{"gname":"University of New South Wales","grp_id":"25","rels":[{"rel_title":"Screening Renin-Aldosterone Profiles and Long-term Cardiovascular Risk After Primary Aldosteronism Evaluation","rel_doi":"10.64898\/2026.11.09.26367682","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367682","rel_abs":"Background: Aldosterone-to-renin ratio (ARR) and plasma renin activity (PRA) are measured at the screening stage of primary aldosteronism (PA) evaluation, but their prognostic relevance after confirmatory classification and subsequent treatment remains uncertain. Methods: We linked the seven-hospital Taiwan Primary Aldosteronism Investigation cohort (1991-2023) with nationwide health insurance and mortality data through June 2025. Patients were classified as confirmatory-test-defined essential hypertension (EH), PA without adrenalectomy, or PA with subsequent adrenalectomy. Covariate-adjusted Cox models evaluated screening logARR, logPRA, and logPAC separately in relation to incident major adverse cardiovascular events (MACE; myocardial infarction, stroke, heart failure hospitalization, or cardiovascular death). Results: Among 3,178 participants (EH, 1,433; PA without adrenalectomy, 834; PA with adrenalectomy, 911), 441 (13.9%) experienced MACE during a median 7.9-year follow-up. Adjusted hazard ratios (95% CIs) per 1-unit increase in logARR were 1.09 (1.00-1.19), 1.14 (1.03-1.26), and 0.95 (0.87-1.05), respectively; corresponding logPRA estimates were 0.91 (0.83-0.99), 0.87 (0.79-0.97), and 1.04 (0.93-1.16). LogPAC showed no consistent associations. Primary biomarker-by-phenotype interactions were not significant for logARR (P=0.057) or logPRA (P=0.069); time-varying adrenalectomy analyses were supportive but exploratory. Conclusions: Higher screening ARR and lower PRA were associated with subsequent MACE in confirmatory-test-defined EH and PA without adrenalectomy, but not clearly in PA with subsequent adrenalectomy.","rel_num_authors":6,"rel_authors":[{"author_name":"Heng-Chih Pan","author_inst":"Linkou Chang Gung Memorial Hospital"},{"author_name":"Kuang-Hung Chen","author_inst":"National Taiwan University Hospital"},{"author_name":"Cheng-Hsuan Tsai","author_inst":"National Taiwan University Hospital Cardiovascular Center"},{"author_name":"Yen-Hung Lin","author_inst":"National Taiwan University Hospital"},{"author_name":"Cheng-Yi Wang","author_inst":"Cardinal Tien Hospital"},{"author_name":"Vin-Cent Wu","author_inst":"College of Medicine, National Taiwan University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Browser-Based Video Supports Scalable Computer Vision Analysis for Open Surgical Skill Assessment","rel_doi":"10.64898\/2026.11.09.26367680","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367680","rel_abs":"Purpose: Objective assessment of open surgical skills remains limited by expert availability. Machine learning (ML)-based hand keypoint detection offers potential for automated, on-demand assessment, but performance in accessible browser-based recording environments (laptop-webcam video recorded in a web browser) is unknown. We hypothesized that browser-based recordings would achieve acceptable keypoint localization (percentage of correct keypoints [PCK] >70%). Methods: Retrospective technical validation of prospectively collected video from 14 PGY-1 interns at one academic center (July to August 2024). We annotated 203 frames (101 browser-based, 1280x720\/854x480; 102 overhead, 3840x2160\/1920x1080), yielding 6,232 ground-truth keypoints. An internally developed pipeline and MediaPipe Hands were evaluated. The primary endpoint was PCK normalized to the index-proximal bone; bounding-box-normalized PCK, detection rate, and per-region accuracy were also evaluated. Results: Primary PCK, normalized to a fixed anatomical hand scale, was 85.9% (95% CI, 80.3-91.0) for browser-based recordings and 81.5% (95% CI, 76.7-87.0) for overhead recordings. Secondary bounding-box-normalized PCK showed a similar pattern (91.6% vs 90.6%), and detection rates were high in both environments (94.9% vs 97.7%). In contrast, MediaPipe detection rates were only 5.3% for browser-based recordings and 15.4% for overhead recordings, resulting in substantially lower accuracy. Conclusion: Hand keypoint detection performance was comparable between browser-based and overhead recordings using the internally developed pipeline. These findings suggest that browser-based video acquisition can provide data of sufficient quality for ML-based hand keypoint detection, offering a scalable pathway for surgical skill assessment without specialized recording hardware.","rel_num_authors":12,"rel_authors":[{"author_name":"Azad Khan","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Soham Kulkarni","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Shuo-Lun Lai","author_inst":"National Taiwan University Hospital"},{"author_name":"Xiaohan Wang","author_inst":"Stanford University"},{"author_name":"Idan Farber","author_inst":"Soroka University Medical Center"},{"author_name":"Guillaume Kugener","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Ankit Pal","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Sofia Volpi","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Orr Zohar","author_inst":"Stanford University"},{"author_name":"Chi-Sheng Chen","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Serena Yeung-Levy","author_inst":"Stanford University"},{"author_name":"Gabriel Brat","author_inst":"Beth Israel Deaconess Medical Center"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Handheld, quantitative phase imaging probe for skin evaluation at subcellular resolution in vivo, in real-time, and in 3D","rel_doi":"10.64898\/2026.11.10.26367486","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367486","rel_abs":"Skin cancer is the most common malignancy in the United States. The gold standard for diagnosis of skin cancer is histopathological analysis via tissue biopsy. However, identifying which lesions to biopsy remains a significant clinical challenge, particularly at early stages of disease. In this work, we present a volumetric quantitative oblique back-illumination microscopy (qOBM) probe, a highly maneuverable, handheld imaging system capable of providing high-resolution, 3D visualization of the skin microstructure. We show the probe is capable of visualizing the dynamic, layered microstructure of the epidermis and the top of the dermis across all Fitzpatrick skin types in human skin in vivo. The easy maneuverability of the probe is highlighted by imaging anatomically challenging areas typically hard to reach for bulkier systems. Finally, we present additional case studies in ex vivo murine models and in vivo human nevi that further illustrate the potential clinical applications of the volumetric handheld probe. These results establish a low-cost, easy to use, high-resolution, compact system that combines the strengths of its predecessors -- the excellent maneuverability of the widely-used dermatoscopes and 3D, high-resolution imaging of prior bulkier systems -- to improve screening of dermatological lesions at the bedside.","rel_num_authors":13,"rel_authors":[{"author_name":"Srinidhi Bharadwaj","author_inst":"Georgia Institute of Technology"},{"author_name":"Zhe Guang","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Lukas A Clark","author_inst":"Georgia Institute of Technology"},{"author_name":"Jacob P Callaway","author_inst":"School of Medicine, University of North Carolina, Chapel Hill"},{"author_name":"Zhenmin Li","author_inst":"Georgia Institute of Technology"},{"author_name":"Christopher L Suhr","author_inst":"Georgia Institute of Technology"},{"author_name":"Samuel N Lucas","author_inst":"Georgia Institute of Technology"},{"author_name":"Caroline Serafini","author_inst":"Emory University"},{"author_name":"Jimena Garcia-Nuno","author_inst":"Georgia Institute of Technology"},{"author_name":"Zachary Wolner","author_inst":"Emory University"},{"author_name":"Mohammad K Khan","author_inst":"Emory University"},{"author_name":"Susan Napier Thomas","author_inst":"Georgia Institute of Technology"},{"author_name":"Francisco E Robles","author_inst":"St. Jude Children's Research Hospital"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Measuring community building in group antenatal care: Evidence from a randomized trial in Malawi","rel_doi":"10.64898\/2026.11.10.26367565","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.10.26367565","rel_abs":"Improving the quality of antenatal care is essential for reducing persistently high maternal and neonatal mortality in Malawi. Group antenatal care has demonstrated improvements in quality, satisfaction, health behaviors, and outcomes. However, the impact of community building, one of the models core components, has not previously been quantitatively assessed. This study examined the measurement properties of two community building measures, assessed the impact of group antenatal care on these measures, and explored their potential role as mediators of health outcomes. This secondary analysis used quantitative data from the parent study testing the effectiveness of group antenatal care at seven clinics in Blantyre District, Malawi. The Perinatal Peer Support Scale and the Provider Connectedness subscale of the Pregnancy Related Empowerment Scale were used to measure community building and were validated using factor analyses. Results supported a two-factor structure for perinatal peer support (relational support and peer network) and a unidimensional structure for provider connectedness. Using generalized linear modeling, we found that participation in group antenatal care was associated with significantly stronger community building across all measures when compared to usual individual antenatal care. Women in group antenatal care demonstrated higher relational support score, peer network, and provider connectedness scores compared with women in individual antenatal care (p < 0.001). However, we found no evidence that community building had direct or indirect (mediating) effects on maternal psychological distress or infant birthweight. This study strengthens the evidence base for group antenatal care by validating measures of community building and showing that relational support, peer networks, and provider connectedness are important benefits of participation. Although community building did not mediate the outcomes examined here, the findings highlight the need to further test of theoretical pathways linking group antenatal care to maternal and child health outcomes.","rel_num_authors":6,"rel_authors":[{"author_name":"Anne Batchelder","author_inst":"Johns Hopkins University School of Nursing"},{"author_name":"Ginger  C Hanson","author_inst":"Johns Hopkins School of Nursing"},{"author_name":"Esnath Kapito","author_inst":"Kamuzu University of Health Sciences"},{"author_name":"Ellen Chirwa","author_inst":"Kamuzu University of Health Sciences"},{"author_name":"Crystal  L. Patil","author_inst":"University of Michigan"},{"author_name":"Nancy Glass","author_inst":"Johns Hopkins University School of Nursing"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"How Many Time-Critical Emergencies? A Population-Based National Estimate of Attended Events per 100,000 US Residents","rel_doi":"10.64898\/2026.11.09.26367629","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367629","rel_abs":"Objectives. To estimate how many time-critical emergencies fire and emergency medical services (EMS) crews attend each year per 100,000 US residents. We counted events in which a crew reached a living patient or a trapped person whose outcome plausibly depends on how soon effective treatment starts. Methods. For 30 medical conditions, we took annual counts from US registries and datasets, or multiplied a national incidence count by the share of patients EMS attended. A condition was Tier A when a published study linked a measured delay, from minutes to a few hours, to death or major disability. Conditions whose time sensitivity rests on guidelines or expert consensus were Tier B. Fire and rescue events came from twelve months of National Emergency Response Information System public data, scaled to national totals. We removed double counting between conditions. Results. Crews attended an estimated 589 time-critical events per 100,000 residents a year (494 to 697 with every condition at its low or high value), equal to 4.3% of 9-1-1 EMS activations. Medical conditions accounted for 583 after removing overlap. Of these, 350 were Tier A, led by ischemic stroke (120.2) and EMS-treated cardiac arrest (78.7). Opioid overdose (123.4) led the 233 Tier B events. Those three conditions made up 55% of the medical total. Fire and rescue events added 6. Conclusions. At national rates, a US community of 100,000 can expect its fire and EMS crews to attend about 589 events a year in which time to treatment may change the outcome. That is roughly 11 a week, nearly all of them medical. The count measures how often response time can matter in the events crews attend, and it gives a denominator for valuing a faster response.","rel_num_authors":3,"rel_authors":[{"author_name":"Daniel Haight","author_inst":"Darkhorse Emergency, Edmonton, Alberta, Canada"},{"author_name":"Kelly A. Nisbet","author_inst":"Darkhorse Emergency, Edmonton, Alberta, Canada; University of Alberta, Edmonton, Alberta, Canada"},{"author_name":"Sunny Li","author_inst":"Darkhorse Emergency, Edmonton, Alberta, Canada; University of Chicago, Chicago, Illinois, USA"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Streamlined Point-of-Care Ultrasound Examination for Pulmonary Tuberculosis","rel_doi":"10.64898\/2026.11.09.26367649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367649","rel_abs":"Background: Point-of-care ultrasound (POCUS) is a low-cost, radiation-free triage tool but lacks standardized acquisition protocols for tuberculosis (TB). We developed and evaluated a streamlined symmetric POCUS protocol for pulmonary TB in a high-burden setting. Methods: Ugandan participants aged [&ge;]13 years with confirmed pulmonary TB, household TB exposure, or a non-TB respiratory condition underwent an 18-position POCUS examination (12 lung zones and 6 pre-established extrapulmonary positions). Random Forest classifiers using prespecified pathologic features were developed in a fixed stratified 75\/25 training\/holdout split. All symmetric 2-, 4-, and 6-zone combinations were evaluated in training data. The best protocol of each size was locked and tested in the holdout set. Results: Among 318 analyzed participants, 118 (37.1%) had pulmonary TB and 200 were TB-negative, including 102 with other respiratory conditions (ORC). The model-selected 6-zone protocol comprised bilateral anterior-superior, lateral-superior, and posterior-superior lung zones. For TB versus all TB-negative participants, the AUCs for the 6-zone, 12-zone, and 18-position protocols were 0.82 (95% CI, 0.73-0.92), 0.81 (0.70--0.92), and 0.81 (0.71--0.91), respectively (all P > 0.76). For TB versus ORC, AUCs were 0.81 (0.70--0.91), 0.85 (0.76--0.93), and 0.85 (0.76--0.94), respectively (all P > 0.45). The 2-zone protocol had a lower AUC than the 6-zone protocol for TB versus all TB-negative participants (P = 0.004). Shred sign, consolidation, and B-lines with irregular pleura were the strongest TB-associated findings. Conclusions: A fixed 6-zone lung POCUS examination showed similar discrimination for TB to more comprehensive 12-lung-zone and 18-position protocols. This supports a simpler, scalable approach to TB triage","rel_num_authors":22,"rel_authors":[{"author_name":"Lydia Nakiyingi","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda; Makerere University, Infectious Diseases Institute, Kampala, Uganda"},{"author_name":"Rohan Dhamdhere","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA"},{"author_name":"Wycliff Nate","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Keith Guevarra","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eva Nabawanuka","author_inst":"Mulago National Referral Hospital, Department of Radiology, Kampala, Uganda"},{"author_name":"Elena Jovanovska Janeva","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Raphael Shankman","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eria Lwanga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Elizabeth Nakabugo","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Emmanuel Nasinghe","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Sarah Nakayenga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Guadalupe Astorga","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Thejaswini Anapakula Sridhar","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Hyndavi Krishna Javvaji","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Emily Clark","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Deborah Handler","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Padmini Salgame","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"David Alland","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Moses Joloba","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Jerrold Ellner","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Anant Madabhushi","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA; Atlanta Veterans Aff"},{"author_name":"Yingda L. Xie","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Streamlined Point-of-Care Ultrasound Examination for Pulmonary Tuberculosis","rel_doi":"10.64898\/2026.11.09.26367649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367649","rel_abs":"Background: Point-of-care ultrasound (POCUS) is a low-cost, radiation-free triage tool but lacks standardized acquisition protocols for tuberculosis (TB). We developed and evaluated a streamlined symmetric POCUS protocol for pulmonary TB in a high-burden setting. Methods: Ugandan participants aged [&ge;]13 years with confirmed pulmonary TB, household TB exposure, or a non-TB respiratory condition underwent an 18-position POCUS examination (12 lung zones and 6 pre-established extrapulmonary positions). Random Forest classifiers using prespecified pathologic features were developed in a fixed stratified 75\/25 training\/holdout split. All symmetric 2-, 4-, and 6-zone combinations were evaluated in training data. The best protocol of each size was locked and tested in the holdout set. Results: Among 318 analyzed participants, 118 (37.1%) had pulmonary TB and 200 were TB-negative, including 102 with other respiratory conditions (ORC). The model-selected 6-zone protocol comprised bilateral anterior-superior, lateral-superior, and posterior-superior lung zones. For TB versus all TB-negative participants, the AUCs for the 6-zone, 12-zone, and 18-position protocols were 0.82 (95% CI, 0.73-0.92), 0.81 (0.70--0.92), and 0.81 (0.71--0.91), respectively (all P > 0.76). For TB versus ORC, AUCs were 0.81 (0.70--0.91), 0.85 (0.76--0.93), and 0.85 (0.76--0.94), respectively (all P > 0.45). The 2-zone protocol had a lower AUC than the 6-zone protocol for TB versus all TB-negative participants (P = 0.004). Shred sign, consolidation, and B-lines with irregular pleura were the strongest TB-associated findings. Conclusions: A fixed 6-zone lung POCUS examination showed similar discrimination for TB to more comprehensive 12-lung-zone and 18-position protocols. This supports a simpler, scalable approach to TB triage","rel_num_authors":22,"rel_authors":[{"author_name":"Lydia Nakiyingi","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda; Makerere University, Infectious Diseases Institute, Kampala, Uganda"},{"author_name":"Rohan Dhamdhere","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA"},{"author_name":"Wycliff Nate","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Keith Guevarra","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eva Nabawanuka","author_inst":"Mulago National Referral Hospital, Department of Radiology, Kampala, Uganda"},{"author_name":"Elena Jovanovska Janeva","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Raphael Shankman","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eria Lwanga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Elizabeth