author_name":"Michael D. Greicius","author_inst":"Stanford University"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Prevalence and risk factors for human papillomavirus infection among women living with HIV in Sierra Leone: A cross-sectional study","rel_doi":"10.64898\/2026.11.11.26367873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367873","rel_abs":"Abstract BackgroundCervical cancer, a malignancy affecting the cervix, is the fourth most common cancer and cause of cancer-related mortality among women worldwide. This burden disproportionately affects low-resource regions, where approximately 90% of cases occur. HIV-positive women are at high risk of persistent Human Papillomavirus (HPV) infection and cervical cancer, but screening for this cancer is not yet integrated into HIV care in Sierra Leone. This study aimed to assess the prevalence and risk factors of high-risk HPV infection among women living with HIV (WLHIV) attending Connaught Hospital in Sierra Leone. Methods We conducted a cross-sectional study of women living with HIV aged 25-65 years attending the HIV clinic at Connaught Teaching Hospital in Freetown between September and December 2024. Endocervical swabs were collected for HPV DNA testing. Data was analyzed using R (v4.4.0). Logistic regression analysis was used to determine the independent risk factors for HPV positivity. Results A total of 191 WLHIV were enrolled. The mean age was 36.8 years; 44.5% were single, and 67% were employed. High-risk HPV DNA was detected in 60 (31.4%) (95% CI 25.3%-38.3%) participants, with 50% (30\/60)  having multiple serotypes. The most common genotype was HPV 52, followed by 16 and 51. Only 30% of HPV-positive women had genotypes 16 or 18, targeted by the bivalent vaccine. On multivariable analysis, former contraceptive use was independently associated with increased HPV positivity (aOR=4.86, 95% CI: 1.65-17.37,   p = 0.0032). Conclusion The high prevalence of high-risk  HPV infection and predominance of non 16\/18 genotypes among WLHIV in Sierra Leone underscore the need to integrate HPV screening within HIV services and consider broader HPV vaccine coverage in Sierra Leone. Former contraceptive use is an independent predictor of HPV positivity, emphasizing the need for robust screening strategies in women using contraceptives.","rel_num_authors":17,"rel_authors":[{"author_name":"Darlinda  Fatmata Jiba","author_inst":"College of Medicine and Allied Health Sciences, University of Sierra Leone"},{"author_name":"Guang Yang","author_inst":"Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, China"},{"author_name":"Tian Zhang","author_inst":"Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, China."},{"author_name":"Lili Zhao","author_inst":"Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, China."},{"author_name":"Andrew  J Dykens","author_inst":"Department of Family and Community Medicine, University of Illinois Chicago, Chicago, Illinois, United States"},{"author_name":"Gibrilla  F Deen","author_inst":"College of Medicine and Allied Health Sciences, University of Sierra Leone, New England, Freetown, Sierra Leone"},{"author_name":"Enanga  S Namanga","author_inst":"Ministry of Health and Sanitation, Government of Sierra Leone, New England, Freetown, Sierra Leone."},{"author_name":"Matilda  N Kamara","author_inst":"Ministry of Health and Sanitation, Government of Sierra Leone, New England, Freetown, Sierra Leone."},{"author_name":"Umu Barrie","author_inst":"Infectious Disease Research Network, Freetown, Sierra Leone"},{"author_name":"Abu  Bakarr Kallon","author_inst":"Ministry of Health and Sanitation, Government of Sierra Leone, New England, Freetown, Sierra Leone"},{"author_name":"Daniel Sesay","author_inst":"Ministry of Health and Sanitation, Government of Sierra Leone, New England, Freetown, Sierra Leone"},{"author_name":"Sattu Issa","author_inst":"Ministry of Health and Sanitation, Government of Sierra Leone, New England, Freetown, Sierra Leone"},{"author_name":"Umu Sesay","author_inst":"Ministry of Health and Sanitation, Government of Sierra Leone, New England, Freetown, Sierra Leone"},{"author_name":"Miama Amy Sam-Kpakra","author_inst":"Ministry of Health and Sanitation, Government of Sierra Leone, New England, Freetown, Sierra Leone"},{"author_name":"Olukemi Adekanmbi","author_inst":"Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria  \/ Department of Medicine, University College Hospital, Ibadan, Ibadan, Niger"},{"author_name":"Babatunde Duduyemi","author_inst":"College of Medicine and Allied Health Sciences, University of Sierra Leone, New England, Freetown, Sierra Leone"},{"author_name":"Sulaiman Lakoh","author_inst":"College of Medicine and Allied Health Sciences, University of Sierra Leone, New England, Freetown, Sierra Leone"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Socioeconomic Position, Kidney Outcomes, and Mortality: A Longitudinal Cohort Study from the All of Us Research Program","rel_doi":"10.64898\/2026.11.11.26367876","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367876","rel_abs":"Background: Socioeconomic position is associated with kidney disease, but it remains unclear whether these differences are greater for worsening kidney function than for a first recorded diagnosis. We examined how household income, education, and neighborhood deprivation relate to mortality and kidney outcomes. Methods and findings: We conducted a retrospective cohort study involving 218,098 individuals using data from the All of Us Research Program, with follow-up to January 1, 2025. Primary outcomes involved all-cause mortality and sustained 40% estimated glomerular filtration rate decline. Secondary outcomes were incident recorded chronic kidney disease (CKD) diagnosis, incident recorded CKD category G3a or worse, and kidney failure. We also evaluated income inequalities and estimated standardized 3-year mortality risks for each baseline kidney state. Median follow-up was 3.62 years for mortality and 2.76 years for kidney outcomes. Among 218,098 individuals, 4,777 deaths, 6,423 sustained declines, 7,870 incident recorded chronic kidney disease diagnoses, 4,716 incident category G3a-or-worse events, and 1,799 kidney failure events were observed. Adjusted hazard ratios (95% CIs) for household income below $25,000 compared with $200,000 or more were 2.68 (2.31-3.12), 3.57 (3.08-4.13), 2.13 (1.90-2.38), 2.15 (1.86-2.49), and 3.08 (2.30-4.11), respectively. Relative index of inequality estimates were approximately twice as large for sustained decline and kidney failure than for recorded CKD diagnosis. Within baseline kidney states, standardized 3-year absolute mortality differences by income did not differ significantly across states. The main limitations are the observational design, baseline creatinine measured up to a year after the survey, and outcome ascertainment from health records that may differ by income. Conclusions: Lower income was associated with higher mortality and greater risk of all kidney outcomes. Education and neighborhood deprivation showed different patterns of association, which supports considering individual and neighborhood circumstances together.","rel_num_authors":8,"rel_authors":[{"author_name":"Atalay Demiray","author_inst":"Yale University School of Public Health"},{"author_name":"Ibrahim Gulmaliyev","author_inst":"Koc University"},{"author_name":"Mehmet Ali Enlice","author_inst":"Koc University"},{"author_name":"Sidar Copur","author_inst":"Koc University"},{"author_name":"Metehan Berkkan","author_inst":"Koc University"},{"author_name":"Francesca Mallamaci","author_inst":"Associazione Ipertensione Nefrologia Trapianto (IPNET)"},{"author_name":"Carmine Zoccali","author_inst":"Renal Research Institute"},{"author_name":"Mehmet Kanbay","author_inst":"Koc University"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Socioeconomic Position, Kidney Outcomes, and Mortality: A Longitudinal Cohort Study from the All of Us Research Program","rel_doi":"10.64898\/2026.11.11.26367876","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367876","rel_abs":"Background: Socioeconomic position is associated with kidney disease, but it remains unclear whether these differences are greater for worsening kidney function than for a first recorded diagnosis. We examined how household income, education, and neighborhood deprivation relate to mortality and kidney outcomes. Methods and findings: We conducted a retrospective cohort study involving 218,098 individuals using data from the All of Us Research Program, with follow-up to January 1, 2025. Primary outcomes involved all-cause mortality and sustained 40% estimated glomerular filtration rate decline. Secondary outcomes were incident recorded chronic kidney disease (CKD) diagnosis, incident recorded CKD category G3a or worse, and kidney failure. We also evaluated income inequalities and estimated standardized 3-year mortality risks for each baseline kidney state. Median follow-up was 3.62 years for mortality and 2.76 years for kidney outcomes. Among 218,098 individuals, 4,777 deaths, 6,423 sustained declines, 7,870 incident recorded chronic kidney disease diagnoses, 4,716 incident category G3a-or-worse events, and 1,799 kidney failure events were observed. Adjusted hazard ratios (95% CIs) for household income below $25,000 compared with $200,000 or more were 2.68 (2.31-3.12), 3.57 (3.08-4.13), 2.13 (1.90-2.38), 2.15 (1.86-2.49), and 3.08 (2.30-4.11), respectively. Relative index of inequality estimates were approximately twice as large for sustained decline and kidney failure than for recorded CKD diagnosis. Within baseline kidney states, standardized 3-year absolute mortality differences by income did not differ significantly across states. The main limitations are the observational design, baseline creatinine measured up to a year after the survey, and outcome ascertainment from health records that may differ by income. Conclusions: Lower income was associated with higher mortality and greater risk of all kidney outcomes. Education and neighborhood deprivation showed different patterns of association, which supports considering individual and neighborhood circumstances together.","rel_num_authors":8,"rel_authors":[{"author_name":"Atalay Demiray","author_inst":"Yale University School of Public Health"},{"author_name":"Ibrahim Gulmaliyev","author_inst":"Koc University"},{"author_name":"Mehmet Ali Enlice","author_inst":"Koc University"},{"author_name":"Sidar Copur","author_inst":"Koc University"},{"author_name":"Metehan Berkkan","author_inst":"Koc University"},{"author_name":"Francesca Mallamaci","author_inst":"Associazione Ipertensione Nefrologia Trapianto (IPNET)"},{"author_name":"Carmine Zoccali","author_inst":"Renal Research Institute"},{"author_name":"Mehmet Kanbay","author_inst":"Koc University"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Type 2 Diabetes Mellitus and Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis","rel_doi":"10.64898\/2026.11.13.26367733","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.13.26367733","rel_abs":"Epidemiologic studies suggest that type 2 diabetes mellitus (T2DM) is associated with an increased risk of colorectal cancer (CRC). However, prior meta-analyses have relied heavily on studies published more than a decade ago and have often combined distinct epidemiologic effect measures. We conducted an updated systematic review and meta-analysis of observational studies published from January 2012 through January 2026 evaluating the association between T2DM and incident CRC. PubMed, Embase, Web of Science, CENTRAL, and Scopus were searched, and eligible studies reporting associations between T2DM and CRC were included. Effect estimates were synthesized separately using random-effects models to calculate pooled estimates with 95% confidence intervals (CIs). Sex-specific and leave-one-out sensitivity analyses were also conducted. Fourteen studies were included, comprising nine cohort and five case-control studies; six reported odds ratios (ORs), seven reported hazard ratios (HRs), and one reported a standardized incidence ratio (SIR). T2DM was associated with higher odds of incident CRC (OR, 1.28; 95% CI, 1.13-1.46) and a higher hazard of incident CRC (HR, 1.27; 95% CI, 1.23-1.31). The study reporting an SIR also showed higher CRC incidence among individuals with T2DM (SIR, 1.40; 95% CI, 1.39-1.45). Sex-specific analyses generally showed positive associations in both females and males, and sensitivity analyses supported the robustness of the pooled findings. Overall, T2DM was associated with an increased risk of incident CRC, with a consistent direction of association across distinct epidemiologic effect measures. These findings provide updated evidence supporting consideration of T2DM as a marker of increased CRC risk and may inform CRC prevention strategies among individuals with T2DM.","rel_num_authors":4,"rel_authors":[{"author_name":"Shengyang Wang","author_inst":"Indiana University Bloomington"},{"author_name":"Anna Porter","author_inst":"Yale University"},{"author_name":"Nianjun Liu","author_inst":"Indiana University"},{"author_name":"Lin Ge","author_inst":"Indiana University Bloomington"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Protocol and Statistical Analysis Plan for the Hyperangulated versus Standard Geometry Laryngoscope Blade (ANGLE) Trial","rel_doi":"10.64898\/2026.11.11.26367862","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367862","rel_abs":"Background: Emergency tracheal intubation is common and high risk. Although guidelines recommend using a video laryngoscope to intubate critically ill adults, whether a hyperangulated or standard-geometry blade is more likely to achieve successful intubation on the first attempt remains unknown. Research Question: Does the use of a video laryngoscope with a hyperangulated blade increase the incidence of successful intubation on the first attempt among adults undergoing emergency tracheal intubation, compared to use of a video laryngoscope with a standard-geometry blade? Study Design and Methods: The HyperANgulated versus Standard Geometry Laryngoscope BladE (ANGLE) trial is a pragmatic, multicenter, unblinded, parallel-group, randomized trial being conducted in 28 sites (10 emergency departments and 18 intensive care units) in the United States. The trial compares use of a video laryngoscope with a hyperangulated blade versus a standard-geometry blade among 2,500 critically ill adults undergoing emergency tracheal intubation. The primary outcome is successful intubation on the first attempt. The secondary outcome is the incidence of hypoxemia during intubation. Enrollment began on December 30, 2025, and is expected to conclude in 2027. Interpretation: The ANGLE trial will provide important data on the effects of the use of a video laryngoscope with a hyperangulated blade versus standard-geometry blade on successful intubation on the first attempt and other outcomes of emergency tracheal intubation. Specifying the protocol and statistical analysis plan before the conclusion of enrollment increases the rigor, reproducibility, and transparency of the trial. Trial Registry: ClinicalTrials.gov; No.: NCT07223762; URL: www.clinicaltrials.gov","rel_num_authors":65,"rel_authors":[{"author_name":"Stephanie C. DeMasi","author_inst":"Vanderbilt Health; Vanderbilt Institute for Clinical and Translational Research"},{"author_name":"Matthew W. Semler","author_inst":"Vanderbilt Health; Vanderbilt Institute for Clinical and Translational Research"},{"author_name":"Aaron E. Robinson","author_inst":"Hennepin County Medical Center"},{"author_name":"Heath D. White","author_inst":"Baylor Scott & White Medical Center Temple"},{"author_name":"Kevin G. Buell","author_inst":"Rush University Medical Center"},{"author_name":"Carolynn Lyle","author_inst":"Denver Health Medical Center"},{"author_name":"Michael Gottlieb","author_inst":"Rush University Medical Center"},{"author_name":"LuAnn H. Barnett","author_inst":"Louisiana State University Health Sciences Center New Orleans; Our Lady of the Lake Regional Medical Center"},{"author_name":"Nida Qadir","author_inst":"David Geffen School of Medicine at UCLA"},{"author_name":"Amy L. Kloosterboer","author_inst":"Stanford University School of Medicine"},{"author_name":"Daniel Resnick-Ault","author_inst":"University of Colorado Anschutz School of Medicine"},{"author_name":"Sheetal Gandotra","author_inst":"University of Maryland School of Medicine"},{"author_name":"Logan L. Beach","author_inst":"University of Alabama at Birmingham Heersink School of Medicine"},{"author_name":"Derek J. Vonderhaar","author_inst":"Ochsner Health"},{"author_name":"Taya Haas","author_inst":"Hennepin County Medical Center"},{"author_name":"Matthew J. Barraza","author_inst":"The Ohio State University"},{"author_name":"Alexandra June Gordon","author_inst":"Stanford University School of Medicine"},{"author_name":"Kevin R. Landefeld","author_inst":"David Geffen School of Medicine at UCLA"},{"author_name":"Kevin W. Gibbs","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Calvin A. Brown III","author_inst":"Lahey Clinic and UMass Chan-Lahey School of Medicine"},{"author_name":"R. Gentry Wilkerson","author_inst":"University of Maryland School of Medicine"},{"author_name":"Stephen C. Lim","author_inst":"Louisiana State University Health Sciences Center New Orleans"},{"author_name":"Akram Khan","author_inst":"Oregon Health & Science University"},{"author_name":"Amelia L. Muhs","author_inst":"Louisiana State University Health Sciences Center New Orleans"},{"author_name":"Xian Qiao","author_inst":"Eastern Virginia Medical School, Macon & Joan Brock Virginia Health Sciences at Old Dominion University"},{"author_name":"Taylor Herbert","author_inst":"Duke University School of Medicine"},{"author_name":"James E. Walker","author_inst":"Our Lady of the Lake Regional Medical Center; Louisiana State University Health Sciences Center New Orleans"},{"author_name":"Jason C. Brainard","author_inst":"University of Colorado Anschutz School of Medicine"},{"author_name":"David J. Douin","author_inst":"University of Colorado Anschutz School of Medicine"},{"author_name":"Derek W. Russell","author_inst":"University of Alabama at Birmingham Heersink School of Medicine"},{"author_name":"Shekhar A. Ghamande","author_inst":"Baylor Scott & White Medical Center Temple"},{"author_name":"Karen E. Jackson","author_inst":"Rush University Medical Center"},{"author_name":"Thomas Alcorn","author_inst":"Rush University Medical Center"},{"author_name":"Shannon M. Alwood","author_inst":"Louisiana State University Health Sciences Center New Orleans; Our Lady of the Lake Regional Medical Center"},{"author_name":"Jason Kirincich","author_inst":"David Geffen School of Medicine at UCLA"},{"author_name":"Andrew P. Bartuska","author_inst":"Stanford University School of Medicine"},{"author_name":"Emily K. Bowery","author_inst":"University of Colorado Anschutz School of Medicine"},{"author_name":"Nicholas Sachs","author_inst":"University of Maryland School of Medicine"},{"author_name":"Micah R. Whitson","author_inst":"University of Alabama at Birmingham Heersink School of Medicine"},{"author_name":"Alex P. Brueder","author_inst":"Ochsner Health"},{"author_name":"Amy L. Martin","author_inst":"Hennepin County Medical Center"},{"author_name":"Jonathan C. Henricks","author_inst":"The Ohio State University"},{"author_name":"Pranjal B. Gupta","author_inst":"Stanford University School of Medicine"},{"author_name":"Oscar A. Estrada Paz","author_inst":"David Geffen School of Medicine at UCLA"},{"author_name":"Jessica A. Palakshappa","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Michael S. Char","author_inst":"Lahey Clinic and UMass Chan-Lahey School of Medicine"},{"author_name":"Kami M. Hu","author_inst":"University of Maryland School of Medicine"},{"author_name":"David A. Rayburn","author_inst":"Louisiana State University Health Sciences Center New Orleans"},{"author_name":"Aaron Trimble","author_inst":"Oregon Health & Science University"},{"author_name":"Yasin A. Khan","author_inst":"Tulane University School of Medicine"},{"author_name":"Vijay Krishnamoorthy","author_inst":"Duke University School of Medicine"},{"author_name":"Nicholas Raush","author_inst":"Lady of the Lake Regional Medical Center; Louisiana State University Health Sciences Center New Orleans"},{"author_name":"Franklin L. Wright","author_inst":"University of Colorado Anschutz School of Medicine"},{"author_name":"Samuel D. Gilliland","author_inst":"University of Colorado Anschutz School of Medicine"},{"author_name":"Lauren Daley","author_inst":"University of Alabama at Birmingham Heersink School of Medicine"},{"author_name":"Adit A. Ginde","author_inst":"University of Colorado Anschutz School of Medicine"},{"author_name":"Ariel A. Lewis","author_inst":"Vanderbilt Institute for Clinical and Translational Research"},{"author_name":"Todd W. Rice","author_inst":"Vanderbilt Institute for Clinical and Translational Research; Vanderbilt Health"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt Health; Vanderbilt Institute for Clinical and Translational Research"},{"author_name":"Brant Imhoff","author_inst":"Vanderbilt Health"},{"author_name":"Li Wang","author_inst":"Vanderbilt Health"},{"author_name":"Matthew E. Prekker","author_inst":"Hennepin County Medical Center"},{"author_name":"Brian E. Driver","author_inst":"Hennepin County Medical Center"},{"author_name":"Jonathan D. Casey","author_inst":"Vanderbilt Health; Vanderbilt Institute for Clinical and Translational Research"},{"author_name":"Stacy A. Trent","author_inst":"Denver Health Medical Center; University of Colorado Anschutz School of Medicine"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Enrollees and Early Lessons from an Agentic Healthcare Platform with Physicians in the Loop","rel_doi":"10.64898\/2026.11.12.26367291","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.12.26367291","rel_abs":"Agentic healthcare platforms that combine large language models with physician oversight are growing quickly, but little is known about who uses them. We characterized 3,223 enrollees of Lotus AI, a free, physician-supervised agentic platform, who completed onboarding, messaged the agent, and had a linked health record between February and July 2026, and compared them with national benchmarks. Median age was 51 years and 62% were male. Chronic condition prevalence exceeded 2024 National Health Interview Survey estimates in every age band by 4 to 7 percentage points; 18% had a functional or symptom-defined disorder; among the 30% with four or more ambulatory visits in the prior year, care was spread across nearly five providers, with 44% meeting a threshold for high fragmentation. Users with functional disorders generated 1.8 times as many physician escalations and 2.6 times as many laboratory orders as other users, but no more prescriptions. This profile differs from the younger, predominantly female populations reported for direct-to-consumer telemedicine. It moves chronic disease management, functional disorder pathways, and care coordination from aspirations to design requirements, and we argue that deployed AI care platforms should characterize their populations against national benchmarks early.","rel_num_authors":6,"rel_authors":[{"author_name":"Zili Shen","author_inst":"Yale University"},{"author_name":"Anu Ramachandran","author_inst":"University of California San Francisco"},{"author_name":"Elaine Hsiang","author_inst":"Stanford University"},{"author_name":"Jasleen Gill","author_inst":"Harvard University"},{"author_name":"Ryan Miller","author_inst":"UCLA"},{"author_name":"Nicholas R Stark","author_inst":"University of California San Francisco"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"DxToniaNet: A Neural Network for Estimating the Severity of Leg Dystonia in Children with Cerebral Palsy","rel_doi":"10.64898\/2026.11.11.26367859","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367859","rel_abs":"Importance: Leg dystonia affects 50-80% of children with cerebral palsy (CP), but severity assessment remains subjective and time-consuming. Objective tools are urgently needed to quantify leg dystonia severity in clinical care and clinical trials. Objective: To develop and validate a deep neural network (DxToniaNet) for leg dystonia severity estimation using 2D clinical video recordings. Design, Setting, and Participants: We retrospectively analyzed video recordings of 298 children with cerebral palsy undergoing a seated hand open-close task as part of routine clinical care (Center 1: 193 videos, 720p\/30fps; Center 2: 105 videos, 4K\/60fps). Videos were rated for leg dystonia severity by a group of 7 experts using the Global Dystonia Rating Scale (GDRS) leg subscore (range 0-40) which has a minimum clinically important difference (MCID) of 4 points. Videos displaying leg dystonia (median expert GDRS score [&ge;]1) were used to develop and test a machine learning model (DxToniaNet) for estimating leg dystonia severity. Open-source software (OpenPose) estimated bilateral knee, ankle, and toe coordinates, normalized for height and camera positioning, and 69 variance and amplitude features were calculated based on established expert-cited features of leg dystonia. A neural network, DxToniaNet, was developed, trained and validated using 5-fold cross-validation on Center 1 videos before final testing on independent Center 2 videos. Main Outcome(s) and Measure(s): Mean absolute error (MAE), root mean square error (RMSE), and accuracy in differentiating between videos with clinically meaningful differences in GDRS scores were calculated relative to experts' median GDRS scores. Results: When estimating experts' leg GDRS scores in testing data, the proposed machine learning (ML) model yielded a MAE of 1.71 {+\/-} 1.68 and RMSE of 2.21 {+\/-} 0.34 (significantly less than the GDRS MCID of 4), and 90-94% accuracy in differentiating between videos with greater than a 4-point difference in the GDRS. Conclusions and Relevance: We have demonstrated that DxToniaNet can accurately estimate leg dystonia severity compared to experts' assessments with a small (clinically insignificant) error margin. Our methodology supports generalizability since DxToniaNet was developed and tested using independent videos datasets from different centers, recorded under different conditions. In the future, DxToniaNet may help facilitate standardized leg dystonia severity estimation in clinical care and clinical trials.","rel_num_authors":17,"rel_authors":[{"author_name":"Rishabh Bajpai PhD","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Alyssa Rust MD","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Emma Lott AS","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Susie Kim BS","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Sushma Gandham BS","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Keerthana Chintalapati BS","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Joanna Blackburn MD","author_inst":"Department of Pediatrics, Northwestern University, Chicago, IL"},{"author_name":"Rose Gelineau-Morel MD","author_inst":"Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA"},{"author_name":"Michael C. Kruer MD","author_inst":"Department of Child Health, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA"},{"author_name":"Dararat Mingbunjerdsuk MD","author_inst":"Department of Neurology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA"},{"author_name":"Jennifer O'Malley MD","author_inst":"Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, USA"},{"author_name":"Laura Tochen MD","author_inst":"Department of Neurology and Rehabilitation Medicine, George Washington School of Medicine and Health Sciences, Washington DC, USA"},{"author_name":"Jeff L. Waugh MD","author_inst":"Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Steve Wu MD","author_inst":"Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA"},{"author_name":"Timothy Feyma MD","author_inst":"Department of Neurology, Gillette Children's Specialty Healthcare, St Paul, MN, USA"},{"author_name":"Joel S. Perlmutter MD","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Departments of Radiology, Neuroscience, Physical Therapy and Occupational"},{"author_name":"Bhooma R. Aravamuthan MD, DPhil","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Socioeconomic position, socioenvironmental conditions, and subjective cognitive decline among midlife and older LGBTQIA+ adults in California","rel_doi":"10.64898\/2026.11.11.26367750","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367750","rel_abs":"Objectives: To examine which measure of socioeconomic position and socioenvironmental conditions has the strongest relationship with subjective cognitive decline (SCD) among midlife and older lesbian, gay, bisexual, transgender, queer, intersex, asexual, and other sexual and gender minority (LGBTQIA+) adults. Methods: We conducted a cross-sectional analysis of 3869 LGBTQIA+ adults aged 50 years or older participating in a community-engaged survey in California. Using logistic regression, we examined overall associations between each indicator of socioeconomic position and socioenvironmental conditions and SCD. We used a dominance analysis to assess the relative importance of each indicator based on the proportion of variance in SCD it explained. Results: Overall, 14.7% of the sample reported SCD. Midlife and older LGBTQIA+ adults in a lower socioeconomic position (i.e., lower education, unemployment, lower household income, fewer assets, financial insecurity, food insecurity, and unstable housing) had higher odds of SCD than those in a higher position, with significant odds ratios (OR) ranging from 1.44 to 1.93. In contrast, perceiving one's community as safe for LGBTQIA+ people was associated with lower odds of SCD (OR, 0.60; 95% CI, 0.48, 0.76). Dominance analysis indicated that household assets was the most important factor, explaining 2.8% of the variance in SCD (95% CI 2.2%, 3.6%), followed by household income (1.9%; 95% CI 1.2%, 2.7%) and perceived community safety (1.6%; 95% CI 1.1%, 2.3%). Discussion: Supporting the cognitive health of LGBTQIA+ people may require attention to both financial security across the life course and the broader social environments.","rel_num_authors":6,"rel_authors":[{"author_name":"Nguyen K Tran","author_inst":"Stanford University"},{"author_name":"Ethan Cicero","author_inst":"Emory University"},{"author_name":"Nicole Rosendale","author_inst":"University of California San Francisco"},{"author_name":"Gowri Sunder","author_inst":"Temple University"},{"author_name":"Carol Dawson-Rose","author_inst":"University of California San Francisco"},{"author_name":"Annesa Flentje","author_inst":"Stanford University"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"Genomic diversity of respiratory pathogens in clinical versus community surveillance: a comparative analysis of SARS-CoV-2, RSV, and influenza viruses in Washington State","rel_doi":"10.64898\/2026.11.11.26367863","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367863","rel_abs":"Background Genomic surveillance of respiratory viruses typically relies on sequences from individuals seeking health care, and whether these sequences represent the viruses circulating in the community is not well-characterized. We aimed to compare the diversity, proportion, and dynamics of influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 between clinical and community samples. Methods In this retrospective comparative genomic analysis, we used whole-genome sequences from community-based surveillance studies in the Seattle area, and clinical sequences from the Washington State Department of Health. We compared clade proportions and dynamics, sequence-cluster diversity, non-synonymous mutations, and Ct values between clinical and community samples. Findings We analyzed 538 RSV sequences collected between 2019 and 2021 (278 community, 260 clinical), 1506 influenza sequences (260 community, 1246 clinical) between 2019 and 2020, and 8660 SARS-CoV-2 sequences (5923 community, 2737 clinical) from 2020 to 2022. Clade proportions did not differ between clinical and community samples for RSV or influenza, but differed for SARS-CoV-2: clades 21J (Delta) and 21K (Omicron BA.1) were more frequent in community samples and clade 22B (Omicron BA.5) in clinical samples. SARS-CoV-2 clinical sequence clusters were more diverse than community clusters, whereas RSV and influenza showed no significant difference. Several spike mutations associated with monoclonal antibody resistance were more prevalent in community samples for SARS-CoV-2. Ct values were lower in clinical samples for multiple SARS-CoV-2, RSV, and influenza clades. Interpretation Seasonal respiratory viruses had similar dynamics and diversity in clinical and community samples, whereas pandemic SARS-CoV-2 differed between settings. Genomic surveillance programs should combine clinical and community sampling, particularly during pandemics in order to better capture viral diversity.","rel_num_authors":8,"rel_authors":[{"author_name":"Joshua M Kirsch","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"},{"author_name":"Anna Elias-Warren","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Lauren Frisbie","author_inst":"Washington State Department of Health, Shoreline, WA"},{"author_name":"Christina Lockwood","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"},{"author_name":"Ana A Weil","author_inst":"Departments of Medicine and Global Health, University of Washington, Seattle, WA; Center for Emerging and Re-emerging Infectious Diseases, Department of Medicin"},{"author_name":"Allison Black","author_inst":"Washington State Department of Health, Shoreline, WA"},{"author_name":"Helen Y. Chu","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA; Center for Emerging and Re-emerging Infectious Diseases, Department of Medicine"},{"author_name":"Pavitra Roychoudhury","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, "}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"The phenomic landscape of rare gain- and loss-of-function variation","rel_doi":"10.64898\/2026.11.11.26367788","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367788","rel_abs":"Current large-scale phenome-wide association studies do not distinguish between genetic variants with distinct functional consequences, despite evidence that gain-of-function (GoF) and loss-of-function (LoF) variants can produce different phenotypes. Consequently, the phenotypic consequences of variants stratified by predicted GoF and LoF effects have not been systematically characterized at scale. Here, we systematically analyzed rare predicted GoF and LoF variants in 18,214 genes across 1,244 binary and 202 quantitative traits using whole-exome sequencing and electronic health records from the Mount Sinai Million Health Discoveries Program, a phenotypically rich hospital-based biobank comprised of 50,067 participants, primarily representing African, Admixed American and European ancestries. We identified numerous established and previously unreported ancestry-specific and shared gene- and variant-level associations, many of which were supported by complementary evidence from both diagnostic phenotypes and clinical measurements. Proteomic evaluation of the previously unreported association between VNN1 LoF variants and body mass index in the Multi-Ethnic Study of Atherosclerosis revealed reduced circulating vanin-1 levels with LoF variants, which in turn were associated with body composition and additional cardiometabolic phenotypes. Functional stratification of predicted GoF and LoF variants revealed gene-trait associations that were attenuated when these variants were combined, demonstrating that traditional aggregation of variants with different functional effects can obscure association signals. These findings underscore the importance of incorporating predicted functional consequences into association analyses and establish a comprehensive resource linking exome-wide predicted GoF and LoF variants to the human phenome across ancestry-specific and multi-ancestry analyses.","rel_num_authors":17,"rel_authors":[{"author_name":"Meltem Ece Kars","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"David Stein","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Yiming Wu","author_inst":"College of Life Science, China West Normal University"},{"author_name":"Zsu-Zsu Chen","author_inst":"Harvard Medical School"},{"author_name":"Shuliang Deng","author_inst":"Harvard Medical School"},{"author_name":"Hanna Abe","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Peter D Stenson","author_inst":"Cardiff University"},{"author_name":"David N Cooper","author_inst":"Cardiff University"},{"author_name":"Laura M Raffield","author_inst":"University of North Carolina School of Medicine"},{"author_name":"Leslie A Lange","author_inst":"University of Colorado Denver"},{"author_name":"Michael Tsai","author_inst":"University of Minnesota Twin Cities"},{"author_name":"Mark O Goodarzi","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Stephen S Rich","author_inst":"University of Virginia"},{"author_name":"Jerome I Rotter","author_inst":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center"},{"author_name":"Paul Cohen","author_inst":"The Rockefeller University"},{"author_name":"Robert E Gerszten","author_inst":"Harvard Medical School"},{"author_name":"Yuval Itan","author_inst":"Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-11-13","rel_site":"medrxiv"},{"rel_title":"The FraA adhesin and Ebp pili mediate Enterococcus faecalis adhesion under fluid flow","rel_doi":"10.64898\/2026.11.12.766216","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766216","rel_abs":"Enterococcus faecalis is a frequent cause of infective endocarditis and catheter-associated urinary tract infections (CAUTI). Successful colonization is challenged by blood and urine flow and relies on a strong and resilient bacterial attachment. Here, we identify molecular determinants that enable E. faecalis to maintain adhesion under flow, notably the flow-related adhesin (FraA), a previously uncharacterized adhesion factor encoded by OG1RF_11764. Transcriptomic analysis revealed increased fraA expression in surface-attached bacteria exposed to shear stress. Structural predictions identified an N-terminal region with homology to characterized Gram-positive adhesins, followed by tandem CLIPPER repeats with putative isopeptide-bond-forming residues and a C-terminal cell-wall sorting signal. Using microfluidics and single-cell tracking, we found that deletion of fraA accelerated detachment from hydrophobic abiotic surfaces under fluid flow. In line with this finding, loss of fraA reduced catheter colonization in a murine CAUTI model. Analysis of 9,192 E. faecalis genomes identified FraA in 50.8% of isolates, spanning clinical and non-clinical sources, with sequence type-associated variation in CLIPPER repeat number. Another determinant, Ebp pilus, enhances adhesion at high shear stress and contributes to a shear-enhanced adhesion pattern. Collectively, these findings identify FraA as an adhesion factor contributing to medical-device colonization and together with Ebp pili support attachment across different hydrodynamic conditions. Identifying these adhesion mechanisms could inform strategies to prevent colonization of medical devices exposed to fluid flow.","rel_num_authors":8,"rel_authors":[{"author_name":"Haris Antypas","author_inst":"Nanyang Technological University"},{"author_name":"M\u00e9lanie Roch","author_inst":"University of Geneva"},{"author_name":"Kenneth Kok Fei Ng","author_inst":"Nanyang Technological University"},{"author_name":"Brenda Silva Rosa da Luz","author_inst":"University of Geneva"},{"author_name":"Rachel Tan Jing Wen","author_inst":"Nanyang Technological University"},{"author_name":"Riya Zita Thomas","author_inst":"Nanyang Technological University"},{"author_name":"Alain Filloux","author_inst":"Nanyang Technological University"},{"author_name":"Kimberly A. Kline","author_inst":"University of Geneva"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Chimera: Cross-Species Single-Cell Generative Modeling of Expression Deployment Relative to Protein Conservation","rel_doi":"10.64898\/2026.11.11.766029","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.766029","rel_abs":"A protein's sequence says what a gene could do in another species; the cells of that species say what it does there. Comparative genomics measures the first. Chimera measures the second, a gene's deployment, on the same genes and reports the difference. It aligns single-cell atlases across species in one generative model and returns, for every one-to-one ortholog, the evidence in the counts for a shared expression pattern, and {Delta}[a], the position of that evidence above or below what the protein's identity predicts. This difference is not sequence constraint under another name: across eight tissues, protein identity tracks dN\/dS, whereas {Delta}[a] tracks neither. A gene therefore has two coordinates, not one, and the second can contradict the first: spermatocyte genes such as ZPBP2 keep their stage pattern on less conserved proteins, in eight held-out species, whereas conserved hepatocyte enzymes such as ALAS1 share their pattern but not their level. More broadly, genes of specialized cells sit above what their proteins predict in 23 of 24 cohorts, and approved drug targets do so more often than matched genes. Even among nearly identical proteins, where sequence can no longer tell genes apart, the count evidence still does. Nor does this rest on the model alone: independent data support the count evidence in liver and testis and, in a pre-specified test, {Delta}[a] in liver. With both coordinates, one can ask whether another species uses a gene as humans do, the premise of every animal model of a disease gene or drug target.","rel_num_authors":4,"rel_authors":[{"author_name":"Kemal Inecik","author_inst":"Helmholtz Center Munich"},{"author_name":"Eylul Sevinc Sevinc","author_inst":"Koc University"},{"author_name":"Erkmen Erken","author_inst":"Koc University"},{"author_name":"Fabian Theis","author_inst":"Helmholtz Center Munich"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Repeated exposure to a conserved antigen drives dynamic clonal and epitope succession","rel_doi":"10.64898\/2026.11.12.763997","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.763997","rel_abs":"Defining the dynamics of T cell memory formation with epitope-level resolution can inform vaccine design. Longitudinal T cell receptor (TCR) sequencing after COVID-19 mRNA vaccination has enabled detailed tracking of T cell responses; however, connecting expanded clonotypes following antigen exposure to their cognate epitopes remains a challenge due to limited curated paired \/{beta}TCR information. To fill this gap, we used TIRTL-seq to identify paired \/{beta}TCRs from CD8+ T cell lineages associated with mRNA immunization in serial samples across 38 healthy donors over multiple rounds of vaccinations. Vaccine-associated paired \/{beta}TCRs, identified based on their longitudinal kinetics, were grouped according to sequence similarity to infer their shared epitope specificities. We assigned epitope specificity to 1,109 clonotypes, recognizing 15 SARS-CoV-2 spike targets, identifying multiple previously undescribed responses, and confirming putative specificities experimentally. This approach uncovered a striking pattern of clonal succession in anti-spike T cell memory lineages resulting from repeated vaccination, characterized by a transition from low-avidity clones recognizing conserved coronavirus epitopes to high-avidity clones targeting epitopes unique to SARS-CoV-2. These results highlight the surprisingly dynamic responses underlying homologous boosting, suggest avenues for improving vaccine strategies, and pave the way for repertoire-based monitoring of antigen-specific T cell immunity.","rel_num_authors":22,"rel_authors":[{"author_name":"Hiroyasu Aoki","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Mikhail V. Pogorelyy","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Philip Bradley","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Cecilia Adragna","author_inst":"Institute for Research in Biomedicine"},{"author_name":"Stefan A. Schattgen","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Anastasia A. Minervina","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Koshlan Harlan Mayer-Blackwell","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Kasi Vegesana","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Zachary B. Scott","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Velmurugan Balaraman","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"E. Kaitlynn Allen","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Masahiro Kitabatake","author_inst":"Nara Medical University"},{"author_name":"Noriko Ouji-Sageshima","author_inst":"Nara Medical University"},{"author_name":"Atsushi Hara","author_inst":"Nara Medical University"},{"author_name":"Peng Xu","author_inst":"Tokyo University of Science"},{"author_name":"Chihiro Motozono","author_inst":"Kumamoto University"},{"author_name":"Kouji Matsushima","author_inst":"Tokyo University of Science"},{"author_name":"Federica Sallusto","author_inst":"Institute for Research in Biomedicine"},{"author_name":"Antonio Lanzavecchia","author_inst":"National Institute of Molecular Genetics"},{"author_name":"Satoshi Ueha","author_inst":"Tokyo University of Science"},{"author_name":"Toshihiro Ito","author_inst":"Nara Medical University"},{"author_name":"Paul G. Thomas","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Exploratory positional differences in observed CDRH2 lineage-state transitions following HIV-1 germline-targeting vaccination","rel_doi":"10.64898\/2026.11.07.765060","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.765060","rel_abs":"Background: Germline-targeting HIV-1 vaccination recruits VRC01-class B-cell precursors, but the positional patterns of observed longitudinal B-cell receptor lineage-state changes remain incompletely described. We compared CDRH2 profiles between homologous and heterologous boosting regimens using published IAVI G002 data. Methods: Participant-specific Week-8 lineages were prospectively matched to Week-24 observations. Germline-to-nongermline changes in sampled lineage-modal residues were evaluated at seven IGHV1-2*02 CDRH2 positions using participant-balanced, mean-centered profiles and exact participant-label permutation inference. Sampling-depth and sorting-probe sensitivity analyses assessed observability. A separate participant-held-out benchmark evaluated antibody-language-model representations for predicting observed Week-24 lineage detection. Results: The CDRH2 analysis included 332 lineages, 15 participants, 2,179 eligible lineage-position observations, and 241 observed state changes. The regional profile statistic was 0.027066 (exact p = 0.001709; six-region adjusted q = 0.010256), with descriptive differences at V-relative positions 51, 54, and 55. Most eligible longitudinal observations had one assessable cell per visit. In seven Group-1 participants, Week-24 dual-probe sampling recovered 181 baseline lineages with eOD-GT8 and 143 with Cg28v2, including 60 detected by both probes. In a separate cohort of 2,739 lineages from 17 participants, IgBERT and AbLang-2 representations did not improve participant-balanced average precision over a four-feature biological baseline. Conclusions: Observed CDRH2 lineage-modal-state profiles differed between regimens in this exploratory secondary analysis. Sparse sampling, potentially probe-related ascertainment, and absent linked functional validation preclude inference about mutation timing, functional improvement, or causal booster effects.","rel_num_authors":2,"rel_authors":[{"author_name":"Kazi Tanzina Begum","author_inst":"Rutgers University - Camden"},{"author_name":"Kazi Abdul Gofur Rafea","author_inst":"University of Science and Technology Chittagong"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"T cell receptors from CD8 regulatory T cells direct the development of natural intraepithelial lymphocytes","rel_doi":"10.64898\/2026.11.11.765811","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765811","rel_abs":"CD8 regulatory T cells (CD8 Tregs) in mice have been identified by their expression of the surface receptor family Ly49 and the transcription factor Helios. To our surprise, many Ly49+ and Helios+ T cells express neither CD4 nor CD8, and many express only CD8. We found that CD8 Tregs in the spleen are linked to the CD8{beta}- natural intraepithelial lymphocytes (IELs) that reside in the small intestine. Blocking trafficking to the intestine increased splenic CD8 Treg frequency, and transferred splenic CD8 Tregs gave rise to natural IELs. Unexpectedly, Helios was dispensable for natural IEL development, arguing against its role as a shared lineage-determining transcription factor. Instead, we found that T cell receptors (TCRs) from splenic Ly49+ CD8 Tregs deterministically direct natural IEL development. Our findings suggest that CD8 Tregs may derive from the same TCR-directed developmental program that generates natural IELs and shed light on the origins of these immunoregulatory cells.","rel_num_authors":8,"rel_authors":[{"author_name":"Samuel J.H. Murphy","author_inst":"Washington University in St Louis School of Medicine, St Louis"},{"author_name":"Jevon Bonner","author_inst":"Washington University in St Louis School of Medicine, St Louis"},{"author_name":"Tony Yao","author_inst":"Washington University in St Louis School of Medicine, St Louis"},{"author_name":"Chandrani Thakur","author_inst":"Washington University in St Louis School of Medicine, St Louis"},{"author_name":"Julia Bals","author_inst":"Washington University in St Louis School of Medicine, St Louis"},{"author_name":"Wayne M Yokoyama","author_inst":"Washington University School of Medicine"},{"author_name":"Nicholas Borcherding","author_inst":"Washington University in St Louis School of Medicine, St Louis"},{"author_name":"Naresha Saligrama","author_inst":"Washington University in St Louis School of Medicine, St Louis"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Multi-specific nanobody-Fc fusions against TcdB protect in vivo from diverse Clostridioides difficile strains","rel_doi":"10.64898\/2026.11.12.766007","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766007","rel_abs":"Clostridioides difficile infection (CDI) is an urgent antibiotic-associated threat and the leading cause of nosocomial diarrhea in the United States, with a high rate of recurrence. Antibiotics are the standard of care for treating CDI but can prolong microbial dysbiosis in the gut. The only FDA-approved monoclonal antibody (mAb) for the prevention of recurrent CDI, Zinplava (bezlotoxumab), was discontinued in January 2025. The target of bezlotoxumab is the dominant virulence factor of C. difficile, the exotoxin B (TcdB). However, TcdB sequences vary across strains and encompass twelve distinct subtypes. Consequently, sequence variation between subtypes presents a challenge for the identification of pan-neutralizing mAb therapeutics. Here, we describe the generation of three bi-specific and one tri-specific nanobody-Fc fusions targeting TcdB. Each fusion neutralizes TcdB in vitro across clinically relevant subtypes with greater potency than bezlotoxumab. In a mouse model of CDI, using three diverse C. difficile strains, several of the fusion proteins improve infection outcomes over bezlotoxumab when administered prophylactically. We also highlight one fusion that improves survival in a therapeutic mouse model of CDI. These data demonstrate multi-specific nanobody-Fc fusions as a strategy to improve potency and mitigate the impact of sequence variation within the toxin. Our fusions outperform the standards established by bezlotoxumab and represent strong candidates for translation.","rel_num_authors":8,"rel_authors":[{"author_name":"Alyssa G. Ehni","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Bruno B. C. Lan\u00e7a","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Heather K. Kroh","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Anna J. Smith","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Audrey K. Thomas","author_inst":"Vanderbilt University Medical Center"},{"author_name":"M. Kay Washington","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Benjamin W. Spiller","author_inst":"Vanderbilt University Medical Center"},{"author_name":"D. Borden Lacy","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Unsupervised Deep Learning for Cryo-EM\/ET Particle Classification","rel_doi":"10.64898\/2026.11.12.766036","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766036","rel_abs":"Cryogenic electron microscopy (cryo-EM) is widely used to determine protein structures from purified samples. With cryogenic electron tomography (cryo-ET), it is possible to image thin sections of cells and directly visualize diverse proteins in their native environment. However, separating the massive mixture of different types of proteins inside cells remains challenging, especially without human intervention. In this work, we present an unsupervised deep learning framework for classifying cryo-EM\/ET particle images that jointly optimizes for pose and structure through an autoencoder-based multi-stage pipeline. On single-particle cryo-EM datasets, our framework can capture the continuous variation in particle views and separate images of real particles from contamination. Using in silico mixtures of multiple types of proteins, we demonstrated our method's capability of separating the protein classes without supervision. Finally in a real cryo-ET dataset of algal chloroplast, our deep learning model successfully detected the four main protein complexes of photosynthesis on native thylakoid membranes. Taken together, these results demonstrate that our framework offers a scalable, annotation-free solution for robust structural discovery across diverse cryo-EM and cryo-ET applications.","rel_num_authors":6,"rel_authors":[{"author_name":"Mostofa Rafid Uddin","author_inst":"Carnegie Mellon University"},{"author_name":"Seonghui Min","author_inst":"Carnegie Mellon University"},{"author_name":"Qifeng Wu","author_inst":"Carnegie Mellon University"},{"author_name":"Xueying Zhan","author_inst":"Carnegie Mellon University"},{"author_name":"Muyuan Chen","author_inst":"SLAC"},{"author_name":"Min Xu","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"HieraPTM: From PTM Site Recognition to Functional Phosphosite Prediction through Hierarchical Context and Protein Mechanics","rel_doi":"10.64898\/2026.11.12.766127","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766127","rel_abs":"Protein post-translational modifications (PTMs) regulate cellular signaling and protein function, making accurate site identification essential for understanding protein regulation. However, PTM site recognition and functional phosphosite prediction are largely modeled independently, limiting the transfer of large-scale recognition knowledge to functional prioritization. Here, we introduce HieraPTM-HieraFuncPhos, a cross-task hierarchical framework that separately models and conditionally integrates transferable PTM recognition representations and function-specific mechanical evidence. HieraPTM integrates local sequence patterns, protein language model representations, and three-dimensional structural information to recognize multiple PTM types. HieraFuncPhos transfers these representations through parameter-efficient adaptation and adaptively retrieves local and distal mechanical evidence conditioned on functional representations. At HSP90AA1 T36 and T115, the model reveals distinct mechanical response patterns consistent with published nuclear magnetic resonance (NMR) observations, suggesting that the framework not only prioritizes functional phosphosites but also provides biophysically grounded, testable hypotheses regarding site-specific regulation. HieraPTM achieved macro-averaged AUROC and AUPRC values of 0.9237 and 0.8425 across eight PTM tasks, while maintaining competitive performance on severely imbalanced external benchmarks. HieraFuncPhos achieved an AUROC of 0.8274 and an AUPRC of 0.8188, outperforming existing comparison methods. Together, this framework connects PTM site recognition, functional prioritization, and structure-informed hypotheses regarding potential regulatory processes.","rel_num_authors":13,"rel_authors":[{"author_name":"Yuzhi Yuan","author_inst":"Lanzhou University"},{"author_name":"Di Wang","author_inst":"Lanzhou University"},{"author_name":"Pengyu Chen","author_inst":"Lanzhou University"},{"author_name":"Yanze Niu","author_inst":"Lanzhou University"},{"author_name":"Zhiyuan Yang","author_inst":"Lanzhou University"},{"author_name":"Hengjia Zhang","author_inst":"Lanzhou University"},{"author_name":"Xicheng He","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Hao Li","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Ziwei Su","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Changwei Lin","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Tianhang Chen","author_inst":"City University of Hong Kong"},{"author_name":"Chang Ye","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Tianchi LU","author_inst":"The Hong Kong  Polytechnic University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Darwinian and Wallacean evolution both explain sexual dichromatism in avian iridescence.","rel_doi":"10.64898\/2026.11.11.765350","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765350","rel_abs":"One of the longest-standing arguments in evolutionary biology is that between Darwin and Wallace on the evolution of sexual dichromatism, and which sex changed colour over time. While Darwin argued that males became more colourful over time, Wallace argued that females became less colourful, and numerous studies have lent support to each hypothesis over time. Iridescent colouration provides a particularly interesting system for studying sexual dichromatism because its conspicuousness is often associated with sexual selection and it has evolved multiple times. Here, using a dataset on iridescent colouration of 25,432 patches from 3,151 bird species, we provide one of the most comprehensive tests to date of the evolutionary origins of sexual dichromatism. We show that both hypotheses explain the evolution of iridescent sexual dichromatism in birds, but that Darwin's hypothesis is more strongly supported with males contributing stronger to evolutionary changes in dichromatism. Furthermore, our analyses support Darwin's prediction that sexual selection is associated to the evolution of dichromatism, but also Wallace's prediction that safer nests facilitate more colourful females (and males), and mostly in patches exposed during incubation.","rel_num_authors":7,"rel_authors":[{"author_name":"Michael P.J. Nicolai","author_inst":"Ugent"},{"author_name":"Gerben Deburyn","author_inst":"UGent"},{"author_name":"Rauri C K Bowie","author_inst":"University of California Berkeley"},{"author_name":"Scott V. Edwards","author_inst":"x"},{"author_name":"Miguel Carneiro","author_inst":"Universidade do Porto"},{"author_name":"Liliana D'Alba","author_inst":"UGent"},{"author_name":"Matthew Shawkey","author_inst":"Ghent University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Amyloidosis and tauopathy progressively disrupt near-critical dynamics in selectively vulnerable circuits","rel_doi":"10.64898\/2026.11.11.766020","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.766020","rel_abs":"Mechanistically distinct neurodegenerative diseases result in similar cognitive deficits, and pathology is often concentrated in a set of circuits known to be selectively vulnerable. Selective vulnerability is an intrinsic property of a circuit: in APP\/PS1 mice, where plaques are global, functional disruptions are confined to circuits within the default mode network. What characterizes the dynamics of vulnerable circuits from those of spared circuits is unknown. We asked whether the distinguishing property is the proximity of population dynamics to criticality, a homeostatic set-point of network activity that determines computational capacity. We recorded single units simultaneously in three selectively vulnerable regions (retrosplenial cortex, anterior cingulate cortex, and CA1 hippocampus) and in primary visual cortex of freely behaving young and old APP\/PS1 and wild-type mice. Firing rate and spike-time variability differed by genotype inconsistently across regions and ages. In contrast, three measures from criticality theory each revealed deficits that emerged only with age and only in the vulnerable regions. No measure detected a progressive change in V1. Avalanche scaling is not fixed in neural activity, but varies along a scaling line as the network state changes. As a result, the lines generated by each genotype revealed a constitutive effect of the transgene in young animals, which inverted with age in amyloid-bearing animals, but only in vulnerable circuits. If the destabilization of near-critical dynamics directly reflects a circuit's functional capacity, the same signature should identify a mechanistically distinct degenerative disease. In a model of tauopathy (P301S\/E4), CA1 dynamics were displaced from the control scaling line with the same age-dependent reversal observed in APP\/PS1. Our results suggest a network-level principle of neurodegenerative diseases: molecularly unrelated pathologies converge on the loss of near-critical dynamics in selectively vulnerable circuits.","rel_num_authors":13,"rel_authors":[{"author_name":"James N. McGregor","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Leandro J. Fosque","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Samuel J. Brunwasser","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Clayton Farris","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Bryan T. Higashikubo","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Zachary D. Berriman-Rozen","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Halla Elmore","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Kylee Kest","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Jennifer D. Whitesell","author_inst":"Allen Institute for Brain Science"},{"author_name":"Julie A. Harris","author_inst":"Allen Institute for Brain Science"},{"author_name":"Woodrow L. Shew","author_inst":"Department of Physics, University of Arkansas"},{"author_name":"David M. Holtzman","author_inst":"Department of Neurology, Washington University School of Medicine"},{"author_name":"Keith B Hengen","author_inst":"Washington University In St. Louis"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Amyloidosis and tauopathy progressively disrupt near-critical dynamics in selectively vulnerable circuits","rel_doi":"10.64898\/2026.11.11.766020","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.766020","rel_abs":"Mechanistically distinct neurodegenerative diseases result in similar cognitive deficits, and pathology is often concentrated in a set of circuits known to be selectively vulnerable. Selective vulnerability is an intrinsic property of a circuit: in APP\/PS1 mice, where plaques are global, functional disruptions are confined to circuits within the default mode network. What characterizes the dynamics of vulnerable circuits from those of spared circuits is unknown. We asked whether the distinguishing property is the proximity of population dynamics to criticality, a homeostatic set-point of network activity that determines computational capacity. We recorded single units simultaneously in three selectively vulnerable regions (retrosplenial cortex, anterior cingulate cortex, and CA1 hippocampus) and in primary visual cortex of freely behaving young and old APP\/PS1 and wild-type mice. Firing rate and spike-time variability differed by genotype inconsistently across regions and ages. In contrast, three measures from criticality theory each revealed deficits that emerged only with age and only in the vulnerable regions. No measure detected a progressive change in V1. Avalanche scaling is not fixed in neural activity, but varies along a scaling line as the network state changes. As a result, the lines generated by each genotype revealed a constitutive effect of the transgene in young animals, which inverted with age in amyloid-bearing animals, but only in vulnerable circuits. If the destabilization of near-critical dynamics directly reflects a circuit's functional capacity, the same signature should identify a mechanistically distinct degenerative disease. In a model of tauopathy (P301S\/E4), CA1 dynamics were displaced from the control scaling line with the same age-dependent reversal observed in APP\/PS1. Our results suggest a network-level principle of neurodegenerative diseases: molecularly unrelated pathologies converge on the loss of near-critical dynamics in selectively vulnerable circuits.","rel_num_authors":13,"rel_authors":[{"author_name":"James N. McGregor","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Leandro J. Fosque","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Samuel J. Brunwasser","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Clayton Farris","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Bryan T. Higashikubo","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Zachary D. Berriman-Rozen","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Halla Elmore","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Kylee Kest","author_inst":"Department of Biology, Washington University in St. Louis"},{"author_name":"Jennifer D. Whitesell","author_inst":"Allen Institute for Brain Science"},{"author_name":"Julie A. Harris","author_inst":"Allen Institute for Brain Science"},{"author_name":"Woodrow L. Shew","author_inst":"Department of Physics, University of Arkansas"},{"author_name":"David M. Holtzman","author_inst":"Department of Neurology, Washington University School of Medicine"},{"author_name":"Keith B Hengen","author_inst":"Washington University In St. Louis"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Perinatal high-fat diet induces systemic inflammation via altered tight junction complex organization during development and decreases expression of intestinal satiety peptides in male offspring.","rel_doi":"10.64898\/2026.11.12.766002","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766002","rel_abs":"Objective Epidemiological evidence suggests that maternal obesity increases risk for offspring obesity and comorbidities, pointing to the significance of critical periods of development. Adverse metabolic effects of high fat (HF) diet consumption on the gut microbiome and inflammation have been well documented in obesity models. Emerging evidence demonstrates that the gut microbiome may play a role in transgenerational obesity, however, underlying mechanisms still need to be elucidated to identify intervention targets. Methods A rat model was used to demonstrate whether maternal HF diet during gestation and lactation results in gut-brain axis deficits in rat offspring. Gene expression of small intestinal satiety hormones and C-fiber innervation in the nucleus of the solitary tract (NTS) were measured in adult offspring. At weaning, circulating inflammatory mediators and colonic microbial metabolites were measured in offspring. Results In adulthood, HF males had reduced vagal innervation in the NTS and reduced small intestinal expression of CCK, GLP-1, and PYY. At weaning, HF offspring had elevated levels of CRP and IL-1{beta} and depleted levels of microbially produced colonic short chain fatty acids (SCFAs), which are critical for maintaining intestinal barrier function. HF males had reduced colocalization between tight junction proteins, Claudin-1 and ZO-1 at weaning, while HF females did not. Conclusion Disorganization of tight junction complexes in HF male offspring during development may play a role in the gut-brain axis deficits seen in HF males in adulthood. Together, these data demonstrate that inflammation-induced by HF diet can negatively impact gut-brain axis development and function.","rel_num_authors":12,"rel_authors":[{"author_name":"Lindsey K Macias","author_inst":"Johns Hopkins University"},{"author_name":"Akul Kesarwani","author_inst":"Johns Hopkins University"},{"author_name":"Jason Perez","author_inst":"Johns Hopkins University"},{"author_name":"Jasmine Shakir","author_inst":"Johns Hopkins University"},{"author_name":"Sean Andrew Aston","author_inst":"Johns Hopkins University"},{"author_name":"Zachary A Cordner","author_inst":"Johns Hopkins University"},{"author_name":"Yuma Kitase","author_inst":"Johns Hopkins University"},{"author_name":"Lauren L Jantzie","author_inst":"Johns Hopkins University"},{"author_name":"Claire B de La Serre","author_inst":"Colorado State University"},{"author_name":"Ken Hui","author_inst":"Johns Hopkins University"},{"author_name":"Timothy H Moran","author_inst":"Johns Hopkins University"},{"author_name":"Kellie L Tamashiro","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"A unique sixth-order reversible assembly of hexameric mimetic nucleic acid","rel_doi":"10.64898\/2026.11.12.766261","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766261","rel_abs":"Complementary dipeptides bearing the non-canonical nucleobases melamine and cyanuric acid (alpha DPNA) assemble into a cylindrical hexameric structure containing a stacked heterocyclic core with its beta-sheet peptide backbones on the surface. Circular dichroism spectroscopy and singular-value decomposition show that the evolution of CD spectra after mixing equimolar strands is an apparent two-state process, accounted for by only the spectra of free strands and the assembled hexamer, with no detectable intermediates. Equilibrium measurements reveal a highly cooperative, enthalpically driven assembly with a molecularity of 6.2 +\/- 0.2 and an association constant of (2.3 +\/- 0.2)X10^22 \" \" M^(-5). Over total strand concentrations of 20 to 100 micromolar, the assembly progress curves are described by an apparent reversible sixth-order macroscopic rate law. This deceptively simple behavior cannot represent an elementary six-strand collision. The apparent forward rate constant has a negative activation energy, showing that the observed rate law masks additional steps in the assembly reaction. A minimal model in which strand pre-isomerization precedes hexamer formation restores a physically reasonable positive activation energy while retaining the observed two-state CD behavior. Constrained simulations further show that a sequential pathway with low-population, spectroscopically silent, intermediates can give rise to the same deceptively simple sixth-order progress curve. These results provide an unusual example of highly cooperative hexamer formation and show how a simple high-order macroscopic rate law can conceal a more complex microscopic assembly mechanism. The thermodynamics and kinetics provide insights into how and why the hexamer assembles, offering some design principles for supramolecular assemblies in water.","rel_num_authors":4,"rel_authors":[{"author_name":"Sajena Kanangat Saraswathy","author_inst":"Georgia Institute of Technology"},{"author_name":"Gary B Schuster","author_inst":"Georgia Institute of Technology"},{"author_name":"Jonathan Chaires","author_inst":"University of Louisville"},{"author_name":"Nicholas V. Hud","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Binary Patterning as a Probe of Protein Language Model Representations","rel_doi":"10.64898\/2026.11.11.765943","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765943","rel_abs":"Do protein language models (pLMs) encode the physical rules that govern protein folding? The four-helix bundle provides a classic test case because binary patterning, the ordered placement of polar and nonpolar residues along an amphipathic -helix, is sufficient to generate folded proteins with high probability. Here, we ask whether ESM2 captures the sequence grammar underlying this design strategy. Libraries of synthetic sequences constrained only by binary patterning were predicted by ESMFold to form four-helix bundles. Predicted helicity, compactness, and topological diversity changed with sequence length in the same direction as experimentally characterized libraries, although the model did not distinguish successful from unsuccessful individual designs. Principal component analysis of ESM2 embeddings revealed representations of hydrophobic patterning, helix-loop boundaries, and heptad register. Extending the analysis to all 128 heptad binary patterns produced a jellyfish-shaped manifold in which hydrophobic composition formed the dominant axis, while paired components encoded pattern phase. Manifold geometry depended on amino-acid chemistry, repeat number, and linker sequence, and collapsed when amino acids were assigned to arbitrary categories. ESM2 therefore combines general repeat recognition with protein-specific physicochemical information. More broadly, synthetic sequence libraries provide experimentally grounded probes of protein language model representations and their relationship to protein biophysics.","rel_num_authors":3,"rel_authors":[{"author_name":"Dylan Klein","author_inst":"Rutgers University"},{"author_name":"Michael Hecht","author_inst":"Princeton University"},{"author_name":"Vikas Nanda","author_inst":"Rutgers Department of Biochemistry and Molecular Biology"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"A statistical framework for identifying candidate genetic interactions from adaptive laboratory evolution data","rel_doi":"10.64898\/2026.11.12.766281","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766281","rel_abs":"Background Adaptive laboratory evolution (ALE) is widely used to improve microbial fitness under defined selective pressures. Mutations accumulated during ALE may interact epistatically, with the effect of one mutation depending on another. Understanding these interactions can help explain adaptive phenotypes and inform combinatorial strain engineering, but experimentally testing all mutation combinations is impractical. We