Nakabugo","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Emmanuel Nasinghe","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Sarah Nakayenga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Guadalupe Astorga","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Thejaswini Anapakula Sridhar","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Hyndavi Krishna Javvaji","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Emily Clark","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Deborah Handler","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Padmini Salgame","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"David Alland","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Moses Joloba","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Jerrold Ellner","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Anant Madabhushi","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA; Atlanta Veterans Aff"},{"author_name":"Yingda L. Xie","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Streamlined Point-of-Care Ultrasound Examination for Pulmonary Tuberculosis","rel_doi":"10.64898\/2026.11.09.26367649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367649","rel_abs":"Background: Point-of-care ultrasound (POCUS) is a low-cost, radiation-free triage tool but lacks standardized acquisition protocols for tuberculosis (TB). We developed and evaluated a streamlined symmetric POCUS protocol for pulmonary TB in a high-burden setting. Methods: Ugandan participants aged [&ge;]13 years with confirmed pulmonary TB, household TB exposure, or a non-TB respiratory condition underwent an 18-position POCUS examination (12 lung zones and 6 pre-established extrapulmonary positions). Random Forest classifiers using prespecified pathologic features were developed in a fixed stratified 75\/25 training\/holdout split. All symmetric 2-, 4-, and 6-zone combinations were evaluated in training data. The best protocol of each size was locked and tested in the holdout set. Results: Among 318 analyzed participants, 118 (37.1%) had pulmonary TB and 200 were TB-negative, including 102 with other respiratory conditions (ORC). The model-selected 6-zone protocol comprised bilateral anterior-superior, lateral-superior, and posterior-superior lung zones. For TB versus all TB-negative participants, the AUCs for the 6-zone, 12-zone, and 18-position protocols were 0.82 (95% CI, 0.73-0.92), 0.81 (0.70--0.92), and 0.81 (0.71--0.91), respectively (all P > 0.76). For TB versus ORC, AUCs were 0.81 (0.70--0.91), 0.85 (0.76--0.93), and 0.85 (0.76--0.94), respectively (all P > 0.45). The 2-zone protocol had a lower AUC than the 6-zone protocol for TB versus all TB-negative participants (P = 0.004). Shred sign, consolidation, and B-lines with irregular pleura were the strongest TB-associated findings. Conclusions: A fixed 6-zone lung POCUS examination showed similar discrimination for TB to more comprehensive 12-lung-zone and 18-position protocols. This supports a simpler, scalable approach to TB triage","rel_num_authors":22,"rel_authors":[{"author_name":"Lydia Nakiyingi","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda; Makerere University, Infectious Diseases Institute, Kampala, Uganda"},{"author_name":"Rohan Dhamdhere","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA"},{"author_name":"Wycliff Nate","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Keith Guevarra","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eva Nabawanuka","author_inst":"Mulago National Referral Hospital, Department of Radiology, Kampala, Uganda"},{"author_name":"Elena Jovanovska Janeva","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Raphael Shankman","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Eria Lwanga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Elizabeth Nakabugo","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Emmanuel Nasinghe","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Sarah Nakayenga","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Guadalupe Astorga","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Thejaswini Anapakula Sridhar","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Hyndavi Krishna Javvaji","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Emily Clark","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Deborah Handler","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Padmini Salgame","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"David Alland","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Moses Joloba","author_inst":"Makerere University, Makerere Biomedical Research Centre, Kampala, Uganda"},{"author_name":"Jerrold Ellner","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"},{"author_name":"Anant Madabhushi","author_inst":"The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA; Atlanta Veterans Aff"},{"author_name":"Yingda L. Xie","author_inst":"Rutgers New Jersey Medical School, Department of Medicine, Newark, NJ, USA"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Lamina Cribrosa Strain as a Glaucoma Prognostic Factor: The STRAIN Study Methodology and Initial Outcomes","rel_doi":"10.64898\/2026.11.09.26367640","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367640","rel_abs":"Objective: To estimate the lamina cribrosa (LC) strain response to intraocular pressure (IOP) change in open angle glaucoma (OAG) patients and examine associations between LC strain and demographic and clinical characteristics relevant to OAG in an ongoing longitudinal study. Design: Cohort study Participants: Adult patients with OAG (205 eyes of 119 patients) Methods: The STRAIN study is an ongoing longitudinal study designed to determine whether LC biomechanical strain is associated with present, prior, and future OAG damage. In this initial analysis, patients either temporarily stopped [&ge;] 1 eye drop, initiated an eye drop, or underwent selective laser trabeculoplasty to produce IOP change. Optical coherence tomography (OCT) scans of the optic nerve head (ONH) acquired before and up to several weeks after IOP change were analyzed using digital volume correlation (DVC) to estimate LC strain. Strain measurements were compared with age, race, sex, axial length, central corneal thickness (CCT), corneal hysteresis, optic disc area, years of known OAG, retinal nerve fiber layer (RNFL) thickness, and visual field mean deviation (MD). Main Outcome Measures: LC strain estimated by DVC from OCT scans acquired before and after IOP alteration. Results: Axial LC strain (Ezz) was tensile with IOP decrease and compressive with IOP increase. Maximum principal strain was tensile (mean Emax = 1.09%), and maximum shear strain was positive (mean{Gamma} max = 1.16%) in the radial-axial plane. Both increased quadratically with the IOP change. Older age was significantly related to greater tensile circumferential strain (p = 0.02) and lower{Gamma} max (p = 0.01). Sex, CCT, corneal hysteresis, and optic disc area were not significantly associated with LC strain. In combined multivariable models adjusting for IOP change, demographics, and accounting for correlations between eyes from the same patient, eyes with thinner inferior-quadrant RNFL had smaller{Gamma} max for a given IOP change (p = 0.02). Conclusions: LC strain in patients with OAG is associated with the degree of neuronal loss, age, and axial length, supporting a relationship between the LC biomechanical response and factors relevant to glaucomatous damage.","rel_num_authors":12,"rel_authors":[{"author_name":"Patricia M. Sabin","author_inst":"Johns Hopkins University"},{"author_name":"Farzaneh Dadvar","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Rebecca Mirville","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Yulia Nam","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Fatma Hamid","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Chris Bradley","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Jithin Yohannan","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Kelly A. Clingo","author_inst":"Johns Hopkins University"},{"author_name":"Thomas V. Johnson","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Bryce Chiang","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Harry A. Quigley","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Thao D. Nguyen","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"LLM Embeddings Complement Theory-Driven Language Features and Cognitive Scores for APOE4 and A\u03b2 Prediction","rel_doi":"10.64898\/2026.11.09.26367620","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367620","rel_abs":"Spontaneous language offers a scalable, noninvasive approach for identifying biological indicators of preclinical Alzheimer's disease (AD). We examined prediction of APOE4 carrier status and cerebral amyloid-beta burden using Cookie Theft picture descriptions from two cohorts of Hebrew- and English-speaking participants (IRAP, N=134; WRAP, N=1,541). Amyloid-beta burden was classified using lowest-quartile, median, and highest-quartile cutoffs, capturing accumulation below conventional amyloid-positivity thresholds. We compared embeddings from pretrained large language models (LLMs) with standard cognitive test scores, reflecting conventional clinical assessment, and theory-driven linguistic features, reflecting traditional language analysis. Embedding-based models achieved the highest F1 scores among constituent models in five of eight tasks involving APOE4 status and global amyloid-beta burden. High prediction disagreement suggested complementary signals across approaches. An any-positive ensemble significantly outperformed every constituent model and a prior-informed random baseline across all eight tasks, and significantly outperformed all constituent models in 21 of 24 regional amyloid-beta tasks. These findings highlight the complementarity of LLM-based, theory-driven, and cognitive measures for predicting AD-related genetic risk and amyloid pathology, and support further investigation of their potential for early screening approaches.","rel_num_authors":16,"rel_authors":[{"author_name":"Maya Zadok","author_inst":"Technion IIT"},{"author_name":"Nitay Calderon","author_inst":"Technion IIT"},{"author_name":"Yoav Wald","author_inst":"Technion IIT"},{"author_name":"Netaniel Rein","author_inst":"Department of Neurology and Agnes Ginges Center for Human Neurogenetics, Hadassah Medical Organization, Israel"},{"author_name":"Ithamar Ganmore","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Orit Lesman-Segev","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Ganit Almog","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Tamar Shamir","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Rotem Ackler","author_inst":"Technion IIT"},{"author_name":"Shaked Yafa Leviner","author_inst":"Technion IIT"},{"author_name":"Gal Noimark","author_inst":"Technion IIT"},{"author_name":"Gil Levy","author_inst":"Technion IIT"},{"author_name":"Kimberly Diggle Mueller","author_inst":"Department of Communication Sciences and Disorders, University of Wisconsin-Madison, United States"},{"author_name":"Ramit Ravona Springer","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel"},{"author_name":"Michal Schnaider Beeri","author_inst":"Herbert and Jacqueline Krieger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers University, United States"},{"author_name":"Roi Reichart","author_inst":"Technion IIT"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"WALRUS: Robust and Transferable Deep Learning for Water and Lipid Removal in 1H-MRSI","rel_doi":"10.64898\/2026.11.09.26366974","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26366974","rel_abs":"Proton magnetic resonance spectroscopic imaging (1H-MRSI) enables non-invasive mapping of brain metabolism, but reliable quantification is challenged by residual water and extracranial lipid contamination. Recent work demonstrated that a deep learning model trained on simulated metabolite spectra combined with in vivo-derived water and lipid signals can outperform conventional nuisance-removal methods. However, this approach relied on heuristic simulation parameter distributions and a subject-specific L2-derived lipid estimate as an auxiliary network input, requiring subject-specific lipid masks and L2 processing during inference. Here, we introduce WALRUS (Water And Lipid Removal Using Spectral Learning), a fitting-consistent and empirically calibrated framework developed through a systematic evaluation of simulation realism, architectural priors, and network optimization. WALRUS uses the same metabolite basis as downstream spectral fitting and calibrates deliberately broadened simulation distributions from in vivo measurements. Controlled 7 T experiments demonstrate that empirical simulator calibration substantially improves nuisance removal and metabolite quantification compared with heuristic training distributions. With the optimized simulator, a capacity-matched comparison reveals no clear additional benefit from the L2-derived prior, allowing its removal and substantially simplifying inference. Further improvements are achieved with the final higher-capacity U-Net, while on-the-fly simulation improves generalization compared with training on a fixed synthetic dataset. The same framework was subsequently recalibrated and retrained at 3 T, where WALRUS outperformed conventional HLSVD+L2 processing on held-out data. Together, WALRUS combines these advances into an optimized framework that improves nuisance removal and downstream metabolite fitting, requires no subject-specific lipid segmentation or L2-derived auxiliary input during inference, and can be systematically adapted to different acquisition settings.","rel_num_authors":21,"rel_authors":[{"author_name":"Hauke Fischer","author_inst":"Medical University of Vienna"},{"author_name":"Stanislav Motyka","author_inst":"Medical University of Vienna"},{"author_name":"Paul Weiser","author_inst":"Athinoula A. Martinos Center for Biomedical Imaging, Cambridge, United States of America"},{"author_name":"Bernhard Strasser","author_inst":"Medical University of Vienna"},{"author_name":"Lukas Hingerl","author_inst":"Medical University of Vienna"},{"author_name":"Korbinian Eckstein","author_inst":"Medical University of Vienna"},{"author_name":"Korawig Chaknam","author_inst":"Medical University of Vienna"},{"author_name":"Aaron Paul Osburg","author_inst":"Medical University of Vienna"},{"author_name":"Anton Altmeyer","author_inst":"Medical University of Vienna"},{"author_name":"Bernardo Campilho","author_inst":"Medical University of Vienna"},{"author_name":"Ekaterina Sazonova","author_inst":"Medical University of Vienna"},{"author_name":"Yan Li","author_inst":"University Of California, San Francisco"},{"author_name":"Jing Liu","author_inst":"University Of California, San Francisco"},{"author_name":"Barbara Dymerska","author_inst":"University College London"},{"author_name":"Zeinab Eftekhari","author_inst":"The University of Queensland"},{"author_name":"Thomas B Shaw","author_inst":"The University of Queensland"},{"author_name":"Markus Barth","author_inst":"The University of Queensland"},{"author_name":"Gilbert Hangel","author_inst":"Medical University of Vienna"},{"author_name":"Sumit Kaushik","author_inst":"Technical University of Ostrava"},{"author_name":"Lukas Haider","author_inst":"Medical University of Vienna"},{"author_name":"Wolfgang Bogner","author_inst":"Medical University of Vienna"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Age-related Trust and its Association with Cost-related Medication Nonadherence","rel_doi":"10.64898\/2026.11.09.26367639","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367639","rel_abs":"Trust operates foundationally at the personal and societal levels, a vital force that drives social connection, cooperation, and positive outcomes. In healthcare, trust is instrumental in improving patient outcomes as it forms the foundation for shared decision-making and patient-provider relationships. With growing evidence that generalized trust toward other people grows with age and behaviors such as cost-related medication non-adherence (CRN) decrease with age we study whether lack of trust is a force that drives up CRN and its variability in effects across age groups, controlling for other risk factors. The data consists of 680 Medicare diabetes patients at high risk of hospitalization enrolled in a randomized controlled trial of the effect of the Comprehensive Care Physician model (CCP) at an academic medical center between November 2012 and June 2016. This study provides first-of-its-kind evidence that lack of trust is an important force that drives up CRN and the effect of lack of trust decreased even though the lack of trust decreased by age increments. The effect of lack of trust is particularly pronounced among younger patients. For practice and policy, it shows the potential promising prospect that a more trusting attitude may be conducive to more productive health. More research is needed on how to build trust at the societal level and in healthcare specifically, and how generalized trust and target-specific trust of providers are correlated.","rel_num_authors":2,"rel_authors":[{"author_name":"James X Zhang","author_inst":"The University of Chicago"},{"author_name":"David Meltzer","author_inst":"The University of Chicago"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Patterns of Childhood Exposomes, White Matter Development and Behaviors Link to Future Cognition and Psychopathology in Youth","rel_doi":"10.64898\/2026.11.09.26367658","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367658","rel_abs":"Environmental exposures during childhood strongly impact individuals' cognitive and socioemotional development, and psychiatric vulnerability. However, childhood exposures rarely occur in isolation. Instead, they form a highly correlated 'exposome' whose multidimensional relationships with brain development and behavioral outcomes remain poorly understood. Elucidating the complex interplay between brain, behavior, and environment requires a multivariate approach. This study used regularized multiset canonical correlation analysis on longitudinal data from 8,113 preadolescents in the Adolescent Brain Cognitive Development study to characterize latent multivariate dimensions linking diverse environmental exposures, tract-wisely resolved measures of white matter (WM) development and integrity, and multi-domain behavioral phenotypes and relate them to concurrent and future psychopathology. Two distinct multivariate dimensions were identified exhibiting different exposure, WM development, and behavior patterns. The first linked greater socioeconomic resources to more advanced WM development, particularly in dorsal-association tracts, and superior cognitive performance. The second dimension linked stronger psychosocial support with higher WM integrity, more advanced development of limbic tracts, and lower levels of psychopathology. Longitudinal analyses revealed differential contributions of these dimensions to follow-up cognitive, socioemotional and psychiatric outcomes. Moreover, WM and exposomic variates in these dimensions moderated the effects of childhood adversity on transdiagnostic psychiatric disorder risk, in sex- and context-specific fashions. Together, these findings clarify how childhood environmental exposures and the linked WM developmental differences relate to cognition and psychopathology risk, potentially informing the identification of candidate neural targets for future interventions.","rel_num_authors":14,"rel_authors":[{"author_name":"DANNI WANG","author_inst":"National Institute on Drug Abuse"},{"author_name":"Christopher J Hammond","author_inst":"Johns Hopkins University"},{"author_name":"Betty Jo Salmeron","author_inst":"National Institute on Drug Abuse"},{"author_name":"Xiang Xiao","author_inst":"National Institute on Drug Abuse"},{"author_name":"Laura Murray","author_inst":"National Institute on Drug Abuse"},{"author_name":"Hong Gu","author_inst":"National Institute on Drug Abuse"},{"author_name":"Tianye Zhai","author_inst":"National