developed a computational framework that uses gene-pair co-occurrence and mutual exclusivity patterns to identify candidates for experimental investigation of epistasis. Results We applied the framework to a curated compendium of 141 Escherichia coli ALE experiments from ALEdb, using the Fisher exact test and DISCOVER as complementary statistical screens. Testing and multiple-testing correction were performed separately within each experiment, method, and direction (co-occurrence and mutual exclusivity). At a 5% false discovery rate threshold, the Fisher exact test identified 74 significant gene pairs, comprising 36 co-occurrences and 38 mutual exclusivities. DISCOVER identified 5 significant pairs, all for mutual exclusivity and also significant under the Fisher exact test. These shared pairs suggested alternative adaptive routes involving temperature tolerance, glycerol utilization, and associations between RNA polymerase subunit genes. The two methods produced similar expected overlaps for Fisher-significant pairs, but the broader null distributions of DISCOVER yielded larger raw p-values. Of the 69 pairs significant only under the Fisher exact test, 60 arose in experiments with multiple strain labels or involved a gene with only one distinct mutation recorded across all affected endpoints (final samples from lineages evolved in parallel), highlighting the need to examine genetic backgrounds and mutation origins when interpreting the results. Power analysis indicated that the Fisher exact test required 70 independent endpoints for co-occurrence and 215 for mutual exclusivity to achieve 80% power under pre-specified scenarios. We implemented the framework as a reusable Nextflow pipeline that automates statistical screening of ALEdb and user-supplied mutation datasets. Conclusions By combining gene-pair screening with mutation-level interpretation, this reproducible framework narrows the search space for experimental investigation of epistasis and can contribute to combinatorial strain design. The power analysis provides sample-size benchmarks for planning future ALE experiments with adequate power to screen for candidate genetic interactions.","rel_num_authors":4,"rel_authors":[{"author_name":"Binhuan Sun","author_inst":"Technical University of Denmark"},{"author_name":"Adam Feist","author_inst":"University of California San Diego"},{"author_name":"Patrick V. Phaneuf","author_inst":"Technical University of Denmark"},{"author_name":"Alberto Santos","author_inst":"Technical University of Denmark"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Spindle: Scalable Indexing of Spatial-Omics Data for Fast Querying","rel_doi":"10.64898\/2026.11.12.766059","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766059","rel_abs":"Spatial transcriptomics (ST) has unlocked new avenues for biological discovery by jointly capturing gene expression and spatial context. ST datasets are typically stored as gene expression matrices paired with spatial coordinates, supporting queries based on expression levels at individual locations. However, characterizing how genes vary together requires representations of relationships between genes, such as covariance matrices computed over spatial neighborhoods. These gene--gene co-expression patterns capture coordinated biological variation and can reveal spatially localized gene programs. As datasets grow to atlas scale, efficiently searching for such patterns becomes a central computational bottleneck due to the combination of high dimensionality, extreme sparsity, and variability in gene expression across large numbers of spatial regions. Such searches require repeated access to second-order statistics, motivating a compact, searchable representation of spatial co-expression. We address this problem with Spindle, a platform-agnostic indexing algorithm for efficiently searching spatial gene co-expression patterns. Spindle exploits the approximate block-diagonal structure of gene--gene covariance matrices over spatial regions, in which covariances between blocks are small in magnitude, to selectively store informative components while compactly representing recurring covariance patterns. This yields a compressed yet searchable index suitable for atlas-scale spatial datasets. Across multiple real-world biological datasets (87,000--817,000 cells), Spindle indexes are 113--197 times smaller than the whole covariance matrices. A complete query, including query preprocessing, takes 2.8--28 ms on one CPU core, 5.1--16 times faster than a scan over the whole covariance matrices, and the tiles it returns recover a median of 81% of the exact near neighbors. In breast cancer, the regions retrieved by covariance search closely match the cell-type composition of the query (median cell-type composition difference 0.15, compared with 0.54 for random regions). Spindle supports both partial covariance queries and queries specified as gene lists, as well as retrieval across measurement platforms.","rel_num_authors":4,"rel_authors":[{"author_name":"Souvik Ghosh","author_inst":"Vanderbilt University"},{"author_name":"Stavros Sintos","author_inst":"University of Illinois Chicago"},{"author_name":"Anrin Chakraborti","author_inst":"University of Illinois Chicago"},{"author_name":"Hirak Sarkar","author_inst":"Vanderbilt University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Spindle: Scalable Indexing of Spatial-Omics Data for Fast Querying","rel_doi":"10.64898\/2026.11.12.766059","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766059","rel_abs":"Spatial transcriptomics (ST) has unlocked new avenues for biological discovery by jointly capturing gene expression and spatial context. ST datasets are typically stored as gene expression matrices paired with spatial coordinates, supporting queries based on expression levels at individual locations. However, characterizing how genes vary together requires representations of relationships between genes, such as covariance matrices computed over spatial neighborhoods. These gene--gene co-expression patterns capture coordinated biological variation and can reveal spatially localized gene programs. As datasets grow to atlas scale, efficiently searching for such patterns becomes a central computational bottleneck due to the combination of high dimensionality, extreme sparsity, and variability in gene expression across large numbers of spatial regions. Such searches require repeated access to second-order statistics, motivating a compact, searchable representation of spatial co-expression. We address this problem with Spindle, a platform-agnostic indexing algorithm for efficiently searching spatial gene co-expression patterns. Spindle exploits the approximate block-diagonal structure of gene--gene covariance matrices over spatial regions, in which covariances between blocks are small in magnitude, to selectively store informative components while compactly representing recurring covariance patterns. This yields a compressed yet searchable index suitable for atlas-scale spatial datasets. Across multiple real-world biological datasets (87,000--817,000 cells), Spindle indexes are 113--197 times smaller than the whole covariance matrices. A complete query, including query preprocessing, takes 2.8--28 ms on one CPU core, 5.1--16 times faster than a scan over the whole covariance matrices, and the tiles it returns recover a median of 81% of the exact near neighbors. In breast cancer, the regions retrieved by covariance search closely match the cell-type composition of the query (median cell-type composition difference 0.15, compared with 0.54 for random regions). Spindle supports both partial covariance queries and queries specified as gene lists, as well as retrieval across measurement platforms.","rel_num_authors":4,"rel_authors":[{"author_name":"Souvik Ghosh","author_inst":"Vanderbilt University"},{"author_name":"Stavros Sintos","author_inst":"University of Illinois Chicago"},{"author_name":"Anrin Chakraborti","author_inst":"University of Illinois Chicago"},{"author_name":"Hirak Sarkar","author_inst":"Vanderbilt University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"MAUDE-Py: A Python Implementation for Analyzing Sorting-Based Pooled CRISPR Screens","rel_doi":"10.64898\/2026.11.12.766045","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766045","rel_abs":"The Python programming language is gaining popularity in bioinformatics owing to its versatility in computing-heavy applications. An area of particular interest where computational power can be leveraged is analyzing and interpreting pooled CRISPR screens. Here, we replicate the core functionality of an existing platform, Mean Alterations Using Discrete Expression (MAUDE), in Python (MAUDE-Py) to analyze pooled CRISPR screens. Our tool complements the original R MAUDE software as a robust and user-friendly Python package that integrates with existing CRISPR analysis workflows. While preserving the core probabilistic framework of MAUDE, MAUDE-Py introduces notable enhancements. These enhancements include automated baseline calculations, a more robust null-sampling methodology for determining significance at both the gene and non-coding element levels, and an integrated visualization suite for displaying the analyzed results. Benchmarking MAUDE-Py against the original MAUDE on a series of datasets demonstrates a 2.09x to 4.19x speedup in execution time while achieving near-perfect consistency, confirming that our Python implementation is a highly accurate and viable alternative for such analyses.","rel_num_authors":2,"rel_authors":[{"author_name":"Avirral Agarwal","author_inst":"University of California, Los Angeles"},{"author_name":"Jennifer L Moy","author_inst":"University of California, San Diego"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Biochemical reassessment of the activation of PANK1 by SGLT2 inhibitors","rel_doi":"10.64898\/2026.11.09.765291","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765291","rel_abs":"Although SGLT2 inhibitors (SGLT2i) show cardiovascular benefits in addition to glycemic control, their molecular target for cardiovascular effect remains unclear. A recent study reported that two SGLT2i, empagliflozin and dapagliflozin, directly activate pantothenate kinase 1 (PANK1), which mediate their cardioprotective effect. PANK1 phosphorylates pantothenate with ATP to yield 4'-phosphopantothenate and ADP, representing the rate-limiting enzyme of coenzyme A (CoA) biosynthesis. We therefore reassessed this claim using purified recombinant human PANK1. The malachite green assay detected free inorganic phosphate (Pi) but neither ADP nor 4'-phosphopantothenate and its signals do not reflect PANK1 activity. In the ADP-Glo assay, empagliflozin and dapagliflozin did not stimulate PANK1 under either basal conditions or acetyl-CoA feedback inhibition, while the activator PZ-2891 enhanced the activity of PANK1. These results show that SGLT2i do not directly activate PANK1, challenging the proposed PANK1-dependent cardioprotection mechanism.","rel_num_authors":3,"rel_authors":[{"author_name":"Zihao Guo","author_inst":"Peking University"},{"author_name":"Jiahe Zang","author_inst":"Peking University"},{"author_name":"Lei Chen","author_inst":"Peking University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Loss of the mitochondrial redox gene GLRX2 underlies somersaulting behavior in Darwin's pigeons","rel_doi":"10.64898\/2026.11.12.766293","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766293","rel_abs":"Darwin described the somersaulting behavior of pigeons as \"one of the most remarkable inherited habits ever recorded\", yet its molecular basis remained unknown. We show that somersaulting pigeon brains exhibit mitochondrial redox dysfunction and identify an 11-bp frameshifting deletion in GLRX2, a mitochondrial redox enzyme, that abolishes protein function and is highly-enriched in two independently selected breeds. GLRX2 deficiency in mice and zebrafish recapitulates mitochondrial dysfunction, oxidative stress and impaired motor coordination seen in pigeons. Single-nucleus transcriptomics identifies cerebellar Golgi and Purkinje cells as selectively vulnerable, with disrupted inhibitory signaling and synaptic remodeling. These findings demonstrate how relaxation of purifying selection during domestication can expose a deleterious mitochondrial variant to artificial selection, allowing gene loss to serve as a substrate for behavioral evolution.","rel_num_authors":35,"rel_authors":[{"author_name":"Si Si","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Ling-Yan Su","author_inst":"Yunnan Agricultural University"},{"author_name":"Lan Long","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"You Qian","author_inst":"Yunnan Agricultural University"},{"author_name":"Wen-Di Ma","author_inst":"Shandong Agricultural University"},{"author_name":"Xin Gan","author_inst":"Yunnan Agricultural University"},{"author_name":"Kun Jiang","author_inst":"Tsinghua University"},{"author_name":"Guo-Hao Wang","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Zoltan Bagi","author_inst":"University of Debrecen"},{"author_name":"Daniele Bigi","author_inst":"University of Bologna"},{"author_name":"Hamed Kharrati-Koopaee","author_inst":"Shiraz University"},{"author_name":"Guang-Ze Zheng","author_inst":"The University of Hong Kong"},{"author_name":"Li Ma","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Zhuang Wu","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Ming-Li Li","author_inst":"Yale School of Medicine"},{"author_name":"Hong-Man Chen","author_inst":"Yunnan Agricultural University"},{"author_name":"Qiu Pan","author_inst":"Southwest University"},{"author_name":"Wen-Jing Peng","author_inst":"Southwest University"},{"author_name":"Zhu Bu","author_inst":"Jiangsu Institute of Poultry Science"},{"author_name":"Wen Gao","author_inst":"Jiangsu Institute of Poultry Science"},{"author_name":"Jian Li","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Ci-Rong Liu","author_inst":"Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology"},{"author_name":"Jia Pan","author_inst":"The University of Hong Kong"},{"author_name":"Jiu-Lin Du","author_inst":"Institute of Neuroscience, Key Laboratory of Brain Cognition and Brain-Inspired Intelligence Technolog"},{"author_name":"Zhen Liu","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Chang Zhang","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Chen Yan","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Yong-Gang Yao","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Lihong Gu","author_inst":"Hainan Academy of Agricultural Sciences"},{"author_name":"Li-Zhi Lu","author_inst":"Zhejiang Academy of Agricultural Sciences"},{"author_name":"Jun Lu","author_inst":"Southwest University"},{"author_name":"Kusza Szilvia","author_inst":"University of Debrecen"},{"author_name":"Ali Esmailizadeh","author_inst":"Shahid Bahonar University of Kerman"},{"author_name":"Guojie Zhang","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Ming-Shan Wang","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Loss of the mitochondrial redox gene GLRX2 underlies somersaulting behavior in Darwin's pigeons","rel_doi":"10.64898\/2026.11.12.766293","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766293","rel_abs":"Darwin described the somersaulting behavior of pigeons as \"one of the most remarkable inherited habits ever recorded\", yet its molecular basis remained unknown. We show that somersaulting pigeon brains exhibit mitochondrial redox dysfunction and identify an 11-bp frameshifting deletion in GLRX2, a mitochondrial redox enzyme, that abolishes protein function and is highly-enriched in two independently selected breeds. GLRX2 deficiency in mice and zebrafish recapitulates mitochondrial dysfunction, oxidative stress and impaired motor coordination seen in pigeons. Single-nucleus transcriptomics identifies cerebellar Golgi and Purkinje cells as selectively vulnerable, with disrupted inhibitory signaling and synaptic remodeling. These findings demonstrate how relaxation of purifying selection during domestication can expose a deleterious mitochondrial variant to artificial selection, allowing gene loss to serve as a substrate for behavioral evolution.","rel_num_authors":35,"rel_authors":[{"author_name":"Si Si","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Ling-Yan Su","author_inst":"Yunnan Agricultural University"},{"author_name":"Lan Long","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"You Qian","author_inst":"Yunnan Agricultural University"},{"author_name":"Wen-Di Ma","author_inst":"Shandong Agricultural University"},{"author_name":"Xin Gan","author_inst":"Yunnan Agricultural University"},{"author_name":"Kun Jiang","author_inst":"Tsinghua University"},{"author_name":"Guo-Hao Wang","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Zoltan Bagi","author_inst":"University of Debrecen"},{"author_name":"Daniele Bigi","author_inst":"University of Bologna"},{"author_name":"Hamed Kharrati-Koopaee","author_inst":"Shiraz University"},{"author_name":"Guang-Ze Zheng","author_inst":"The University of Hong Kong"},{"author_name":"Li Ma","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Zhuang Wu","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Ming-Li Li","author_inst":"Yale School of Medicine"},{"author_name":"Hong-Man Chen","author_inst":"Yunnan Agricultural University"},{"author_name":"Qiu Pan","author_inst":"Southwest University"},{"author_name":"Wen-Jing Peng","author_inst":"Southwest University"},{"author_name":"Zhu Bu","author_inst":"Jiangsu Institute of Poultry Science"},{"author_name":"Wen Gao","author_inst":"Jiangsu Institute of Poultry Science"},{"author_name":"Jian Li","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Ci-Rong Liu","author_inst":"Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology"},{"author_name":"Jia Pan","author_inst":"The University of Hong Kong"},{"author_name":"Jiu-Lin Du","author_inst":"Institute of Neuroscience, Key Laboratory of Brain Cognition and Brain-Inspired Intelligence Technolog"},{"author_name":"Zhen Liu","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Chang Zhang","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Chen Yan","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Yong-Gang Yao","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Lihong Gu","author_inst":"Hainan Academy of Agricultural Sciences"},{"author_name":"Li-Zhi Lu","author_inst":"Zhejiang Academy of Agricultural Sciences"},{"author_name":"Jun Lu","author_inst":"Southwest University"},{"author_name":"Kusza Szilvia","author_inst":"University of Debrecen"},{"author_name":"Ali Esmailizadeh","author_inst":"Shahid Bahonar University of Kerman"},{"author_name":"Guojie Zhang","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Ming-Shan Wang","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"A polarized genome is required for fitness of the obligate intracellular, tick-borne pathogen Rickettsia parkeri","rel_doi":"10.64898\/2026.11.11.765969","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765969","rel_abs":"Alphaproteobacteria of the order Rickettsiales include biomedically important, yet understudied arthropod-borne human pathogens. These pathogens lack obvious morphological asymmetry, but encode homologs of key mediators of polar processes in the model Alphaproteobacterium Caulobacter crescentus. These include the polar organizing protein PopZ, the chromosome segregation proteins ParA and ParB, and the spatial regulator of cell division MipZ. Motivated by this observation, we used the tick-borne human pathogen Rickettsia parkeri to ask if the chromosome is polarized and coordinated with cell division in this group. Consistent with that hypothesis, we found that transposon insertion mutants in parA, parB, mipZ, or popZ resulted in cell division defects. Fluorescence imaging revealed cell cycle-dependent unipolar-to-bipolar localization dynamics of ParB and MipZ, and pole-to-midcell dynamics of the division protein ZapA. This patterning parallels the model of chromosome segregation and cell division site selection established in Caulobacter. Unlike its unipolar-to-bipolar dynamics in Caulobacter, however, PopZ remained at a single cell pole throughout the cell cycle in R. parkeri. PopZ maintained its direct interaction with ParA and ParB. Interestingly, disruption of parA or parB, but not popZ or mipZ, caused a small plaque phenotype, suggesting a defect in growth or spread in a monolayer of host cells in the absence of proper chromosome segregation. We propose that genome polarization in R. parkeri and other rickettsiae is critical both for fundamental cellular processes and for interactions with host cells that promote fitness in their infectious niche.","rel_num_authors":8,"rel_authors":[{"author_name":"Trung Nguyen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Andrew C Krusenstjerna","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Mathilde Gonin","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Wanda M Figueroa-Cuilan","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Erika L Smith","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Aayush Sapkota","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Himaja Maddali","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Erin D Goley","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"A polarized genome is required for fitness of the obligate intracellular, tick-borne pathogen Rickettsia parkeri","rel_doi":"10.64898\/2026.11.11.765969","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765969","rel_abs":"Alphaproteobacteria of the order Rickettsiales include biomedically important, yet understudied arthropod-borne human pathogens. These pathogens lack obvious morphological asymmetry, but encode homologs of key mediators of polar processes in the model Alphaproteobacterium Caulobacter crescentus. These include the polar organizing protein PopZ, the chromosome segregation proteins ParA and ParB, and the spatial regulator of cell division MipZ. Motivated by this observation, we used the tick-borne human pathogen Rickettsia parkeri to ask if the chromosome is polarized and coordinated with cell division in this group. Consistent with that hypothesis, we found that transposon insertion mutants in parA, parB, mipZ, or popZ resulted in cell division defects. Fluorescence imaging revealed cell cycle-dependent unipolar-to-bipolar localization dynamics of ParB and MipZ, and pole-to-midcell dynamics of the division protein ZapA. This patterning parallels the model of chromosome segregation and cell division site selection established in Caulobacter. Unlike its unipolar-to-bipolar dynamics in Caulobacter, however, PopZ remained at a single cell pole throughout the cell cycle in R. parkeri. PopZ maintained its direct interaction with ParA and ParB. Interestingly, disruption of parA or parB, but not popZ or mipZ, caused a small plaque phenotype, suggesting a defect in growth or spread in a monolayer of host cells in the absence of proper chromosome segregation. We propose that genome polarization in R. parkeri and other rickettsiae is critical both for fundamental cellular processes and for interactions with host cells that promote fitness in their infectious niche.","rel_num_authors":8,"rel_authors":[{"author_name":"Trung Nguyen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Andrew C Krusenstjerna","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Mathilde Gonin","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Wanda M Figueroa-Cuilan","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Erika L Smith","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Aayush Sapkota","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Himaja Maddali","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Erin D Goley","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Selective ultrasonic suppression of pathological brain hyperactivity via an endogenous CAV3-NCX1 axis","rel_doi":"10.64898\/2026.11.11.765847","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765847","rel_abs":"Selective suppression of pathological hyperactivity is a major therapeutic challenge across brain disorders. Ultrasound stimulation can modulate neural activity, yet the molecular basis of its inhibitory effects and its ability to selectively inhibit hyperactive rather than basally active cells remain unclear. Here, we identify the caveolin-3 (CAV3)-sodium-calcium exchanger-1 (NCX1) complex as a previously unknown mediator of state-dependent ultrasound-induced neural inhibition. Prolonged ultra-low-intensity ultrasound stimulation engages NCX1-mediated Ca2+ extrusion in hyperactive neurons and astrocytes, sparing cells with basal activity. NCX1 is both necessary and sufficient for this inhibitory response, and disruption of the CAV3-NCX1 interface abolishes the ultrasound-induced effects. In vivo, targeted ultrasound stimulation suppresses fear-evoked hyperactivity and freezing in an NCX1-dependent manner and attenuates neuropathic pain-associated hyperactivity, allodynia, and hippocampal epileptiform activity. These findings establish a molecular mechanism for state-dependent ultrasound inhibition, providing a basis for a new approach to neuromodulation that selectively targets pathological hyperactivity.","rel_num_authors":11,"rel_authors":[{"author_name":"Keunhyung Lee","author_inst":"Sungkyunkwan University"},{"author_name":"Jung Moo Lee","author_inst":"Institute for Basic Science"},{"author_name":"Ho-Jeong Kim","author_inst":"Institute for Basic Science; Ulsan National Institute of Science and Technology (UNIST)"},{"author_name":"Minseok Koo","author_inst":"Sungkyunkwan University"},{"author_name":"Seolhee Lee","author_inst":"Institute for Basic Science; Ulsan National Institute of Science and Technology (UNIST)"},{"author_name":"Sangyep shin","author_inst":"Institute for Basic Science"},{"author_name":"Wongu Youn","author_inst":"Institute for Basic Science"},{"author_name":"Tien Thuy Phan","author_inst":"Institute for Basic Science"},{"author_name":"C. Justin Justin Lee","author_inst":"Institute for Basic Sciences"},{"author_name":"Jinhyoung Park","author_inst":"Sungkyunkwan University"},{"author_name":"JOO MIN PARK","author_inst":"Institute for Basic Science"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"The Xist locus on the X chromosome of males regulates cognition and metabolism despite minimal expression","rel_doi":"10.64898\/2026.11.11.766005","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.766005","rel_abs":"The long non-coding RNA Xist is the master regulator of X chromosome inactivation (XCI) in females, but its functional significance in males, where Xist expression is normally minimal, is unknown. Here we investigated whether the Xist locus influences male physiology and brain function across the lifespan using mice carrying a targeted Xist deletion ({Delta}Xist). Xist deletion produced a small further reduction in the very low, residual Xist signal in aged male hippocampus. Metabolically, Xist deletion lowered fasting blood glucose in old, not young, males, without affecting body weight. In the brain, Xist deletion modestly improved spatial memory at 24 hours in the Morris water maze in young males, with a similar trend at middle age in an interactive place avoidance task, independent of anxiety-like behavior or locomotor activity. This early cognitive benefit did not persist with aging and motor function on the rotarod was unaffected by genotype at any age. Together, these findings indicate that the Xist locus exerts age- and domain-specific effects on male metabolic and cognitive functions despite near-absent baseline Xist expression. These data identify an unexpected role for a canonically female-associated regulatory locus in males and raise the possibility that Xist-associated mechanisms contribute to male brain function and metabolism.","rel_num_authors":4,"rel_authors":[{"author_name":"Nilla Sivakumar","author_inst":"University of California, San Francisco"},{"author_name":"Dan Wang","author_inst":"University of California, San Francisco"},{"author_name":"Dena B Dubal","author_inst":"University of California, San Francisco"},{"author_name":"Samira Abdulai-Saiku","author_inst":"Temple University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Excitatory neurons downregulate synaptic proteins before motor onset and glia reduce neuronal support in Huntington disease mice","rel_doi":"10.64898\/2026.11.12.766120","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766120","rel_abs":"Background: Huntington's disease burdens protein homeostasis and affects neurons and glia differently across brain regions, but how these two main cell populations respond as the disease progresses remains unresolved. Whole-tissue proteomes mix these cell types and hide how the proteome of each changes. We therefore measured the proteome of each cell type separately at different disease stages. Methods: We metabolically labelled cell-type-specific proteomes in living R6\/1 mice and wild-type littermates for 15 days at different disease stages. We examined cortical and hippocampal excitatory neurons at 1.5, 3 and 7 months, cerebellar inhibitory neurons at 3 and 7 months, and cortical, striatal and cerebellar glia at 7 months. We combined mass spectrometry with functional enrichment and competitive protein-set tests to understand the differential proteostatic response to mutant huntingtin across disease progression, brain regions and cell types. Differential abundance was tested with a peptide-centric linear mixed model (msqRob, Benjamini-Hochberg q < 0.1), and proteins whose levels varied together in cortical and hippocampal neurons were grouped into modules by weighted correlation network analysis. Results: Hippocampal excitatory neurons showed broader and more coordinated regulation than cortical neurons already before motor onset, whereas the cortical response increased with age and no cortical protein module differed between genotypes before the most severe stage. All three neuronal populations upregulated ubiquitin-proteasome system (UPS) proteins as the disease advanced. Protein folding changed, with more subunits of the chaperonin CCT\/TRiC but fewer J-domain proteins and, in excitatory neurons, fewer HSP70 chaperones. At the most severe stage, glia of the three studied regions regulated mainly different proteins, but all increased UPS proteins and decreased key proteins of neuronal support, among them the main glial glutamate transporter GLT-1. Cholesterol-related proteins decreased in cortical and cerebellar glia, and respiratory-chain proteins in striatal glia. Conclusions: Synaptic proteins decreased early in cortical and hippocampal neurons and were not restored at later ages. A later and broader maintenance response coexisted with their continued and increasing downregulation. In this first cell-type-resolved view of the labelled proteome in a Huntington's disease mouse model, progression appears as a change in the coordination of cellular functions, which whole-tissue measurements would dilute.","rel_num_authors":14,"rel_authors":[{"author_name":"Rodrigo Alvarez Pardo","author_inst":"Complutense University of Madrid"},{"author_name":"Sicheng Luo","author_inst":"University of Gottingen Medical Center"},{"author_name":"Patricia Rodriguez","author_inst":"Karolinska Institute"},{"author_name":"Javier Lazaro Sanchez","author_inst":"Biochemistry and Molecular Biology Department, Veterinary School, Complutense University of Madrid, Madrid, Spain"},{"author_name":"Hector Albert-Gasco","author_inst":"Department of Medicine, Faculty of Health Sciences, Jaume I University, Castellon de la Plana, Spain"},{"author_name":"Cristina Olmedo Salinas","author_inst":"Biochemistry and Molecular Biology Department, Veterinary School, Complutense University of Madrid, Madrid, Spain"},{"author_name":"Kristina Desch","author_inst":"Max Planck Institute for Brain Research"},{"author_name":"Max Gubert-Olive","author_inst":"Genomics and Bioinformatics Platform, Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain"},{"author_name":"Josep Muncunill","author_inst":"Genomics and Bioinformatics Platform, Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain"},{"author_name":"Miguel Diaz-Hernandez","author_inst":"Biochemistry and Molecular Biology Department, Veterinary School, Complutense University of Madrid, Madrid, Spain"},{"author_name":"Eugenio F Fornasiero","author_inst":"University of Gottingen Medical Center"},{"author_name":"Marko Jovanovic","author_inst":"Columbia University"},{"author_name":"Ella Doron-Mandel","author_inst":"Columbia University"},{"author_name":"Beatriz Alvarez-Castelao","author_inst":"Complutense University of Madrid"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Structural characterization of Posaconazole- parechovirus A3 capsid interaction using molecular simulations and cell infection assays","rel_doi":"10.64898\/2026.11.11.765989","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765989","rel_abs":"Parechovirus-A3 (PeV-A3) is a major cause of central nervous system infections in neonates, associated with meningoencephalitis and neurodevelopmental delays. Yet there are no specific antivirals against PeV-A3 infection. A newer clade of PeV-A3 has emerged post COVID-19, and our preliminary data shows that infants are not immune to the emerging variants, underscoring the need for a focused therapeutic discovery. Posaconazole (POS) is seen to attenuate PeV-A3 entry and infection, but the mechanistic understanding of drug-capsid interaction remains unknown. To this end, we combined mechanistic interrogation of drug-capsid interactions and conformational dynamics, with experimental infection assays. We identify two POS binding sites: a VP0-VP1 interface in the 2009 isolate (US WI-09), and a VP3-VP1 groove in the 2022 isolate (9C-CMKC) and a laboratory-selected POS-resistant variant (US WI-09 POSA P14). Apo simulations showed congruent trajectories of POS: to the VP0 face in US WI-09, and to the VP3 arm in 9C-CMKC and US WI-09 POSA P14. The relative contribution of VP0 to the drug-capsid interaction decreased from 86% in US WI-09 to zero in both 9C-CMKC and US WI-09 POSA P14, indicating a redistribution of binding interactions across capsid subunits. Cysteine or arginine substitutions to VP1 Tyr224 abolished the Tyr224-VP3 anchor. Functionally, 0.3 {micro}M POS inhibited replication of US WI-09 and 9C-CMKC in Vero-P cells but only US WI-09 in receptor-overexpressing Vero-MYADM cells. These findings suggest that POS efficacy depends on binding-site localization near the MYADM-engaging VP0 interface, revealing how emerging PeV-A3 variants may retain drug binding while evading antiviral inhibition.","rel_num_authors":4,"rel_authors":[{"author_name":"Rahil Salehi","author_inst":"Iowa State University of Science and Technology"},{"author_name":"Debarpan Dhar","author_inst":"Children's Mercy Research Institute"},{"author_name":"Rangaraj Selvarangan","author_inst":"Children's Mercy Research Institute"},{"author_name":"Ratul Chowdhury","author_inst":"Iowa State University of Science and Technology: Iowa State University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Regional Signals Matter: Rethinking Global Pooling for mRNA Foundation Models","rel_doi":"10.64898\/2026.11.12.766253","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766253","rel_abs":"RNA foundation models with diverse architectures have shown promise for learning representations of messenger RNA (mRNA) sequences. However, existing benchmarks commonly reduce token-level embeddings to transcript-level representations through global mean pooling before fitting a downstream probe. This aggregation does not explicitly preserve the identities of biologically distinct mRNA regions. Consequently, signals associated with short regulatory regions may be diluted, confounding assessments of representation quality with the information preserved by the readout. We introduce an architecture-agnostic, region-aware readout that separately averages embeddings within the 5$'$ untranslated region (UTR), coding sequence, and 3$'$ UTR and concatenates the resulting representations for linear probing. We reproduce mRNABench evaluations for 20 frozen models from 18 families, with a median absolute score difference of 0.0009 across 380 model--dataset--target evaluations published for 19 models, and construct a region-aware benchmark using the same models, tasks, and splits. Relative to global mean pooling, region-aware pooling increases Pearson correlation, averaged across the 20 models, by 11--25\\% on translation and stability tasks, with no statistically significant decreases detected for any model on the regression tasks. On classification tasks, relative changes in the area under the precision--recall curve range from $-3\\%$ to $+11\\%$. Boundary randomization and displacement generally reduce performance, while dimensionality-matched and sequence-composition controls indicate that the gains are not explained solely by increased feature dimensionality, region length, or guanine--cytosine (GC) content. Learned attention pooling approaches region-aware performance only when supplied with one query per region. In silico perturbations reveal stronger sensitivity to upstream AUGs (uAUGs) and their Kozak context, while analyses of endogenous transcripts show approximately threefold greater recovery of length- and GC-adjusted uAUG-associated differences than global-mean probes. Both readouts capture codon optimality. Model rankings averaged over the regression tasks remain largely stable, while within a task models move by several places. Our region-aware benchmark therefore provides a biologically structured and complementary evaluation of mRNA foundation models, revealing regulatory information that is less accessible to linear probes after global mean pooling. The code is available at \\url{https:\/\/github.com\/Sanford-Labs\/rnaregionpooling","rel_num_authors":6,"rel_authors":[{"author_name":"Saiyang Na","author_inst":"Sanford Labs"},{"author_name":"Zhijie Qi","author_inst":"Sanford Laboratories for Innovative Medicines"},{"author_name":"Deevanshu Goyal","author_inst":"Sanford Laboratories for Innovative Medicines"},{"author_name":"Junzhou Huang","author_inst":"The University of Texas at Arlington"},{"author_name":"Gene W Yeo","author_inst":"University of California, San Diego"},{"author_name":"WENHAO JIN","author_inst":"Sanford Laboratories for Innovative Medicines"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Adaptive tracking contributes to the invasion success of a global pest insect","rel_doi":"10.64898\/2026.11.12.766304","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766304","rel_abs":"Invasive species are a threat to biodiversity, natural resources, and the economy. Preventing future invasions requires the ability to predict which species will be successful invaders. Invading a new region often requires coping with novel environmental conditions, yet how invading populations adapt to environmental conditions encountered in their introduced range is not always clear. One process that may facilitate invasion in temperate environments is seasonal adaptive tracking, a rapid evolutionary process in which allele frequencies and phenotypes shift in response to seasonal environmental fluctuations, promoting the long-term maintenance of polymorphisms. Here, we test the hypothesis that adaptive tracking is a key contributor to the invasion success of the globally invasive fly Drosophila suzukii. We demonstrate that adaptive tracking results in predictable, rapid evolution of a key thermal tolerance trait (critical thermal minimum) essential for coping with climate variability. We also detect adaptive tracking in several genomic regions enriched for seasonally fluctuating alleles, and these alleles map to loci implicated in diverse traits, including thermal tolerance, pesticide resistance, and olfactory behavior. Finally, we find that loci undergoing adaptive tracking are significantly enriched for alleles associated with invasion in North American populations, suggesting that rapid evolution of seasonal traits may contribute to the success of this invasive species.","rel_num_authors":13,"rel_authors":[{"author_name":"Eleanor McCabe","author_inst":"University of Kentucky"},{"author_name":"Mathieu Gautier","author_inst":"INRA"},{"author_name":"Kit Eller","author_inst":"University of Vermont"},{"author_name":"Miles Garvin","author_inst":"University of Vermont"},{"author_name":"Andrew McCracken","author_inst":"University of Vermont"},{"author_name":"Sebastian Redondo","author_inst":"University of Vermont"},{"author_name":"Micheal Darrington","author_inst":"University of Kentucky"},{"author_name":"Mark Gracia","author_inst":"Southwester Oklahoma State University"},{"author_name":"Alan O. Bergland","author_inst":"University of Virginia"},{"author_name":"Alyssa Bangerter","author_inst":"University of Virginia"},{"author_name":"Katie Lotterhos","author_inst":"Northeastern University"},{"author_name":"Joaquin C. B. Nunez","author_inst":"University of Vermont"},{"author_name":"Nicholas M. Teets","author_inst":"University of Kentucky"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Metaplasia Orchestrates Tissue Recovery and Immune Remodeling Through CD73 in Chronic Pancreatitis","rel_doi":"10.64898\/2026.11.11.765912","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765912","rel_abs":"Chronic inflammatory injury promotes epithelial metaplasia, and progression from metaplasia to dysplasia is a recognized initiating event in carcinogenesis, as metaplastic cells exhibit heightened susceptibility to genetic alterations. In the pancreas, persistent acinar-to-ductal metaplasia (ADM) can progress to pancreatic intraepithelial neoplasia (PanIN), yet the mechanisms that determine whether ADM resolves or persists with fibrosis and sustained inflammation remain poorly defined. Here, we identify CD73 as a central regulator of ADM fate, tissue repair, and immune microenvironment remodeling during chronic pancreatic injury. Analysis of previously published single-cell RNA sequencing dataset from chronic pancreatitis (CP) tissues identified enrichment of Nt5e, which encodes CD73, within Hnf1{beta} ADM populations. Hnf1bCreERT2 and CD73fl\/fl;Hnf1bCreERT2 mice were treated with caerulein for 4 weeks to induce pancreatitis and ADM prior to tamoxifen-induced deletion of CD73 in HNF1B-expressing metaplastic epithelial cells. Histologic phenotyping and immune profiling were performed using immunohistochemistry and imaging mass cytometry. Metaplasia-specific CD73 deletion exacerbated pancreatic injury and fibrosis, impaired epithelial proliferation and recovery of the acinar compartment, and altered the abundance and spatial organization of inflammatory cells. Ex vivo ADM assays further demonstrated that CD73 loss increased ADM formation and the production of MCP-1 and TIMP-1. These findings identify CD73 as a context-dependent checkpoint linking epithelial plasticity and immune modulation during chronic pancreatic injury and tissue repair.","rel_num_authors":17,"rel_authors":[{"author_name":"Urvinder Kaur Sardarni","author_inst":"University of Nebraska Medical Center"},{"author_name":"Nicolette R. Mardik","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Victoria A. Gaeth","author_inst":"Vanderbilt University"},{"author_name":"Brenda Jarvis","author_inst":"Vanderbilt University"},{"author_name":"Khadija Turabi","author_inst":"The University of Nebraska Medical Center"},{"author_name":"Junjun Zheng","author_inst":"Houston Methodist Research Institute"},{"author_name":"Yitian Xu","author_inst":"Houston Methodist"},{"author_name":"Xuebo Chen","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Jurgen Schrader","author_inst":"Heinrich-Heine-Universitat Dusseldorf"},{"author_name":"Shu-hsai Chen","author_inst":"Houston Methodist Research Institute"},{"author_name":"Benjamin J. Swanson","author_inst":"The University of Nebraska Medical Center"},{"author_name":"Jesse L. Cox","author_inst":"The University of Nebraska Medical Center"},{"author_name":"Kurt W. Fisher","author_inst":"University of Nebraska Medical Center"},{"author_name":"Holger K. Eltzschig","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Richard J. DiPaolo","author_inst":"Saint Louis University"},{"author_name":"Kathleen E DelGiorno","author_inst":"Vanderbilt University"},{"author_name":"Jennifer M. Bailey-Lundberg","author_inst":"University of Nebraska Medical Center"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"HUH-tag conjugation enables accessible, site-specific functionalization of DNA origami with signaling-competent proteins","rel_doi":"10.64898\/2026.11.11.765849","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765849","rel_abs":"DNA origami enables precise nanometer scale control over the number, spacing, and geometry of biomolecules, making it a powerful tool for dissecting spatially organized biological processes such as receptor signaling. However, functionalizing origami with proteins remains a bottleneck restricting the technology to specialized laboratories. Here we show that viral-derived HUH endonuclease tags, small (~10 kDa) domains that form a covalent phosphotyrosine bond with short unmodified ssDNA, provide a simple and cost-effective route to decorating DNA origami with functional proteins. Using interleukin-1{beta} (IL-1{beta}) as a model ligand, we generated recombinant IL-1{beta}-HUH, achieved efficient site-specific conjugation to unmodified ssDNA within minutes, and coupled the conjugates to a DNA origami pegboard with tunable stoichiometry. IL-1{beta}-functionalized origami triggered ligand-dependent signalling in living cells and allowed visualization of the recruitment of downstream signaling molecules, confirming that HUH-tag conjugation preserves functionality. Because this strategy requires only standard molecular biology equipment and unmodified DNA, it lowers a technical and financial barrier to DNA origami-based experimentation, opening the approach to a broader range of biological questions and laboratories outside the DNA nanotechnology field.","rel_num_authors":6,"rel_authors":[{"author_name":"Alina Ehrl","author_inst":"MPI for Infection Biology"},{"author_name":"Elke Ziska","author_inst":"MPI for Infection Biology"},{"author_name":"Konlin Shen","author_inst":"University of California, San Francisco"},{"author_name":"Meghan A Morrissey","author_inst":"UCSB"},{"author_name":"Shawn M Douglas","author_inst":"UCSF"},{"author_name":"Marcus J Taylor","author_inst":"MPI for Infection Biology"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Mitochondrial dysfunction activates a translational stress response that drives diabetic pain","rel_doi":"10.64898\/2026.11.11.765941","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765941","rel_abs":"Neuropathic pain is common and debilitating among diabetics. The reactive glycolytic metabolite methylglyoxal (MGO) is strongly associated with painful diabetic neuropathy. MGO triggers pain through activation of the integrated stress response (ISR). The underlying molecular mechanisms are unclear. Here, we show that general control nonderepressible 2 (GCN2) kinase acts as a conserved sensor that bridges glycolytic and mitochondrial dysfunction to pain hypersensitivity. In human sensory neurons derived from dorsal root ganglion (DRG), MGO increased eIF2 phosphorylation and suppressed global translation. These effects were blocked upon inhibition of GCN2. Unbiased ribosome profiling of mouse DRG revealed that MGO triggered repression of mRNAs that encode components of the electron transport chain. Based on this observation, mitochondrial dysfunction was examined as a potential upstream trigger for GCN2 activation. MGO directly glycated mitochondrial complex I and increased the NADH\/NAD+ ratio. Correcting this redox imbalance via expression of a mitochondrial-targeted bacterial NADH oxidase (mitoLbNOX) prevented ISR activation by MGO. In a streptozotocin-induced mouse model of diabetic neuropathy, pharmacological GCN2 inhibition or sensory neuron-specific conditional deletion significantly attenuated mechanical allodynia. Calcium imaging revealed that genetic deletion of GCN2 reduced calcium influx in response to an agonist of TRPA1. Finally, expression of mitoLbNOX using adeno-associated viruses (AAV) in DRG sensory neurons in vivo reduced streptozotocin-induced mechanical hypersensitivity. Our findings demonstrate that GCN2 is a central, conserved driver of translational dysregulation downstream of mitochondrial redox stress in diabetic pain. This work highlights the critical role of mitochondrial function and translational control as key drivers of painful diabetic neuropathy.","rel_num_authors":7,"rel_authors":[{"author_name":"Angela R. Meyer","author_inst":"UW-Madison"},{"author_name":"Guadalupe Garcia","author_inst":"UW-Madison"},{"author_name":"Shea Ruhly","author_inst":"UW-Madison"},{"author_name":"Alexander R. Mikesell","author_inst":"UW-Madison"},{"author_name":"Jacob B. Shapiro","author_inst":"UW-Madison"},{"author_name":"Rebecca Chase","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Zachary T. Campbell","author_inst":"UW-Madison"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"deepTools4: Faster, Scalable, and Modernized Genomic Data Analysis","rel_doi":"10.64898\/2026.11.11.765524","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765524","rel_abs":"The deepTools suite is widely used for quality control, summarization, and visualization of high-throughput sequencing data. However, as genomic datasets grow in scale and depth, existing tools often become computational bottlenecks. We present deepTools4, a modernized framework designed for high performance, scalability, and enhanced usability, while maintaining seamless integration with the Galaxy platform. Core functionality has been rewritten and thoroughly benchmarked, achieving substantial computational speed-ups. Visualization tools have been modernized to provide more intuitive, high-quality graphical outputs. In addition, our testing framework has been expanded to facilitate continuous development and ensure robustness. We demonstrate the utility of deepTools4 across diverse epigenomics and transcriptomics datasets, highlighting its ability to summarize genome-wide signals, apply a wide range of common normalization methods, and visualize enrichment patterns. The enhanced deepTools4 framework delivers a faster, more scalable solution for reproducible genome-wide analysis and interpretation across many sequencing modalities. Availability: https:\/\/github.com\/deeptools\/deepTools\/","rel_num_authors":12,"rel_authors":[{"author_name":"Ward Deboutte","author_inst":"Max Planck Institute of Immunobiology and Epigenetics"},{"author_name":"Adrian Salatino","author_inst":"Max Planck Institute of Immunobiology and Epigenetics"},{"author_name":"Wolfgang Maier","author_inst":"University of Freiburg"},{"author_name":"Pavankumar Videm","author_inst":"University of Freiburg"},{"author_name":"Mohit Navandar","author_inst":"Max Planck Institute of Immunobiology and Epigenetics"},{"author_name":"Galina Erikson","author_inst":"Max Planck Institute of Immunobiology and Epigenetics"},{"author_name":"Saim Momin","author_inst":"University of Freiburg"},{"author_name":"Juan Caballero-Perez","author_inst":"Max Planck Institute of Immunobiology and Epigenetics"},{"author_name":"Leily Rabbani","author_inst":"Max Planck Institute of Immunobiology and Epigenetics"},{"author_name":"Lucille Lopez-Delisle","author_inst":"University of Geneva"},{"author_name":"Bj\u00f6rn Gr\u00fcning","author_inst":"University of Freiburg"},{"author_name":"Thomas Manke","author_inst":"Max Planck Institute of Immunobiology and Epigenetics"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Peptide-centric proteomics reveals molecular subtypes of sporadic Alzheimer's disease","rel_doi":"10.64898\/2026.11.12.766321","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766321","rel_abs":"Alzheimer's disease (AD) is a complex, age-related disease that continues to increase in incidence worldwide. Although some cases are caused by known pathogenic mutations, the majority of cases are sporadic, with uncertain etiology and commonly complicated by comorbid diseases. To better understand the molecular landscape of AD we constructed a unique brain sample set free from neuropathologic comorbidities. This cohort consists of autosomal dominant AD dementia, sporadic AD dementia, cognitively normal individuals with high AD neuropathologic change - a condition called resilient to AD, and cognitively normal cases with no or minimal AD neuropathologic change. Through quantitative mass spectrometry proteomics we obtain measures of peptides mapping to A-beta; and to tau, capturing differences in the histopathologic burden of disease. Correlations of these peptide abundance differences within sporadic AD dementia cases in the superior and medial temporal gyrus indicate the presence of two separate sporadic AD phenotypes. Additional differences are characterized at a peptide level between sporadic AD dementia and autosomal dominant AD dementia in the inferior parietal lobe and caudate nucleus. These findings indicate both shared and distinct molecular features in AD influenced by cause and age of onset of disease.","rel_num_authors":10,"rel_authors":[{"author_name":"Deanna L L Plubell","author_inst":"University of Washington"},{"author_name":"Gennifer E. E Merrihew","author_inst":"University of Washington"},{"author_name":"Jea Park","author_inst":"University of Washington"},{"author_name":"Karynne Patterson","author_inst":"University of Washington"},{"author_name":"Josh D Smith","author_inst":"University of Washington"},{"author_name":"Chris Hsu","author_inst":"University of Washington"},{"author_name":"Christine C Wu","author_inst":"University of Washington"},{"author_name":"C Dirk Keene","author_inst":"University of California San Diego"},{"author_name":"Thomas J Montine","author_inst":"Stanford University"},{"author_name":"Michael J. MacCoss","author_inst":"University of Washington"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"NRF2-driven thiol metabolism creates a selective vulnerability to selenite","rel_doi":"10.64898\/2026.11.12.766318","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.12.766318","rel_abs":"NRF2 hyperactivation caused by mutations in KEAP1 or NFE2L2 occurs in 20-30% of non-small cell lung cancers and confers therapy resistance. Here we show that NRF2-driven metabolic reprogramming creates a selective vulnerability to selenite. NRF2-dependent thiol export promotes the extracellular reduction of selenite to selenide. Our data support a model in which selenide enters cells and reaches mitochondria, where sulfide-quinone oxidoreductase uses selenide and glutathione to generate the selenopersulfide GS-SeH. A four-hour pulse of selenite was sufficient to induce cell death after washout, consistent with a selenium redox cycle that consumes NADPH and regenerates selenide. Within hours, selenite abolished aconitase activity and impaired mitochondrial respiration. The resulting cell death occurred independently of apoptosis, ferroptosis, pyroptosis, necroptosis and disulfidptosis. In mice, a selenite-rich diet selectively suppressed the growth of NRF2-hyperactive tumors. These findings identify an NRF2-driven metabolic vulnerability and support further investigation of selenite as a therapeutic strategy for NRF2-hyperactive cancers.","rel_num_authors":20,"rel_authors":[{"author_name":"Ting Chao","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Yun Huang","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Niklas B Thompson","author_inst":"University of Chicago"},{"author_name":"Jing-Chun Lin","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Ryan Martin","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Rithwik Paladugu","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Yi-Han Tang","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Svitlana Altukhova","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Shayla Pham","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Basma A Yasseen","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Feroza K Choudhury","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Archi Patel","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Min Liu","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Bin Fang","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"John Koomen","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Jose Serrano-Velez","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"W. Gregory Sawyer","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Hardik Shah","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"},{"author_name":"Mingxiang Teng","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Chang Jiang","author_inst":"H. Lee Moffitt Cancer Center and Research Institute"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Pervasive ethanol in the fruits and floral nectars consumed by tropical frugivores","rel_doi":"10.64898\/2026.11.11.766018","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.766018","rel_abs":"Dietary ethanol has long been proposed as a selective force shaping the diets and physiology of tropical frugivores and nectarivores, yet this idea has rested on measurements from only a few species and sites. Here, we present the first global survey of ethanol in wild fruits and flowers (591 and 37 species, respectively, across 18 countries) and test ecological and phylogenetic predictors of its variation. We detected ethanol in the ripened fruits of 72% of angiosperm species (211 species, N [&ge;] 3 per species; 0.021% - 3.9% alcohol by volume (ABV)). Ethanol was also detected in the flowers of 12 species (0.037% - 0.73% ABV). Maximum fruit ethanol varied with temperature, humidity, and phylogenetic relatedness, and it was higher in ripe fruits collected from the forest floor relative to their canopy counterparts. We then extrapolated potential daily ethanol consumption for 10 primate species. Estimated maximum daily ethanol ingestion for primates ranged from negligible to 0.72 g\/kg\/day on average (equivalent to 5.1 international standard drinks, 10 g ethanol each, for a 70 kg human). Our findings show that ethanol is widespread in plant reproductive tissues and shaped by both phylogeny and environment, supporting the hypothesis that dietary ethanol has been a pervasive selective pressure on fruit- and nectar-feeding animals.","rel_num_authors":57,"rel_authors":[{"author_name":"Julia G. Casorso","author_inst":"Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada."},{"author_name":"Konstans Wells","author_inst":"Department of Biosciences, Swansea University, Swansea, Wales, UK."},{"author_name":"Allegra N DePasquale","author_inst":"University of Calgary"},{"author_name":"Anna C. Bowland","author_inst":"Centre for Ecology and Conservation, Faculty of Environment, Science and Economy, University of Exeter, Penryn Campus, Penryn, Cornwall, UK."},{"author_name":"William D. Aguado","author_inst":"Department of Anthropology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.; The Center for Human Evolutionary Studies, New Brunswi"},{"author_name":"Sylvia Alsisto","author_inst":"Sabah Wildlife Department, Kota Kinabalu, Sabah, Malaysia."},{"author_name":"Erika B. Alves","author_inst":"Instituto Federal Goiano, Campus Posse, Goias, Brazil."},{"author_name":"Marc Ancrenaz","author_inst":"Hutan, Kota Kinabalu, Sabah, Malaysia."},{"author_name":"Francisca S. Andicene","author_inst":"Department of Science, Gorongosa National Park, Goinha, Sofala, Mozambique."},{"author_name":"Maria Anjum","author_inst":"Centre for Wildlife Studies, Bengaluru, India."},{"author_name":"Filippo Aureli","author_inst":"Universidad Veracruzana, Instituto de Neuroetologia, Xalapa, Mexico.; Research Centre in Evolutionary Anthropology and Palaeoecology, Liverpool John Moores Univ"},{"author_name":"Madelyn A. Barnes","author_inst":"Centre for Ecology and Conservation, Faculty of Environment, Science and Economy, University of Exeter, Penryn Campus, Penryn, Cornwall, UK."},{"author_name":"Elena Bersacola","author_inst":"Centre for Ecology and Conservation, Faculty of Environment, Science and Economy, University of Exeter, Penryn Campus, Penryn, Cornwall, UK."},{"author_name":"Monika Bisht","author_inst":"Department of Anthropology, University of Delhi, New Delhi, Delhi, India."},{"author_name":"Susana Carvalho","author_inst":"Department of Science, Gorongosa National Park, Goinha, Sofala, Mozambique.; PALEO research group, CIBIO\/BIOPOLIS, University of Porto, Porto, Portugal."},{"author_name":"Adriano A. B. Darosci","author_inst":"Instituto Federal Goiano, Campus Ceres, Goias, Brazil."},{"author_name":"Terita R. Deare","author_inst":"Centre for Ecology and Conservation, Faculty of Environment, Science and Economy, University of Exeter, Penryn Campus, Penryn, Cornwall, UK."},{"author_name":"Anthony Di Fiore","author_inst":"Department of Anthropology and Primate Molecular Ecology and Evolution Laboratory, The University of Texas at Austin, Austin, Texas, USA.; Estacion de Biodivers"},{"author_name":"Nathaniel J. Dominy","author_inst":"Departments of Anthropology and Biological Sciences, Dartmouth College, Hanover, New Hampshire, USA."},{"author_name":"Gideon A. Erkenswick","author_inst":"Field Projects International, Escondico, USA."},{"author_name":"Elodie Freymann","author_inst":"Primate Models for Behavioural Evolution Lab, Institute of Human Sciences, Department of Anthropology and Museum Ethnography, University of Oxford, Oxford, Engl"},{"author_name":"Taniya Gill","author_inst":"Department of Anthropology, University of Delhi, New Delhi, Delhi, India."},{"author_name":"Benoit Goossens","author_inst":"Organisms and Environment Division, School of Biosciences, Cardiff University, Cardiff, Wales, UK.; Danau Girang Field Centre, c\/o Sabah Wildlife Department, Wi"},{"author_name":"Luja Guju","author_inst":"Centre for Wildlife Studies, Bengaluru, India."},{"author_name":"Goro Hanya","author_inst":"Center for Primate Field Studies, Graduate School of Science, Kyoto University, Kyoto, Japan."},{"author_name":"Xavier A. Harrison","author_inst":"Centre for Ecology and Conservation, Faculty of Environment, Science and Economy, University of Exeter, Penryn Campus, Penryn, Cornwall, UK."},{"author_name":"Laura T. Hernandez Salazar","author_inst":"Universidad Veracruzana, Instituto de Neuroetologia, Xalapa, Mexico."},{"author_name":"Nadine Hussein","author_inst":"Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada."},{"author_name":"Steig E. Johnson","author_inst":"Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada."},{"author_name":"Fumiya Kakuta","author_inst":"Center for Primate Field Studies, Graduate School of Science, Kyoto University, Kyoto, Japan."},{"author_name":"Rentaro Kimpara","author_inst":"Center for Primate Field Studies, Graduate School of Science, Kyoto University, Kyoto, Japan.; Wildlife Research Center, Kyoto University, Kyoto, Japan."},{"author_name":"Yosuke Kurihara","author_inst":"Center for Education and Research in Field Sciences, Faculty of Agriculture, Shizuoka University, Hamamatsu, Japan."},{"author_name":"Wanyi Lee","author_inst":"International College, National Taiwan University, Taipei City, Taiwan."},{"author_name":"Shelly Masi","author_inst":"UMR7206 Ecoanthropologie, Centre National de la Recherche Scientifique\/Museum National d'Histoire Naturelle\/University Paris Cite, Musee de l'Homme, Paris, Fran"},{"author_name":"Miku Minamikawa","author_inst":"Danau Girang Field Centre, c\/o Sabah Wildlife Department, Wisma MUIS, Kota Kinabalu, Sabah, Malaysia."},{"author_name":"Lara Nellissen","author_inst":"UMR7206 Ecoanthropologie, Centre National de la Recherche Scientifique\/Museum National d'Histoire Naturelle\/University Paris Cite, Musee de l'Homme, Paris, Fran"},{"author_name":"Omer Nevo","author_inst":"Deutsches Zentrum fur Integrative Biodiversitatsforschung (iDiv) Halle-Jena-Leipzig, Leipzig, Saxony, Germany.; Institute of Biodiversity, Ecology and Evolution"},{"author_name":"Julia Ostner","author_inst":"Department for Behavioral Ecology, University of Goettingen, Gottingen, Germany.; Social Evolution in Primates Group, German Primate Center, Leibniz Institute f"},{"author_name":"Melody A. Petersen-Leong","author_inst":"Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada."},{"author_name":"Alice C. Poirier","author_inst":"Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada."},{"author_name":"Ishika Ramakrishna","author_inst":"Centre for Wildlife Studies, Bengaluru, India."},{"author_name":"Hasinala Ramangason","author_inst":"Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada."},{"author_name":"Carlos E. Ramirez Torres","author_inst":"Universidad Veracruzana, Instituto de Neuroetologia, Xalapa, Mexico."},{"author_name":"Diary N. Razafimandimby","author_inst":"Mention Zoologie et Biodiversite Animale, Faculte des Sciences, Universite d'Antananarivo, Antananarivo, Madagascar."},{"author_name":"Leticia V. Rodrigues","author_inst":"Instituto Federal Goiano, Campus Posse, Goias, Brazil."},{"author_name":"Suheidy Romero Morales","author_inst":"Area de Conservacion Guanacaste, La Cruz, Guanacaste, Costa Rica."},{"author_name":"Jessica M. Rothman","author_inst":"Department of Anthropology, Hunter College of the City University of New York, New York, New York, USA."},{"author_name":"Oliver Schulke","author_inst":"Department for Behavioral Ecology, University of Goettingen, Gottingen, Germany.; Social Evolution in Primates Group, German Primate Center, Leibniz Institute f"},{"author_name":"Fred Y. Y. Tuh","author_inst":"Sabah Parks, Kota Kinabalu, Sabah, Malaysia."},{"author_name":"Atsushi Usami","author_inst":"Wildlife Research Center, Kyoto University, Kyoto, Japan."},{"author_name":"Sri Suci Utami Atmoko","author_inst":"Department of Biology, Universitas Nasional, Jakarta, Indonesia.; Primate Research Center, Universitas Nasional, Jakarta, Indonesia."},{"author_name":"Vivek V. Venkataraman","author_inst":"Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada."},{"author_name":"Erin R. Vogel","author_inst":"Department of Anthropology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.; The Center for Human Evolutionary Studies, New Brunswi"},{"author_name":"Mrinalini Watsa","author_inst":"Field Projects International, Escondico, USA.; San Diego Zoo Wildlife Alliance, San Diego, California, USA."},{"author_name":"Matthew A. Carrigan","author_inst":"College of Central Florida, Ocala, Florida, USA.; Environmental Future Institute, Gainesville, Florida, USA."},{"author_name":"Kimberley J. Hockings","author_inst":"Centre for Ecology and Conservation, Faculty of Environment, Science and Economy, University of Exeter, Penryn Campus, Penryn, Cornwall, UK."},{"author_name":"Amanda D. Melin","author_inst":"Department of Anthropology and Archaeology, University of Calgary, Calgary, Alberta, Canada.; Department of Medical Genetics, University of Calgary, Calgary, Al"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Propensity-Adjusted AUC under Nuisance-Model Misspecification","rel_doi":"10.64898\/2026.11.11.765682","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765682","rel_abs":"Propensity adjustment compares medical-image detector scores within groups with similar measured properties, such as stain or focus. We examine its sensitivity to the nuisance model that forms those groups. Under Gaussian latent-index assumptions and exact linear-index strata, a closed-form correlation gives an exact boundary for adjusted AUC to fall below one half. Quadrature matches 36 simulation cells within 0.008. Inflation and attenuation relative to correct adjustment are empirical findings, not general ordering results. An overlap screen and a self-stratified control introduced for this study miss 140 of 141 simulated cells with absolute error above 0.05: checking the fitted propensity cannot certify completeness of the adjustment set. On real pathology corpora, logistic and boosted-tree models using the same 16 features disagree. Among splits where both pass both checks, mean adjusted-AUC gaps are 0.057 on acid-fast bacilli (AFB), 0.048 on Kaggle, and 0.049 on PCam, over three, five, and three splits respectively. These gaps measure model sensitivity; neither estimate is known to be correct. A controlled colour shift moves adjusted AUC relative to model-specific references in the predicted direction in 78 of 80 label-dependent cells. Broader balance and label-fit diagnostics favour trees without certifying their adjusted AUC. We recommend reporting sensitivity across nuisance models alongside these diagnostics. Reversal relative to known truth occurs in constructed stress tests; its frequency in practice remains unknown.","rel_num_authors":5,"rel_authors":[{"author_name":"Caleb Heinzman","author_inst":"University of Missouri"},{"author_name":"Yi Shang","author_inst":"University of Missouri"},{"author_name":"Huazhang Guo","author_inst":"Saint Louis University School of Medicine"},{"author_name":"Ye Duan","author_inst":"Clemson University"},{"author_name":"Mai He","author_inst":"Washington University School of Medicine in St. Louis"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Ferrybots: Programmable Hydrogel Microbots for Rapid Magnetic Navigation and Modular Function","rel_doi":"10.64898\/2026.11.11.763821","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.763821","rel_abs":"Untethered microrobots could enable localized delivery, sensing, and intervention in confined biological and engineered environments. Magnetic actuation is especially attractive for such systems because it provides remote, fuel-free control, but practical magnetic microrobots remain difficult to manufacture and functionalize. High magnetic loading can interfere with polymerization and structural integrity, while integrating application-specific payloads directly into the robot body often requires the entire material formulation to be redesigned. Here, we introduce Ferrybots, programmable hydrogel microrobots that physically separate magnetic navigation from functional cargo. An automated droplet-on-demand microfluidic flow-lithography process confines high-concentration ferrofluid cores within photopolymerized poly (ethylene glycol) diacrylate (PEGDA) structures, enabling magnetic loading to be programmed through core number and spacing without uniformly dispersing magnetic particles throughout the hydrogel. The process achieved a minimum fabrication cycle time of 15 s. Ferrybots exhibited magnetic-dose-dependent translation and rotation, branched-channel steering, out-of-plane obstacle traversal, and rapid translation, with two-core robots following an external magnet at speeds up to the 9000 mm\/min limit of the actuation system. Differences in magnetic loading also enabled sequential selective navigation of distinct Ferrybot populations. Using PEGDA 575 as a common interface material, independently formulated hydrogel cargo modules could subsequently be fused to preformed Ferrybots while preserving navigation. Separately, cargo modules enabled composition-dependent molecular release and oxygen-responsive sensing through 1-mm-thick skin-mimicking optical phantoms representing a broad range of skin types. By decoupling locomotion from function, Ferrybots provide a common magnetic vehicle that can be combined with interchangeable delivery, sensing, or responsive-material modules, offering a general strategy for rapidly adapting microrobots to different applications.","rel_num_authors":13,"rel_authors":[{"author_name":"Vivek Rajasenan","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Timothy Vernon","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Ridhi Pradhan","author_inst":"Texas A&M"},{"author_name":"Artem Goncharov","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Hamed Hosseini-Toudeshki","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Aiden Begole","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Shun Ye","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Yichen Zou","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Nandita Rajagopal","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Thu Phung","author_inst":"University of California Los Angeles"},{"author_name":"Michael McShane","author_inst":"Texas A&M"},{"author_name":"Aydogan Ozcan","author_inst":"Universtiy of Calfornia, Los Angeles"},{"author_name":"Dino Di Carlo","author_inst":"Universtiy of Calfornia, Los Angeles"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Actin Assembly on Biomimetic Lipid-coated and Functionalized Bead Surfaces","rel_doi":"10.64898\/2026.11.11.765950","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765950","rel_abs":"Dynamic assembly of actin filaments drives cell protrusion and other aspects of cell motility. Reconstitution of actin assembly from purified components is a powerful approach for understanding the molecular mechanisms that underlie these processes. Purified preparations of actin, actin-binding proteins, and regulators of actin-binding proteins enable a broad spectrum of reconstitution experiments. Much of this actin filament assembly occurs at the plasma membrane, with exquisite temporal and spatial regulation. We developed a biomimetic reconstitution system using purified lipids or glutathione on the surface of functionalized beads as models for actin assembly at the plasma membrane. The system incorporates two critical pathways for regulation of actin assembly: nucleation of actin polymerization by Arp2\/3 complex and activation of heterodimeric actin capping protein (CP). Arp2\/3 complex and CP are both essentially inactive in the basal resting state of the cytoplasm. The system incorporates membrane-bound activators for Arp2\/3 complex, such as WASP and WAVE family proteins, and for CP, such as CARMILs and other CPI-motif proteins. Membrane-bound components are coupled to beads either through lipids, which allow lateral mobility, or through glutathione groups attached to the bead surface via flexible linkers. Fluorescence microscopy of labeled components, combined with quantitative image analysis, is used to assess the combined effects of the regulators and thereby test molecular mechanisms for regulation of actin assembly. Here, we describe protocols for preparing functionalized beads, coupling regulators to the bead surface, performing actin assembly reactions, and imaging and quantifying the resulting actin networks.","rel_num_authors":4,"rel_authors":[{"author_name":"Oliva L Mooren","author_inst":"Washington University"},{"author_name":"patrick McConnell","author_inst":"Washington University"},{"author_name":"Anshuman Jaysingh","author_inst":"Washington University in St. Louis"},{"author_name":"John Cooper","author_inst":"Washington University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Assembly-independent measurement of human Yq12 heterochromatin reveals population-scale variation and Yq12-derived RNA in testis","rel_doi":"10.64898\/2026.11.11.765874","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765874","rel_abs":"Despite advances in long-read sequencing and telomere-to-telomere assembly, population-scale analysis of large satellite arrays remains challenging. Human Yq12 is a megabase-scale heterochromatic region composed primarily of DYZ1\/HSat3A6 and DYZ2\/HSat1B repeats, whose near-equal proportions are maintained despite extensive variation in total array length. Here, using complete Y-chromosome assemblies, we developed k-mer-based tools to estimate Yq12 size directly from short- and long-read sequencing data without requiring sample-specific complete assemblies. Across 1,597 males from the 1000 Genomes Project, Yq12 length ranged from ~1 to 52 Mb (mean 26.5 Mb) and varied substantially within and between Y haplogroups. Phylogenetic analyses supported long-term constraint of total Yq12 length near an equilibrium of 26 Mb and strongly coupled evolution of DYZ1 and DYZ2 around near-parity composition. In 303 father-son pairs, fathers had longer estimated Yq12 regions in 70.6% of pairs, while sons more often showed DYZ1:DYZ2 ratios closer to 1:1. Testis Iso-Seq identified transcripts containing DYZ1 and DYZ2 satellite sequences, while single-cell RNA-seq revealed their expression in haploid spermatids. These results establish a scalable framework for studying Yq12 population variation, intergenerational dynamics, and transcription, providing new opportunities to investigate how extreme satellite-array variation relates to Y-chromosome evolution and male germ-cell biology.","rel_num_authors":6,"rel_authors":[{"author_name":"Mark Loftus","author_inst":"The University of Connecticut Health Center"},{"author_name":"Pille Hallast","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Gianni V. Martino","author_inst":"Clemson University"},{"author_name":"Gianluca Petris","author_inst":"Fondazione Italiana Fegato"},{"author_name":"Charles Lee","author_inst":"The University of Connecticut Health Center"},{"author_name":"Miriam K. Konkel","author_inst":"Clemson University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"A living organism-level model of subcellular architecture across adult life reveals a midlife architectural state shift","rel_doi":"10.64898\/2026.11.11.765956","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765956","rel_abs":"Many features of subcellular organelle architecture change throughout life and influence aging. However, our understanding of this structural dynamism relies on single cell systems or comparisons between data sets focused on a limited number of organelles or timepoints. To overcome this barrier, we developed Multiorganelle Mapper (MoMA), a C. elegans strain enabling simultaneous imaging of six organelles across all somatic cell types in fully intact, living animals via fluorescence microscopy. We use MoMA to generate an organism-level in vivo map of subcellular architecture throughout adult life to understand how and why organelle organization changes with age. Aging drives a widespread and consistent shift in subcellular architecture throughout the body. Strikingly, most of this remodeling does not accumulate progressively, but emerges abruptly within individuals at midlife, an inflection point we term the midlife architectural state shift (MASS). Through a targeted RNAi screen, we show the MASS is not unique to aging, but instead resembles a generalized reactive state which can be triggered by a range of distinct homeostatic challenges. Finally, we show the MASS both coincides with and can be driven by midlife physiological changes, suggesting that this remodeling may largely reflect a coordinated reaction to the aged organismal state. Together, we present MoMA as a practical approach for visualizing subcellular architecture at organismal scale and demonstrate how it can be used to uncover principles underlying the dynamic regulation of subcellular architecture throughout life.","rel_num_authors":8,"rel_authors":[{"author_name":"Christopher S Morrow","author_inst":"Harvard TH Chan School of Public Health"},{"author_name":"Aditi Prabhakar","author_inst":"Harvard TH Chan School of Public Health"},{"author_name":"Jamie D Kraft","author_inst":"Harvard TH Chan School of Public Health"},{"author_name":"Carlos Giovanni Silva-Garcia","author_inst":"Brown University"},{"author_name":"Praju Vikas Anekal","author_inst":"Harvard Medical School"},{"author_name":"Paula Montero Llopis","author_inst":"Harvard Medical School"},{"author_name":"Jeffrey W Miller","author_inst":"Harvard TH Chan School of Public Health"},{"author_name":"William B Mair","author_inst":"Harvard TH Chan School of Public Health"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Peripheral Immune Cell Shifts Associated With Alzheimer's Disease Vary in Multi-Ancestry Cohorts","rel_doi":"10.64898\/2026.11.11.765813","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765813","rel_abs":"Background: Alzheimer's disease (AD) is heavily influenced by immune system dysregulation, yet the role of peripheral immune processes--and how these vary across ethnicities--remains understudied. Objective: To investigate ancestry-specific immune alterations in AD by profiling peripheral immune cell proportions using high-resolution deconvolution of whole blood RNA-sequencing data, characterizing disease associated cell types, and identifying enriched biological pathways. Methods: We analyzed whole blood RNA-seq data from non-Hispanic White (NHW), African American (AA), Caribbean Hispanic (CariHISP), and Peruvian (PERU) individuals, balanced between AD cases and cognitively normal controls. Immune cell proportions were estimated using CIBERSORTx and compared using linear models (propeller R package) adjusted for age, sex, and APOE genotypes in case-control models. Cell-type-specific differential expression was performed using CARseq, and pathway enrichment analyses performed using MSigDB gene sets. Results: Baseline immune composition differed substantially across cohorts for multiple innate and adaptive cell types. In a multi-ethnic AD versus control analysis, eight cell types reached FDR significance: AD was associated with decreased proportions naive B cells, CD56dim NK cells, B cells, intermediate monocyte I, and double-negative T cells, alongside significant expansion in neutrophils and non-classical monocytes. Interaction analyses revealed heterogeneous group-specific effects, with the broadest shifts in AA and CariHISP. Pathway enrichment indicated shared heme metabolism, interferon, and oxidative phosphorylation programs across groups, with distinct emphases: broad, strong heme metabolism enrichment and the highest oxidative phosphorylation signal (in myeloid populations) in AA; MYC targets in naive B cells and eosinophils in CariHISP; dendritic cell - and T follicular helper cell - centered interferon, inflammatory, and proliferative programs in NHW; and TGF-{beta} and apoptosis signatures, unique to PERU, alongside the broadest cell-type coverage. Conclusions: Peripheral immune dysregulation in AD is characterized by depletion of lymphoid and intermediate monocyte populations with concurrent neutrophil and non-classical monocyte expansion, and these patterns vary meaningfully by ancestry. These findings underscore the need for population-informed biomarkers and therapeutic strategies in AD.","rel_num_authors":19,"rel_authors":[{"author_name":"Yousef Mustafa","author_inst":"Case Western Reserve University"},{"author_name":"Yuchen Yang","author_inst":"Case Western Reserve University"},{"author_name":"Makaela A Mews","author_inst":"Case Western Reserve University"},{"author_name":"Tianjie Gu","author_inst":"University of Miami"},{"author_name":"Lissette Gomez","author_inst":"University of Miami"},{"author_name":"Larry D. Adams","author_inst":"University of Miami"},{"author_name":"Takiyah D. Starks","author_inst":"Wake Forest University"},{"author_name":"Concepcion Silva","author_inst":"Universidad Central Del Caribe, Puerto Rico"},{"author_name":"Katalina F. McInerney","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Jeffery M Vance","author_inst":"University of Miami"},{"author_name":"Michael  L Cuccaro","author_inst":"University of Miami Miller School of Medicine: University of Miami School of Medicine"},{"author_name":"Maryenela Illanes-Manrique","author_inst":"Instituto Nacional de Ciencias Neurologicas, Lima, Peru"},{"author_name":"Mario R Cornejo-Olivas","author_inst":"Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru"},{"author_name":"Briseida E. Feliciano-Astacio","author_inst":"Universidad Central Del Caribe, Puerto Rico"},{"author_name":"Byrd  S. Goldie","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Margaret A. Pericak-Vance","author_inst":"University of Miami"},{"author_name":"Jonathan  L. Haines","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Anthony J Griswold","author_inst":"University of Miami"},{"author_name":"William Bush","author_inst":"Case Western Reserve University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"MicroDUET: a dual-headed genomic foundation model for pathogen surveillance","rel_doi":"10.64898\/2026.11.11.765853","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765853","rel_abs":"Pathogen genomic surveillance works from raw reads, assembled genomes and alignments, representations that are slow and costly to compare at scale. Compact embeddings from genomic language models offer an alternative, but surveillance requires resolving both evolutionary ancestry (phylogeny) and phenotypic capability (function) - which need not co-vary. Here we present MicroDUET, which adapts a 26.6-million-parameter ProkBERT backbone with two 3.5-million-parameter adapter heads: a phylogeny head trained contrastively on genome windows from the same microbes, and a function head trained to identify genes across taxa. On held-out retrieval benchmarks, the phylogeny head returned the correct species for 80.3% and 66.6% of cellular and viral queries, and the function head the correct gene family for 97.3% and 97.2%, reaching 74.4% accuracy on an independent antimicrobial resistance-class benchmark. Across all three benchmarks MicroDUET outranked 17 other genomic encoders. Without training on lineage, clade or drug-susceptibility tasks, MicroDUET identified Mycobacterium tuberculosis and mpox virus lineages and clades (0.965, 0.975 accuracy), discriminated rifampicin resistance without lineage adjustment (AUROC 0.985), and retrospectively identified an emerging mpox lineage as anomalous (AUROC 0.974). MicroDUET operates 10^3 - 10^4 times faster than single-threaded sequence-based alignments. MicroDUET therefore provides a compact, reusable representation for scalable pathogen surveillance and sequence triage.","rel_num_authors":7,"rel_authors":[{"author_name":"Michael Barber","author_inst":"University of Oxford"},{"author_name":"Carl J. E. Suster","author_inst":"Sydney Infectious Diseases Institute, The University of Sydney, Sydney, NSW, Australia"},{"author_name":"Jingyi Lei","author_inst":"Duke-NUS Medical School, Centre for Outbreak Preparedness, Singapore, Singapore"},{"author_name":"Marya Getchell","author_inst":"Duke-NUS Medical School, Centre for Outbreak Preparedness, Singapore, Singapore"},{"author_name":"Suci Wulandari","author_inst":"Duke-NUS Medical School, Centre for Outbreak Preparedness, Singapore, Singapore"},{"author_name":"Vitali Sintchenko","author_inst":"Sydney Infectious Diseases Institute, The University of Sydney, Sydney, NSW, Australia"},{"author_name":"Paul M. Pronyk","author_inst":"Duke-NUS Medical School, Centre for Outbreak Preparedness, Singapore, Singapore"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"Genetic ancestry influences the relative expression of ancestral haplotypes within admixed individuals","rel_doi":"10.64898\/2026.11.11.765740","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.765740","rel_abs":"Allele-specific expression (ASE) reflects differences between the two haplotypes a person carries, but most ASE studies have been done in European-descent samples. Admixed individuals carry haplotypes from different ancestral backgrounds within the same cell, which allows ancestry effects on regulation to be measured directly. We integrated phased whole-blood RNA-seq with local ancestry inference in 779 participants from the MAGENTA cohort, including non-Hispanic White, African American, Caribbean Hispanic, and Peruvian individuals. Higher West African (YRI) ancestry proportion was associated with more ASE-positive genes per person, and the association remained after adjusting for age, sex, Alzheimer's disease status, APOE genotype, and the number of heterozygous genes. Peruvian ancestry showed no significant association. A gene-level test of imbalance across population groups found 2,053 of 15,008 genes with significant differences, including the major histocompatibility complex in all four groups. A genome-wide scan of 2,213 1 Mb windows compared people carrying two haplotypes of different ancestries with those carrying two of the same ancestry. It identified 52 non-redundant loci that replicated across all four population groups, containing 201, 60, and 110 ancestry-associated genes under the CEU, YRI, and PEL reference baselines. A haplotype-resolved directional analysis showed no genome-wide advantage for either ancestry. It found locus-specific dominance at 11 loci, and only chr8:2-3 Mb (CSMD1) showed the same direction in more than one population group. Genetic ancestry therefore shapes allelic regulation at global, gene, and locus scales.","rel_num_authors":6,"rel_authors":[{"author_name":"esteban vazquez-hidalgo","author_inst":"case western reserve university"},{"author_name":"Makaela A Mews","author_inst":"Case Western Reserve University"},{"author_name":"Lissette Gomez","author_inst":"University of Miami"},{"author_name":"tianjie Gu","author_inst":"Univerisity of Miami"},{"author_name":"Anthony J Griswold","author_inst":"University of Miami"},{"author_name":"William Bush","author_inst":"Case Western Reserve University"}],"rel_date":"2026-11-13","rel_site":"biorxiv"},{"rel_title":"DermNet: An Incremental Knowledge Distillation Framework for Accurate and Robust Skin Layer Segmentation","rel_doi":"10.64898\/2026.11.11.26367811","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367811","rel_abs":"Background Accurate segmentation of skin layers in histopathological whole-slide images (WSIs) is important for identifying disease-associated structural changes and supporting computer-aided dermatopathological analysis. However, existing approaches are often restricted to single magnification levels and may inadequately capture the heterogeneous morphological characteristics of individual skin layers. We propose DermNet, a multi-resolution class-incremental learning framework designed to achieve accurate skin layer segmentation while mitigating catastrophic forgetting. Methods DermNet employs a SegFormer backbone within a teacher-student architecture and progressively learns class-specific features from WSIs acquired at 10x, 5x, and 2x magnifications. The framework incorporates exemplar replay, mutual knowledge, distillation, classification, Kullback-Leibler divergence losses, boundary loss, and Elastic Weight Consolidation to preserve previously learned representations while incorporating new tissue classes. The model was trained and evaluated using a publicly available dataset of 290 WSIs, with segmentation focused on the epidermis, papillary dermis, reticular dermis, hypodermis, keratin, and background. Results DermNet consistently outperformed U-Net and alternative SegFormer training strategies across all three magnification levels. At 10x magnification, DermNet achieved Dice scores of 0.95 for epidermis, 0.92 for papillary dermis, 0.94 for reticular dermis, 0.97 for keratin, and 0.98 for hypodermis, outperforming UNet++ and DeepLabv3+. TransUNet, SwinUNet, and nnU-Net under the same experimental conditions. Evaluation on an independent publicly available dataset further demonstrated cross-dataset generalizability, with Dice scores ranging from 0.89 to 0.97 across classes. Conclusion DermNet enables accurate and robust multi-resolution skin layer segmentation by combining class-incremental learning with knowledge distillation and mechanisms for preserving previously learned features. Its performance across magnification levels and an independent dataset supports its potential for scalable and generalizable automated dermatopathological image analysis.","rel_num_authors":8,"rel_authors":[{"author_name":"Anum Abdul Salam","author_inst":"Computer and Software Engineering, National University of Sciences and Technology, Islamabad 44000, Punjab, Pakistan"},{"author_name":"Muhammad Usman Akram","author_inst":"Computer and Software Engineering, National University of Sciences and Technology, Islamabad 44000, Punjab, Pakistan"},{"author_name":"Soyiba Jawed","author_inst":"Computer and Software Engineering, National University of Sciences and Technology, Islamabad 44000, Punjab, Pakistan"},{"author_name":"Tehmina Shehryar","author_inst":"Byers Eye Institute, Stanford University School of Medicine, Palo Alto 94303, CA, United States; Software Engineering, Mirpur University of Science and Technolo"},{"author_name":"Zoha Zahid Fazal","author_inst":"Stanford Medicine"},{"author_name":"Muhammad Haroon Yousaf","author_inst":"Computer Engineering, University of Engineering and Technology, Taxila, Pakistan; Swarm Robotics Lab, National Centre of Robotics and Automation, Pakistan"},{"author_name":"Babar Rao","author_inst":"Dermatology, Weill Cornell School of Medicine, NYC, United States; Dermatology and Pathology, Rutgers RWJ Medical School, New Brunswick, NJ, United States"},{"author_name":"Norah Saleh Alghamdi","author_inst":"Computer Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"DermNet: An Incremental Knowledge Distillation Framework for Accurate and Robust Skin Layer Segmentation","rel_doi":"10.64898\/2026.11.11.26367811","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367811","rel_abs":"Background Accurate segmentation of skin layers in histopathological whole-slide images (WSIs) is important for identifying disease-associated structural changes and supporting computer-aided dermatopathological analysis. However, existing approaches are often restricted to single magnification levels and may inadequately capture the heterogeneous morphological characteristics of individual skin layers. We propose DermNet, a multi-resolution class-incremental learning framework designed to achieve accurate skin layer segmentation while mitigating catastrophic forgetting. Methods DermNet employs a SegFormer backbone within a teacher-student architecture and progressively learns class-specific features from WSIs acquired at 10x, 5x, and 2x magnifications. The framework incorporates exemplar replay, mutual knowledge, distillation, classification, Kullback-Leibler divergence losses, boundary loss, and Elastic Weight Consolidation to preserve previously learned representations while incorporating new tissue classes. The model was trained and evaluated using a publicly available dataset of 290 WSIs, with segmentation focused on the epidermis, papillary dermis, reticular dermis, hypodermis, keratin, and background. Results DermNet consistently outperformed U-Net and alternative SegFormer training strategies across all three magnification levels. At 10x magnification, DermNet achieved Dice scores of 0.95 for epidermis, 0.92 for papillary dermis, 0.94 for reticular dermis, 0.97 for keratin, and 0.98 for hypodermis, outperforming UNet++ and DeepLabv3+. TransUNet, SwinUNet, and nnU-Net under the same experimental conditions. Evaluation on an independent publicly available dataset further demonstrated cross-dataset generalizability, with Dice scores ranging from 0.89 to 0.97 across classes. Conclusion DermNet enables accurate and robust multi-resolution skin layer segmentation by combining class-incremental learning with knowledge distillation and mechanisms for preserving previously learned features. Its performance across magnification levels and an independent dataset supports its potential for scalable and generalizable automated dermatopathological image analysis.","rel_num_authors":8,"rel_authors":[{"author_name":"Anum Abdul Salam","author_inst":"Computer and Software Engineering, National University of Sciences and Technology, Islamabad 44000, Punjab, Pakistan"},{"author_name":"Muhammad Usman Akram","author_inst":"Computer and Software Engineering, National University of Sciences and Technology, Islamabad 44000, Punjab, Pakistan"},{"author_name":"Soyiba Jawed","author_inst":"Computer and Software Engineering, National University of Sciences and Technology, Islamabad 44000, Punjab, Pakistan"},{"author_name":"Tehmina Shehryar","author_inst":"Byers Eye Institute, Stanford University School of Medicine, Palo Alto 94303, CA, United States; Software Engineering, Mirpur University of Science and Technolo"},{"author_name":"Zoha Zahid Fazal","author_inst":"Stanford Medicine"},{"author_name":"Muhammad Haroon Yousaf","author_inst":"Computer Engineering, University of Engineering and Technology, Taxila, Pakistan; Swarm Robotics Lab, National Centre of Robotics and Automation, Pakistan"},{"author_name":"Babar Rao","author_inst":"Dermatology, Weill Cornell School of Medicine, NYC, United States; Dermatology and Pathology, Rutgers RWJ Medical School, New Brunswick, NJ, United States"},{"author_name":"Norah Saleh Alghamdi","author_inst":"Computer Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Robust Feature Engineering Techniques for Designing Efficient Motor Imagery-Based Systems Using Multidomain Electroencephalography","rel_doi":"10.64898\/2026.11.11.26367815","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367815","rel_abs":"Motor imagery-based brain-computer interfaces (BCIs) have potential applications in neurorehabilitation; however, the high dimensionality and complexity of electroencephalography (EEG) signals present challenges for accurate classification. This study aimed to improve the classification of motor and motor imagery activities using multidomain feature engineering and feature selection on the MILimbEEG dataset. Time-domain, frequency-domain, and wavelet-based features were extracted from 16-channel EEG signals, yielding 416 features. Maximum relevance minimum redundancy (MRMR) was then applied to select the four most informative and minimally redundant features. These features were used to train support vector machine (SVM), K-nearest neighbors (KNN), Naive Bayes, and decision tree classifiers, with performance evaluated using 10-fold cross-validation based on testing accuracy, precision, recall, and F1-score. The Gaussian-kernel SVM achieved the highest testing accuracies of 92.50% for motor activities and 95.48% for motor imagery activities. For the highest-performing motor imagery classification, precision, recall, and F1-score were 86.97%, 88.33%, and 87.04%, respectively. These findings demonstrate that reducing 416 multidomain EEG features to four discriminative features using MRMR can maintain strong classification performance. The proposed feature-engineering framework may support the development of computationally efficient EEG-based BCI systems for neurorehabilitation applications.","rel_num_authors":7,"rel_authors":[{"author_name":"Syed Saim Ahmed","author_inst":"Biomedical Engineering, Faculty of Engineering, Salim Habib University, Karachi, Pakistan"},{"author_name":"Soyiba Jawed","author_inst":"Computer Software Engineering, College of Electrical and Mechanical Engineering, NUST, Islamabad, Pakistan"},{"author_name":"Mahnoor Ahmed Khan","author_inst":"Department of Physics, Faculty of Applied Sciences, Riphah International University, Islamabad, Pakistan"},{"author_name":"Zoha Zahid Fazal","author_inst":"Medical College, Aga Khan University, Karachi, Pakistan; Byers Eye Institute, Stanford University School of Medicine, Palo Alto, United States"},{"author_name":"Tehmina Shehryar","author_inst":"Byers Eye Institute, Stanford University School of Medicine, Palo Alto, United States; Department of Software Engineering, Mirpur University of Science and Tech"},{"author_name":"Syeda Muneeba Bukhari","author_inst":"Biomedical Engineering, Faculty of Engineering, NED University, Karachi, Pakistan"},{"author_name":"Rizwan Ahmed Khan","author_inst":"Department of Computer Science, School of Mathematics and Computer Science, Institute of Business Administration, Karachi, Pakistan"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"CCL17-CCR4 Signalling Attenuates Pressure Overload-Induced Cardiac Remodelling Through IGFBP6 Suppression in Cardiac Fibroblasts","rel_doi":"10.64898\/2026.11.11.26367804","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367804","rel_abs":"Background and Aims Chemokines regulate immune-cell trafficking, inflammation, and tissue repair in cardiovascular disease. C-C motif chemokine ligand 17 (CCL17) has been linked to adverse remodelling after myocardial infarction and neurohumoral stress, but its role during sustained mechanical pressure overload remains unclear. We investigated whether CCL17 regulates ventricular remodelling through signalling in cardiac fibroblasts. Methods We performed serum proteomic screening and assessed CCL17 in human serum and myocardial samples. We evaluated CCL17 function in mice subjected to transverse aortic constriction using global Ccl17 deletion and adeno-associated virus-mediated CCL17 augmentation. We used cardiac transcriptomics and pharmacological, small interfering RNA, and promoter-reporter experiments in cardiac fibroblasts to investigate downstream signalling. We tested the functional contribution of Igfbp6 in vivo using fibroblast-directed silencing. Results Serum CCL17 concentrations and myocardial CCL17 abundance were higher in patients with aortic stenosis than in controls. Cardiac and circulating CCL17 increased rapidly after transverse aortic constriction. Ccl17 deletion aggravated systolic dysfunction, hypertrophy, and fibrosis after pressure overload, whereas CCL17 augmentation attenuated these changes. Cardiac transcriptomics identified insulin-like growth factor-binding protein 6 (IGFBP6) as a candidate downstream mediator. In cardiac fibroblasts, CCL17 reduced cellular and secreted IGFBP6 levels and alpha-smooth muscle actin expression through C-C chemokine receptor 4 (CCR4)-dependent signalling, accompanied by suppression of early growth response 1 (EGR1). Genetic perturbation and promoter-reporter experiments supported a role for EGR1 in the regulation of Igfbp6 downstream of CCR4. Fibroblast-directed Igfbp6 silencing improved systolic function and reduced hypertrophy and fibrosis in Ccl17-deficient mice after transverse aortic constriction. Conclusions CCL17 attenuates maladaptive cardiac remodelling in mice subjected to pressure overload. The findings support a mechanism in which CCL17 acts through CCR4 and EGR1 to suppress IGFBP6 in cardiac fibroblasts. Keywords: Aortic stenosis, CCL17, cardiac fibrosis, fibroblasts, IGFBP6, pressure overload","rel_num_authors":10,"rel_authors":[{"author_name":"Yuxiang Dai","author_inst":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China"},{"author_name":"Wei Guo","author_inst":"Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yang Zhang","author_inst":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China"},{"author_name":"Wendi Yan","author_inst":"Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China"},{"author_name":"Pingjing Zheng","author_inst":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China"},{"author_name":"Zhipeng Lian","author_inst":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China"},{"author_name":"Gaocheng Gu","author_inst":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China"},{"author_name":"Xin Wang","author_inst":"Oriental Panvascular Devices Innovations College, University of Shanghai for Science and Technology, Shanghai, China"},{"author_name":"Xin Chen","author_inst":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China"},{"author_name":"ChunKa Wong","author_inst":"Cardiology Division, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Altered herpesvirus-specific immune response is associated with long COVID","rel_doi":"10.64898\/2026.11.11.26367525","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367525","rel_abs":"Long COVID is associated with persistent immune dysregulation, but whether immunity to latent viruses is also altered remains unclear. We profiled herpesvirus-specific antibodies and T-cell responses in people with long COVID and recovered convalescent controls at 4, 8, and 24 months after SAR-CoV-2 infection. Overall antibody reactivity and abundance against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) responder frequencies and circulating B-cell subsets were broadly preserved, but early antibody avidity and virus-specific CD4 T cell response magnitude were reduced. Neither virus nucleic acid was detected in plasma or stool at 4 or 8 months. Here, we show that long COVID is associated with selective, time-dependent alteration of herpesvirus-specific immune memory, including relatively preserved or enhanced CD8 responses and greater representation of selected herpesvirus-associated T-cell receptor clonotypes. Together, these findings indicate altered herpesvirus-specific antibody quality despite broadly preserved antibody abundance. Lower EBV avidity was associated with poorer quality of life and unrecovered status.","rel_num_authors":19,"rel_authors":[{"author_name":"Ruchika V Joshi","author_inst":"The Kirby Institute, University of New South Wales, New South Wales, Australia"},{"author_name":"Rizwan MR Khan","author_inst":"The Kirby Institute, University of New South Wales, New South Wales, Australia"},{"author_name":"Katherine JL Jackson","author_inst":"Garvan Institute for Medical research, New South Wales, Australia"},{"author_name":"Sara Ballouz","author_inst":"School of Computer Science and Engineering, Faculty of Engineering, University of New South Wales, Australia"},{"author_name":"Brendan Jacka","author_inst":"The Kirby Institute, University of New South Wales, New South Wales, Australia"},{"author_name":"Leon Ni","author_inst":"The Kirby Institute, University of New South Wales, New South Wales, Australia"},{"author_name":"Nicholas Findell-Aghnatios","author_inst":"The Kirby Institute, University of New South Wales, New South Wales, Australia"},{"author_name":"Anupriya Aggarwal","author_inst":"The Kirby Institute, University of New South Wales, New South Wales, Australia"},{"author_name":"Stuart G Turville","author_inst":"The Kirby Institute, University of New South Wales, New South Wales, Australia"},{"author_name":"Manu Singh","author_inst":"Garvan Institute for Medical research, New South Wales, Australia"},{"author_name":"Ki Wook Kim","author_inst":"BABs, University of New South Wales"},{"author_name":"Cynthia Yau","author_inst":"BABs, University of New South Wales"},{"author_name":"Anthony Byrne","author_inst":"St Vincents Hospital, Sydney"},{"author_name":"Bruce J Brew","author_inst":"St Vincents Centre for Applied Medical Research, Sydney, Australia"},{"author_name":"Gregoery J Dore","author_inst":"The Kirby Institute, University of New South Wales, New South Wales, Australia"},{"author_name":"David R Darley","author_inst":"St Vincents Hospital, Darlinghurst, New South Wales, Australia"},{"author_name":"Gail V Matthews","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Anthony D Kelleher","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Chansavath Phetsouphanh","author_inst":"The Kirby Institute, University of New South Wales"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Multilevel Interventions to Improve Colonoscopy Completion After Abnormal Fecal Immunochemical Testing in a Safety-Net Health System: Preliminary Findings from the IMPACTT Study","rel_doi":"10.64898\/2026.11.10.26367784","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367784","rel_abs":"Background: Timely diagnostic colonoscopy is a critical step after an abnormal fecal immunochemical test (FIT), yet many patients do not complete follow-up within recommended timeframes, particularly in safety-net settings. Barriers occur across multiple levels and stages of care, suggesting a need for interventions that address both clinic processes and patient-level barriers. Methods: IMProving Adherence to Colonoscopy through Teams and Technology (IMPACTT) evaluated two concurrent interventions across 12 adult primary care clinics in the San Francisco Health Network. A clinic-level Best Practice Bundle (BPB), implemented in a stepped-wedge rollout, included patient tracking, standardized electronic health record documentation, standardized education and communication, and audit and feedback. In parallel, we randomly assigned eligible patients to a patient-level instruction and navigation (PIN) intervention or usual care. PIN provided targeted outreach to patients who were neither referred nor scheduled, as well as multilingual text reminders that allowed patients to confirm, cancel, or reschedule their colonoscopy. The primary outcome was colonoscopy completion within 180 days of an abnormal FIT. This preliminary analysis reports unadjusted comparisons among patients with sufficient follow-up at the data cutoff. Results: Among 2,303 patients with an abnormal FIT, 1,136 were identified before and 1,167 after their clinic implemented the BPB. Colonoscopy completion within 180 days was 44.1% before BPB implementation and 60.1% after implementation (risk difference, 16.0 percentage points; 95% CI, 11.8 to 20.1; p<0.001). Referral to gastroenterology within 42 days increased from 69.8% to 84.2%, and among patients who completed colonoscopy, the median time from FIT to colonoscopy decreased from 131 to 86 days. In the randomized PIN trial, we assigned 1,415 patients to usual care (n=698) or PIN (n=717). Colonoscopy completion within 180 days did not differ between usual care and PIN (58.4% vs 57.7%; risk difference, -0.7 percentage points; 95% CI, -5.9 to 4.6; p=0.9). PIN also did not improve referral within 42 days or scheduling within 56 days. Conclusions: In preliminary unadjusted analyses, implementation of a clinic-level bundle targeting tracking, communication, documentation, and feedback was associated with improved timely follow-up after abnormal FIT, whereas a randomized technology-supported patient instruction and navigation intervention did not improve colonoscopy completion. Prespecified analyses accounting for calendar time, clinic-level clustering, patient characteristics, and concurrent intervention assignment are forthcoming. Trial registration: ClinicalTrials.gov NCT06191185.","rel_num_authors":8,"rel_authors":[{"author_name":"Urmimala Sarkar","author_inst":"University of California, San Francisco"},{"author_name":"Jeanette Wong","author_inst":"University of California, San Francisco"},{"author_name":"Kristan Olazo","author_inst":"University of California, San Francisco"},{"author_name":"Sara Colom Brana","author_inst":"University of California, San Francisco"},{"author_name":"Shreya Patel","author_inst":"University of California, San Francisco"},{"author_name":"Rena Pasick","author_inst":"University of California, San Francisco"},{"author_name":"Charles McCulloch","author_inst":"University of California, San Francisco"},{"author_name":"Ma Somsouk","author_inst":"University of California, San Francisco"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"MENTOR: An Evidence-Informed Large Language Model-Based Multi-Agent System for Efficient Selection of Institution-Specific Negative Control Outcomes","rel_doi":"10.64898\/2026.11.10.26367768","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367768","rel_abs":"Objective Negative control outcomes (NCOs) help detect and correct systematic error in observational studies, yet their selection remains largely manual. The Common Evidence Model (CEM) can generate candidate lists, but researchers must still screen them for plausibility as true nulls and for sufficient observation in each institution's data. We developed and evaluated