Institute on Drug Abuse"},{"author_name":"Nanyu Kuang","author_inst":"National Institute on Drug Abuse"},{"author_name":"Hui Zheng","author_inst":"National Institute on Drug Abuse"},{"author_name":"Justine Hill","author_inst":"National Institute on Drug Abuse"},{"author_name":"Hanbing Lu","author_inst":"National Institute on Drug Abuse"},{"author_name":"Amy Janes","author_inst":"National Institute on Drug Abuse"},{"author_name":"Thomas J Ross","author_inst":"National Institute on Drug Abuse"},{"author_name":"Yihong Yang","author_inst":"National Institute on Drug Abuse"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"User-Informed Design of a Psychological Support Social Pet Robot for Community-Dwelling People With Long-Term Physical Disabilities: A Formative Study","rel_doi":"10.64898\/2026.11.09.26367593","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367593","rel_abs":"Background. Community-dwelling people with long-term physical disabilities may experience pain that interferes with daily and social activities and is associated with poorer mental wellbeing. A home-based psychological support social pet robot could offer mood check-ins, companionship, supportive interaction, and mindfulness guidance for community-dwelling people with long-term physical disabilities. Preliminary evidence is needed to understand their preferences and translate them into candidate design requirements. Objective. This study aimed to identify preliminary needs and preferences to inform a psychological support social pet robot for community-dwelling people with long-term physical disabilities, offering mood check-ins, companionship, and mindfulness guidance at home. Methods. We conducted a 3-phase formative user-informed design study comprising initial concept development, qualitative target user interviews, and a design workshop. Six community-dwelling adults with long-term physical disabilities took part in the interviews, and one participant also answered the workshop questions by telephone. Four authors used modified workshop materials to synthesize the interview findings and separate responses into an early product plan. Results. Qualitative content analysis of the interview transcripts produced 5 themes. These were emotional support, soft touch and appearance, mindfulness delivery, context of use, and ease of use and accessibility. Participants expressed preferences about companionship, touch, use settings, and interaction effort. The author workshop combined these findings with author and technical judgments to develop candidate requirements for dialogue and mindfulness delivery. The resulting psychological support concept combined mood check-ins and companion-oriented interaction with flexible mindfulness guidance. The design also needed to consider pain and daily routines. After the workshop, the authors developed a physical proof-of-concept prototype. It implemented only part of the candidate requirements and included additional author or technical choices. Conclusions. For this small community-dwelling sample, target user input showed that home use, physical access, companionship, and flexible support were important. Mindfulness was one component of the broader psychological support role, alongside mood check-ins and optional companion interaction. The prototype illustrates but does not validate the early requirements. Further studies should include people with a wider range of long-term physical disabilities and test usability, accessibility, privacy, and nursing value. Keywords. social pet robots; user-informed design; psychological support; mindfulness; long-term physical disabilities; community dwelling; user centered design; human robot interaction; mental health; qualitative research","rel_num_authors":9,"rel_authors":[{"author_name":"Yufei Lu","author_inst":"School of Nursing, Hong Kong Polytechnic University"},{"author_name":"Xiaobin Chen","author_inst":"School of Fashion and Textiles, The Hong Kong Polytechnic University"},{"author_name":"Ruomu Hui","author_inst":"School of Fashion and Textiles, The Hong Kong Polytechnic University"},{"author_name":"Yushen Dai","author_inst":"School of Nursing, The Hong Kong Polytechnic University"},{"author_name":"Xiaoxiao Mei","author_inst":"School of Nursing, The Hong Kong Polytechnic University"},{"author_name":"Ho So","author_inst":"Department of Medicine and Therapeutics, The Chinese University of Hong Kong"},{"author_name":"Chen Li","author_inst":"Department of Computing, The Hong Kong Polytechnic University"},{"author_name":"Xiaoming Tao","author_inst":"School of Fashion and Textiles, The Hong Kong Polytechnic University"},{"author_name":"Yan Li","author_inst":"School of Nursing, The Hong Kong Polytechnic University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"The Antipsychotic Load (AP_Load2026): a normalised prescribed-dose index for schizophrenia research","rel_doi":"10.64898\/2026.11.09.26367598","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367598","rel_abs":"Background and Hypothesis Schizophrenia research routinely reduces antipsychotic treatment to a single number, but the available summaries disagree. Chlorpromazine equivalents, the WHO Defined Daily Dose (DDD) and the percentage of the licensed maximum (%BNFmax) rank the same patient differently, most of all for clozapine, whose dose-concentration relationship varies several-fold with sex and smoking. We hypothesised that referencing clozapine dose to a target individualised for sex and smoking would track plasma clozapine better than dose-proportional measures. Study Design In the Antipsychotic Load (AP_Load2026), each daily dose is expressed as a percentage of a reference dose, summed without a cap. Clozapine is referenced to a target individualised for sex and cigarettes per day, under two published anchor schemes, and other antipsychotics to a dose reconciling the WHO DDD and the licensed maximum. The clozapine term was tested against plasma clozapine (1316 assessments, 255 patients) with log-log mixed-effects models, and the non-clozapine reference against independently derived published doses. Study Results The individualised reference tracked plasma clozapine better than any dose-proportional measure (marginal R^2 0.249 vs. 0.166; deltaR^2 0.082, 95% CI 0.044-0.120). The scheme with the larger smoking correction fitted better (0.249 vs. 0.231), an ordering robust to quality-control variants and co-prescription. Of five candidate references for other antipsychotics, %BNFmax was the least consistent with external criteria. Conclusions AP_Load2026 is a transparent framework for normalising prescribed antipsychotic dose. Its clozapine reference is validated against a biomarker, whereas the reference for other antipsychotics is a calibrated convention at least comparable with existing alternatives. The index is particularly suited to treatment-resistant and clozapine-enriched cohorts.","rel_num_authors":6,"rel_authors":[{"author_name":"Emilio Fernandez-Egea","author_inst":"Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Rajeev Krishnadas","author_inst":"Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Christopher Jenkins","author_inst":"Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Rashmi Patel","author_inst":"Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Rudolf N. Cardinal","author_inst":"Department of Psychiatry, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, UK"},{"author_name":"Noham Wolpe","author_inst":"Tel Aviv University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Nurse-Led Heart Failure Education and Patient Outcomes: A Mixed-Methods Prospective Registry Study","rel_doi":"10.64898\/2026.11.08.26367583","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.08.26367583","rel_abs":"Background Patient understanding of heart failure (HF) self-care varies widely and is inconsistently associated with clinical outcomes. We examined knowledge acquisition and patient experiences related to structured HF education using a patient handbook. Methods and Results Between April and December 2021, 56 patients hospitalized for acute HF (mean age 74 years, 35% women, 46% HFrEF) were enrolled from 176 screened patients at a single center. A 20-item knowledge assessment was administered before and after nurse led HF education and at first outpatient follow-up. Thirty patients met criteria for knowledge improvement ([&ge;]5-point increase or baseline [&ge;]15), while 25 did not. Knowledge gaps were most evident in exercise, medication effects, salt restriction, and recognition of exacerbating factors. Patients with knowledge improvement had higher post-education scores (16 vs. 12), sustained knowledge at follow-up, higher serum albumin levels, better inpatient dietary intake. One-year mortality and HF readmission did not differ. A nested qualitative analysis of four readmitted patients identified 94 codes grouped into 9 categories, highlighting personalized symptom recording, persistent self-management challenges despite handbook use, enhanced communication with healthcare professionals, reflection on future care, and a desire for earlier HF education. Conclusions Patients who achieved higher HF knowledge scores demonstrated better nutritional status but similar one-year clinical outcomes. Qualitative findings underscore ongoing challenges in long-term HF self-care.","rel_num_authors":9,"rel_authors":[{"author_name":"Erica Nagata","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Reona Sasamoto","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Ami Endo","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Shino Miura","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Haruna Goto","author_inst":"Department of Nursing, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Hiroaki Sukegawa","author_inst":"Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Yoshinori Mano","author_inst":"Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Takahiro Ohki","author_inst":"Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan"},{"author_name":"Mitsuaki Sawano","author_inst":"Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan; Teikyo University Academic Research Center, Itabashi, Japan"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Reduced serum carboxymethyllysine is independently associated with Alzheimer's disease","rel_doi":"10.64898\/2026.11.08.26367562","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.08.26367562","rel_abs":"INTRODUCTION: Advanced glycation end products accumulate in Alzheimer's disease (AD) brain, but the clinical significance of circulating N{varepsilon}-(carboxymethyl)lysine (CML) remains uncertain. We evaluated serum CML as a complementary peripheral biomarker of AD. METHODS: This observational case-control study enrolled 101 patients with clinically diagnosed AD and 91 healthy controls. Serum CML was quantified in 191 participants. Multivariable logistic regression and receiver operating characteristic analyses assessed association and discrimination. A randomly selected subcohort underwent ultrasensitive measurement of amyloid-, tau-, glial-, and neuroaxonal-related biomarkers. RESULTS: Serum CML was lower in AD than controls (median 15.26 versus 23.72 ng\/mL; P<0.001). In a complete-case model (n=178), each 1-ng\/mL increase was associated with lower odds of AD (adjusted odds ratio 0.727, 95% confidence interval 0.656-0.804). CML alone yielded an area under the curve (AUC) of 0.883. Five-fold cross-validation yielded AUCs of 0.727 for a clinical model and 0.911 after adding CML. In the biomarker subcohort, AD showed lower A{beta}42\/A{beta}40 and higher p-tau217; exploratory CML plus p-tau217 discrimination reached an AUC of 0.966 (n=60). DISCUSSION: Reduced serum CML was independently associated with clinically diagnosed AD and may reflect a systemic glycoxidative dimension complementary to canonical biomarkers. Its biological origins and clinical value require external, longitudinal, and biomarker-defined validation.","rel_num_authors":5,"rel_authors":[{"author_name":"Yihong Li","author_inst":"Ningbo No.2 Hospital, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences"},{"author_name":"Mei Yang","author_inst":"Affiliated Kangning Hospital of Ningbo University"},{"author_name":"Xing Feng","author_inst":"Ningbo No.2 Hospital,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences"},{"author_name":"Guosheng Gao","author_inst":"Ningbo No.2 Hospital Department of Liver disease"},{"author_name":"Huadong Fan","author_inst":"Ningbo No.2 Hospital, Ningbo Institue of Life and Health Industry, University of Chinese Academy of Sciences"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Myeloid subpopulations correlate with responsiveness to therapy in a prospective, longitudinal study on RA patients","rel_doi":"10.64898\/2026.11.02.26367113","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.02.26367113","rel_abs":"Background: Rheumatoid arthritis (RA) is an autoimmune disease associated with the destruction of cartilage and bone, increased risk of cardiovascular disease and a higher mortality rate. Despite the many therapies that exist for RA, there is little information to guide selection of the most effective treatment for an individual patient. Ultrasound-guided synovial biopsies have created an opportunity to investigate the target tissue. While a number of studies have characterized the stromal and immune cell populations using single-cell technology on synovial biopsy samples, here we performed a longitudinal study, where we collected comprehensive clinical data over a one-year period on each patient in the process of changing their therapy. Methods: Samples from minimally invasive, ultrasound-guided synovial biopsies were collected from RA patients at baseline prior to start of a new therapy and 4-6-week follow-up under IRB-approved protocols with informed consent. Comprehensive clinical data from each appointment were recorded into a shared REDCap database. Failure to respond to therapy was based on clinical disease activity index (CDAI) for RA after 12-18 weeks post therapy. Biopsied samples were dissociated, enriched for CD45 or CD45CD11b cells, and processed on the 10X Genomics Chromium platform to generate libraries for single-cell RNA sequencing with cell-surface protein detection (CITE-seq). Spatial transcriptomics were performed on formalin-fixed paraffin embedded sections analyzed with 10X Xenium and NanoString CosMx. Results: We performed CITE-seq analysis on ~38,000 CD45+ synovial cells isolated from 17 patients who failed a conventional or biologic DMARD and planned to change therapy. We then subclustered on the myeloid population to reveal 12 myeloid subpopulations that consist of macrophages (n = 8), Osteoclast-like cells, DCs (n = 2) and proliferating cells. The proportion of cDCs was significantly higher in responders, while the proportion of macrophages was significantly lower in responders. The proportion of ISG15+ and THBS1+macrophages were enriched in the non-responder patients. Spatial transcriptomics revealed that ISG15+ macrophages were preferentially localized to the synovial lining, while the THBS1+ macrophages are likely interacting with lymphoid cells within the sublining tissue. Conclusions: These data are among the first to prospectively profile macrophage populations as predictors of response to therapy. Future studies are required to verify whether myeloid subpopulation associations hold across specific therapies.","rel_num_authors":22,"rel_authors":[{"author_name":"Mohammad Daud Khan","author_inst":"Northwestern University"},{"author_name":"Matthew Dapas","author_inst":"Northwestern University"},{"author_name":"Salina T. Dominguez","author_inst":"Northwestern University"},{"author_name":"Tyler Therron","author_inst":"Northwestern University"},{"author_name":"Kathleen Aren","author_inst":"Northwestern University"},{"author_name":"Mary Carns","author_inst":"Northwestern University"},{"author_name":"Hadijat M. Makinde","author_inst":"Northwestern University"},{"author_name":"Yidan Wang","author_inst":"Northwestern University"},{"author_name":"Samuel D. Dowling","author_inst":"Northwestern University"},{"author_name":"Richard M. Pope","author_inst":"Northwestern University"},{"author_name":"Arthur M. Mandelin II","author_inst":"Northwestern University"},{"author_name":"Eric M. Ruderman","author_inst":"Northwestern University"},{"author_name":"Joan M. Bathon","author_inst":"Columbia University"},{"author_name":"Laura B. Geraldino-Pardilla","author_inst":"Columbia University"},{"author_name":"Lutfiyya N. Muhammad","author_inst":"Northwestern University"},{"author_name":"Anh Chung","author_inst":"Northwestern University"},{"author_name":"John F. Seagrist","author_inst":"Northwestern University"},{"author_name":"Ruth Misha","author_inst":"Northwestern University"},{"author_name":"Yvonne C. Lee","author_inst":"Northwestern University"},{"author_name":"Carla M. Cuda","author_inst":"Northwestern University"},{"author_name":"Deborah R. Winter","author_inst":"Northwestern University"},{"author_name":"Harris Perlman","author_inst":"Northwestern University"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Gabapentinoid to Loop Diuretic Prescribing Cascade: A Systematic Review and Meta-Analysis of Observational Studies","rel_doi":"10.64898\/2026.11.08.26367537","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.08.26367537","rel_abs":"Introduction. Gabapentinoid-induced peripheral edema may be misinterpreted as a new condition and treated with a loop diuretic, creating a prescribing cascade. Objective. To synthesize evidence on the gabapentinoid-to-loop diuretic prescribing cascade in adults: its magnitude, dose- and drug-related gradients, timing, and downstream harms. Methods. We searched MEDLINE, Embase, PubMed, and Web of Science to 23 April 2026 (PROSPERO CRD420261379968) for studies of loop diuretic initiation after gabapentinoid initiation and assessed risk of bias with ROBINS-I. Findings were synthesized by study design, and adjusted sequence ratios were pooled in a random-effects meta-analysis. Results. Nine studies from five countries (>1.8 million new gabapentinoid users) were included: five sequence symmetry analyses, three cohort studies, and one chart review; six were restricted to older adults and two were available only as conference reports. All five sequence symmetry analyses and both cohort studies with an unexposed comparison group found more diuretic prescribing after gabapentinoid initiation. Sequence ratios ranged from 1.23 to 1.69, with a pooled adjusted sequence ratio of 1.37 (95% CI 1.14-1.64; I2= 96%; five estimates from four studies). Both of these cohort studies reported an adjusted hazard ratio of 1.44 (loop diuretics in one, any diuretic in the other). Higher doses were associated with larger estimates in four of the five studies that examined dose. In one chart review, 23.3% of patients had a potential harm within 60 days of starting a loop diuretic. Conclusions. Gabapentinoid initiation was associated with subsequent loop diuretic prescribing, mainly in older adults, consistent with a prescribing cascade. Clinicians may consider a recently started gabapentinoid as a possible cause of new edema before adding a loop diuretic.","rel_num_authors":24,"rel_authors":[{"author_name":"Abdallah Alami","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Lucia de la Mora Vargas","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Isabella Prada Betancourt","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Lucia Lopez-Paternostro","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Emilio A. Flores Boggiano","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Joao Victor M. S. Martelli","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Livian Scabeni Pan","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Paulina Vivanco-Aravena","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Oscar Munoz-Narvaez","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Daniel Montanini","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Marcela Borba Osorio","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Sara Baroom","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Rossy Cruz-Vicioso","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Yuri Ramirez","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Daniela Abele","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Manuel Santos-Salce","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Carlos Collado","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Isabela Resende da Gloria","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Fatima Ramos","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Tatiane De Miranda","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Lidiz Mora-Marquez","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Abdul Haseeb","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Federica Rossetto","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Guilherme Franceschini Machado","author_inst":"Harvard T.H. Chan School of Public Health"}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Genetic effects on serum and urine metabolites across ancestries and their links to disease","rel_doi":"10.64898\/2026.11.09.26367601","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367601","rel_abs":"Genome-wide association studies of the metabolome have predominantly examined European-ancestry populations using a single biofluid, constraining both the discovery of metabolite quantitative trait loci (mQTLs) and the resolution of causal variant finemapping. Here, we report a multi-ancestry genome-wide association study of 1,955 serum and urine metabolites in 4,431 European American and African American participants from the Atherosclerosis Risk in Communities study. We identify 969 mQTLs for 553 metabolites, 30% unreported in studies of matched biofluid and ancestry, and replicate 91-99% of testable mQTLs in two independent cohorts. In the African American sample with balanced sample sizes, 36% of metabolites with mQTLs are serum-specific, 39% urine-specific, and 25% shared, demonstrating complementary genetic architecture. Only 23 of 632 candidate ancestry-specific mQTLs show heterogeneous effects beyond variant availability and power, yet allele frequency differences expose functional variants such as an SLC28A1 splice variant, virtually absent in Europeans, that increases urine uridine excretion, implicating impaired CNT1-mediated renal nucleoside reabsorption. Multi-ancestry finemapping improves credible set resolution, and colocalization with the Million Veteran Program phenome links the catalog to cardiometabolic, kidney and liver traits consistent with prioritized gene function. Integrating biofluids and ancestries enhances genetic discovery and mechanistic characterization of the human metabolome.","rel_num_authors":22,"rel_authors":[{"author_name":"Inga Steinbrenner","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Ruiyuan Zhang","author_inst":"Department of Epidemiology, Peter O'Donnell School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Nora Scherer","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Yura Lee","author_inst":"Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States; Department of Epidemiology"},{"author_name":"Ngoc Quynh H Nguyen","author_inst":"Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States; Department of Epidemiology"},{"author_name":"Alex Waterhoelter","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology"},{"author_name":"Zulema Rodriguez-Hernandez","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Oleg Borisov","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Dmitrii Zakharenko","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Aditya Surapaneni","author_inst":"Division of Precision Medicine, New York University Grossman School of Medicine, New York, New York, United States"},{"author_name":"Sara Monteiro-Martins","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Yong Li","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany"},{"author_name":"Tanika N. Kelly","author_inst":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine, University of Illinois Chicago, Chicago, IL, USA"},{"author_name":"Jing Chen","author_inst":"Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Jiang He","author_inst":"Department of Epidemiology, Peter O'Donnell School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Anna Koettgen","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns "},{"author_name":"Eric Boerwinkle","author_inst":"Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States; Department of Epidemiology"},{"author_name":"Josef Coresh","author_inst":"Optimal Aging Institute and Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States; Division of Epidemiology, Depa"},{"author_name":"Morgan E. Grams","author_inst":"Division of Precision Medicine, New York University Grossman School of Medicine, New York, New York, United States"},{"author_name":"Changwei Li","author_inst":"Department of Epidemiology, Peter O'Donnell School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Bing Yu","author_inst":"Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States; Department of Epidemiology"},{"author_name":"Pascal Schlosser","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns "}],"rel_date":"2026-11-10","rel_site":"medrxiv"},{"rel_title":"Multiple adaptive trajectories shape antimalarial resistance evolution in Ethiopian Plasmodium falciparum","rel_doi":"10.64898\/2026.11.09.764565","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.764565","rel_abs":"Plasmodium falciparum malaria continues to impose a substantial public health burden across sub-Saharan Africa, with Ethiopia experiencing a recent resurgence in malaria cases. We analysed whole genome data from 120 P. falciparum isolates collected in 2024 across five ecologically and epidemiologically diverse transmission settings in Ethiopia and placed these in the context of 1,220 publicly available genomes. Parasite populations were highly structured within Ethiopia, while Horn of Africa isolates formed a genetically distinct regional cluster relative to East and West African populations. We identified evidence of recent positive selection surrounding the artemisinin resistance associated PfK13 R622I variant and detected co-occurrence with Pfcrt mutations together with recurrent selection signals at genes within the PfK13-associated haemoglobin endocytosis pathway, including Pfmca2, Pfkic7, Pfkic8 and Pfkic9. We further observed the emergence of the PfPX1 D384A-PIN haplotype, with shared identity-by-descent linking Ethiopian and Ugandan carriers, supporting a recent introduction followed by local selection. Widespread Pfhrp2\/3 deletions occurred on diverse genetic backgrounds. Together, these findings reveal a complex adaptive landscape shaped by antimalarial and diagnostic selection pressures and suggest that parasite evolution in the Horn of Africa proceeds through multiple adaptive trajectories, rather than through the spread of a single dominant lineage.","rel_num_authors":21,"rel_authors":[{"author_name":"Leen N Vanheer","author_inst":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK; Malaria Centre, London"},{"author_name":"Metmiku Yohannes","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Dagnachew Fenta Workie","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia; Radboud University Medical Centre, Nijmegen, The Netherlands.; Addis Ababa University, Addis Ababa, Et"},{"author_name":"Amanuel Shimelash","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Meklit Shiferaw","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Dawit Hailu Alemayehu","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Yisehak Teshome","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Shewafera Ademu","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Nina Billows","author_inst":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK; Malaria Centre, London"},{"author_name":"Fekadesilassie Mozart Mesafint","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Fikregabrail Aberra Kassa","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Melat Abdo","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Yisihak Abreham Weldehana","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Natnael Lemessa Hundera","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Haimanot Andualem Ayalsew","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Migbaru Keffale Bezabih","author_inst":"Armauer Hansen Research Institute, Addis Ababa, Ethiopia"},{"author_name":"Daniel Neafsey","author_inst":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Infectious Disease and Microbiome Program, Broad "},{"author_name":"Bryan Greenhouse","author_inst":"PPIcenter Research Program, Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA."},{"author_name":"Susana Campino","author_inst":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK; Malaria Centre, London"},{"author_name":"Nicholas Hathaway","author_inst":"PPIcenter Research Program, Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA."},{"author_name":"Fitsum Girma Tadesse","author_inst":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; Malaria Centre, Londo"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Sex-linked genomic variation reveals reproductive skew and male-biased dispersal in polygynous sea lions","rel_doi":"10.64898\/2026.11.06.764841","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764841","rel_abs":"Sex-biased dispersal and the resulting asymmetry in gene flow are important factors in evolution. However, their quantification in natural populations remains challenging, not least because sex-specific reproductive skew, as reflected in the mating system, further influences the relative contributions of males and females to the genetic pool of subsequent generations. Incorporating information from mitochondria (MT) and sex chromosomes (X, Y) alongside the more commonly used autosomal markers (AUT) provides a promising framework to partly disentangle confounding processes. Here, we exemplify this approach in two closely related, polygynous species with observational evidence for male-biased dispersal, the Galapagos sea lion (GSL) and the Steller sea lion (SSL). Using whole-genome resequencing data, we leveraged genetic variation among all four genomic compartments, representing genetic variation with female-only (MT), mixed (X, AUT) and male-only (Y) inheritance, to obtain information on the mating system and test for sex-specific migration across geographic and environmental boundaries. For GSL, genomic signatures were consistent with mild polygyny and a moderately elevated rate of male migration, particularly across habitat boundaries. In SSL, male reproductive skew was substantially greater, and male-biased migration was more pronounced and less habitat-dependent. Our results align with the species' life history and support a link between mating system and dispersal, but were also impacted by confounding biological processes and bioinformatic choices. This study highlights the value and challenges of population genomic approaches integrating multiple genomic compartments to infer variation in individual behaviours.","rel_num_authors":10,"rel_authors":[{"author_name":"Aliya Yakupova","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"},{"author_name":"Camille Kessler","author_inst":"LMU"},{"author_name":"Lara Baggio","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"},{"author_name":"Stefanie Gosser","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"},{"author_name":"Claire R. Peart","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"},{"author_name":"Fidel Botero-Castro","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Amy B. Baird","author_inst":"Department of Natural Sciences, University of Houston"},{"author_name":"John W. Bickham","author_inst":"Department of Ecology and Conservation Biology, Texas AM University"},{"author_name":"Joseph Hoffman","author_inst":"Bielefeld University"},{"author_name":"Jochen B. W. Wolf","author_inst":"Department of Evolutionary Biology, Faculty of Biology, LMU Munich, Martinsried-Planegg, Germany"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Epigenetic Mechanisms Inhibit Smad7 and Contribute to Fibrosis in Crohn's Disease","rel_doi":"10.64898\/2026.11.09.765430","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765430","rel_abs":"Background & Aims: TGF-beta1 is a central regulator of profibrotic gene expression, extracellular matrix deposition, and the development of intestinal fibrosis in patients with fibrostenotic Crohns disease (CD). Unlike the increased expression of Smad7 in mucosal and lamina propria monocytes, where it impairs Treg function, mesenchymal cells from patients with fibrostenotic CD do not exhibit elevated Smad7 expression and instead display sustained TGF-beta1 signaling. We therefore sought to elucidate the mechanisms underlying the unexpected silencing of Smad7 in fibrostenotic CD. Methods: Subepithelial myofibroblasts (SEMFs) and muscularis smooth muscle cells were isolated from paired normal and affected ileal tissues obtained from the same patients with each Montreal phenotype of CD, as well as from non-CD controls. Gene expression, RNA-binding affinity, transcriptional activity, promoter methylation, protein levels, and the mechanisms that regulate Smad7 expression were evaluated in ex vivo tissues and primary cultured cells. MicroRNA-21 (miR-21) localization was assessed by RNAscope. miR-21-mediated suppression of Smad7 was investigated using antagomiR-21. Smad7 silencing through promoter hypermethylation was confirmed using 5-Azacytidine treatment and DNA methyltransferase 1 (DNMT1) knockdown. Smad7 lysine acetylation and Smurf1\/2-mediated ubiquitination were examined using selective inhibitors and proximity ligation assays. Results: In SEMFs from patients with fibrostenotic CD, aberrant silencing of Smad7 resulted from DNMT1-dependent promoter hypermethylation and pSmad3-driven, miR-21-mediated degradation of Smad7 mRNA. In addition, Smurf1\/2 promoted ubiquitination and proteasomal degradation of acetylated Smad7 protein. Inhibition of miR-21 with antagomiR-21 restored Smad7 expression and reduced TGF-beta 1-dependent profibrotic gene expression. Likewise, demethylation with 5-Azacytidine or knockdown of DNMT1 induced Smad7 promoter hypomethylation and restored Smad7 expression. Furthermore, modulation of the balance between p300 acetyltransferase and histone deacetylase 1 (HDAC1) stabilized Smad7 protein by protecting it from degradation. Conclusions: A distinctive pattern of epigenetic silencing and post-translational regulation of Smad7 was identified in patients with fibrostenotic CD. These mechanisms collectively promote unrestrained TGF-beta1 signaling by suppressing Smad7 expression and stability in SEMFs, thereby contributing to the development of intestinal fibrosis.","rel_num_authors":6,"rel_authors":[{"author_name":"Chao Li","author_inst":"Washington University School of Medicine"},{"author_name":"Karnam Murthy","author_inst":"Virginia Commonwealth University"},{"author_name":"Jaime Bohl","author_inst":"Virginia Commonwealth University"},{"author_name":"Emily Rivet","author_inst":"Virginia Commonwealth University"},{"author_name":"Nicole Wieghard","author_inst":"Virginia Commonwealth University"},{"author_name":"John Kuemmerle","author_inst":"Virginia Commonwealth University"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Spatial proteomics on repurposed sequencers reveals early astrocytic remodeling in an ALS mouse model","rel_doi":"10.64898\/2026.11.08.765207","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765207","rel_abs":"Spatial proteomics can reveal how disease reshapes cells and their local environments, but extending these measurements across replicated tissue cohorts requires validated antibodies, consistent sample processing and integrated analysis. These requirements are particularly pressing in studies of amyotrophic lateral sclerosis (ALS), where pathology evolves unevenly across spinal-cord regions and disease stages. Here, we established an end-to-end spatial proteomics workflow linking a validated 28-antibody panel to automated fluorescence decoding and imaging on repurposed high-throughput sequencers, followed by multicycle image processing, cellular profiling and probabilistic spatial-neighborhood analysis. We applied it to 70 lumbar spinal-cord sections from nine SOD1-G93A and nine wild-type mice at presymptomatic, disease-onset and symptomatic stages. Spatial neighborhood analysis revealed that the environments surrounding motor neurons were already remodeled at disease onset. GFAP-high neighborhoods expanded in the ventral gray matter, with 43% of motor neurons embedded in these environments in SOD1-G93A mice, compared with 15% in wild-type mice. This early expansion preceded the later decline of non-reactive gray matter and detectable motor-neuron loss. The regional organization of the protein-defined changes shared features with neuronal and astrocytic patterns mapped by spatial transcriptomics in mouse and human ALS. This work enables spatial proteomics across replicated tissue cohorts and identifies localized remodeling of the environments around surviving motor neurons as an early feature of disease in the SOD1-G93A model.","rel_num_authors":12,"rel_authors":[{"author_name":"Kunal Pandit","author_inst":"New York Genome Center"},{"author_name":"Craig Fouts","author_inst":"New York Genome Center; Columbia University (Biomedical Engineering; Herbert Irving Institute for Cancer Dynamics); Uppsala University (Science for Life Laborat"},{"author_name":"Sarah Rodwin","author_inst":"New York Genome Center"},{"author_name":"Silas Maniatis","author_inst":"New York Genome Center"},{"author_name":"Karan Dhingra","author_inst":"New York Genome Center"},{"author_name":"Selma Marrakchi","author_inst":"New York Genome Center"},{"author_name":"Daniel Domovic","author_inst":"New York Genome Center"},{"author_name":"Jagjit Singh","author_inst":"Department of Biomedical Engineering, Columbia University, New York, NY, USA; Herbert Irving Institute for Cancer Dynamics, Columbia University, New York, NY, U"},{"author_name":"Bianca Dumitrascu","author_inst":"Herbert Irving Institute for Cancer Dynamics, Columbia University, New York, NY, USA; Department of Statistics, Columbia University, New York, NY, USA"},{"author_name":"Hemali Phatnani","author_inst":"New York Genome Center, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Maros Pleska","author_inst":"New York Genome Center"},{"author_name":"Sanja Vickovic","author_inst":"New York Genome Center; Columbia University (Biomedical Engineering; Herbert Irving Institute for Cancer Dynamics); Uppsala University (Science for Life Laborat"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"A complete adult Drosophila melanogaster brain tracheolar network","rel_doi":"10.64898\/2026.11.09.765327","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765327","rel_abs":"The tracheal system of the fruit fly, Drosophila melanogaster, is a complex network of epithelial tubules that supplies oxygen and removes carbon dioxide throughout the organism, with gases entering and exiting through spiracles along the body. While tracheal development and patterning in the embryonic and larval stages have been extensively studied, particularly in the body, much less is known about tracheal and tracheolar organization within the adult brain. To address this gap, we manually traced every tracheole in the brain of a female adult Drosophila using the Full Adult Fly Brain (FAFB) open-access electron microscopy dataset. We reconstructed 117 tracheoles that branch within the parenchyma, terminating in 1,376 endings without forming an interconnected network. Joint analysis of these skeleton reconstructions with volumetric mesh segmentations from the FlyWire connectome revealed that tracheole volume fraction is heterogeneous across neuropils and largely symmetric in overall tracheation between left and right hemispheres. We observe that synapses are not preferentially positioned near tracheoles, and are instead slightly depleted from a region approximately 