MENTOR (Multi-agent Evidence-informed Negative conTrol Outcome selection with Reasoning), a multi-agent system of large language models (LLMs) that combines CEM evidence with LLM reasoning to select institution-specific NCOs. Methods Four LLM agents operate on an institution's Observational Medical Outcomes Partnership common data model. A Curator summarizes drug labels, a Suggester assesses locally frequent candidates with CEM evidence and a first-pass LLM judgment, an Adjudicator resolves their disagreements, and a Diagnostician relaxes the patient-count threshold until a target number of NCOs is met. Using Qwen3.6-27B, we evaluated 349 candidates for three drug pairs in a Korean tertiary hospital's electronic health records (2.9 million patients) against a blinded LLM judge from a different model family, validated by three experts on 90 candidates. We compared accuracy, positive predictive value (PPV), and sensitivity with CEM-only and first-pass-LLM-only selection. Results MENTOR proposed 243 NCOs versus 121 by CEM-only, with higher accuracy (0.83 [0.79-0.87] vs. 0.53 [0.48-0.58]), sensitivity (0.89 vs. 0.41), and PPV (0.86 vs. 0.79). Judge-expert agreement was {kappa}=0.63. Adjudication, needed for 44.1% of candidates, added little accuracy, and only with reasoning mode. Concordant acceptances, which bypass it, contained about half of the false positives. Only 7%-9% of CEM-proposed outcomes had at least 10,000 patients at the institution. Conclusion Combining LLM judgments with CEM evidence and local data yielded more NCOs, with higher PPV, than CEM alone. Restricting reasoning to discordant candidates kept computation time below 40% of that with reasoning in all agents. Every decision comes with its evidence and rationale for investigators' final review.","rel_num_authors":7,"rel_authors":[{"author_name":"Taeseok Yang","author_inst":"Ajou University"},{"author_name":"Junhyuk Chang","author_inst":"Ajou University"},{"author_name":"Yeonghyeon Kim","author_inst":"Seoul National University"},{"author_name":"Jaehyeong Cho","author_inst":"Keimyung University Dongsan Medical Center"},{"author_name":"Kyungseon Choi","author_inst":"Yale University"},{"author_name":"Minkook Son","author_inst":"Dong-A University"},{"author_name":"Chungsoo Kim","author_inst":"Ajou University"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"A Multi-Cohort nnU-Net for White Matter Hyperintensity Segmentation Across 2D and 3D FLAIR Acquisitions","rel_doi":"10.64898\/2026.11.11.26367656","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367656","rel_abs":"Background White matter hyperintensities (WMH) are increasingly pooled across aging, cerebral small vessel disease (CSVD), and dementia cohorts that differ in both disease composition and FLAIR acquisition. Most automated segmentation tools were developed within a narrower range of populations or protocols, and few have been tested for whether segmentation accuracy and error remain consistent across conventional 2D and isotropic 3D FLAIR, or whether the choice of algorithm alters downstream clinical associations. Methods We developed a single nnU-Net model, taking FLAIR and T1-weighted images as inputs, using 460 2D and 3D FLAIR scans from a neurodegenerative cohort (Alzheimer's Disease Neuroimaging Initiative, ADNI), a CSVD-enriched cohort with same-visit paired 2D and 3D FLAIR (Washington University White Matter Ischemic-Hypoxia study, WWISH), and a population-based sample (UK Biobank), holding out 92 scans from 66 participants at the participant-level as an internal test set. We further evaluated the model in an independent ADNI3 3D FLAIR set (n = 25), benchmarking voxel-wise overlap (Dice), volumetric agreement, and lesion-level detection against SHIVA-WMH, segcsvdWMH, and FreeSurfer WMH-SynthSeg, and compared acquisition-specific volume bias in participants with paired 2D and 3D FLAIR. We then compared how WMH volumes from each method predicted incident dementia in cognitively unimpaired adults from ADNI and the Knight Alzheimer Disease Research Center (n = 1,174; 42 incident cases). Results In the internal test set, the model achieved a mean Dice of 0.73 (SD 0.10), compared with 0.50, 0.57, and 0.29 for SHIVA-WMH, segcsvdWMH, and WMH-SynthSeg (all FDR-adjusted p < 0.001). Dice was similar on 2D and 3D FLAIR (0.75 vs. 0.71). In WWISH participants imaged with both acquisitions, mean volume bias differed between 2D and 3D scans by 1.8 mL for the model versus 4.7-9.9 mL for the comparators. Advantages were largest in low-burden scans (<5 mL; Dice 0.66 vs. 0.19-0.54) and for lesions of [&le;]100 voxels (detection 77-87% vs. 14-63%). In ADNI3, the model retained a mean Dice of 0.70 (SD 0.14) without retraining and exceeded all comparators (FDR-adjusted p [&le;] 0.002). Model-derived WMH volume was associated with incident dementia beyond clinical covariates (OR per SD 1.40, 95% CI 1.11-1.77; likelihood-ratio p = 0.009; cross-validated AUC 0.71 vs. 0.68), whereas comparator-derived volumes did not significantly improve model fit. Conclusions Training a single model across disease contexts and FLAIR acquisitions yielded WMH segmentation that was similarly accurate on 2D and 3D FLAIR, sensitive to low-burden disease, transferable to an unseen protocol, and clinically informative, supporting its use in multi-cohort, mixed-etiology studies.","rel_num_authors":8,"rel_authors":[{"author_name":"Yasheng Chen","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO"},{"author_name":"Uttam Khatri","author_inst":"Barrow Neuro Analytics Center, Barrow Neurological Institute, Phoenix, AZ"},{"author_name":"Byron Xu","author_inst":"Barrow Neuro Analytics Center, Barrow Neurological Institute, Phoenix, AZ"},{"author_name":"Serguei V. Astafiev","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO; Mallinckrodt Institute of Radiology, Washington University School of Medicine,"},{"author_name":"Andria Ford","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO; Mallinckrodt Institute of Radiology, Washington University School of Medicine,"},{"author_name":"Jin-Moo Lee","author_inst":"Department of Neurology, Washington University School of Medicine, St. Louis, MO; Mallinckrodt Institute of Radiology, Washington University School of Medicine,"},{"author_name":"Hongyu An","author_inst":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO"},{"author_name":"Chia-Ling Phuah","author_inst":"Barrow Neuro Analytics Center, Barrow Neurological Institute, Phoenix, AZ; Departments of Neurology and Neurosurgery, Barrow Neurological Institute, Phoenix, AZ"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"El Nino Southern Oscillation shapes cholera in Africa","rel_doi":"10.64898\/2026.11.11.26367838","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367838","rel_abs":"Cholera is considered a paradigm for climate-sensitive diseases, yet its relation with El Nino Southern Oscillation (ENSO), the dominant mode of interannual climate variability, remains poorly quantified in Africa where most cholera deaths occur. Using 15 years of surveillance data across 30 African countries and novel statistical and simulation frameworks, we identify five geographically coherent ENSO-cholera teleconnection groups, each characterized by distinct directions, strengths and timing of effects on outbreak occurrence, duration and incidence. For the unfolding major El Nino of 2026-27, we project two- to five-fold greater cholera burden in Eastern and Horn of Africa than under ENSO-neutral conditions. These findings identify immediate priorities for anticipatory action and establish a dynamic framework for attributing burden for outbreak-prone diseases to climate variability.","rel_num_authors":6,"rel_authors":[{"author_name":"Javier Perez-Saez","author_inst":"Institute of Global Health, University of Geneva"},{"author_name":"Elizabeth C. Lee","author_inst":"Institute of Global Health, University of Geneva"},{"author_name":"Qulu Zheng","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University"},{"author_name":"Raoul Kamadjeu","author_inst":"CUNY Graduate School of Public Health and Health Policy"},{"author_name":"Benjamin F. Zaitchik","author_inst":"Department of Earth and Planetary Sciences, Johns Hopkins University"},{"author_name":"Andrew S. Azman","author_inst":"Institute of Global Health, University of Geneva"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"El Nino Southern Oscillation shapes cholera in Africa","rel_doi":"10.64898\/2026.11.11.26367838","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367838","rel_abs":"Cholera is considered a paradigm for climate-sensitive diseases, yet its relation with El Nino Southern Oscillation (ENSO), the dominant mode of interannual climate variability, remains poorly quantified in Africa where most cholera deaths occur. Using 15 years of surveillance data across 30 African countries and novel statistical and simulation frameworks, we identify five geographically coherent ENSO-cholera teleconnection groups, each characterized by distinct directions, strengths and timing of effects on outbreak occurrence, duration and incidence. For the unfolding major El Nino of 2026-27, we project two- to five-fold greater cholera burden in Eastern and Horn of Africa than under ENSO-neutral conditions. These findings identify immediate priorities for anticipatory action and establish a dynamic framework for attributing burden for outbreak-prone diseases to climate variability.","rel_num_authors":6,"rel_authors":[{"author_name":"Javier Perez-Saez","author_inst":"Institute of Global Health, University of Geneva"},{"author_name":"Elizabeth C. Lee","author_inst":"Institute of Global Health, University of Geneva"},{"author_name":"Qulu Zheng","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University"},{"author_name":"Raoul Kamadjeu","author_inst":"CUNY Graduate School of Public Health and Health Policy"},{"author_name":"Benjamin F. Zaitchik","author_inst":"Department of Earth and Planetary Sciences, Johns Hopkins University"},{"author_name":"Andrew S. Azman","author_inst":"Institute of Global Health, University of Geneva"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Impact of vaccination coverage and timing on recent yellow fever outbreaks in Africa: a modeling study","rel_doi":"10.64898\/2026.11.11.26367845","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367845","rel_abs":"Background: Multiple recent yellow fever (YF) outbreaks have occurred despite a highly effective vaccine. Increasing vaccination coverage and decreasing response times have been key components of the Eliminate Yellow Fever Epidemics (EYE) strategy. However, the combined impacts of these factors on YF outbreaks, especially since implementation of the EYE strategy in 2017, remain uncertain. Methods: We developed mathematical models to simulate the effects of vaccination coverage and timing, calibrating them to recent YF outbreaks in Ghana (2021-2022) and South Sudan (2023-2024). We then projected YF morbidity and mortality under different EYE strategy thresholds for vaccination coverage and timing. Results: In Ghana, where reactive vaccination was observed at 22 days with an estimated 70% baseline coverage, modeled delays of 60 and 120 days yielded 62 (95% uncertainty interval [UI] 30-119) and 281 (95% UI 59-927) additional severe cases, respectively. Increasing baseline vaccination coverage to 80% averted an estimated 20 severe cases (95% UI 14-25). In South Sudan, where reactive vaccination occurred at 61 days with estimated 50% baseline coverage, shortening the response time to 20 days and increasing baseline coverage to 80% averted an estimated 80 (95% UI 68-91) and 95 severe cases (95% UI 80-112) independently or 103 severe cases (95% UI 85-120) if combined. Conclusion: Increasing baseline YF vaccination coverage to at least 80% can avert substantial morbidity from YF outbreaks. Decreasing vaccination response time for reactive vaccination can provide additional benefit.","rel_num_authors":8,"rel_authors":[{"author_name":"Seth Judson","author_inst":"UCLA"},{"author_name":"Jeffrey Pennington","author_inst":"Johns Hopkins University"},{"author_name":"Carlos Haring","author_inst":"Johns Hopkins University"},{"author_name":"Nicole Stephan","author_inst":"UCLA"},{"author_name":"Mirava Yuson","author_inst":"UCLA"},{"author_name":"Sayana Lee","author_inst":"Scripps College"},{"author_name":"Ernest Kenu","author_inst":"UG School of Public Health: University of Ghana School of Public Health"},{"author_name":"David Dowdy","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Cancer risk and survival outcomes in germline POT1 variant carriers","rel_doi":"10.64898\/2026.11.10.26367070","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367070","rel_abs":"Background: The prevalence of germline POT1 variants, spectrum of associated tumors, cancer risk and survival outcomes are incompletely described, and clinical management guidelines vary. We evaluated POT1 variant carriers in three biobanks and a clinical cohort to address these limitations. Methods: Prevalence, cancer spectrum and risk associated with germline POT1 pathogenic\/likely pathogenic and additional functionally assessed variants were evaluated in Penn Medicine Biobank (PMBB; n=51,172), Geisinger MyCode (MyCode; n=220,582), UK Biobank (UKBB; n=469,558) and a Penn Medicine clinical cohort. Results: Estimated POT1 variant prevalence ranged from 1:1,279 to 1:2,902. Compared to non-carriers, cancer diagnoses were more frequent among POT1 variant carriers in PMBB (OR 3.41, 95%CI 1.81-6.43, p=1.88x10-4), MyCode (OR 2.23, 95%CI 1.31-3.79, p=0.003), and UKBB (OR 1.40, 95%CI 1.07-1.84, p=0.015). Cancer incidence increased beginning in the mid-30s, without evidence of increased mortality. Along with previously described cancer types, lung cancer was associated with POT1 variant carriers in two biobank cohorts. Conclusion: POT1 is a cancer susceptibility gene associated with a moderate (1.5-3.5-fold) increased cancer risk. Variants are relatively frequent and predispose to a broad tumor spectrum and increased incidence starting in the mid-30s, without increasing mortality. These findings expand understanding of POT1-associated disease and provide data to inform clinical management.","rel_num_authors":18,"rel_authors":[{"author_name":"Anna C Raper","author_inst":"University of Pennsylvania"},{"author_name":"Baergen I Schultz","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jung Kim","author_inst":"National Cancer Institute"},{"author_name":"Bradley S Wubbenhorst","author_inst":"University of Pennsylvania"},{"author_name":"Annika Martin","author_inst":"University of California, Berkeley"},{"author_name":"Mersedeh Rohanizadegan","author_inst":"University of Pennsylvania"},{"author_name":"Tiffiney R Hartman","author_inst":"University of Pennsylvania"},{"author_name":"Stacey Cohen","author_inst":"University of Pennsylvania"},{"author_name":"Teresa Chai","author_inst":"University of Pennsylvania"},{"author_name":"Aniket Dagar","author_inst":"University of Pennsylvania"},{"author_name":"Jeremy Haley","author_inst":"Geisinger Healthcare"},{"author_name":"Jiang Li","author_inst":"Geisinger Healthcare"},{"author_name":"David Carey","author_inst":"Geisinger Healthcare"},{"author_name":"- Regeneron Genetics Center","author_inst":"-"},{"author_name":"- Penn Medicine Biobank","author_inst":"-"},{"author_name":"Dirk Hockemeyer","author_inst":"University of California, Berkeley"},{"author_name":"Douglas R Stewart","author_inst":"National Cancer Institute"},{"author_name":"Katherine  L. Nathanson","author_inst":"University of Pennsylvania"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Sentinel Event Surveillance to Identify Threats to SMC Effectiveness: Association Between Breakthrough Infections, SMC Uptake, Adherence and Parasite Drug Resistance","rel_doi":"10.64898\/2026.11.10.26367777","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367777","rel_abs":"Seasonal malaria chemoprevention (SMC) is an important malaria prevention strategy used widely in areas of West Africa with highly seasonal transmission. Monthly administration of sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) to young children during the high-transmission season substantially reduces malaria morbidity and mortality. SMC has recently been introduced in northern Kenya, where pastoralist communities experience intense malaria transmission. However, implementation in this setting presents unique challenges, including population mobility, vast distances, dispersed settlements, and high levels of parasite resistance to SP in parts of the region. Effective surveillance is needed to identify gaps in SMC delivery and uptake and to monitor threats to program effectiveness. We implemented an innovative sentinel-site surveillance approach in which every malaria case among SMC-eligible children at selected health facilities was investigated to identify gaps in SMC delivery, uptake, and effectiveness. We also assessed the prevalence of parasite alleles associated with SP and AQ resistance and examined their relationship with SMC uptake. Household travel was substantially more common than caregiver refusal among reported reasons for missing an SMC cycle. More than one-third of children presenting with malaria had missed their most recent SMC cycle, while 15% were within a few days of receiving the next scheduled cycle. The prevalence of SP resistance mutations was considerably lower than reported in other parts of East Africa: only 13.4% of infections carried the quintuple mutant haplotype IRNI\/GEAA (PfDHFR 51I, 59R, 108N, PfDHPS 437G, 540E) associated with high level resistance to SP. However, the prevalence of resistance-associated mutations was higher among children who had recently received SMC. The allele associated with reduced susceptibility to AQ was not detected. Sentinel surveillance identified geographic and implementation gaps in real time, allowing program managers to target SMC distribution and community sensitization. Although the prevalence of resistance-associated mutations that could threaten SPAQ effectiveness was low, evidence of intrahost selection among children who had received SMC suggests that continued molecular surveillance will be important as SMC is scaled up in northern Kenya. This sentinel surveillance approach provides a practical framework for monitoring SMC implementation in remote, highly mobile populations while simultaneously tracking emerging threats to SPAQ effectiveness.","rel_num_authors":12,"rel_authors":[{"author_name":"Dancan  M. Wakoli","author_inst":"AMPATH Kenya"},{"author_name":"Beatrice Rotich","author_inst":"AMPATH Kenya"},{"author_name":"Edwin Mbugua","author_inst":"Catholic Relief Services - USCCB"},{"author_name":"Suzanne Van Hulle","author_inst":"Catholic Relief Services - United States Conference of Catholic Bishops"},{"author_name":"Joseph Kipkoech","author_inst":"Duke Global Health Institute"},{"author_name":"Lucy Abel","author_inst":"AMPATH Kenya"},{"author_name":"Thomas Katairo","author_inst":"Infectious Diseases Research Collaboration"},{"author_name":"Emmah Kimachas","author_inst":"AMPATH Kenya"},{"author_name":"Amy Wesolowski","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Melissa Conrad","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Diana Menya","author_inst":"Moi University College of Health Sciences"},{"author_name":"Wendy  Prudhomme O\u2019Meara","author_inst":"Duke University School of Medicine"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Readiness Among Female Community Health Volunteers to Deliver Community Based Tobacco Cessation Counseling in Rural Nepal: A Two-phase Mixed-methods Study","rel_doi":"10.64898\/2026.11.10.26367774","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367774","rel_abs":"Tobacco cessation support is largely absent from health facilities in Nepal, particularly in rural areas. Female community health volunteers(FCHVs) serve communities across the country and could help extend cessation services, but it was unknown whether they can deliver tobacco cessation counseling. We evaluated their readiness to do so. Guided by the Health Belief Model, we conducted a two-phase mixed-methods evaluation with 28 volunteers in rural mid-Western Nepal. We held eight focus group discussions exploring the volunteers knowledge, confidence, and barriers to providing counseling, in two phases, eleven months apart. After the first phase we delivered a tobacco cessation training using lectures and role play, followed by a refresher training after the second phase, and we administered surveys before and after each training. We analyzed the qualitative data with deductive and inductive coding to identify themes, analyzed the surveys with descriptive statistics and Fishers exact test, and integrated the two sources to assess convergence and complementarity. The volunteers mean age was 48 years, one third had secondary education, and three quarters had served as volunteers for more than ten years. We identified five themes. In the first phase, volunteers had good knowledge of tobacco, its health effects, and cessation measures, recognized a role for themselves in counseling, and asked for regular training. In the second phase, their knowledge and confidence had improved, including trust that quitting is achievable, although some misconceptions and hesitation remained. They described personal, social, and policy-level barriers, such as community hesitation to engage in counseling, limited time, and easy access to tobacco products. Community receptivity to counseling improved over time, but the COVID-19 pandemic disrupted their efforts. Surveys showed that volunteers recognized their role and routinely provided counseling, while knowledge, confidence, and perceived barriers remained relatively stable across surveys; concerns about inadequate incentives and motivation rose from 25% to 57.1% between phases. The qualitative and survey findings converged and complemented each other, with the qualitative data providing depth and the surveys showing numerical trends. Female community health volunteers want to provide tobacco cessation counseling, showed good knowledge and confidence, and reported growing community receptivity, but they face several barriers. Qualitative findings suggest that training improved their knowledge and confidence. Policymakers should consider addressing system-level barriers, including training support and the availability of tobacco products, and integrating volunteers into cessation services. Before wider adoption, future studies should evaluate whether volunteer-led tobacco cessation counseling is clinically effective.","rel_num_authors":11,"rel_authors":[{"author_name":"Omkar Jha","author_inst":"Health Foundation Nepal"},{"author_name":"Basanta Chaulagain","author_inst":"Health Foundation Nepal"},{"author_name":"Susagya Bhusal","author_inst":"Health Foundation Nepal"},{"author_name":"Ada Thapa","author_inst":"Health Foundation Nepal"},{"author_name":"Sudim Sharma","author_inst":"Health Foundation Nepal"},{"author_name":"Prayas Gautam","author_inst":"Health Foundation Nepal"},{"author_name":"Austin Seals","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Adipti Pantha","author_inst":"Health Foundation Nepal"},{"author_name":"Manoj Bhattarai","author_inst":"Kidney Specialists of the Palm Beach"},{"author_name":"Bibhav Acharya","author_inst":"University of California San Francisco"},{"author_name":"Yashashwi Pokharel","author_inst":"Wake Forest University School of Medicine"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"AToP: An Explainability Framework for Transformer-Based EHR Predictions Using Attribution-Guided Temporal Pattern Mining","rel_doi":"10.64898\/2026.11.10.26367753","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367753","rel_abs":"Objective: To develop and evaluate AToP (Attribution to Temporal Patterns), a post-hoc explainability framework that converts per-token Integrated Gradients (IG) from a Transformer into structured temporal pattern narratives. Materials and Methods: AToP was applied to a single-stream Transformer trained on MIMIC-IV v3.1 (218,196 patients; 12.6% unplanned 30-day readmission). It mines frequent episodes from salient-token subsequences in the training cohort, aggregates attribution among patients whose records contain each token or pattern, and collapses near-duplicates by patient overlap. Validation used masking, reversed-order analysis, token-level faithfulness tests, and KernelSHAP comparison. Results: The Transformer achieved AUROC 0.77 and PR-AUC 0.34. Population-weighted attribution emphasized high-prevalence codes with small per-patient impact. Carrier-conditional attribution, the mean among patients with the token, surfaced rare high-attribution psychiatric markers including psychosis, self-harm overdose, suicidal ideation (SI), and severe major depressive disorder (MDD). Pattern-level attribution identified within-visit co-occurrences and cross-visit trajectories not captured by token rankings. Risk-increasing patterns included psychiatric sequences ({MDD, SI} [-&gt;] SI) and oncologic progressions (cancer anemia [-&gt;] ascites). Obstetric and chest pain evaluation patterns were associated with lower predicted readmission. Discussion: The framework provides two complementary views of model predictions: carrier-conditional aggregation highlights rare, highly attributed clinical features, while temporal pattern analysis identifies within-visit combinations and cross-visit trajectories missed by token-level rankings. Masking and visit-order reversal provided evidence of correspondence with model behavior, but pattern attributions do not represent unique effects or establish clinical validity. Conclusion: AToP turns a Transformer's attributions into visit-anchored temporal pattern narratives, showing which events, in which order, contribute to its readmission predictions.","rel_num_authors":2,"rel_authors":[{"author_name":"Anas Belouali","author_inst":"Johns Hopkins University"},{"author_name":"Hadi Kharrazi","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Cross-cohort validation of EEG biomarkers using a pre-registered three-criterion framework: a demonstration in amyotrophic lateral sclerosis","rel_doi":"10.64898\/2026.11.10.26367741","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367741","rel_abs":"Background. Despite decades of EEG biomarker development for amyotrophic lateral sclerosis (ALS), no candidate has progressed to clinical deployment, partly because cross-cohort validation is rare. We aimed to develop and demonstrate a pre-registered three-criterion screening framework to identify which candidate EEG features show the combined properties required for biomarker translation: cross-sectional discrimination, within-subject reliability, and cross-cohort effect consistency. Methods. We pre-registered a validation framework adapted from FDA-NIH BEST principles and applied it to 18 EEG features across three independent cohorts: EEGET-ALS (six ALS patients, 170 healthy controls; home recordings over 17 days), UCL\/Penn State (eight ALS patients; clinic recordings over 1-2 months), and a healthy adult test-retest reference (60 participants, three sessions over one month). Features were required to meet three pre-registered criteria: (1) cross-sectional discrimination (Cohen's d > 0.5), (2) within-subject reliability (ICC(3,1) > 0.6 in both ALS cohorts independently), and (3) cross-cohort effect direction consistency. Cross-cohort permutation testing (1000 iterations) and subject-level bootstrap resampling (500 iterations) were applied to assess robustness. Results. Three features met all three pre-registered criteria: gamma power, theta power, and spectral entropy. Cross-cohort permutation testing showed that no permutation, out of 1000, produced any feature in the three-cohort reliability intersection (Monte Carlo p = 0.001). Bootstrap resampling indicated that the composition of the selected set was sensitive to sample composition (median count 1, 95% CI [0, 4]), with gamma power (67% inclusion), spectral entropy (43%), and theta power (32%) the most stable features at a relaxed reliability threshold (ICC > 0.5); at the primary pre-registered threshold (ICC > 0.6), the corresponding inclusion probabilities are lower (57%, 27%, and 19%, respectively). A principal methodological finding was that cross-cohort differences in feature reliability were large relative to the apparent disease-associated signal, most clearly demonstrated by relative beta power (ICC = 0.09 in a home-recorded cohort versus 0.93 in a clinic-recorded cohort); because recording protocol, hardware, setting, population, and preprocessing all differ jointly between cohorts in this dataset, this is evidence of cohort-associated variability that plausibly includes a protocol contribution, not a separately identified, isolated protocol effect. Conclusions. This study provides a pre-registered, multi-cohort EEG biomarker screening framework for ALS with explicit bootstrap-quantified uncertainty. Gamma power, spectral entropy, and theta power are identified as priority candidates for prospective validation. A recurring methodological observation is that protocol-related cohort differences appear to contribute more to cross-cohort variability than disease-related effects within this dataset; because protocol is confounded with cohort, equipment, and preprocessing, this pattern is descriptive rather than causal. The observation nonetheless has direct implications for the design of multi-site EEG biomarker studies in neural engineering.","rel_num_authors":3,"rel_authors":[{"author_name":"Belay Tadesse Gebregergis","author_inst":"Tanz Centre for Research in Neurodegenerative Diseases (Tanz CRND), University of Toronto, Toronto, ON, Canada"},{"author_name":"Haben Girmay Yhdego","author_inst":"Department of Electrical & Computer Engineering, Old Dominion University, Norfolk, VA, USA"},{"author_name":"Tewolde Teklu","author_inst":"Department of Pharmacy, College of Health Sciences and Comprehensive Specialized Hospital, Axum University, Axum, Ethiopia"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"User Experience of a Rehab Community-Based, Affordable Robot Exercise System (Rehab CARES) for Gamified Motor and Cognitive Stroke Rehabilitation","rel_doi":"10.64898\/2026.11.10.26367762","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367762","rel_abs":"Purpose: Robot-assisted therapy predominantly targets motor impairment, although post-stroke motor and cognitive impairments co-occur. We report user experience in a longitudinal deployment of a Rehab Community-based Affordable Robot Exercise System (RehabCARES) for delivering personalized motor\/cognitive training. Methods: Six adults with chronic stroke (FM-UE 20-61; MoCA 22-28) completed 12 therapy visits with THEAbot, a reconfigurable 1-DoF robot. Rehab CARES also included a haptic\/biometric dynamic difficulty adjustment controller and eight games characterized by cognitive processes and motor\/cognitive demand. We report gaming preference, usage, and user experience (pain, exertion, usability, affect, workload) across therapy. Results: User experience varied, but generally, self-reported pain was low, perceived exertion was light to moderate, enjoyment was strong and stable, and sense of control increased while excitement plateaued. Workload showed decreasing frustration and effort. Game selection during therapy was partially consistent with motor\/cognitive clinical profiles; preferences and perceptual abilities may have influenced choices. Usability scores exceeded acceptability at all time points, peaking at the final visit (86 +\/- 4.5 out of 100). Conclusions: RehabCARES provided personalized motor\/cognitive training to a heterogeneous cohort in a community-based setting, delivering a positive user experience. Hardware reconfigurability and motor\/cognitive game variety likely enabled this success.","rel_num_authors":8,"rel_authors":[{"author_name":"Reem M Azar","author_inst":"University of Pennsylvania"},{"author_name":"Yiyang Shang","author_inst":"Drexel University"},{"author_name":"Erica L Waters","author_inst":"Univeristy of Pennsylvania"},{"author_name":"Rochelle J Mendonca","author_inst":"Columbia University"},{"author_name":"Alwyn Johnson","author_inst":"Recupero Robotics, LLC"},{"author_name":"Paul Diefenbach","author_inst":"Drexel University"},{"author_name":"Pamela Z Cacchione","author_inst":"University of Pennsylvania"},{"author_name":"Michelle J Johnson","author_inst":"University of Pennsylvania"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Generative AI Versus Primary Care Physicians from Plan Initiation to Long-Term Maintenance of Chronic Disease Self-Management: A Vignette-Based Validation Study","rel_doi":"10.64898\/2026.11.10.26367736","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367736","rel_abs":"Background Generative artificial intelligence (GenAI) may provide personalised and dynamically adjustable support for chronic disease self-management. However, previous studies have largely focused on isolated questions and a limited range of evaluation dimensions. Objective To compare the quality of self-management advice generated by GenAI and primary care physicians (PCPs) across multiple stages of chronic disease management and evaluation dimensions. Methods We conducted a cross-sectional, source-blinded comparative evaluation using 15 standardised vignettes of diabetes and hypertension derived from authentic primary care follow-up records. Each vignette comprised three sequential management stages, with medical accuracy, readability, and behaviour-change potential assessed across the three simulated stages; individualisation and multidisciplinary integration at plan initiation; contextual adaptability during acute adjustment; and empathy during long-term maintenance. The GenAI system and 22 PCPs independently generated advice which was independently rated by three cliniciansone each from general practice, endocrinology, and cardiology. across seven dimensions. Linear mixed-effects models were used for the primary comparisons, and case-level paired and physician-distribution analyses were conducted as robustness analyses. Results The GenAI system achieved estimated marginal means above 4.0 in all dimensions except readability. It scored significantly higher than PCPs in six of the seven dimensions, with adjusted mean differences ranging from 1.16 to 1.56 points (P<.001). Readability was the only exception, with no significant difference between GenAI and PCPs (-0.22, 95% CI -0.54 to 0.11; P=.19). The GenAI mean exceeded the individual means of all recruited PCPs in the six dimensions but ranked at approximately the 23rd percentile for readability. Conclusions Our findings indicated the GenAI system may generate more highly rated self-management advice than PCPs across most evaluated dimensions but offered no advantage in readability. These findings provide pre-implementation evidence for GenAI as a potential source of structured and adaptive chronic disease self-management support. Patient-level pilot studies and subsequent randomised trials are needed to determine its acceptability and effects on behaviour and clinical outcomes.","rel_num_authors":6,"rel_authors":[{"author_name":"Ziyin Zhao","author_inst":"Peking University"},{"author_name":"Huiming Yang","author_inst":"Guangdong Pharmaceutical University"},{"author_name":"Qiting Wang","author_inst":"Guangdong Second Provincial General Hospital"},{"author_name":"Ying Wang","author_inst":"Sun Yat-Sen University"},{"author_name":"Weibin Cheng","author_inst":"Guangdong Second Provincial General Hospital"},{"author_name":"Xiaochen Ma","author_inst":"Peking University"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Cytokine Signatures of Immune Checkpoint Inhibitor Myocarditis and the Modifying Role of Clonal Hematopoiesis: A Machine-Learning and Multi-Omics Study","rel_doi":"10.64898\/2026.11.11.26367634","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367634","rel_abs":"Background Immune checkpoint inhibitor (ICI) myocarditis affects up to 2% of patients on ICI and has up to a 50% mortality. Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a risk factor for ICI myocarditis. Objectives To leverage a multi-omics approach to evaluate cytokines associated with ICI myocarditis, immunosuppression resistance, CHIP in ICI myocarditis and implicated pathways and cell type contributions. Methods 236 cardio-oncology patients were enrolled, including 88 who were on ICI. Cytokine profiling from patients on ICI were sampled and analyzed using machine learning and explainable artificial intelligence. Single-cell multi-omics of peripheral blood from Yale (n=19), Stanford (n=25), and MGH (n=63) evaluated cell-type contributions of cytokines and implicated pathways. Validation of Yale proteomic analyses was done using the Stanford CYTOF dataset. Results Top features associated with ICI myocarditis included IL13, CXCL10, PDGFA, CCL13, CCL17 and KITlg. Top KEGG pathways associated with ICI myocarditis and immunosuppression resistant ICI myocarditis included JAK STAT signaling, IL17 signaling and lipid\/atherosclerosis pathways. At the single-cell level, the consensus signals distinguishing myocarditis from non-myocarditis across cohorts was predominantly driven by module-level JAK STAT, T cell, and Toll like receptor activation. Similar transcription gene programs were activated in CHIP carriers including modules implicated in the pro-inflammatory immune response, such as NF kappa B, IL17, MAPK, and TNF pathways within CHIP cells spanning lymphoid (cytotoxic CD8+ NKT, and natural killer cells) and myeloid lineages. Conclusions Across cohorts, JAK STAT signaling emerges as a convergent and potentially actionable axis in ICI myocarditis that is further amplified in CHIP carriers, supporting cytokine-guided risk stratification and JAK STAT directed immunosuppression as testable strategies.","rel_num_authors":26,"rel_authors":[{"author_name":"Nancy Manchanda","author_inst":"Yale School of Medicine"},{"author_name":"Rachel Jaber Chehayeb","author_inst":"University of Pennsylvania School of Medicine"},{"author_name":"Dat Hong","author_inst":"Yale School of Management"},{"author_name":"Akarvin Jeyashanmugaraja","author_inst":"Boston University"},{"author_name":"Jaiveer Singh","author_inst":"Yale School of Medicine"},{"author_name":"James L Cross","author_inst":"Yale School of Medicine"},{"author_name":"Avnith Vijayram","author_inst":"Carnegie Mellon University"},{"author_name":"Carlos Matute Martinez","author_inst":"Yale School of Medicine"},{"author_name":"Ritujith Jayakrishnan","author_inst":"Yale New Haven Hospital"},{"author_name":"Anthos Christofides","author_inst":"MD Anderson Cancer Center"},{"author_name":"Derrick Lin","author_inst":"Yale New Haven Hospital"},{"author_name":"Yunju Im","author_inst":"University of Nebraska Medical Center"},{"author_name":"Jennifer VanOudenhove","author_inst":"Section of Hematology, Yale Cancer Center"},{"author_name":"Giulia Biancon","author_inst":"Section of Hematology, Yale Cancer Center"},{"author_name":"Eiman Ibrahim","author_inst":"University of Missouri"},{"author_name":"Anastasia Ardasheva","author_inst":"Section of Hematology, Yale Cancer Center"},{"author_name":"Emily Yuan Shuan Lin","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Ross Levine","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Evaline Cheng","author_inst":"Stanford University School of Medicine"},{"author_name":"Stephanie Halene","author_inst":"Section of Hematology, Yale Cancer Center"},{"author_name":"John Hwa","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Neal Smith","author_inst":"Massachusetts General Hospital"},{"author_name":"Chloe Villani","author_inst":"Massachusetts General Hospital"},{"author_name":"Han Zhu","author_inst":"Stanford University School of Medicine"},{"author_name":"Alokkumar Jha","author_inst":"Weill Cornell Medicine"},{"author_name":"Jennifer M Kwan","author_inst":"Yale School of Medicine"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Cytokine Signatures of Immune Checkpoint Inhibitor Myocarditis and the Modifying Role of Clonal Hematopoiesis: A Machine-Learning and Multi-Omics Study","rel_doi":"10.64898\/2026.11.11.26367634","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367634","rel_abs":"Background Immune checkpoint inhibitor (ICI) myocarditis affects up to 2% of patients on ICI and has up to a 50% mortality. Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a risk factor for ICI myocarditis. Objectives To leverage a multi-omics approach to evaluate cytokines associated with ICI myocarditis, immunosuppression resistance, CHIP in ICI myocarditis and implicated pathways and cell type contributions. Methods 236 cardio-oncology patients were enrolled, including 88 who were on ICI. Cytokine profiling from patients on ICI were sampled and analyzed using machine learning and explainable artificial intelligence. Single-cell multi-omics of peripheral blood from Yale (n=19), Stanford (n=25), and MGH (n=63) evaluated cell-type contributions of cytokines and implicated pathways. Validation of Yale proteomic analyses was done using the Stanford CYTOF dataset. Results Top features associated with ICI myocarditis included IL13, CXCL10, PDGFA, CCL13, CCL17 and KITlg. Top KEGG pathways associated with ICI myocarditis and immunosuppression resistant ICI myocarditis included JAK STAT signaling, IL17 signaling and lipid\/atherosclerosis pathways. At the single-cell level, the consensus signals distinguishing myocarditis from non-myocarditis across cohorts was predominantly driven by module-level JAK STAT, T cell, and Toll like receptor activation. Similar transcription gene programs were activated in CHIP carriers including modules implicated in the pro-inflammatory immune response, such as NF kappa B, IL17, MAPK, and TNF pathways within CHIP cells spanning lymphoid (cytotoxic CD8+ NKT, and natural killer cells) and myeloid lineages. Conclusions Across cohorts, JAK STAT signaling emerges as a convergent and potentially actionable axis in ICI myocarditis that is further amplified in CHIP carriers, supporting cytokine-guided risk stratification and JAK STAT directed immunosuppression as testable strategies.","rel_num_authors":26,"rel_authors":[{"author_name":"Nancy Manchanda","author_inst":"Yale School of Medicine"},{"author_name":"Rachel Jaber Chehayeb","author_inst":"University of Pennsylvania School of Medicine"},{"author_name":"Dat Hong","author_inst":"Yale School of Management"},{"author_name":"Akarvin Jeyashanmugaraja","author_inst":"Boston University"},{"author_name":"Jaiveer Singh","author_inst":"Yale School of Medicine"},{"author_name":"James L Cross","author_inst":"Yale School of Medicine"},{"author_name":"Avnith Vijayram","author_inst":"Carnegie Mellon University"},{"author_name":"Carlos Matute Martinez","author_inst":"Yale School of Medicine"},{"author_name":"Ritujith Jayakrishnan","author_inst":"Yale New Haven Hospital"},{"author_name":"Anthos Christofides","author_inst":"MD Anderson Cancer Center"},{"author_name":"Derrick Lin","author_inst":"Yale New Haven Hospital"},{"author_name":"Yunju Im","author_inst":"University of Nebraska Medical Center"},{"author_name":"Jennifer VanOudenhove","author_inst":"Section of Hematology, Yale Cancer Center"},{"author_name":"Giulia Biancon","author_inst":"Section of Hematology, Yale Cancer Center"},{"author_name":"Eiman Ibrahim","author_inst":"University of Missouri"},{"author_name":"Anastasia Ardasheva","author_inst":"Section of Hematology, Yale Cancer Center"},{"author_name":"Emily Yuan Shuan Lin","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Ross Levine","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Evaline Cheng","author_inst":"Stanford University School of Medicine"},{"author_name":"Stephanie Halene","author_inst":"Section of Hematology, Yale Cancer Center"},{"author_name":"John Hwa","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Neal Smith","author_inst":"Massachusetts General Hospital"},{"author_name":"Chloe Villani","author_inst":"Massachusetts General Hospital"},{"author_name":"Han Zhu","author_inst":"Stanford University School of Medicine"},{"author_name":"Alokkumar Jha","author_inst":"Weill Cornell Medicine"},{"author_name":"Jennifer M Kwan","author_inst":"Yale School of Medicine"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Phylogeography and transmission dynamics of the 2025-2026 Utah-Arizona measles outbreak: a retrospective genomic epidemiology study","rel_doi":"10.64898\/2026.11.10.26367744","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367744","rel_abs":"Background: Measles outbreaks are increasing in frequency globally as vaccine coverage decreases. During the 2025-26 Utah-Arizona border outbreak, identifying where and between whom transmission occurred was essential for directing control measures. However, epidemiological data alone are not sufficient to infer transmission patterns. Methods: As part of the local and state-wide outbreak investigation, we conducted amplicon-based whole genome sequencing on residual diagnostic samples from confirmed measles cases collected from June 15, 2025-April 30, 2026. We reconstructed viral dispersal across Utah using Bayesian phylogeographic analyses. We evaluated genetic distance thresholds for identifying recent transmission by comparing single nucleotide polymorphism (SNP)-based genetic clusters with known epidemiologic linkages. We then assessed pairwise exposures associated with genetically supported transmission linkage using logistic regression, accounting for network and spatial dependence between pairs. Findings: We generated 509 high-quality whole measles virus genomes from 913 patients. In 2025, most viral dispersal events (67.9%) originated in Southwest Utah and Mohave County, Arizona, where the first cases were reported. By 2026, most viral spread (60.5%) occurred outside of this area. A threshold of 0 SNPs identified epidemiologically linked pairs of individuals with a sensitivity of 77.4% and specificity of 92.3%. Household membership (odds ratio (OR): 219.10, 95% credible interval (CI): 112.66-325.53), participation in the same sport (OR: 15.19, 95% CI: 9.75-20.63), and attendance at the same school (OR: 51.5, 95% CI: 36.38-66.61) were independently associated with transmission linkage. Increasing distance between households was associated with reduced odds of linkage (OR: 0.46: 95% CI 0.44-0.48). Interpretation: Repeated introductions of measles virus from southwestern Utah seeded transmission elsewhere in Utah, with household, school, and sports exposures contributing to onward transmission. Validated genome-based linkage measures can complement contact tracing by helping public health teams identify likely transmission networks and prioritize investigation when resources are constrained.","rel_num_authors":7,"rel_authors":[{"author_name":"Abbey Marye","author_inst":"Utah Department of Health and Human Services"},{"author_name":"Kelly Oakeson","author_inst":"Utah Department of Health and Human Services"},{"author_name":"Yu Lan","author_inst":"Yale University School of Public Health"},{"author_name":"Joshua L Warren","author_inst":"Yale University School of Public Health"},{"author_name":"Drew Francis","author_inst":"Arizona Department of Health Services"},{"author_name":"Liam Hicks","author_inst":"Arizona Department of Health Services"},{"author_name":"Katharine Walter","author_inst":"University of Utah Division of Epidemiology"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Personalized HLA-aware TCR measure predicts the risk of symptomatic SARS-CoV-2 infection following booster vaccination","rel_doi":"10.64898\/2026.11.10.26367219","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367219","rel_abs":"HLA-driven heterogeneity and limitations of live T cell functional assays routinely thwart assessment of cell-mediated immunity in vaccination trials. To address this, we developed a T-cell receptor (TCR)-based measure of immunogen recognition and evaluated it in COV-BOOST, a third-dose COVID-19 vaccine trial, during the Delta and Omicron waves (2021-2022, United Kingdom). We estimated HLA-aware Spike-reactive T cell (HA-TS) breadth from participant HLA genotypes, TCR{beta} repertoires, and a novel SARS-CoV-2 S HLA-linked reference catalog. Higher post-boost HA-TS breadth was associated with lower symptomatic infection risk (HR 0.58, 95% CI 0.39-0.86). This association persisted after adjustment for neutralizing antibody titers and IFN-{gamma} responses. Examination of HA-TS across prior studies showed that it reflects participant genotype, exposure intensity, and time from exposure to sampling. These findings highlight the possibility that estimates of antigen-specific T cell repertoire breadth could serve as a correlate of protection to accelerate vaccine development.","rel_num_authors":13,"rel_authors":[{"author_name":"Koshlan Mayer-Blackwell","author_inst":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, USA; Vaccine Immunology Statistical Center, Fred Hutchinson Cancer Center, Seat"},{"author_name":"Khiyam Hussain","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK"},{"author_name":"Narges Ebrahimi","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK"},{"author_name":"Emily S. Ford","author_inst":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, USA; Department of Medicine, University of Washington, Seattle, USA"},{"author_name":"Adam P. Dale","author_inst":"NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust; and Faculty of Medicine and In"},{"author_name":"Jennifer Alderson","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK"},{"author_name":"Sagida Bibi","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK"},{"author_name":"Alasdair P.S. Munro","author_inst":"NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust; and Faculty of Medicine and In"},{"author_name":"Saul N. Faust","author_inst":"NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust; and Faculty of Medicine and In"},{"author_name":"Xinxue Liu","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK"},{"author_name":"Teresa Lambe","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Southampton Clinical Research Facility and Biomedical Research Centre, U"},{"author_name":"Merryn Voysey","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK"},{"author_name":"Andrew Fiore-Gartland","author_inst":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, USA; Vaccine Immunology Statistical Center, Fred Hutchinson Cancer Center, Seat"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"An agent-based model of Epstein-Barr virus transmission and vaccination","rel_doi":"10.64898\/2026.11.10.26367734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367734","rel_abs":"Epstein- Barr virus (EBV) infects over 90\\% of adults worldwide, causing infectious mononucleosis (IM) in adolescents and young adults and contributing to multiple malignancies. Despite its global burden, population- level transmission modeling of EBV remains limited. We present the first population- level agent-based model (ABM) of EBV transmission. The model is implemented with 10,000 agents and calibrated to age-specific seroprevalence data from the US National Health and Nutrition Examination Survey. Two complementary calibration methods are evaluated, each with its own distinct advantages: Approximate Bayesian Computation (ABC) and Bayesian Optimization with Expected Quantile Improvement (BO- EQI). ABC directly yields an approximate distribution of transmission parameters for propagation through vaccination scenarios. BO- EQI uses a limited simulation budget to identify well-fitting parameter vectors, particularly as the number of fitted parameters increases. We estimate parameter uncertainty at each resolution in a separate Gaussian-kernel posterior analysis, which requires additional simulations and an explicit model for discrepancies between simulated and observed prevalence. As an illustrative application, we simulate the population-level effect of hypothetical EBV vaccines over a 100-year projection horizon. Similar to a previous modeling study, our results suggest that vaccine durability is at least as critical as efficacy, and that a vaccine with direct protection against only EBV may persistently shift IM burden to older ages, an effect our longer simulation horizon reveals to be a durable equilibrium shift rather than a transient cohort phenomenon. These findings highlight the importance of careful vaccine target product profile design; in particular, our results suggest that dual efficacy against both EBV infection and IM progression represents the most promising achievable target profile, and should be a core design objective for next-generation EBV vaccines.","rel_num_authors":5,"rel_authors":[{"author_name":"Bridgette Amoako","author_inst":"University of Guelph"},{"author_name":"Zhongda Huang","author_inst":"University of British Columbia"},{"author_name":"Edward Wolfgang Thommes","author_inst":"University of Guelph"},{"author_name":"Warren Hare","author_inst":"University of British Columbia"},{"author_name":"Monica Gabriela Cojocaru","author_inst":"University of Guelph"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Automating postmarketing pharmacovigilance with large language model agents","rel_doi":"10.64898\/2026.11.10.26367711","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367711","rel_abs":"Postmarketing pharmacovigilance relies on spontaneous adverse event reporting and labor-intensive observational studies, which suffer from underreporting and delayed risk detection. Large language model (LLM) agents could automate real-world evidence generation, but generalist agents make ad hoc analytical decisions that compromise epidemiological validity and reproducibility. Here we present MedCheckpoint, a multi-agent LLM system for automated postmarketing pharmacovigilance. MedCheckpoint grounds each analytical stage in a curated, source-traceable medical knowledge base, locks core study-design parameters before execution, performs patient-level analyses with human-written deterministic statistical tools, and enforces checkpoint rules that abort infeasible analyses, with optional human-in-the-loop review. We evaluated MedCheckpoint using a 54-question benchmark on a dual-purpose simulated electronic health record (EHR) testbed of 2.7 million individuals, designed with reliable clinical signals to evaluate routine analytical accuracy alongside spurious signals to stress-test system rigor. Across the benchmark, MedCheckpoint outperformed two coding-agent baselines in report quality across five dimensions rated by three independent LLM judges (overall means 4.81-4.88 versus 4.25-4.55 and 4.02-4.29) and yielded higher run-to-run consistency (mean within-question standard deviation 0.116-0.186 versus up to 0.440). Crucially, while baselines failed on up to 2 of 21 runs when handling infeasible comparisons or unmeasurable outcomes, MedCheckpoint produced no misleading failures across all seven stress-test trap questions with known data limitations. MedCheckpoint enables reliable, auditable, and scalable pharmacovigilance analysis.","rel_num_authors":6,"rel_authors":[{"author_name":"Ruiheng Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Yekai Zhou","author_inst":"The University of Hong Kong"},{"author_name":"Celine S.L. Chui","author_inst":"University of Hong Kong"},{"author_name":"Doris Yu","author_inst":"The University of Hong Kong"},{"author_name":"Zhenqin Wu","author_inst":"The University of Hong Kong"},{"author_name":"Ruibang Luo","author_inst":"The University of Hong Kong"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Transdiagnostic Psychiatric Polygenic Scores Reveal Pleiotropic Effects Across Medical and Laboratory Phenome","rel_doi":"10.64898\/2026.11.10.26367763","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367763","rel_abs":"Summary Background Current psychiatric diagnoses lack biological grounding. Using transdiagnostic psychiatric dimensions derived through data-driven genetic studies with large-scale clinical health records of multiple physiological and clinical outcomes, we can gain new insights into biological similarity and differences between such dimensions, informing nosological discourse. Methods Here, we examined data from 108,182 individuals of European-like ancestry and 13,229 African-like ancestry across two healthcare biobanks. Genetic liabilities of individuals were estimated as polygenic scores for five first-order psychopathology factors (compulsive, thought, neurodevelopmental, substance use, internalizing disorders) and one second-order factor (hierarchical\/p-factor). Phenome-wide and laboratory-wide association scans encompassed 1,520 medical phenotypes and 123 laboratory metrics, meta-analyzed across sites. People with lived experience were involved in the design, preparation, interpretation and reporting of this work. Outcomes We observed robust associations with up to 143 conditions (14 disease categories) for first-order factors and 221 conditions (15 categories) for the hierarchical factor (OR=0.75-1.94). Circulatory, digestive, and respiratory diseases were linked to neurodevelopmental, internalizing, and substance use liabilities. Metabolic conditions were negatively associated with thought and compulsive liabilities but positively associated with the remaining three factors. Laboratory results, particularly lipid and glucose metabolism markers, supported these differential findings. Immune markers also showed differential associations, with C-reactive protein and Complement C4 specifically linked to neurodevelopmental and thought factors, respectively. Similar trends emerged in the smaller African-like ancestry sample. Interpretation Overall, these findings support ongoing efforts to define biologically informed subtypes in psychiatry, such as immuno-metabolic profiles, which can facilitate patient stratification in clinical trials and support transdiagnostic precision psychiatry approaches. Funding The work was supported by funding from the participating institutions. BF's and NRM's contributions were supported by the European Community's Horizon 2020 Programme (H2020\/2014-2020) under grant agreement No. 847879 (PRIME). NRM was also supported by the Netherlands Organisation for Scientific Research (NWO) Innovation Programme (Vidi grant No. 09150172410043). Research reported in this publication was also supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH124851. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.","rel_num_authors":13,"rel_authors":[{"author_name":"Yingjie Shi","author_inst":"Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands"},{"author_name":"Maria Niarchou","author_inst":"Department of AI and Human Health, Icahn School of Medicine, New York, NY"},{"author_name":"Yingzhe Zhang","author_inst":"Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts"},{"author_name":"Younga Heather Lee","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"author_name":"Karmel W. Choi","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"author_name":"Freida Blostein","author_inst":"Department of AI and Human Health, Icahn School of Medicine, New York, NY"},{"author_name":"Peter Straub","author_inst":"Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Tian Ge","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"author_name":"Yen-Chen Anne Feng","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Nina Roth Mota","author_inst":"Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands"},{"author_name":"Emma Sprooten","author_inst":"Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands"},{"author_name":"Barbara Franke","author_inst":"Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands"},{"author_name":"Lea K. Davis","author_inst":"Department of AI and Human Health, Icahn School of Medicine, New York, NY"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Transdiagnostic Psychiatric Polygenic Scores Reveal Pleiotropic Effects Across Medical and Laboratory Phenome","rel_doi":"10.64898\/2026.11.10.26367763","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367763","rel_abs":"Summary Background Current psychiatric diagnoses lack biological grounding. Using transdiagnostic psychiatric dimensions derived through data-driven genetic studies with large-scale clinical health records of multiple physiological and clinical outcomes, we can gain new insights into biological similarity and differences between such dimensions, informing nosological discourse. Methods Here, we examined data from 108,182 individuals of European-like ancestry and 13,229 African-like ancestry across two healthcare biobanks. Genetic liabilities of individuals were estimated as polygenic scores for five first-order psychopathology factors (compulsive, thought, neurodevelopmental, substance use, internalizing disorders) and one second-order factor (hierarchical\/p-factor). Phenome-wide and laboratory-wide association scans encompassed 1,520 medical phenotypes and 123 laboratory metrics, meta-analyzed across sites. People with lived experience were involved in the design, preparation, interpretation and reporting of this work. Outcomes We observed robust associations with up to 143 conditions (14 disease categories) for first-order factors and 221 conditions (15 categories) for the hierarchical factor (OR=0.75-1.94). Circulatory, digestive, and respiratory diseases were linked to neurodevelopmental, internalizing, and substance use liabilities. Metabolic conditions were negatively associated with thought and compulsive liabilities but positively associated with the remaining three factors. Laboratory results, particularly lipid and glucose metabolism markers, supported these differential findings. Immune markers also showed differential associations, with C-reactive protein and Complement C4 specifically linked to neurodevelopmental and thought factors, respectively. Similar trends emerged in the smaller African-like ancestry sample. Interpretation Overall, these findings support ongoing efforts to define biologically informed subtypes in psychiatry, such as immuno-metabolic profiles, which can facilitate patient stratification in clinical trials and support transdiagnostic precision psychiatry approaches. Funding The work was supported by funding from the participating institutions. BF's and NRM's contributions were supported by the European Community's Horizon 2020 Programme (H2020\/2014-2020) under grant agreement No. 847879 (PRIME). NRM was also supported by the Netherlands Organisation for Scientific Research (NWO) Innovation Programme (Vidi grant No. 09150172410043). Research reported in this publication was also supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH124851. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.","rel_num_authors":13,"rel_authors":[{"author_name":"Yingjie Shi","author_inst":"Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands"},{"author_name":"Maria Niarchou","author_inst":"Department of AI and Human Health, Icahn School of Medicine, New York, NY"},{"author_name":"Yingzhe Zhang","author_inst":"Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts"},{"author_name":"Younga Heather Lee","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"author_name":"Karmel W. Choi","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"author_name":"Freida Blostein","author_inst":"Department of AI and Human Health, Icahn School of Medicine, New York, NY"},{"author_name":"Peter Straub","author_inst":"Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Tian Ge","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"author_name":"Yen-Chen Anne Feng","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Nina Roth Mota","author_inst":"Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands"},{"author_name":"Emma Sprooten","author_inst":"Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands"},{"author_name":"Barbara Franke","author_inst":"Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands"},{"author_name":"Lea K. Davis","author_inst":"Department of AI and Human Health, Icahn School of Medicine, New York, NY"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Mapping disordered eating symptoms in the ABCD Study through the Eating Disorder Symptom Index","rel_doi":"10.64898\/2026.11.10.26367686","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367686","rel_abs":"Eating disorders (EDs) are serious psychiatric conditions that typically onset during adolescence and are often marked by a chronic and severe illness course. Capturing ED symptoms as they emerge is critical for charting risk markers and associated outcomes to inform early intervention and treatment efforts. The Adolescent Brain Cognitive Development (ABCD(R)) Study is one such key study that could accelerate these efforts, but has been limited to date by a lack of clear, clinically informed definitions capturing youth at risk for ED-related concerns. The current manuscript aims to address this gap by defining ED symptom indices (EDSI) with a reproducible framework developed in collaboration with ED researchers and clinicians to identify youth with patterns of ED symptoms and behaviors that approximate subthreshold and diagnostic-like presentations. We describe item-level definitions and decision rules used to construct the EDSI, which include symptom indices of anorexia nervosa, bulimia nervosa, binge eating disorder, and other specified feeding or eating disorders. We then compare youth meeting EDSI criteria with those identified by existing ED categorical definitions in ABCD Study data releases. By providing transparent definitions and analytical tools for identifying youth with potentially clinically meaningful ED behaviors, the EDSI framework aims to facilitate more reproducible and interpretable research related to EDs using the ABCD Study dataset, while also providing a structure to examine the emergence, persistence, and change of ED-like symptoms longitudinally across adolescence and into young adulthood in future research.","rel_num_authors":10,"rel_authors":[{"author_name":"Carolina Makowski","author_inst":"University of California San Diego"},{"author_name":"Devansh Bansal","author_inst":"University of Georgia"},{"author_name":"Brooke Moorman","author_inst":"Virginia Commonwealth University"},{"author_name":"Kimberly Garcia","author_inst":"University of California San Diego"},{"author_name":"Laura Ziemer","author_inst":"J Craig Venter Institute"},{"author_name":"Janosch Linkersdorfer","author_inst":"J Craig Venter Institute"},{"author_name":"Deanna Barch","author_inst":"Washington University"},{"author_name":"Kelsey Hagan","author_inst":"Virginia Commonwealth University"},{"author_name":"Kyung  E. Rhee","author_inst":"University of California San Diego"},{"author_name":"Shana Adise","author_inst":"University of Georgia"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Mapping disordered eating symptoms in the ABCD Study through the Eating Disorder Symptom Index","rel_doi":"10.64898\/2026.11.10.26367686","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367686","rel_abs":"Eating disorders (EDs) are serious psychiatric conditions that typically onset during adolescence and are often marked by a chronic and severe illness course. Capturing ED symptoms as they emerge is critical for charting risk markers and associated outcomes to inform early intervention and treatment efforts. The Adolescent Brain Cognitive Development (ABCD(R)) Study is one such key study that could accelerate these efforts, but has been limited to date by a lack of clear, clinically informed definitions capturing youth at risk for ED-related concerns. The current manuscript aims to address this gap by defining ED symptom indices (EDSI) with a reproducible framework developed in collaboration with ED researchers and clinicians to identify youth with patterns of ED symptoms and behaviors that approximate subthreshold and diagnostic-like presentations. We describe item-level definitions and decision rules used to construct the EDSI, which include symptom indices of anorexia nervosa, bulimia nervosa, binge eating disorder, and other specified feeding or eating disorders. We then compare youth meeting EDSI criteria with those identified by existing ED categorical definitions in ABCD Study data releases. By providing transparent definitions and analytical tools for identifying youth with potentially clinically meaningful ED behaviors, the EDSI framework aims to facilitate more reproducible and interpretable research related to EDs using the ABCD Study dataset, while also providing a structure to examine the emergence, persistence, and change of ED-like symptoms longitudinally across adolescence and into young adulthood in future research.","rel_num_authors":10,"rel_authors":[{"author_name":"Carolina Makowski","author_inst":"University of California San Diego"},{"author_name":"Devansh Bansal","author_inst":"University of Georgia"},{"author_name":"Brooke Moorman","author_inst":"Virginia Commonwealth University"},{"author_name":"Kimberly Garcia","author_inst":"University of California San Diego"},{"author_name":"Laura Ziemer","author_inst":"J Craig Venter Institute"},{"author_name":"Janosch Linkersdorfer","author_inst":"J Craig Venter Institute"},{"author_name":"Deanna Barch","author_inst":"Washington University"},{"author_name":"Kelsey Hagan","author_inst":"Virginia Commonwealth University"},{"author_name":"Kyung  E. Rhee","author_inst":"University of California San Diego"},{"author_name":"Shana Adise","author_inst":"University of Georgia"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Associations of drinking water per- and polyfluoroalkyl substances with cause-specific mortality in men with prostate cancer","rel_doi":"10.64898\/2026.11.10.26367726","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367726","rel_abs":"Background: Over 3.5 million US men are living with prostate cancer (PCa). Certain per- and polyfluoroalkyl substances (PFAS) are carcinogenic and impair cardiometabolic health. Due to comorbidities and treatment, men with PCa may be uniquely susceptible to PFAS. Objectives: To develop and validate a model for drinking water perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA), and study associations of each PFAS with all-cause, PCa, and cardiovascular disease (CVD) mortality in PCa survivors. Methods: We conducted a cohort study of 51,289 men with PCa diagnosed from 2006 to 2017 and followed through 2024 from the New Jersey (NJ) cancer registry. PFAS monitoring data (n=26,161 results) were obtained from NJ government evaluations and Community Water Systems (CWS) compliance reports and were used to estimate PFAS concentrations using a two-phase XGBoost model with 67 predictors of PFAS contamination across 566 CWS. PFAS predictions between 2006-2024 were linked to participant address histories. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated from Cox models with sociodemographic, clinical and time-varying neighborhood covariates. Results: There were 19,749 deaths, including 3,778 PCa deaths, and 4,972 CVD deaths over 466,843 person-years. Higher PFOA exposure was associated with all-cause mortality in certain quintiles (aHRQ2vsQ1: 1.07, 95% CI: 1.07-1.12; aHRQ3vsQ1: 1.06, 95% CI: 1.01-1.11) and with CVD mortality (aHRQ5vsQ1: 1.12, 95% CI: 1.01-1.24). Higher PFNA exposure was suggestively associated with all-cause mortality (aHR[&ge;]3.8ng\/L vs <2ng\/L: 1.22, 95% CI: 0.98-1.50) and PCa mortality (aHR[&ge;]3.8ng\/L vs <2ng\/L: 1.42, 95% CI: 0.96-2.10). Associations were strengthened when applying five-year lags. For example, higher PFOA (aHRQ5vsQ1: 1.15, 95% CI: 1.06-1.25), PFOS (aHRQ5vsQ1: 1.16, 95% CI: 1.07-1.25) and PFNA (aHR[&ge;]3.8ng\/L vs <2ng\/L: 1.57, 95% CI: 1.06-2.31) were associated with higher all-cause mortality. Discussion: Exposure to CWS-level PFAS was associated with higher mortality in PCa survivors. Replication is needed to confirm findings.","rel_num_authors":14,"rel_authors":[{"author_name":"Hari S Iyer","author_inst":"Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Megan Shanahan","author_inst":"Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Stefanie A Joseph","author_inst":"Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Julianne Varga","author_inst":"Center for Pharmacoepidemiology and Treatment Science, Rutgers Institute for Health, Healthcare Policy and Aging, New Brunswick, NJ"},{"author_name":"Mike Z He","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Saum Ghodoussipour","author_inst":"Department of Urology, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Antoinette M Stroup","author_inst":"New Jersey State Cancer Registry, New Jersey Department of Health, Trenton, NJ"},{"author_name":"Gerald Harris","author_inst":"New Jersey State Cancer Registry, New Jersey Department of Health, Trenton, NJ"},{"author_name":"Panos Georgopoulos","author_inst":"Environmental and Occupational Health Sciences Institute, Rutgers, the State University of New Jersey, Piscataway, NJ"},{"author_name":"Robert Laumbach","author_inst":"Environmental and Occupational Health Sciences Institute, Rutgers, the State University of New Jersey, Piscataway, NJ"},{"author_name":"Veronica Vieira","author_inst":"Department of Environmental and Occupational Health, Joe C. Wen School of Population & Public Health, University of California, Irvine, CA"},{"author_name":"Jaime E Hart","author_inst":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA"},{"author_name":"Emily S Barrett","author_inst":"Environmental and Occupational Health Sciences Institute, Rutgers, the State University of New Jersey, Piscataway, NJ"},{"author_name":"Elisa V Bandera","author_inst":"Section of Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ"}],"rel_date":"2026-11-12","rel_site":"medrxiv"},{"rel_title":"Cell wall composition drives off-target sensitivity to indaziflam","rel_doi":"10.64898\/2026.11.10.765741","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765741","rel_abs":"Indaziflam is a potent alkylazine herbicide classified as a cellulose biosynthesis inhibitor (CBI) with broad-spectrum pre-emergence activity and long soil persistence. While its efficacy in commercial weed control is established, its off-target ecological footprint across taxa with non-cellulose cell wall compositions remains poorly defined. We evaluated the potential off-target biological impacts of indaziflam across organisms representing distinct cell wall architectures, including the yeast Saccharomyces cerevisiae (chitin\/glucan), the unicellular alga Chlamydomonas reinhardtii (glycoprotein), and the early-diverging bryophyte Marchantia polymorpha (cellulose\/hemicellulose\/pectin). Indaziflam did not inhibit the growth of non-target organisms lacking plant-type cellulose cell walls. In S. cerevisiae, treatment unexpectedly accelerated growth rates to reach ED50 (12.95 h at 3200 pM vs. 16.23 h in control). Similarly, C. reinhardtii showed no growth suppression across concentration ranges up to 100 nM. Conversely, the non-vascular land plant M. polymorpha exhibited marked, dose-dependent sensitivity. In vitro, thallus surface area was significantly suppressed at concentrations above 1600 pM (p<0.05). In greenhouse trials, pre-emergence application of indaziflam at recommended (1X) and elevated (2X, 3X) field rates provided up to 100% control of liverwort establishment and biomass accumulation over an 8-week evaluation period. Off-target activity of indaziflam is strictly confined to land plants (Embryophytes) possessing conserved cellulose-containing cell walls, with no adverse growth effects observed in organisms featuring chitin- or glycoprotein-based wall structures. These findings clarify the selective environmental toxicity profile of indaziflam, demonstrating that its biological activity aligns closely with its CBI classification without causing widespread toxicity across non-plant soil organisms.","rel_num_authors":5,"rel_authors":[{"author_name":"Mohit Mahey","author_inst":"Michigan State University"},{"author_name":"Manjot Kaur Sidhu","author_inst":"University of Maine"},{"author_name":"Timothy D Miles","author_inst":"Michigan State University"},{"author_name":"Peter Knut Lundquist","author_inst":"Michigan State University"},{"author_name":"Eric L Patterson","author_inst":"Michigan State University"}],"rel_date":"2026-11-12","rel_site":"biorxiv"},{"rel_title":"Synthetic Hibernation Suppresses Osteosarcoma Growth and Protects Normal Tissue from Radiation","rel_doi":"10.64898\/2026.11.11.764778","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.764778","rel_abs":"Natural hibernation can arrest tumor growth, but whether this effect can be reproduced through repeated pharmacologically induced synthetic torpor (ST) remains unclear. It is also unknown whether the radioprotection conferred by natural and synthetic torpor extends to tumors, potentially compromising radiotherapy. Here, five 5 AMP induced torpor bouts administered every other day, a protocol designed to mimic repeated hibernation cycles (synthetic hibernation), markedly restrained osteosarcoma growth in female C3H\/HeNRj mice bearing syngeneic LM8 tumors. Interestingly, growth suppression persisted long after the final torpor bout. When 6 Gy total-body X-ray irradiation was delivered during the second bout, tumor growth control was comparable with irradiation under normothermia, whereas ovarian follicular atresia was lower and remained similar to non-irradiated controls. Together, these findings support synthetic hibernation as a strategy to restrain tumor growth and mitigate normal-tissue radiation injury without compromising tumor control.","rel_num_authors":15,"rel_authors":[{"author_name":"Reema Chowdhury","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Emiliana Piscitiello","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Tamara Vitacchio","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Olga Sokol","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Malte Benje","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Julius Oppermann","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Alexander Helm","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Niccolo Edgar Saccone","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Gaia Volpi","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Nivida Shete","author_inst":"Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL 60612, USA"},{"author_name":"Jian Xian Teh","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany"},{"author_name":"Anggraeini Puspitasari Kokko","author_inst":"Holland Proton Therapy Center, 2629 JH Delft, The Netherlands; Department of radiation oncology, Leiden University Medical Center (LUMC), 2333ZA Leiden, The Net"},{"author_name":"Marco Durante","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung, Darmstadt, Germany; Institute of Condensed Matter Physics, Technische Universitaet Darmstadt, Darmstadt, Germany"},{"author_name":"Matteo Cerri","author_inst":"Alma Mater Studiorum, University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, 40126, Italy"},{"author_name":"Walter Tinganelli","author_inst":"GSI Helmholtzzentrum fuer Schwerionenforschung GmbH."}],"rel_date":"2026-11-12","rel_site":"biorxiv"},{"rel_title":"A novel interaction between MNT and CCDC6: structural insights and distinct roles in cell migration and the DNA damage response","rel_doi":"10.64898\/2026.11.10.760688","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.760688","rel_abs":"MNT is a transcription factor of the MYC-MAX-MXD network whose biological functions remain incompletely understood. Here, we identify CCDC6, a tumor suppressor involved in the DNA damage response (DDR), as a novel MNT-interacting protein. Co-immunoprecipitation and interaction mapping analyses identified a part of the CCDC6 coiled-coil domain and the MNT bHLH-LZ region as major determinants of binding. Structural modelling further identified MNT residues predicted to mediate CCDC6 binding that are also critical for MNT-MAX dimerization. Transcriptomic analyses revealed substantial overlap between the gene expression programs regulated by MNT and CCDC6. Loss of either protein promoted cell migration, whereas MNT and CCDC6 cooperated in the regulation of {gamma}H2AX signalling, cisplatin responses and CCDC6 localization during the DDR. Together, our findings uncover a previously unrecognized connection between CCDC6 and the MYC-MAX-MXD network through its interaction with MNT, revealing an additional layer of regulation within this transcriptional network.","rel_num_authors":13,"rel_authors":[{"author_name":"Vanessa Junco","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"Elena Cabez\u00f3n","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"Sandra Lastra","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"Judit Lia\u00f1o-Pons","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"Alba Puente","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"M. Carmen Lafita-Navarro","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"Angela Celetti","author_inst":"CNR-Institute of Endotypes in Oncology, Metabolism and Immunology \"G Salvatore\"-IEOMI, Via Pansini, 5, Naples, Italy"},{"author_name":"Marta Mart\u00ednez-Conde","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"Matilde Murga","author_inst":"Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain."},{"author_name":"Oscar Fern\u00e1ndez-Capetillo","author_inst":"Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain"},{"author_name":"M. Dolores Delgado","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"Javier Le\u00f3n","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"},{"author_name":"Luc\u00eda Garc\u00eda-Guti\u00e9rrez","author_inst":"Institute of Biomedicine and Biotechnology of Cantabria. University of Cantabria-CSIC, Albert Einstein 22, 39011, Santander, Spain"}],"rel_date":"2026-11-12","rel_site":"biorxiv"},{"rel_title":"Overcoming resistance to KRAS inhibition in KRAS\/PIK3CA co-mutated colorectal cancer","rel_doi":"10.64898\/2026.11.10.765758","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765758","rel_abs":"Oncogenic alleles of KRAS drive colorectal cancers (CRC) growth and are associated with worse disease outcomes. Despite potent allele-specific and pan-RAS inhibitors targeting now in clinical test, CRC patients are not experiencing the same therapeutic benefit as patients with other cancers. PI3-Kinase (PI3K) is a direct RAS effector and is co-mutated in about 45% of CRC cases, raising the possibility that frequent oncogenic PI3K mutations contribute to the limited benefit of KRAS inhibition in CRC. Using isogenic colorectal cancer cells engineered to harbor either of the two most common activating PIK3CA mutations, we show that oncogenic PI3K promotes resistance to the pan-RAS inhibitor daraxonrasib (RMC-6236). Global phosphoproteomic profiling revealed that PIK3CA-mutant cells undergo a distinct adaptive response to RAS inhibition, characterized by sustained PI3K-AKT signaling and extensive remodeling of pathways controlling cell-cell adhesion and junction signaling, alongside suppression of apoptotic signaling. Combined RAS and PI3K inhibition overcame this resistance, suppressed signaling through both pathways and induced apoptosis in PIK3CA-mutant cells. Together, these findings identify oncogenic PIK3CA as a determinant of resistance to RAS inhibition in KRAS-mutant colorectal cancer and provide a mechanistic rationale for combined KRAS and PI3K inhibition in KRAS\/PIK3CA co-mutant tumors.","rel_num_authors":10,"rel_authors":[{"author_name":"Lucille Ferret","author_inst":"University of California, San Francisco"},{"author_name":"Jos\u00e9 L Monta\u00f1o","author_inst":"University of California, San Francisco"},{"author_name":"Kasturi B Nayak","author_inst":"University of California, San Francisco"},{"author_name":"Rigney E Turnham","author_inst":"University of California, San Francisco"},{"author_name":"Clarise G Rivera","author_inst":"University of California, San Francisco"},{"author_name":"Raymond Xu","author_inst":"University of California, San Francisco"},{"author_name":"Pornparn Kongpracha","author_inst":"University of California, San Francisco"},{"author_name":"Danielle L Swaney","author_inst":"University of California San Francisco"},{"author_name":"Nevan J Krogan","author_inst":"University of California San Francisco"},{"author_name":"John D Gordan","author_inst":"University of California, San Francisco"}],"rel_date":"2026-11-12","rel_site":"biorxiv"},{"rel_title":"A network of syringe-injectable bioelectronics for closed-loop therapeutic rescue","rel_doi":"10.64898\/2026.11.10.765435","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.10.765435","rel_abs":"An on-body network of sensors and drug delivery implants could transform treatments for rapid-onset morbidities that require bystander intervention. During opioid overdoses, for example, lone and incapacitated victims often cannot self-administer life-saving naloxone in the minutes before respiratory collapse. However, the bulkiness of existing closed-loop systems threatens patient acceptance. Here, we present the Rapid Emergency Subcutaneous platform (RES-Q), a network of wearable sensors and syringe-implantable autoinjectors for closed-loop therapy. RES-Q implants are similar in size to FDA-approved drug rod implants and fit inside 6-gauge needles to facilitate outpatient administration. Informed by implant fibrosis fracture mechanics, RES-Q employs miniature jet injectors that deliver 0.4 mg human-relevant doses of naloxone through fibrotic encapsulation for rapid uptake. RES-Q implants communicate with wearable sensors through tissue conductivity, resulting in 25 nA standby current draws that ensure long-term functionality. In swine, we sequentially trigger multiple implants using ionic tissue communication. In rats, RES-Q detects fentanyl overdoses using wearable photoplethysmography sensors and performs autonomous, dose-titratable rescue in < 6 minutes.","rel_num_authors":15,"rel_authors":[{"author_name":"Joy Jackson","author_inst":"Georgia Institute of Technology"},{"author_name":"Wonbum Sohn","author_inst":"Georgia State University"},{"author_name":"Lolita Testu","author_inst":"Georgia Institute of Technology"},{"author_name":"Ramy Ghanim","author_inst":"Georgia Institute of Technology"},{"author_name":"Maryam Aamir","author_inst":"Georgia Institute of Technology"},{"author_name":"Maya Angia","author_inst":"Georgia Institute of Technology"},{"author_name":"Alaz Cig","author_inst":"Georgia Institute of Technology"},{"author_name":"Sean Healy","author_inst":"Georgia Institute of Technology"},{"author_name":"Zachary Lee","author_inst":"Georgia Institute of Technology"},{"author_name":"Jason Y Chin","author_inst":"Georgia Institute of Technology"},{"author_name":"Julia Z Ding","author_inst":"Georgia Institute of Technology"},{"author_name":"Jihoon Park","author_inst":"Georgia Institute of Technology"},{"author_name":"Jannatim Maisha","author_inst":"Georgia State University"},{"author_name":"Yoon Jae Lee","author_inst":"Georgia State University"},{"author_name":"Alex Abramson","author_inst":"Georgia Institute of Technology, Emory University School of Medicine"}],"rel_date":"2026-11-12","rel_site":"biorxiv"},{"rel_title":"Quantification of Local Mesostructural Deformation of the Myocardium using DENSE MRI and a Novel Set of Strain Attributes","rel_doi":"10.64898\/2026.11.11.766054","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.11.766054","rel_abs":"Measuring myocardial deformation is central to understanding the mechanical behavior of both the healthy and the diseased heart. While myocardial deformation is quantified via medical imaging in the form of strain, numerous definitions have been used in the engineering and clinical literature, resulting in inconsistencies in interpreting mechanistic changes in myocardial function. Additionally, current strain definitions lack the robustness required to relate quantitative changes in strain to changes in the myocardial mesostructure. Hence, the goal of this work was to propose a novel set of logarithmic, mesostructure-based strain attributes, by leveraging the upper triangular (QR) decomposition theorem. These strain attributes were then compared with the polar Green strain, the most widely used strain definition for the myocardium. Ten healthy subjects were scanned via displacement encoding with stimulated echoes (DENSE). From these images, a 3-dimensional (3D) displacement field was obtained, from which both 3D Green strains and strain attributes were calculated and compared. The results of this work revealed that the two strain definitions yield significantly different deformation profiles of the myocardium (p < 0.05), with strain attributes predicting relatively more spatial heterogeneity compared to the Green strains -- a finding consistent with similar studies that quantified mesostructural myocardial deformation. Additionally, the strain attributes revealed the myocardium to be compressible, challenging the common assumption of incompressibility. By capturing the deformation along the mesostructure, the strain attributes enable intuitive characterizations of cardiac disease, providing clinicians with deeper mechanistic insights into left ventricular function and serving as predictive markers of adverse remodeling.","rel_num_authors":2,"rel_authors":[{"author_name":"Tawfik Hussein","author_inst":"Georgia Institute of Technology"},{"author_name":"John  N. Oshinski","author_inst":"Emory University"}],"rel_date":"2026-11-12","rel_site":"biorxiv"},{"rel_title":"Dysregulated B Cell Education Drives Autoimmunity and Immunodeficiency in Down Syndrome","rel_doi":"10.64898\/2026.11.11.26367301","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.11.26367301","rel_abs":"Individuals with Down syndrome (DS) present with both increased rates of autoimmunity and immunodeficiency. To understand this paradox, we first examined lymph node (LN) architecture and immune cell composition in infants with and without DS, as well as peripheral blood B cells from unrelated adults with and without DS. Most strikingly, LNs from individuals with DS exhibited a marked paucity of germinal centers compared with typical lymph nodes. Stromal cells within DS LNs expressed significantly lower levels of the adhesion molecules ICAM1 and VCAM1, accompanied by significantly reduced CXCR5 expression within B cell follicles, suggesting impaired B cell migration and follicular organization. Although fibroblastic reticular cells (FRCs) were present at comparable frequencies in DS and control LNs, MARCO lymphatic endothelial cells (MARCO-LECs), another critical stromal cell population supporting LN architecture, were significantly reduced. In addition, follicular dendritic cells (FDCs), which are essential for antigen retention and B cell selection within germinal centers, were also substantially reduced. To determine the consequences of these abnormalities on humoral immunity, we performed paired single-cell RNA sequencing and V(D)J sequencing of peripheral blood B cells from adults with and without DS. DS memory and CD86+ switched memory B cell populations exhibited significantly elevated reactive oxygen species and PI3K-AKT-mTOR signaling gene signatures, coupled with reduced levels of somatic hypermutation in the memory population and increase usage of the autoreactivity-associated IGHV4-34 heavy-chain gene. Collectively, these findings suggest that early-life disruption of LN architecture, characterized by reduced expression of adhesion molecules, selective loss of MARCO-LECs, and depletion of FDCs, impairs germinal center function and B cell education. This defective microenvironment likely contributes to inadequate affinity maturation, as reflected by diminished somatic hypermutation and a more autoreactive B cell repertoire in adults with Down syndrome.","rel_num_authors":10,"rel_authors":[{"author_name":"Meredith Ramba","author_inst":"Columbia University Medical Campus"},{"author_name":"Sofija Buta Panov","author_inst":"Columbia University Medical Campus"},{"author_name":"Haley E Randolph","author_inst":"Columbia University Medical Campus"},{"author_name":"O'Jay Stewart","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Anass Abbad","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Amy Ku","author_inst":"Columbia University Medical Campus"},{"author_name":"Rachel Brody","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Gyu Ho Lee","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Florian Krammer","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Dusan Bogunovic","author_inst":"Columbia University Medical Campus"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Use of AI-Related CPT Codes by Patient, Geographic, and Payer Characteristics in the U.S., 2021-2026","rel_doi":"10.64898\/2026.11.09.26367689","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367689","rel_abs":"ImportancePayment policy for clinical artificial intelligence (AI) is changing quickly, yet national data on which AI-enabled services are used, and for whom, are limited.\n\nObjectiveTo describe national trends in the use of AI-related Current Procedural Terminology (CPT) codes and how use differs by patient, geographic, and payer characteristics.\n\nDesign, Setting, and ParticipantsThis serial cross-sectional study used Epic Cosmos, a deidentified electronic health record dataset, to examine 11,605,867,309 encounters among 233,628,292 US patients from January 1, 2021, to April 14, 2026.\n\nExposures: Calendar year, age, sex, race, ethnicity, rurality, area-level social vulnerability, census region, and primary payer.\n\nMain Outcomes and MeasuresEncounters with any of 65 CPT codes that require AI, identified by matching the CPT code set to US Food and Drug Administration-listed AI-enabled devices and classified as assistive, augmentative, or autonomous using the CPT Appendix S taxonomy.\n\nResultsOf 11.6 billion encounters, 335,349 (2.9 per 100,000) included an AI-required CPT code. The odds of an encounter with an AI-required code were 9.88 (95% CI, 9.71-10.06) times higher in 2025 than in 2021. In unadjusted comparisons, use was higher among patients aged 65 to 85 years and among those with Medicare (OR, 5.11) or Medicare Advantage (OR, 5.12) vs commercial insurance. Use was lower among Black (OR, 0.72) and Hispanic or Latino (OR, 0.34) patients, Medicaid enrollees (OR, 0.65), residents of the most socially vulnerable areas (OR, 0.53), and residents of the most rural areas (OR, 0.86). Use of automated diabetic retinopathy screening increased after the service was added to a HEDIS quality measure. One newer code (quantitative brain MRI) appeared in rural areas within months of becoming effective, whereas older codes such as retinopathy screening took years.\n\nConclusions and RelevanceIn this cross-sectional study, billed use of AI-enabled services remained rare but grew substantially and was concentrated among older and Medicare-insured patients, with lower use among Medicaid enrollees and residents of socially vulnerable areas. As the Centers for Medicare & Medicaid Services restructures payment for software and launches outcome-based models, tracking who receives AI-enabled care across payment pathways will be important for equitable access.\n\nKEY POINTSO_ST_ABSQuestionC_ST_ABSHow has billed use of artificial intelligence (AI)-related CPT codes changed nationally since 2021, and how does use differ by patient, geographic, and payer characteristics?\n\nFindingsIn this cross-sectional study of 11.6 billion US encounters, 2.9 per 100,000 included an AI-required CPT code. Odds of use were nearly 10 times higher in 2025 than in 2021, higher among Medicare beneficiaries, and lower among Medicaid enrollees and residents of socially vulnerable areas.\n\nMeaningBilled AI use remains rare and uneven across payers and communities, so payment policy for AI may need to be paired with monitoring of who receives AI-enabled care.","rel_num_authors":20,"rel_authors":[{"author_name":"Eileen J Kim","author_inst":"University of California, San Diego"},{"author_name":"Sophie Chang","author_inst":"University of California, San Diego"},{"author_name":"Jean Feng","author_inst":"University of California, San Francisco"},{"author_name":"Poova Satish Bedmutha","author_inst":"University of California, San Diego"},{"author_name":"Lily Poursoltan","author_inst":"University of California, San Diego"},{"author_name":"Jie Cao","author_inst":"University of California, San Diego"},{"author_name":"Alex Wellsjo","author_inst":"University of California, San Diego"},{"author_name":"Eric Floyd","author_inst":"University of California, San Diego"},{"author_name":"Danqi Luo","author_inst":"University of California, San Diego"},{"author_name":"Kevin Zhu","author_inst":"University of California, San Diego"},{"author_name":"Aaron J Boussina","author_inst":"University of California, San Diego"},{"author_name":"Jennifer Holland","author_inst":"University of California, San Diego"},{"author_name":"Amy Sitapati","author_inst":"University of California, San Diego"},{"author_name":"Shahin Hallaj","author_inst":"University of California, San Diego"},{"author_name":"Shamim Nemati","author_inst":"University of California, San Diego"},{"author_name":"Rodney Gabriel","author_inst":"University of California, San Diego"},{"author_name":"Alexander Khalessi","author_inst":"University of California, San Diego"},{"author_name":"Chris Longhurst","author_inst":"Seattle Children's"},{"author_name":"Karandeep Singh","author_inst":"University of California, San Diego"},{"author_name":"Mattheus Ramsis","author_inst":"University of California, San Diego"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Use of AI-Related CPT Codes by Patient, Geographic, and Payer Characteristics in the U.S., 2021-2026","rel_doi":"10.64898\/2026.11.09.26367689","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367689","rel_abs":"ImportancePayment policy for clinical artificial intelligence (AI) is changing quickly, yet national data on which AI-enabled services are used, and for whom, are limited.\n\nObjectiveTo describe national trends in the use of AI-related Current Procedural Terminology (CPT) codes and how use differs by patient, geographic, and payer characteristics.\n\nDesign, Setting, and ParticipantsThis serial cross-sectional study used Epic Cosmos, a deidentified electronic health record dataset, to examine 11,605,867,309 encounters among 233,628,292 US patients from January 1, 2021, to April 14, 2026.\n\nExposures: Calendar year, age, sex, race, ethnicity, rurality, area-level social vulnerability, census region, and primary payer.\n\nMain Outcomes and MeasuresEncounters with any of 65 CPT codes that require AI, identified by matching the CPT code set to US Food and Drug Administration-listed AI-enabled devices and classified as assistive, augmentative, or autonomous using the CPT Appendix S taxonomy.\n\nResultsOf 11.6 billion encounters, 335,349 (2.9 per 100,000) included an AI-required CPT code. The odds of an encounter with an AI-required code were 9.88 (95% CI, 9.71-10.06) times higher in 2025 than in 2021. In unadjusted comparisons, use was higher among patients aged 65 to 85 years and among those with Medicare (OR, 5.11) or Medicare Advantage (OR, 5.12) vs commercial insurance. Use was lower among Black (OR, 0.72) and Hispanic or Latino (OR, 0.34) patients, Medicaid enrollees (OR, 0.65), residents of the most socially vulnerable areas (OR, 0.53), and residents of the most rural areas (OR, 0.86). Use of automated diabetic retinopathy screening increased after the service was added to a HEDIS quality measure. One newer code (quantitative brain MRI) appeared in rural areas within months of becoming effective, whereas older codes such as retinopathy screening took years.\n\nConclusions and RelevanceIn this cross-sectional study, billed use of AI-enabled services remained rare but grew substantially and was concentrated among older and Medicare-insured patients, with lower use among Medicaid enrollees and residents of socially vulnerable areas. As the Centers for Medicare & Medicaid Services restructures payment for software and launches outcome-based models, tracking who receives AI-enabled care across payment pathways will be important for equitable access.\n\nKEY POINTSO_ST_ABSQuestionC_ST_ABSHow has billed use of artificial intelligence (AI)-related CPT codes changed nationally since 2021, and how does use differ by patient, geographic, and payer characteristics?\n\nFindingsIn this cross-sectional study of 11.6 billion US encounters, 2.9 per 100,000 included an AI-required CPT code. Odds of use were nearly 10 times higher in 2025 than in 2021, higher among Medicare beneficiaries, and lower among Medicaid enrollees and residents of socially vulnerable areas.\n\nMeaningBilled AI use remains rare and uneven across payers and communities, so payment policy for AI may need to be paired with monitoring of who receives AI-enabled care.","rel_num_authors":20,"rel_authors":[{"author_name":"Eileen J Kim","author_inst":"University of California, San Diego"},{"author_name":"Sophie Chang","author_inst":"University of California, San Diego"},{"author_name":"Jean Feng","author_inst":"University of California, San Francisco"},{"author_name":"Poova Satish Bedmutha","author_inst":"University of California, San Diego"},{"author_name":"Lily Poursoltan","author_inst":"University of California, San Diego"},{"author_name":"Jie Cao","author_inst":"University of California, San Diego"},{"author_name":"Alex Wellsjo","author_inst":"University of California, San Diego"},{"author_name":"Eric Floyd","author_inst":"University of California, San Diego"},{"author_name":"Danqi Luo","author_inst":"University of California, San Diego"},{"author_name":"Kevin Zhu","author_inst":"University of California, San Diego"},{"author_name":"Aaron J Boussina","author_inst":"University of California, San Diego"},{"author_name":"Jennifer Holland","author_inst":"University of California, San Diego"},{"author_name":"Amy Sitapati","author_inst":"University of California, San Diego"},{"author_name":"Shahin Hallaj","author_inst":"University of California, San Diego"},{"author_name":"Shamim Nemati","author_inst":"University of California, San Diego"},{"author_name":"Rodney Gabriel","author_inst":"University of California, San Diego"},{"author_name":"Alexander Khalessi","author_inst":"University of California, San Diego"},{"author_name":"Chris Longhurst","author_inst":"Seattle Children's"},{"author_name":"Karandeep Singh","author_inst":"University of California, San Diego"},{"author_name":"Mattheus Ramsis","author_inst":"University of California, San Diego"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Menstrual Cycle Exacerbation of ADHD Symptoms in Adults: Common, Person-Specific, and Not Confined to the Luteal Phase","rel_doi":"10.64898\/2026.11.09.26367690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367690","rel_abs":"ObjectivePatients often describe menstrual-cycle worsening of attention-deficit\/hyperactivity disorder (ADHD). We prospectively evaluated sample- and person-level cycle effects on ADHD symptoms and their independence from cyclical negative affect and pain.\n\nMethodsIn an intensive longitudinal cohort (2019-2024), 106 naturally cycling adults meeting DSM-5 ADHD criteria on integrated assessment rated daily inattention and hyperactivity-impulsivity (Barkley Adult ADHD Rating Scale-IV), negative affect, and pain (median, 41 days) and provided daily salivary estradiol and progesterone for ovulation coding and phase-aligned cycle time (PACTS). Generalized additive models estimated sample-level and person-specific cycle curves; robust cyclicity was tested against each participants own time-shuffle null. Lab cognitive testing at four counterbalanced phases provided post hoc validation.\n\nResultsSample-average cycle effects were significant yet small (<1% of daily variance), but 54% of 87 participants tested individually were robustly cyclical in ADHD symptoms (95% CI, 44%-64%; inattention 43%, hyperactivity-impulsivity 26%), more often with informant-confirmed ADHD (69% vs 36%). Among them, the cycle explained median 52% and 51% of symptom variance, a mean swing of 2.6 and 2.1 DSM-5 criteria. Most remained cyclical after adjustment for affect (68%) or pain (81%). Worsening most often peaked at and after menses rather than premenstrually; no cycle met prospective criteria for premenstrual dysphoric disorder (PMDD). Hormones did not differ by cyclicity.\n\nConclusionsAbout half of these adults with ADHD showed robust cyclical symptom change, mostly not reducible to cyclical affect or pain and usually outside the premenstrual window. Future work should test its stability and whether a DSM-5 cyclical specifier is warranted.","rel_num_authors":9,"rel_authors":[{"author_name":"Tory A. Eisenlohr-Moul","author_inst":"University of Chicago"},{"author_name":"Ashley Ross","author_inst":"University of Illinois Chicago"},{"author_name":"Jessica R. Peters","author_inst":"Warren Alpert Medical School of Brown University"},{"author_name":"Anisha Nagpal","author_inst":"University of Illinois Chicago"},{"author_name":"Katja Schmalenberger","author_inst":"Ulm University"},{"author_name":"Kelsey K. Wiggs","author_inst":"Purdue University"},{"author_name":"Emily Knapp","author_inst":"University of Kentucky"},{"author_name":"Anna Patterson","author_inst":"University of Illinois Chicago"},{"author_name":"Michelle Martel","author_inst":"University of Kentucky"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Menstrual Cycle Exacerbation of ADHD Symptoms in Adults: Common, Person-Specific, and Not Confined to the Luteal Phase","rel_doi":"10.64898\/2026.11.09.26367690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367690","rel_abs":"ObjectivePatients often describe menstrual-cycle worsening of attention-deficit\/hyperactivity disorder (ADHD). We prospectively evaluated sample- and person-level cycle effects on ADHD symptoms and their independence from cyclical negative affect and pain.\n\nMethodsIn an intensive longitudinal cohort (2019-2024), 106 naturally cycling adults meeting DSM-5 ADHD criteria on integrated assessment rated daily inattention and hyperactivity-impulsivity (Barkley Adult ADHD Rating Scale-IV), negative affect, and pain (median, 41 days) and provided daily salivary estradiol and progesterone for ovulation coding and phase-aligned cycle time (PACTS). Generalized additive models estimated sample-level and person-specific cycle curves; robust cyclicity was tested against each participants own time-shuffle null. Lab cognitive testing at four counterbalanced phases provided post hoc validation.\n\nResultsSample-average cycle effects were significant yet small (<1% of daily variance), but 54% of 87 participants tested individually were robustly cyclical in ADHD symptoms (95% CI, 44%-64%; inattention 43%, hyperactivity-impulsivity 26%), more often with informant-confirmed ADHD (69% vs 36%). Among them, the cycle explained median 52% and 51% of symptom variance, a mean swing of 2.6 and 2.1 DSM-5 criteria. Most remained cyclical after adjustment for affect (68%) or pain (81%). Worsening most often peaked at and after menses rather than premenstrually; no cycle met prospective criteria for premenstrual dysphoric disorder (PMDD). Hormones did not differ by cyclicity.\n\nConclusionsAbout half of these adults with ADHD showed robust cyclical symptom change, mostly not reducible to cyclical affect or pain and usually outside the premenstrual window. Future work should test its stability and whether a DSM-5 cyclical specifier is warranted.","rel_num_authors":9,"rel_authors":[{"author_name":"Tory A. Eisenlohr-Moul","author_inst":"University of Chicago"},{"author_name":"Ashley Ross","author_inst":"University of Illinois Chicago"},{"author_name":"Jessica R. Peters","author_inst":"Warren Alpert Medical School of Brown University"},{"author_name":"Anisha Nagpal","author_inst":"University of Illinois Chicago"},{"author_name":"Katja Schmalenberger","author_inst":"Ulm University"},{"author_name":"Kelsey K. Wiggs","author_inst":"Purdue University"},{"author_name":"Emily Knapp","author_inst":"University of Kentucky"},{"author_name":"Anna Patterson","author_inst":"University of Illinois Chicago"},{"author_name":"Michelle Martel","author_inst":"University of Kentucky"}],"rel_date":"2026-11-11","rel_site":"medrxiv"},{"rel_title":"Menstrual Cycle Exacerbation of ADHD Symptoms in Adults: Common, Person-Specific, and Not Confined to the Luteal Phase","rel_doi":"10.64898\/2026.11.09.26367690","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367690","rel_abs":"ObjectivePatients often describe menstrual-cycle worsening of attention-deficit\/hyperactivity disorder (ADHD). We prospectively evaluated sample- and person-level cycle effects on ADHD symptoms and their independence from cyclical negative affect and pain.\n\nMethodsIn an intensive longitudinal cohort (2019-2024), 106 naturally cycling adults meeting DSM-5 ADHD criteria on integrated assessment rated daily inattention and hyperactivity-impulsivity (Barkley Adult ADHD Rating Scale-IV), negative affect, and pain (median, 41 days) and provided daily salivary estradiol and progesterone for ovulation coding and phase-aligned cycle time (PACTS). Generalized additive models estimated sample-level and person-specific cycle curves; robust cyclicity was tested against each participants own time-shuffle null. Lab cognitive testing at four counterbalanced phases provided post hoc validation.\n\nResultsSample-average cycle effects were significant yet small (<1% of daily variance), but 54% of 87 participants tested individually were robustly cyclical in ADHD symptoms (95% CI, 44%-64%; inattention 43%, hyperactivity-impulsivity 26%), more often with informant-confirmed ADHD (69% vs 36%). Among them, the cycle explained median 52% and 51% of symptom variance, a mean swing of 2.6 and 2.1 DSM-5 criteria. Most remained cyclical after adjustment for affect (68%) or pain (81%). Worsening most often peaked at and after menses rather than premenstrually; no cycle met prospective criteria for premenstrual dysphoric disorder (PMDD). Hormones did not differ by cyclicity.\n\nConclusionsAbout half of these adults with ADHD showed robust cyclical symptom change, mostly not reducible to cyclical affect or pain and usually outside the premenstrual window. Future work should test its stability and whether a DSM-5 cyclical specifier is warranted.","rel_num_authors":9,"rel_authors":[{"author_name":"Tory A. Eisenlohr-Moul","author_inst":"University of Chicago"},{"author_name":"Ashley Ross","author_inst":"University of Illinois Chicago"},{"author_name":"Jessica R. Peters","author_inst":"Warren Alpert Medical School of Brown University"},{"author_name":"Anisha Nagpal","author_inst":"University of Illinois Chicago"},{"author_name":"Katja Schmalenberger","author_inst":"Ulm University"},{"author_name":"Kelsey K. Wiggs","author_inst":"Purdue University"},{"author_name":"Emily Knapp","author_inst":"University of Kentucky"},{"author_name":"Anna Patterson","author_inst":"University of Illinois Chicago"},{"author_name":"Michelle Martel","author_inst":"University of Kentucky"}],"rel_date":"2026-11-11","rel_site":"medrxiv"}]}