15 um around tracheoles, relative to other points along the same neurons. We also quantify the relative proximity of neurotransmitter-specific synapses and cables to tracheoles across neuropils. This detailed anatomical description of the tracheolar network establishes a reference for future studies examining how neuronal patterning, activity, and metabolic demand couple with tracheole development and function.","rel_num_authors":22,"rel_authors":[{"author_name":"Haneul Cho","author_inst":"Mount Holyoke College"},{"author_name":"Thea Ng","author_inst":"Mount Holyoke College"},{"author_name":"Kira Schoenberg","author_inst":"Mount Holyoke College"},{"author_name":"Sommer Huntress","author_inst":"Mount Holyoke College"},{"author_name":"Jimin Suh","author_inst":"Mount Holyoke College"},{"author_name":"Athena Manandhar","author_inst":"Mount Holyoke College"},{"author_name":"Shuojia Lin","author_inst":"Mount Holyoke College"},{"author_name":"Bethelehem M. Woldetsadik","author_inst":"Mount Holyoke College"},{"author_name":"Rachel S. Kang","author_inst":"Mount Holyoke College"},{"author_name":"Mai Bui","author_inst":"Mount Holyoke College"},{"author_name":"Louisa M. Zebrowski","author_inst":"Mount Holyoke College"},{"author_name":"Fiona Reynolds-Cornell","author_inst":"Mount Holyoke College"},{"author_name":"Elizabeth Agbedun","author_inst":"Mount Holyoke College"},{"author_name":"Yaslyn Cruz","author_inst":"Mount Holyoke College"},{"author_name":"Caroline A. Lewis","author_inst":"Mount Holyoke College"},{"author_name":"Kesshni Bhasiin","author_inst":"Mount Holyoke College"},{"author_name":"Keying Lin","author_inst":"Mount Holyoke College"},{"author_name":"Carmela Mooney","author_inst":"Mount Holyoke College"},{"author_name":"Andrew M. Dacks","author_inst":"Case Western Reserve University"},{"author_name":"Philipp Schlegel","author_inst":"MRC Laboratory of Molecular Biology"},{"author_name":"Davi D. Bock","author_inst":"University of Vermont"},{"author_name":"Kenneth J. Colodner","author_inst":"Mount Holyoke College"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Molecular Mechanisms of Quizartinib Resistance in FLT3 Mutants","rel_doi":"10.64898\/2026.11.09.765260","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765260","rel_abs":"Quizartinib, a type II FLT3 inhibitor approved for FLT3-ITD-positive acute myeloid leukemia (AML), is frequently limited by acquired resistance, which arises in up to 40% of patients with disease progression and is driven largely by the D835Y and F691L kinase-domain mutations. To define the underlying mechanisms, we performed triplicate 200-ns all-atom molecular dynamics simulations of wild-type FLT3, FLT3-D835Y, and FLT3-F691L in complex with Quizartinib, combining conformational analysis, MM-GBSA binding free-energy calculations, and binding-pocket characterization. Both mutations destabilized the inactive DFG-out conformation required for type II inhibitor binding, with mean binding free-energy reductions of 5 kcal\/mol for D835Y and 10 kcal\/mol for F691L relative to wild-type. D835Y disrupted the activation-loop electrostatic network and reduced Cys694 hydrogen-bond occupancy from 85% to 45%, whereas F691L abolished key van der Waals contacts and opened a 120 cubic Angstrom hydrophobic void at the gatekeeper position. Both mutants sampled a wider range of conformations and lost 14-17% of binding-pocket volume. These predictions were corroborated by CCK-8 viability assays and Western blotting of p-FLT3 (Y591) in Ba\/F3 cells, which reproduced the predicted resistance hierarchy (F691L > D835Y > WT) at the cellular level. Together, these results indicate that D835Y and F691L confer resistance through distinct electrostatic and hydrophobic mechanisms that converge on destabilization of the inactive kinase conformation, providing a structural basis for the design of next-generation FLT3 inhibitors.","rel_num_authors":11,"rel_authors":[{"author_name":"Duoduo Zhao","author_inst":"Zhejiang University"},{"author_name":"Yongjian Li","author_inst":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematolo"},{"author_name":"Andrew Vu","author_inst":"Keck School of Medicine, University of Southern California"},{"author_name":"Yutong Miao","author_inst":"Department of Cardiovascular Medicine, University of Pennsylvania"},{"author_name":"Xuwen Wang","author_inst":"College of Information Science and Electronic Engineering, Zhejiang University"},{"author_name":"Binben Wang","author_inst":"School of Mathematical Sciences, Zhejiang University"},{"author_name":"Yi Qiao","author_inst":"Shanghai Sixth People's Hospital"},{"author_name":"Siyuan Song","author_inst":"Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine"},{"author_name":"Xinnuo Yang","author_inst":"Department of Cardiology of The Second Affiliated Hospital, School of Medicine, Zhejiang University"},{"author_name":"Zhehua Shao","author_inst":"Second Affiliated Hospital of Zhejiang University School of Medicine"},{"author_name":"Jinliang Nan","author_inst":"School of Medicine, Zhejiang University"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Ultra-low-dose same-target combinations control drug resistance across stages","rel_doi":"10.64898\/2026.11.08.764983","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.764983","rel_abs":"The emergence of drug resistance continues to limit the long term effectiveness of cancer therapies [1], as tumour cells adapt to therapeutic selective pressure through diverse genetic and non-genetic routes [2,3]. Despite advances in more potent and next generation inhibitors and mechanism based combination therapies [4,5], durable disease control remains difficult to achieve. Here we tested an alternative strategy: combining multiple inhibitors directed against the same oncogenic driver, each at ultra low doses with minimal individual activity, to delay resistance emergence. In epidermal growth factor receptor (EGFR) driven cancer models, such ultra low dose same target combinations (ULDCs) distributed individually weak perturbations across multiple inhibitors directed against the same target and achieved substantial growth inhibition in vitro and antitumour activity in vivo despite weak effects of the corresponding single agents. Under similar levels of growth inhibition (~50%), single-agent EGFR inhibitors generated resistant outgrowth, whereas a five drug ULDC delayed resistance emergence. Increasing the number of inhibitors further delayed resistance emergence, with no detectable resistant outgrowth observed for combinations containing 8 to 14 inhibitors within the experimental timeframe. The five drug ULDC also retained measurable growth inhibitory activity against gefitinib resistant PC-9\/GR cells, and resistant cells arising under five drug ULDC treatment exhibited markedly greater reversibility following drug withdrawal than those arising under single agent treatment. Although pharmacological additivity or synergy may contribute to the collective growth inhibitory effects of ULDCs, the divergent long term resistance outcomes observed under similar levels of growth inhibition indicate that resistance behaviour is not determined by inhibitory strength alone. Instead, our findings support a model in which increasing same target inhibitor diversity progressively constrains the adaptive trajectories available during resistance evolution, while therapeutic perturbation architecture may also influence the stability of resistant states that emerge. More broadly, these findings support the concept of same target collective suppression, in which multiple individually weak perturbations directed against the same target can collectively produce substantial antitumour activity and constrain resistance evolution across multiple stages. We propose that increasing same target inhibitor diversity may restrict accessible adaptive trajectories, while therapeutic perturbation architecture may also influence the stability of resistant states.","rel_num_authors":7,"rel_authors":[{"author_name":"Zhi-Gao Zhao","author_inst":"College of Life Science and Engineering, Southwest Jiaotong University"},{"author_name":"Shao-Qing Cai","author_inst":"School of Pharmaceutical Sciences, Peking University"},{"author_name":"Rui Tan","author_inst":"College of Life Science and Engineering, Southwest Jiaotong University"},{"author_name":"Weijing Cai","author_inst":"Department of Medicinal Chemistry, College of Pharmacy, University of Florida"},{"author_name":"Qian Zhao","author_inst":"School of Pharmaceutical Sciences, Peking University"},{"author_name":"Xuan Wang","author_inst":"School of Pharmaceutical Sciences, Peking University"},{"author_name":"Feng Xu","author_inst":"School of Pharmaceutical Sciences, Peking University"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Unavoidable Disasters: the Hsp70 Chaperone Can Only Prevent Aggregation Over a Limited Time Span","rel_doi":"10.64898\/2026.11.09.765239","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765239","rel_abs":"Cells must attain and maintain proper protein folding and avoid aggregation: this is a pervasive challenge across all domains of life. Molecular chaperones are central to this process, acting through mechanisms shaped by the free-energy landscapes of their client proteins. The impact of chaperones on client-specific kinetic and thermodynamic characteristics, however, remains poorly characterized. Here, we develop the CHAMPION70 computational model to perform kinetic simulations on the E. Coli Hsp70 chaperone system in the presence of client-protein folding and aggregation. Experimentally determined folding\/unfolding\/aggregation rate constants are taken into account. In the case of weakly aggregation-prone clients, CHAMPION70 predicts that Hsp70 prevents aggregation only over timescales approaching the average human lifespan (79 years). For strongly aggregation-prone clients, however, aggregation inevitably occurs starting from a few minutes, even at higher-than-physiological Hsp70 concentrations. Thus, the Hsp70 chaperone system merely delays, yet surprisingly does not eliminate, the onset of aggregation. Further, CHAMPION70 predicts that Hsp70 most effectively retards the aggregation of slow-folding, thermodynamically stable clients. In contrast, thermodynamically unstable clients remain engaged with Hsp70 for prolonged periods even when aggregation propensity is low, thereby consuming chaperone capacity and reducing the extent of productive folding. This outcome suggests that condensate formation by proteins containing disordered regions may serve to mitigate unnecessary Hsp70 engagement. In all, our results provide a quantitative framework for understanding how client-specific kinetic and thermodynamic properties shape chaperone activity and show that the Hsp70 chaperone system does not altogether prevent aggregation: it merely retards it.","rel_num_authors":7,"rel_authors":[{"author_name":"Miranda F. Mecha","author_inst":"University of Wisconsin-Madison"},{"author_name":"Matias J. Dahl","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jasmine K. Machhi","author_inst":"University of Wisconsin-Madison"},{"author_name":"Samuel C. Carey","author_inst":"University of Wisconsin-Madison"},{"author_name":"Hanming Yang","author_inst":"University of Wisconsin-Madison"},{"author_name":"Xi Chen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Silvia Cavagnero","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Unavoidable Disasters: the Hsp70 Chaperone Can Only Prevent Aggregation Over a Limited Time Span","rel_doi":"10.64898\/2026.11.09.765239","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765239","rel_abs":"Cells must attain and maintain proper protein folding and avoid aggregation: this is a pervasive challenge across all domains of life. Molecular chaperones are central to this process, acting through mechanisms shaped by the free-energy landscapes of their client proteins. The impact of chaperones on client-specific kinetic and thermodynamic characteristics, however, remains poorly characterized. Here, we develop the CHAMPION70 computational model to perform kinetic simulations on the E. Coli Hsp70 chaperone system in the presence of client-protein folding and aggregation. Experimentally determined folding\/unfolding\/aggregation rate constants are taken into account. In the case of weakly aggregation-prone clients, CHAMPION70 predicts that Hsp70 prevents aggregation only over timescales approaching the average human lifespan (79 years). For strongly aggregation-prone clients, however, aggregation inevitably occurs starting from a few minutes, even at higher-than-physiological Hsp70 concentrations. Thus, the Hsp70 chaperone system merely delays, yet surprisingly does not eliminate, the onset of aggregation. Further, CHAMPION70 predicts that Hsp70 most effectively retards the aggregation of slow-folding, thermodynamically stable clients. In contrast, thermodynamically unstable clients remain engaged with Hsp70 for prolonged periods even when aggregation propensity is low, thereby consuming chaperone capacity and reducing the extent of productive folding. This outcome suggests that condensate formation by proteins containing disordered regions may serve to mitigate unnecessary Hsp70 engagement. In all, our results provide a quantitative framework for understanding how client-specific kinetic and thermodynamic properties shape chaperone activity and show that the Hsp70 chaperone system does not altogether prevent aggregation: it merely retards it.","rel_num_authors":7,"rel_authors":[{"author_name":"Miranda F. Mecha","author_inst":"University of Wisconsin-Madison"},{"author_name":"Matias J. Dahl","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jasmine K. Machhi","author_inst":"University of Wisconsin-Madison"},{"author_name":"Samuel C. Carey","author_inst":"University of Wisconsin-Madison"},{"author_name":"Hanming Yang","author_inst":"University of Wisconsin-Madison"},{"author_name":"Xi Chen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Silvia Cavagnero","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Automated Continuous LLM-driven Biomedical Literature Mining for a Large-Scale Hepatotoxicity Knowledge Base","rel_doi":"10.64898\/2026.11.09.765369","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765369","rel_abs":"Predicting whether a chemical disturbs liver and mitochondrial function matters for drug safety and environmental risk assessment, but the data available for training such models are small and mostly curated by hand. We describe an automated pipeline that uses a large language model (LLM) to collect hepatotoxicity findings from the biomedical literature. The pipeline runs a PubMed\/PMC query, downloads the matching full texts or abstracts, asks the LLM to record each reported effect in a fixed schema (tested chemical, biomarker, direction of change, and related fields) with controlled vocabularies, and writes de-duplicated records to a database that is updated as new papers appear. The current snapshot holds 189,212 findings on 17,002 chemicals from 53,575 articles (1995-2026), covering 235 biomarkers reported for at least 20 chemicals. In a manual check of 217 findings from 35 articles, 208 findings (from 33 articles) were fully correct; the other 9, all from 2 articles, were incorrect. As a use case, we train structure-based QSAR models, both graph neural networks and classic baselines, for each biomarker; at this data scale the classic models remain competitive. The pipeline and the knowledge base will be made publicly available.","rel_num_authors":4,"rel_authors":[{"author_name":"Ji Qiu","author_inst":"Columbia University"},{"author_name":"Yamini Chitikela","author_inst":"old dominion university"},{"author_name":"Zhenquan Jia","author_inst":"UNC Greensboro"},{"author_name":"Chunjiang Zhu","author_inst":"Old Dominion University"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"ProClust provides reliable statistical significance of clusters for single-cell transcriptomic data","rel_doi":"10.64898\/2026.11.08.764985","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.764985","rel_abs":"Clustering of single-cell RNA sequencing (scRNA-seq) data is widely used to identify cell populations. However, overclustering can partition a single cell population into multiple clusters, potentially leading to spurious identification of cell subpopulations. Assessing the statistical significance of clusters is therefore needed to support their biological interpretation. We propose ProClust, a statistical test for clustering significance in scRNA-seq data. ProClust defines a single cluster as a log-concave distribution and adopts a projection-based approach to quantify clustering uncertainty through p-values. These projections can also provide interpretable visual evidence for individual clusterings. ProClust merges clusters when there is insufficient evidence to reject the single-cluster null hypothesis, refining an initial overclustering without prespecifying the final number of clusters. Across parametric and PBMC-based semi-synthetic simulations, ProClust avoided false subdivisions under single-population null settings while consistently recovering the underlying population structure across different numbers of true populations. In real scRNA-seq datasets from the Human Lung Cell Atlas, Tabula Muris, and Hydra, ProClust produced clustering solutions that showed overall agreement with reference annotations while retaining supported substructure and merging groups with insufficient evidence for separation. Together, these results demonstrate that ProClust provides a statistically principled and interpretable framework for refining an initial overclustering and distinguishing supported cellular heterogeneity. The ProClust R package is available at https:\/\/github.com\/Anonym027\/ProClust.","rel_num_authors":5,"rel_authors":[{"author_name":"Haina Qian","author_inst":"University of Michigan"},{"author_name":"Haoze Wu","author_inst":"University of Michigan"},{"author_name":"Yifan Dai","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Guanao Yan","author_inst":"Michigan State University"},{"author_name":"Yufeng Liu","author_inst":"University of Michigan"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Broad-spectrum in situ genetic reprogramming of native microbiomes","rel_doi":"10.64898\/2026.11.03.764085","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.03.764085","rel_abs":"Complex microbial communities are found throughout terrestrial, aquatic, and animal-associated ecosystems. Genetic modification of discrete microbial taxa within native communities represents a powerful tool to study and augment microbiome functions. Herein, we develop Synthetic Phage Assisted Reprogrammable and Targetable Addition (SPARTA) as a one-step strategy for packaging, delivering, and integrating large synthetic DNA into a broad range of native microbiomes. SPARTA leverages a broad-spectrum synthetic phage particle for in situ genome engineering within complex soil, freshwater, and mammalian fecal microbiomes, reprogramming 59 native species across 16 families. By modulating SPARTA components, we further demonstrated tunability of SPARTA towards targeted microbiome population. Additionally, we built a novel companion tool to quantitatively identify engineered taxa, named 16S crRNA-guided inference of bacterial engineering sequencing or ScRibe-seq. The SPARTA-ScRibe-seq pipeline delivered and validated functional synthetic gene clusters in diverse native microbiomes while preserving the original microbial community structure. Together, this novel genome engineering framework constitutes an end-to-end programmable platform for rational and customizable reprogramming of native microbiomes.","rel_num_authors":10,"rel_authors":[{"author_name":"Jeongsoo Hur","author_inst":"California Institute of Technology"},{"author_name":"Charles Sanfiorenzo","author_inst":"California Institute of Technology"},{"author_name":"Benjamin Simpson","author_inst":"California Institute of Technology"},{"author_name":"Anastasiya Oguienko","author_inst":"California Institute of Technology"},{"author_name":"Jianyi Huang","author_inst":"California Institute of Technology"},{"author_name":"Mikel Lipschitz","author_inst":"California Institute of Technology"},{"author_name":"Raymond J Zhang","author_inst":"California Institute of Technology"},{"author_name":"Tomasz Gawda","author_inst":"California Institute of Technology"},{"author_name":"Sarkis Mazmanian","author_inst":"California Institute of Technology"},{"author_name":"Kaihang Wang","author_inst":"California Institute of Technology"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Why don't transcription factors exploit inter-nucleotide correlations in binding motifs? Evolution of information encoding strategies on DNA","rel_doi":"10.64898\/2026.11.09.765386","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765386","rel_abs":"Transcription factors have been shown to predominantly rely on independent contributions from each position of their target sequence motifs, even though sequence motifs can encode information through correlations among nucleotide positions. As a result, the position-weight matrix, a simple modeling approach that assumes independence among positions, has long since become the dominant model of TF-DNA binding. Why evolution would favor this comparatively simple strategy, known as single locus information (SI), over a correlation-based one remains unaddressed. Here, we use analytical derivations, numerical approaches and evolutionary simulations to show that SI is intrinsically more robust to mutation than correlated (multi-locus) encodings and is therefore indirectly favored under selection for functional transcriptional regulatory networks. At the same time, we show that SI smooths the affinity landscape, ensuring the evolvability of regulatory interactions. We find the same marked bias toward SI in the genetic code, suggesting that the preference for SI is not specific to transcriptional regulation, but may be a general property of biological codes that must reliably store information on DNA in the face of mutational noise.","rel_num_authors":3,"rel_authors":[{"author_name":"Emmanuel Mekasha","author_inst":"University of Maryland, Baltimore County"},{"author_name":"Elia Mascolo","author_inst":"Institute of Science and Technology Austria"},{"author_name":"Ivan Erill","author_inst":"Universitat Aut\u00f2noma de Barcelona"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"A coral-linked adaptive radiation in butterflyfishes","rel_doi":"10.64898\/2026.11.09.765357","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.09.765357","rel_abs":"Coral reefs harbour a disproportionate share of marine biodiversity, yet whether reef fish diversity reflects steady accumulation or rapid, ecologically driven diversification remains unclear. Butterflyfishes and bannerfishes (Chaetodontidae) include more than half of all coral-feeding fish species, making them a natural test of adaptive radiation on coral reefs. Here we present a time-calibrated phylogeny of 120 of the 138 species, built from 1,009 ultraconserved elements. The species-rich butterflyfishes (Chaetodontinae) are a recent radiation that originated in the Late Miocene (7.78 million years ago; 95% highest posterior density 7.13 to 8.49 million years ago), with much of their extant species diversity arising within the past 2 million years. The crown diversification rate of butterflyfishes is the highest among 29 comparator reef-fish lineages. Ancestral state reconstructions indicate that the ancestor of Chaetodontinae was a facultative corallivore, that a unique jaw joint arose before obligate corallivory, and that obligate corallivory then evolved repeatedly from facultative ancestors, alongside derived tooth morphologies. Together, these results suggest that Late Miocene coral reef turnover and the diversification of branching corals generated an ecological opportunity that functional innovations allowed butterflyfishes to exploit, extending the adaptive radiation framework to open marine seascapes beyond the island and lake systems where it has most often been applied.","rel_num_authors":6,"rel_authors":[{"author_name":"Konstantinos Andriotis","author_inst":"Department of Ecology and Evolutionary Biology, Yale University; New Haven, CT 06520, USA"},{"author_name":"Jennifer R. Hodge","author_inst":"The University of Western Australia (UWA) Oceans Institute and School of Biological Sciences, The University of Western Australia; Perth, WA, 6009, Australia"},{"author_name":"Chase D. Brownstein","author_inst":"Department of Ecology and Evolutionary Biology, Yale University; New Haven, CT 06520, USA"},{"author_name":"Michael E. Alfaro","author_inst":"Department of Ecology and Evolutionary Biology, University of California; Los Angeles, CA 90095, USA"},{"author_name":"Peter C. Wainwright","author_inst":"Department of Evolution and Ecology, University of California Davis; Davis, CA 95616, USA"},{"author_name":"Thomas J. Near","author_inst":"Department of Ecology and Evolutionary Biology, Yale University; New Haven, CT 06520, USA"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"The co-evolution of adhesion and F-actin gives rise to hierarchical cellular force generation","rel_doi":"10.64898\/2026.11.08.765126","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765126","rel_abs":"Cells --- the basic units of life --- dynamically adhere to their micro-environment, build their F-actin cytoskeleton, and apply molecular-motor generated contractile forces to it in a remarkably broad range of biological processes and physiological functions, in both health and disease. Yet, how these processes are orchestrated over multiple spatiotemporal scales is not fully understood. Using several experimental approaches and a theoretical framework, we show that adhesion assembly, on-adhesion F-actin accumulation and the contractile force itself all follow the same time evolution over tens of minutes, the cellular force timescale, at well-defined adhesion sites. We also show that the F-actin distribution away from the adhesion site features a multiplicative space-time decomposition. Finally, we show that F-actin retrograde flow --- central in the so-called molecular motor-clutch models --- is markedly faster than force generation rates, that it does not slow down over maturing adhesions and that its density drops at adhesion sites. These findings suggest a hierarchical, multi- scale force generation process that is controlled by slow adhesion recruitment, which is accompanied by rapid, bursty linear actin polymerization. The linear F-actin slowly accumulates with adhesion recruitment to form an extended near-adhesion F-actin network to which molecular motors attach and apply elastic-like contraction.","rel_num_authors":6,"rel_authors":[{"author_name":"Yuanning Guo","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Noam Ottolenghi","author_inst":"Weizmann Institute of Science"},{"author_name":"Malak Amer","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Jiayu He","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Eran Bouchbinder","author_inst":"Weizmann Institute of Science"},{"author_name":"Haguy Wolfenson","author_inst":"Technion-Israel Institute of Technology"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"KAT6 and KAT7 actively maintain mitotic chromatin composition and acetylation to preserve developmental competence","rel_doi":"10.64898\/2026.11.07.765049","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.765049","rel_abs":"Mitotic bookmarking enables transmission of regulatory information across cell division, yet how active chromatin states are molecularly preserved during mitosis and how they contribute to postmitotic cell fate decisions remain unresolved. Here, we demonstrate that the acetyltransferases KAT6 and KAT7 remain chromatin-bound and catalytically active throughout mitosis in mouse and human pluripotent stem cells. Acute KAT6\/7 depletion disrupts mitotic histone acetylation and the retention of multiple chromatin regulators with minimal effects on chromatin accessibility. Mechanistically, KAT6\/7 bookmark both self renewal and developmental gene loci, where they are required for post-mitotic transcriptional reactivation and priming of lineage-specific programs. Consistently, genes impaired during postmitotic reactivation also fail to activate during neuronal differentiation upon continuous KAT6\/7 perturbation, compromising the establishment of the neuronal program and identity. Altogether, our findings identify KAT6 and KAT7 as a cooperative mitotic chromatin maintenance system that couples active histone acetylation to preservation of chromatin composition, transcriptional memory, and developmental competence across cell division, extending the bookmarking function beyond transcriptional memory. These findings also provide a new framework for understanding KAT6\/7 function in neurodevelopmental disorders and cancer.","rel_num_authors":15,"rel_authors":[{"author_name":"Alejandra Laguillo-Diego","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA."},{"author_name":"UkJin Lee","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA. Molecular Biology Program, Graduate "},{"author_name":"Xiao Liu","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA,  Tri-Institutional Program in Comput"},{"author_name":"Abigail Lidoski","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Kritika Kasliwal","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, 10 Weill Cornell Medicine, New York, NY, USA.  Molecular Biology Program, Gradua"},{"author_name":"Urko del Castillo","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Jin Joo Kang","author_inst":"Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA. Department of Computational Biology, Cornell University, Ithaca, NY, USA."},{"author_name":"Stephanie Stransky","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York,  USA."},{"author_name":"Spencer Kaufman","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Bryce J Katch","author_inst":"Tri-Institutional MD-PhD Program, The Rockefeller University, Weill Cornell Medical College, and Memorial Sloan Kettering Cancer Center, New York, NY, USA."},{"author_name":"Paraskevi Giannakakou","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Simone Sidoli","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York,  USA."},{"author_name":"Haiyuan Yu","author_inst":"Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA. Department of Computational Biology, Cornell University, Ithaca, NY, USA."},{"author_name":"Matthias Stadtfeld","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Effie Apostolou","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA."}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"KAT6 and KAT7 actively maintain mitotic chromatin composition and acetylation to preserve developmental competence","rel_doi":"10.64898\/2026.11.07.765049","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.765049","rel_abs":"Mitotic bookmarking enables transmission of regulatory information across cell division, yet how active chromatin states are molecularly preserved during mitosis and how they contribute to postmitotic cell fate decisions remain unresolved. Here, we demonstrate that the acetyltransferases KAT6 and KAT7 remain chromatin-bound and catalytically active throughout mitosis in mouse and human pluripotent stem cells. Acute KAT6\/7 depletion disrupts mitotic histone acetylation and the retention of multiple chromatin regulators with minimal effects on chromatin accessibility. Mechanistically, KAT6\/7 bookmark both self renewal and developmental gene loci, where they are required for post-mitotic transcriptional reactivation and priming of lineage-specific programs. Consistently, genes impaired during postmitotic reactivation also fail to activate during neuronal differentiation upon continuous KAT6\/7 perturbation, compromising the establishment of the neuronal program and identity. Altogether, our findings identify KAT6 and KAT7 as a cooperative mitotic chromatin maintenance system that couples active histone acetylation to preservation of chromatin composition, transcriptional memory, and developmental competence across cell division, extending the bookmarking function beyond transcriptional memory. These findings also provide a new framework for understanding KAT6\/7 function in neurodevelopmental disorders and cancer.","rel_num_authors":15,"rel_authors":[{"author_name":"Alejandra Laguillo-Diego","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA."},{"author_name":"UkJin Lee","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA. Molecular Biology Program, Graduate "},{"author_name":"Xiao Liu","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA,  Tri-Institutional Program in Comput"},{"author_name":"Abigail Lidoski","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Kritika Kasliwal","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, 10 Weill Cornell Medicine, New York, NY, USA.  Molecular Biology Program, Gradua"},{"author_name":"Urko del Castillo","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Jin Joo Kang","author_inst":"Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA. Department of Computational Biology, Cornell University, Ithaca, NY, USA."},{"author_name":"Stephanie Stransky","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York,  USA."},{"author_name":"Spencer Kaufman","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Bryce J Katch","author_inst":"Tri-Institutional MD-PhD Program, The Rockefeller University, Weill Cornell Medical College, and Memorial Sloan Kettering Cancer Center, New York, NY, USA."},{"author_name":"Paraskevi Giannakakou","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Simone Sidoli","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York,  USA."},{"author_name":"Haiyuan Yu","author_inst":"Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA. Department of Computational Biology, Cornell University, Ithaca, NY, USA."},{"author_name":"Matthias Stadtfeld","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA."},{"author_name":"Effie Apostolou","author_inst":"Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center,  Weill Cornell Medicine, New York, NY, USA."}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Early visual experience redistributes cFos-tagged neurons toward the cortex while preserving presynaptic spatial stereotypy","rel_doi":"10.64898\/2026.11.08.765223","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765223","rel_abs":"The macroscale functional organization of the brain is spatially stereotyped across individuals, but whether this extends to finer spatial scales is not known. Furthermore, how experience shapes this organization across the brain remains unclear. To address this, we developed cFos promoter-driven reporter mouse lines that permanently label either the cell bodies or presynaptic terminals of neurons during defined temporal windows. Using serial two-photon tomography and voxel-wise statistics, we mapped brain-wide distributions of cFos-tagged somata or their presynaptic terminals during the first week of visual experience or its deprivation. We found that midbrain and subcortical regions show greater stereotypy for cFos-tagged neurons and their presynaptic terminals compared to cortical regions. This fine-scale spatial stereotypy remained largely preserved despite visual deprivation, which shifted the relative recruitment of cFos-tagged neurons from cortical toward the highly stereotyped midbrain and subcortical regions. Our findings identify heterogeneous, spatially constrained functional organization across the brain that is conserved across subjects yet accommodates experience-dependent reorganization of neuronal recruitment.","rel_num_authors":7,"rel_authors":[{"author_name":"Oliver J LEsperance","author_inst":"University of Kansas"},{"author_name":"Daniel Ryskamp Rijsketic","author_inst":"Stanford University School of Medicine"},{"author_name":"Nicholas Pritchett","author_inst":"Unviersity of Kansas"},{"author_name":"Tristan Meier","author_inst":"University of Kansas"},{"author_name":"Ethan Hunt","author_inst":"University of Kansas"},{"author_name":"Boris D Heifets","author_inst":"Stanford University School of Medicine"},{"author_name":"Jaichandar Subramanian","author_inst":"University of Kansas"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Inductive bias anchors a scaling law for biological learning","rel_doi":"10.64898\/2026.11.08.765173","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765173","rel_abs":"The speed of animal learning varies substantially across individuals and task domains, and does not always track intuitive notions of task complexity. A nominally simple binary decision task can take thousands of rewards to reach proficiency, whereas seemingly complex naturalistic tasks can be learned within dozens. A long-standing explanation is that learning speed reflects the alignment between an animal's inductive biases and the task at hand. However, without a precise notion of alignment, it is difficult to translate this idea into quantitative predictions. Here, modeling an animal as a Bayesian learner that improves through iterative reward feedback, we use statistical learning theory to derive a scaling law for biological learning. The law makes two predictions. First, inductive bias multiplicatively sets the speed of learning through a single quantity, the effective complexity. This quantity measures how well the task aligns with the animal's prior, and corresponds to the number of bits required to represent the task solution under that prior. We demonstrate this multiplicative scaling in a human motor learning dataset, where behavioral measurements before learning can precisely predict subsequent learning speed. Second, task performance improves as a power law in experience. We validate this power law in a large-scale mouse learning dataset and show that a two-parameter rescaling collapses individual learning curves onto a universal function predicted by the theory. These results suggest that behavioral measurements before learning can be used to predict task-dependent learning speeds, and they explain why learning speed reflects alignment with prior knowledge rather than nominal task complexity.","rel_num_authors":6,"rel_authors":[{"author_name":"Ling-Qi Zhang","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute"},{"author_name":"Nakul Verma","author_inst":"Columbia University"},{"author_name":"Luke T Coddington","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute"},{"author_name":"Joshua T Dudman","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute"},{"author_name":"Kristin Branson","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute"},{"author_name":"Ann M Hermundstad","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"In situ single-cell CRISPR screens uncover context-dependent rewiring of glioma states and immune recruitment","rel_doi":"10.64898\/2026.11.08.765171","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765171","rel_abs":"In vivo single-cell CRISPR screens can resolve perturbation effects in native tissues, but few combine cell-type-restricted delivery, somatic tumor initiation, and combinatorial perturbation. Here we developed an RCAS-TVA-based single-cell CRISPR screening approach coupling oncogenic transformation with single- or dual-guide perturbation in defined neural progenitors. In glioma, tumor suppressor loss produced distinct genotype-dependent transcriptional states, including an NF1-loss-associated increase in mesenchymal programs. Introducing a fixed Cdkn2a(ARF) perturbation altered malignant-cell state composition, immune-cell abundance, and the effects of additional tumor-suppressor perturbations, including increased representation of Pten- and Rb1-deficient cells, suggestive of the relief of an ARF-dependent genetic barrier. These perturbations converged on transcriptional states resembling pharmacologic p53 activation in human glioblastoma. Across mouse tumors and human glioblastoma models, this response was associated with increased astrocyte-like state representation. These findings establish a framework for single-cell analysis of context-dependent somatic perturbations during tumor initiation in vivo.","rel_num_authors":14,"rel_authors":[{"author_name":"Nicholas Hou","author_inst":"Columbia University"},{"author_name":"Ioana-Teodora Lia","author_inst":"Columbia University"},{"author_name":"Ross M Giglio","author_inst":"Columbia University"},{"author_name":"Bailey T Van","author_inst":"Columbia University"},{"author_name":"Sebastian Pallais-Aks","author_inst":"Columbia University"},{"author_name":"Mathini Vaikunthan","author_inst":"Columbia University"},{"author_name":"Vivian Lu","author_inst":"Columbia University"},{"author_name":"Jonathan Guo","author_inst":"Columbia University"},{"author_name":"Destinee Williams","author_inst":"Spelman College"},{"author_name":"Tiffany Camila Nieto","author_inst":"St. John's University"},{"author_name":"Lingting Shi","author_inst":"Columbia University"},{"author_name":"Cody Slater","author_inst":"Columbia University"},{"author_name":"Elham Azizi","author_inst":"Columbia University"},{"author_name":"Jose L McFaline-Figueroa","author_inst":"Columbia University"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Dissecting human embryonic patterning during organogenesis reveals a rostral midline progenitor population for mesoendoderm induction","rel_doi":"10.64898\/2026.11.07.765055","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.765055","rel_abs":"Understanding how human organogenesis is accomplished via intricate spatiotemporal patterning of organ primordia requires spatial atlases at cellular resolution. However, existing human embryo spatial atlases are built using sequencing-based platforms such as Stereo-seq, which have limited spatial resolution and blurred anatomical boundaries, leading to misclassification across adjacent cells. Here, we integrate in situ imaging-based transcriptomics (Xenium) with transcriptome-wide spatial profiling (Visium-HD) of Carnegie stages 9-12 embryos to delineate the patterning of core embryonic tissues at single-cell resolution, including the brain, spinal cord, somites, neural crest, notochord, heart, and gut tube. A new finding enabled by spatial single-cell resolution is the identification of rostral midline progenitors (RMPs), a cell population co-expressing SOX2, TBXT, and OTX2. Transcriptionally, RMPs are distinct from both neuromesodermal progenitors (NMPs) and prechordal mesoderm, and in vivo clonal barcoding in mice indicates that RMPs share a common developmental origin with rostral neural ectoderm. To interrogate their functional significance, we leveraged our spatial transcriptome data to recapitulate RMP-like cells from human pluripotent stem cells and showed that these cells can induce epiblast-like cells to acquire mesendodermal and endodermal fates, while themselves adopting an ectodermal fate consistent with their in vivo counterparts. This work provides a 3D, stage-resolved molecular cell atlas of tissue patterning in human embryo that serves as a reference for in vitro models.","rel_num_authors":21,"rel_authors":[{"author_name":"Ying Yang","author_inst":"Westlake University School of Life Sciences"},{"author_name":"Hongan Ren","author_inst":"Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Mengyang Lu","author_inst":"Westlake University School of Life Sciences"},{"author_name":"Guanhui Tan","author_inst":"Westlake University School of Life Sciences"},{"author_name":"Yixuan Wang","author_inst":"Westlake Laboratory of Life Sciences and Biomedicine"},{"author_name":"Qingyu Cai","author_inst":"Westlake University School of Life Sciences"},{"author_name":"Junyao Jiang","author_inst":"Westlake University School of Life Sciences"},{"author_name":"Chenyu Guo","author_inst":"Westlake University School of Life Sciences"},{"author_name":"Yixin Li","author_inst":"Westlake University School of Life Sciences"},{"author_name":"Naixin Chen","author_inst":"Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Hong Chen","author_inst":"Chongqing Medical University"},{"author_name":"Fei Han","author_inst":"Chongqing Medical University"},{"author_name":"Niya Zhou","author_inst":"Women and Children's Hospital of Chongqing Medical University"},{"author_name":"Xia Lan","author_inst":"Women and Children's Hospital of Chongqing Medical University"},{"author_name":"Rong Li","author_inst":"Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Shigehito Yamada","author_inst":"Kyoto University"},{"author_name":"Guojun Sheng","author_inst":"Kumamoto University"},{"author_name":"Weike Pei","author_inst":"Westlake University School of Life Sciences"},{"author_name":"TaiHang Liu","author_inst":"Chongqing Medical University"},{"author_name":"Leqian Yu","author_inst":"Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Lizhong Liu","author_inst":"Westlake Laboratory of Life Sciences and Biomedicine; Westlake University School of Life Sciences"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Nucleobase-Specific Recognition of DNA by Protamine","rel_doi":"10.64898\/2026.11.07.765086","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.765086","rel_abs":"Protamines--arginine (Arg)-rich, intrinsically disordered proteins (IDPs)--replace histones to compact DNA in the sperm nucleus. While folded domains can bind DNA site-specifically, whether IDPs exhibit DNA-sequence specificity remains open. Here, we used all-atom molecular dynamics simulations to characterize protamine-DNA binding. Eight copies of salmon protamine (33 residues with 21 Arg) rapidly wrap around a 35-bp DNA molecule. In addition to salt bridges with DNA phosphates, Arg hydrogen-bonds with multiple nucleobases on both strands or the same strand. At the major groove, protamine prefers GC over AT by a 2.6-to-1 ratio, with guanine's O6 and N7 atoms as hydrogen-bond acceptors; the preference is especially strong at G-tracts. This selectivity reverses at the minor groove, where AT overtakes GC by a 2.1-to-1 margin. The net effect is a moderate bias for GC over AT in protamine-base interactions. Additional simulations with 20-bp DNA molecules and free-energy calculations reinforce these observations. For experimental validation, we designed DNA sequences with 0-40% GC content. Protamine-DNA mixtures form aggregates, with an increasing propensity at higher GC content and upon shuffling into G-tracts. This work demonstrates that IDPs can bind DNA in a nucleobase-specific manner, with implications for protamine-mediated transcription silencing and remodeling of paternal chromatin.","rel_num_authors":3,"rel_authors":[{"author_name":"Anshika Dhiman","author_inst":"University of Illinois Chicago"},{"author_name":"Hashini Ekanayake Mudiyanselage","author_inst":"University of Illinois Chicago"},{"author_name":"Huan-Xiang Zhou","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"A global post-transcriptional regulator directs Acinetobacter baumannii carbon preference and gut colonization","rel_doi":"10.64898\/2026.11.07.762903","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.762903","rel_abs":"Acinetobacter baumannii is a multidrug-resistant pathogen that colonizes the gut, increasing the risk of subsequent infection and transmission. Recent work showed that A. baumannii catabolizes ornithine, a non-preferred carbon source, to colonize the gut. However, the mechanisms of carbon preference were unknown in A. baumannii. Here, experimental evolution identified the conserved RNA-binding protein CsrA as a regulator of carbon preference in A. baumannii, a previously unreported CsrA function. RNA immunoprecipitation sequencing (RIP-Seq) revealed hundreds of CsrA-associated transcripts. A. baumannii CsrA directly bound and repressed expression of the ast arginine\/ornithine catabolic operons. The Pseudomonas aeruginosa CsrA homolog RsmA repressed arginine\/ornithine catabolic operon expression, suggesting this CsrA function extends to other bacterial taxa. Finally, CsrA was required for competitive fitness during A. baumannii gut colonization. These findings uncover a previously unrecognized role for a global regulator in A. baumannii carbon preference and persistence in the gut, a critical reservoir for multidrug-resistant pathogens.","rel_num_authors":5,"rel_authors":[{"author_name":"R. Mason Clark","author_inst":"University of Illinois Chicago"},{"author_name":"Rosa L. Sava","author_inst":"University of Iowa"},{"author_name":"Kia J.A. Holt","author_inst":"University of Illinois Chicago"},{"author_name":"Michael J. Gebhardt","author_inst":"University of Iowa"},{"author_name":"Lauren D Palmer","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"A global post-transcriptional regulator directs Acinetobacter baumannii carbon preference and gut colonization","rel_doi":"10.64898\/2026.11.07.762903","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.762903","rel_abs":"Acinetobacter baumannii is a multidrug-resistant pathogen that colonizes the gut, increasing the risk of subsequent infection and transmission. Recent work showed that A. baumannii catabolizes ornithine, a non-preferred carbon source, to colonize the gut. However, the mechanisms of carbon preference were unknown in A. baumannii. Here, experimental evolution identified the conserved RNA-binding protein CsrA as a regulator of carbon preference in A. baumannii, a previously unreported CsrA function. RNA immunoprecipitation sequencing (RIP-Seq) revealed hundreds of CsrA-associated transcripts. A. baumannii CsrA directly bound and repressed expression of the ast arginine\/ornithine catabolic operons. The Pseudomonas aeruginosa CsrA homolog RsmA repressed arginine\/ornithine catabolic operon expression, suggesting this CsrA function extends to other bacterial taxa. Finally, CsrA was required for competitive fitness during A. baumannii gut colonization. These findings uncover a previously unrecognized role for a global regulator in A. baumannii carbon preference and persistence in the gut, a critical reservoir for multidrug-resistant pathogens.","rel_num_authors":5,"rel_authors":[{"author_name":"R. Mason Clark","author_inst":"University of Illinois Chicago"},{"author_name":"Rosa L. Sava","author_inst":"University of Iowa"},{"author_name":"Kia J.A. Holt","author_inst":"University of Illinois Chicago"},{"author_name":"Michael J. Gebhardt","author_inst":"University of Iowa"},{"author_name":"Lauren D Palmer","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"One high-order ion-coupling mechanism generates multiple SLC1A stoichiometries","rel_doi":"10.64898\/2026.11.07.764996","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.764996","rel_abs":"Human excitatory amino acid transporter 2 (hEAAT2) is a glial transporter that clears glutamate and aspartate from the extracellular space to terminate neurotransmission. When this essential role is disrupted, excess extracellular glutamate causes excitotoxicity and neurological disease. hEAAT2 transports amino acids into cells against their concentration gradients by coupling uptake to the co-transport of Na+ and H+, and counter-transport of K+. Substrate transport also activates a thermodynamically uncoupled Cl- conductance, whose significance is unknown. Here, to dissect the molecular mechanisms underlying coupled and uncoupled ion transport by EAATs, we leverage the tractable Drosophila melanogaster homologue dEAAT2, which transports taurine as well as glutamate and aspartate. By functionally characterising dEAAT2, we confirmed it has features of a canonical EAAT transport cycle, including an uncoupled Cl- conductance. However, it functions an ion-independent electroneutral exchanger, in stark contrast to its ion-coupled electrogenic human counterpart. Cryo-electron microscopy (cryo-EM) and computational simulations confirmed the inability of dEAAT2 to transport cations, but just two point mutations conferred Na+, H+, and K+ dependence, reconstituting the complex ion coupling profile of human transporters in the Drosophila exchanger. We also showed that dEAAT2 transports taurine in a complex with Cl-, bestowing a unique Cl--dependence on taurine transport, independent of uncoupled Cl- flux. Our findings show that ancestral exchangers in the EAAT family preserve the machinery to achieve complex ion-coupled transport, revealing the molecular basis of high-order ion coupling in hEAATs.","rel_num_authors":10,"rel_authors":[{"author_name":"Renae M Ryan","author_inst":"University of Sydney"},{"author_name":"Qianyi Wu","author_inst":"Weill Cornell Medicine"},{"author_name":"Yan Jiang","author_inst":"University of Sydney"},{"author_name":"Chelsea Briot","author_inst":"University of Sydney"},{"author_name":"Ashkan Fakharzadeh","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Morgan M Dooley","author_inst":"University of South Florida"},{"author_name":"Shashank Pant","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Hariprasad Venugopal","author_inst":"Monash University"},{"author_name":"Krishna D Reddy","author_inst":"University of South Florida"},{"author_name":"Emad Tajkhorshid","author_inst":"University of Illinois at Urbana-Champaign"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Lifestyle-mediated shifts in the gut microbiome and host genetics modulate gene expression in intestinal organoids","rel_doi":"10.64898\/2026.11.07.765058","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.765058","rel_abs":"Industrialization-associated shifts in the gut microbiome have been linked to disease, but the mechanisms by which microbial communities influence host gene regulation remain poorly understood. We developed a live microbiome-colonic organoid (colonoid) co-culture system to investigate genotype-dependent host responses to gut microbial community variation. Colonoid 2D monolayers from healthy donors were co-cultured with live gut microbial communities from individuals living urban or rural lifestyles, followed by RNA-sequencing. Urban and rural microbiomes elicited largely shared transcriptional responses, however they induced distinct host genetic effects on gene expression. We identified 511 host genes with microbiome-dependent allele-specific expression (ASE) which were involved in epithelial architecture, cell-matrix interactions and structural integrity. Notably, 149 host genes had distinct allelic effects between Urban and Rural microbiomes (urban-rural condition specific ASE or cASE), revealing genotype-dependent host responses to lifestyle-associated microbiomes. Urban-rural cASE was associated with microbial community composition, predominantly involving Prevotella and Bacteroides species. Targeted Prevotella copri spike-in recapitulated Prevotella-associated allelic effects at specific loci, including one in the IBD-associated autophagy gene, ATG4B. Together, these findings establish an experimental framework to investigate genotype-by-microbiome interactions, and demonstrate that lifestyle-mediated shifts in the microbiome modify host cis-regulatory genetic effects on gene expression.","rel_num_authors":11,"rel_authors":[{"author_name":"Shreya Nirmalan","author_inst":"Wayne State University, University of Chicago"},{"author_name":"Sabrina Arif","author_inst":"University of Chicago"},{"author_name":"Gabrielle Garlicki","author_inst":"University of Chicago"},{"author_name":"Adnan Alazizi","author_inst":"Wayne State University"},{"author_name":"Kaitlyn Hutchins","author_inst":"University of Chicago"},{"author_name":"Mathilde Poyet","author_inst":"Kiel University, Massachusetts Institute of Technology"},{"author_name":"Mathieu Groussin","author_inst":"Kiel University, Massachusetts Institute of Technology"},{"author_name":"Peter Carbonetto","author_inst":"University of Chicago"},{"author_name":"Roger Pique-Regi","author_inst":"Wayne State University"},{"author_name":"Ran Blekhman","author_inst":"University of Chicago"},{"author_name":"Francesca Luca","author_inst":"University of Chicago"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Maternal separation remodels Purkinje cell circuits and impairs cerebellar synaptic plasticity","rel_doi":"10.64898\/2026.11.08.765140","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765140","rel_abs":"Introduction: Early-life adversity has been associated with cerebellar abnormalities, but the cellular and circuit-level changes involved and their persistence across development remain poorly understood. We examined whether maternal separation (MS) disrupts cerebellar circuit maturation and whether these changes are accompanied by alterations in synaptic function and behavior. Methods: CD1 mice underwent daily maternal separation from postnatal day 2 to 18, whereas control litters remained undisturbed. Cerebellar alterations were assessed using transcriptomic and DNA methylation profiling, RT-qPCR, immunoblotting, Purkinje-cell morphometric analysis, and VGLUT1\/VGLUT2 immunofluorescence. Patch-clamp electrophysiology was used to examine synaptic transmission and plasticity. Motor coordination, spontaneous locomotion, social approach, and stress-coping behavior were also evaluated. Results: RNA sequencing of whole cerebellar tissue revealed early transcriptional remodeling, involving synaptic transmission, neuronal architecture, and plasticity-related pathways. Consistent with this profile, we found that MS altered Purkinje cell dendritic arborization and excitatory input remodeling, together with deficits in cerebellar long-term synaptic plasticity and reduced BDNF-related signaling. In parallel, methylation analysis revealed hypermethylation of the glucocorticoid receptor promoter and reduced cerebellar receptor expression, indicating that early-life stress also engages stress-related epigenetic mechanisms in this region. Importantly, these neurobiological changes were associated with motor coordination deficits, altered stress-coping behavior, and impaired social interaction. Discussion: These findings identify the developing cerebellum as a target of early-life adversity and suggest that disrupted cerebellar maturation may contribute to lasting functional consequences. This study extends our understanding of the effects of maternal separation beyond the brain regions traditionally associated with stress responses.","rel_num_authors":17,"rel_authors":[{"author_name":"Pellegrino Lippiello","author_inst":"University of Naples Federico II"},{"author_name":"Eriola Hoxha","author_inst":"University of Turin"},{"author_name":"Claudia Cristiano","author_inst":"University of Naples Federico II"},{"author_name":"Silvia Pascarella","author_inst":"University of Naples Federico II"},{"author_name":"Floriana Volpicelli","author_inst":"University of Naples Federico II"},{"author_name":"Luisa Speranza","author_inst":"University of Naples Federico II"},{"author_name":"Mariella Cuomo","author_inst":"University of Naples Federico II"},{"author_name":"Maria Grazia Ferraro","author_inst":"University of Naples Federico II"},{"author_name":"Adrien Stanley","author_inst":"Allen Institute"},{"author_name":"Anita Maria Rominto","author_inst":"University of Turin"},{"author_name":"Kardelen Dalim Filiz","author_inst":"University of Naples"},{"author_name":"Fabrizio Liguori","author_inst":"University of Naples"},{"author_name":"Daniela Tropea","author_inst":"Trinity College"},{"author_name":"Silvia Di Angelantonio","author_inst":"University of Rome Sapienza"},{"author_name":"Lorenzo Chiariotti","author_inst":"University of Naples Federico II"},{"author_name":"David Sulzer","author_inst":"Columbia University"},{"author_name":"Maria Concetta Miniaci","author_inst":"University of Naples Federico II"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Maternal separation remodels Purkinje cell circuits and impairs cerebellar synaptic plasticity","rel_doi":"10.64898\/2026.11.08.765140","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765140","rel_abs":"Introduction: Early-life adversity has been associated with cerebellar abnormalities, but the cellular and circuit-level changes involved and their persistence across development remain poorly understood. We examined whether maternal separation (MS) disrupts cerebellar circuit maturation and whether these changes are accompanied by alterations in synaptic function and behavior. Methods: CD1 mice underwent daily maternal separation from postnatal day 2 to 18, whereas control litters remained undisturbed. Cerebellar alterations were assessed using transcriptomic and DNA methylation profiling, RT-qPCR, immunoblotting, Purkinje-cell morphometric analysis, and VGLUT1\/VGLUT2 immunofluorescence. Patch-clamp electrophysiology was used to examine synaptic transmission and plasticity. Motor coordination, spontaneous locomotion, social approach, and stress-coping behavior were also evaluated. Results: RNA sequencing of whole cerebellar tissue revealed early transcriptional remodeling, involving synaptic transmission, neuronal architecture, and plasticity-related pathways. Consistent with this profile, we found that MS altered Purkinje cell dendritic arborization and excitatory input remodeling, together with deficits in cerebellar long-term synaptic plasticity and reduced BDNF-related signaling. In parallel, methylation analysis revealed hypermethylation of the glucocorticoid receptor promoter and reduced cerebellar receptor expression, indicating that early-life stress also engages stress-related epigenetic mechanisms in this region. Importantly, these neurobiological changes were associated with motor coordination deficits, altered stress-coping behavior, and impaired social interaction. Discussion: These findings identify the developing cerebellum as a target of early-life adversity and suggest that disrupted cerebellar maturation may contribute to lasting functional consequences. This study extends our understanding of the effects of maternal separation beyond the brain regions traditionally associated with stress responses.","rel_num_authors":17,"rel_authors":[{"author_name":"Pellegrino Lippiello","author_inst":"University of Naples Federico II"},{"author_name":"Eriola Hoxha","author_inst":"University of Turin"},{"author_name":"Claudia Cristiano","author_inst":"University of Naples Federico II"},{"author_name":"Silvia Pascarella","author_inst":"University of Naples Federico II"},{"author_name":"Floriana Volpicelli","author_inst":"University of Naples Federico II"},{"author_name":"Luisa Speranza","author_inst":"University of Naples Federico II"},{"author_name":"Mariella Cuomo","author_inst":"University of Naples Federico II"},{"author_name":"Maria Grazia Ferraro","author_inst":"University of Naples Federico II"},{"author_name":"Adrien Stanley","author_inst":"Allen Institute"},{"author_name":"Anita Maria Rominto","author_inst":"University of Turin"},{"author_name":"Kardelen Dalim Filiz","author_inst":"University of Naples"},{"author_name":"Fabrizio Liguori","author_inst":"University of Naples"},{"author_name":"Daniela Tropea","author_inst":"Trinity College"},{"author_name":"Silvia Di Angelantonio","author_inst":"University of Rome Sapienza"},{"author_name":"Lorenzo Chiariotti","author_inst":"University of Naples Federico II"},{"author_name":"David Sulzer","author_inst":"Columbia University"},{"author_name":"Maria Concetta Miniaci","author_inst":"University of Naples Federico II"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Statistical significance testing for spatial domain detection in spatial transcriptomics","rel_doi":"10.64898\/2026.11.07.765075","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.765075","rel_abs":"In spatial transcriptomics, domain-detection methods group platform-specific spatial measurement units--cells, bins or multicellular spots--into spatial domains for comparing molecular programs, cellular composition and interactions among tissue regions. However, the number of candidate domains detected in the same tissue can vary with user-specified parameters or model-selection criteria. Whether candidate domains should be merged can be framed as a test of a single-domain null hypothesis, under which each gene has constant mean expression across all spatial units in the combined region. However, testing candidate domains on the same gene-expression data used to detect them may induce post-selection bias and yield anti-conservative p-values, increasing the risk of oversegmentation. To address these challenges, we introduce SigDoTS (statistical Significance testing for Domain deTection in Spatial transcriptomics), a hypothesis-testing framework for spatial domain detection. SigDoTS uses hierarchical testing to determine which candidate domains to retain or merge, with adjustment for family-wise error control. It accounts for gene-gene covariance and spatial dependence and computes p-values by rerunning the upstream domain-detection pipeline on datasets simulated under the fitted single-domain null. In simulations, SigDoTS controlled the type I error rate at the root node under the single-domain null and improved recovery of the true spatial domains when multiple domains were present. In human dorsolateral prefrontal cortex, SigDoTS retained superficial and deep Layer 6 domains but merged Layer 3 candidate domains across different initial numbers of candidate domains. In ovarian and colorectal cancers, SigDoTS retained epithelial domains with different gene-expression programs and local immune environments, together with immune, stromal and vascular domains.","rel_num_authors":5,"rel_authors":[{"author_name":"Huairui Wang","author_inst":"Michigan State University"},{"author_name":"Feiyu Cao","author_inst":"Michigan State University"},{"author_name":"Hui Shen","author_inst":"McGill University"},{"author_name":"Yufeng Liu","author_inst":"University of Michigan"},{"author_name":"Guanao Yan","author_inst":"Michigan State University"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"LOca-1: A minimal calcium-activated arginyl-specific orthocaspase from the Loki's Castle hydrothermal vent field","rel_doi":"10.64898\/2026.11.04.764195","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.04.764195","rel_abs":"Orthocaspases are prokaryotic homologs of metacaspases within the C14 family of cysteine proteases, yet their biochemical properties and cellular roles remain poorly understood. Here, we report the discovery and comprehensive characterization of LOca-1, a metagenome-derived orthocaspase from the Loki's Castle hydrothermal vent field. LOca-1 consists primarily of a single, conserved p20 catalytic domain and undergoes calcium-dependent activation through cleavage at a conserved arginine residue. Once activated, LOca-1 displays strict arginyl-specific proteolytic activity and strong selectivity for residues surrounding the cleavage site. The enzyme is both thermoactive and thermostable, exhibiting maximal activity at 65 {degrees}C and a melting temperature of approximately 72 {degrees}C. Structural modelling revealed conservation of the catalytic core relative to plant metacaspases despite substantial sequence divergence. To our knowledge, LOca-1 is only the second biochemically characterized orthocaspase and the first reported from a deep-sea hydrothermal vent environment. LOca-1 expands the known biochemical diversity of prokaryotic metacaspase homologs and provides insights into the properties of a minimal p20-domain orthocaspase. Together, our findings establish LOca-1 as a thermostable, calcium-activated arginyl-specific orthocaspase and provide a foundation for future studies of orthocaspase function in prokaryotes.","rel_num_authors":10,"rel_authors":[{"author_name":"Hasan Ars\u0131n","author_inst":"University of Bergamo"},{"author_name":"Petra Hribov\u0161ek","author_inst":"University of Bergen"},{"author_name":"Liam Urich","author_inst":"University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences"},{"author_name":"Anita-Elin Fed\u00f8y","author_inst":"University of Bergen"},{"author_name":"Runar Stokke","author_inst":"University of Bergen"},{"author_name":"Pawe\u0142 Mak","author_inst":"Jagiellonian University"},{"author_name":"Anna-Karina Kaczorowska","author_inst":"University of Gdansk"},{"author_name":"Anthony  John O\u2019Donoghue","author_inst":"University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences"},{"author_name":"Tadeusz Kaczorowski","author_inst":"University of Gdansk"},{"author_name":"Ida  Helene Steen","author_inst":"University of Bergen"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Large seed size accompanying GmSDP1 suppression is linked to cellular remodeling and phytohormone regulation","rel_doi":"10.64898\/2026.11.08.765164","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.08.765164","rel_abs":"Soybean (Glycine max) seeds contain approximately 20% oil and 40% protein and are important for food, feed, and biofuel. Improving soybean productivity and seed quality requires optimizing carbon partitioning during seed development. Previously, seed-specific suppression of the lipase-encoding gene Sugar-Dependent 1 (SDP1) increased seed oil content by approximately 5% while slightly reducing raffinose family oligosaccharides without compromising protein content. Seed-specific SDP1 suppression also increased seed size by 18-25% without affecting seed number, resulting in greater seed biomass per plant. To determine the developmental basis of the increased seed size, we investigated the cellular and molecular mechanisms underlying this phenotype. Microscopy and biochemical analyses showed that larger seeds were associated with increased seed cell size and enhanced lignocellulosic cell wall accumulation. Temporal biochemical and transcriptomic analyses further revealed coordinated changes in hormone homeostasis, including altered levels of abscisic acid, 12-oxo-phytodienoic acid, and jasmonoyl-isoleucine, together with differential expression of F-box and RING\/U-box family genes. The results indicate that the enhanced seed size resulting from SDP1 suppression is associated with coordinated changes in cellular development, cell wall accumulation, hormone homeostasis, and regulation of gene expression during seed development. Developmental and metabolic changes associated with the increased seed size phenotype support SDP1 manipulation as a potential strategy for improving soybean seed yield and quality.","rel_num_authors":13,"rel_authors":[{"author_name":"Thiya Mukherjee","author_inst":"Texas A and M University - San Antonio"},{"author_name":"Sophia Crowley","author_inst":"Donald Danforth Plant Science Center"},{"author_name":"Maneesh Lingwan","author_inst":"Donald Danforth Plant Science Center"},{"author_name":"Kevin Chu","author_inst":"Bayer"},{"author_name":"Katherine M Murphy","author_inst":"Donald Danforth Plant Science Center"},{"author_name":"Katia Gutierrez","author_inst":"Donald Danforth Plant Science Center"},{"author_name":"Anastasiya Klebanovych","author_inst":"Donald Danforth Plant Science Center"},{"author_name":"Russell Williams","author_inst":"Donald Danforth Plant Science Center"},{"author_name":"Anuradha Dhingra","author_inst":"Washington University in St Louis"},{"author_name":"Kirk J Czymmek","author_inst":"Donald Danforth Plant Science Center"},{"author_name":"Ben Mansfeld","author_inst":"Washington University in St Louis"},{"author_name":"Timothy P Durrett","author_inst":"Kansas State University"},{"author_name":"Douglas Allen","author_inst":"Donald Danforth Plant Science Center"}],"rel_date":"2026-11-10","rel_site":"biorxiv"},{"rel_title":"Sex- and Age-Specific Associations of Blood Lead Levels with Child Growth and Haemoglobin in Bangladesh: A Nationally Representative Study","rel_doi":"10.64898\/2026.11.07.26367484","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367484","rel_abs":"Evidence on sex- and age-specific associations between lead levels and childhood growth remains limited. We analyzed 10,324 children aged 12-59 months from the Bangladesh Multiple Indicator Cluster Survey 2025 using survey-weighted multivariable linear regression to examine sex- and age-specific associations of blood lead level (BLL) with anthropometric measures and haemoglobin levels. The geometric mean BLL was 4.43 {micro}g\/dL, and 66.3% of children had concentrations above the Centers for Disease Control and Prevention (CDC) threshold ([&ge;]3.5 {micro}g\/dL). Higher BLL was associated with lower height-for-age z-score (HAZ) ({beta} = -0.129, 95% CI: -0.182 to -0.076), weight-for-age z-score (WAZ) ({beta} = -0.108, 95% CI: -0.156 to -0.060), and weight-for-height z-score (WHZ) ({beta} = -0.052, 95% CI: -0.101 to -0.002). Higher BLL was also associated with lower HAZ and WAZ among boys (HAZ: {beta} = -0.114, 95% CI: -0.188 to -0.040; WAZ: {beta} = -0.113, 95% CI: -0.179 to -0.046) and girls (HAZ: {beta} = -0.150, 95% CI: -0.225 to -0.075; WAZ: {beta} = -0.104, 95% CI: -0.171 to -0.036), while higher BLL was associated with lower WHZ among boys ({beta} = -0.076, 95% CI: -0.144 to -0.007). Higher BLL was associated with lower HAZ ({beta} = -0.266, 95% CI: -0.408 to -0.125) and WAZ ({beta} = -0.206, 95% CI: -0.326 to -0.086) among boys aged 24-35 months, while among girls aged 36-59 months, corresponding estimates were -0.211 (95% CI: -0.310 to -0.113) and -0.106 (95% CI: -0.191 to -0.022). The findings suggest that longitudinal studies are needed to clarify the temporal and developmental patterns underlying these associations.","rel_num_authors":5,"rel_authors":[{"author_name":"Muhammad Mainuddin Patwary","author_inst":"Environment and Sustainability Research Initiative, Khulna, Bangladesh"},{"author_name":"Sadia Ashraf","author_inst":"Environmental Science Discipline, Life Science School, Khulna University, Khulna, Bangladesh"},{"author_name":"Md Atikul Islam","author_inst":"Environmental Science Discipline, Life Science School, Khulna University, Khulna, Bangladesh"},{"author_name":"Matthew  H. E. M. Browning","author_inst":"Department of Park, Recreation and Tourism Management, Clemson University, Clemson, SC USA"},{"author_name":"Michelle L. Bell","author_inst":"Yale School of the Environment, Yale University, New Haven, CT, USA"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Investigating Biological Aging Measures, Neurocognitive Performance, and Depressive Symptoms: Moderating Effects of HIV and Childhood Maltreatment","rel_doi":"10.64898\/2026.11.08.26367522","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.08.26367522","rel_abs":"Introduction: Neurocognitive impairment and depression remain common among people with HIV (PWH), and childhood maltreatment (CM) may further increase vulnerability. In this cohort, we previously reported that PWH exhibited shorter absolute telomere length, lower MRI-based brain-predicted age difference, and greater epigenetic age acceleration (AA) compared to controls, with limited associations with CM severity. Building on this, the present study examines whether these markers are linked to neurocognitive performance and depressive symptoms, and whether HIV status or CM severity moderates such associations. Methods: In this study of 238 women (122 PWH), biological aging was assessed using absolute telomere length, mitochondrial DNA copy number, MRI-based brain-predicted age difference, and DNA methylation AA measures, including Horvath, Hannum, PhenoAge, Horvath intrinsic epigenetic, and Hannum intrinsic epigenetic and extrinsic epigenetic AA. Neurocognitive performance was measured using a standardised assessment battery and global deficit scores (GDS) were derived. Depressive symptoms were assessed with the Centre for Epidemiologic Studies - Depression Scale. Linear regression models examined associations with GDS and depressive symptoms, with interaction models evaluating moderation by HIV status and CM severity. Results: Biological aging markers were not associated with either neurocognitive performance or depressive symptoms. Though HIV infection in combination with higher mitochondrial DNA copy number and extrinsic epigenetic AA was nominally associated with higher GDS (p = 0.012 and p = 0.047, respectively), these associations did not survive correction for multiple testing. Neither HIV nor CM moderated the association between biological aging markers and depression scores. Conclusions: Despite accelerated biological aging being evident in PWH, we found limited evidence of association with neurocognitive performance or depressive symptoms, underscoring their multifactorial nature. Larger longitudinal studies are needed to determine whether these markers predict neurocognitive and psychiatric trajectories.","rel_num_authors":7,"rel_authors":[{"author_name":"Kabelo Mabokane Simon Maloka","author_inst":"Stellenbosch University"},{"author_name":"Georgina Spies","author_inst":"University of Cape Town"},{"author_name":"Stefan du Plessis","author_inst":"Stellenbosch University"},{"author_name":"Sian Megan Joanna Hemmings","author_inst":"Stellenbosch University"},{"author_name":"Scott Letendre","author_inst":"University of California San Diego"},{"author_name":"Soraya Seedat","author_inst":"Stellenbosch University"},{"author_name":"Jacqueline Samantha Womersley","author_inst":"University of Cape Town"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms","rel_doi":"10.64898\/2026.11.07.26367466","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367466","rel_abs":"The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.","rel_num_authors":19,"rel_authors":[{"author_name":"Brittanie Winfield","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Samuel A McLean","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Erica M Branham","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Natalie Stanley","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine"},{"author_name":"Francesca L Beaudoin","author_inst":"Brown University"},{"author_name":"Jennifer S Stevens","author_inst":"Emory University School of Medicine"},{"author_name":"Thomas C Neylan","author_inst":"University of California San Francisco"},{"author_name":"Gari D Clifford","author_inst":"Johns Hopkins University"},{"author_name":"Laura T Germine","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John P Haran","author_inst":"University of Massachusetts Medical School"},{"author_name":"Alan B Storrow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Christopher Lewandowski","author_inst":"Henry Ford Health System"},{"author_name":"Paul I Musey Jr.","author_inst":"Indiana University School of Medicine"},{"author_name":"Phyllis L Hendry","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Sophia Sheikh","author_inst":"University of Florida College of Medicine - Jacksonville"},{"author_name":"Ronald C Kessler","author_inst":"Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"Harvard Medical School"},{"author_name":"Sarah D Linnstaedt","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Risk Factors for Progressive Cardiorenal Syndrome Events in Patients with Chronic Kidney Disease: The CRIC Study","rel_doi":"10.64898\/2026.10.30.26366964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.30.26366964","rel_abs":"Background: Cardiorenal syndrome (CRS) is associated with poor outcomes. Risk factors for progressive CRS are not understood in patients with chronic kidney disease (CKD). Objectives: This study aimed to determine the incidence of progressive CRS and risk factors in individuals with CKD. Methods: Adults with CKD in the Chronic Renal Insufficiency Cohort (CRIC) study excluding those with heart failure (HF) at baseline were included (n = 3,557). We defined progressive CRS as developing HF and end-stage kidney disease (ESKD) within 12 months. ESKD was defined as needing renal replacement therapy or renal transplant. The associations of baseline risk factors with progressive CRS were examined using Cox proportional hazards models. A sensitivity analysis assessed risk factors in those who developed HF before ESKD and vice versa. Results: 161 patients (4.5%) developed progressive CRS. Traditional risk factors [multivariable-adjusted hazard ratios (HR) (95% CI)] associated with progressive CRS in multivariable models included lower education [1.90 (1.28,2.83)], cardiovascular disease [1.53 (1.07,2.18)], lower estimated glomerular filtration rate [0.64 (0.51,0.82)] and higher albumin to creatinine ratio [2.44 (1.98,3.02)]. Novel risk factors associated included higher levels of alkaline phosphatase, brain natriuretic peptide (BNP), tumor necrosis factor alpha (TNF-?), growth differentiation factor 15 (GDF-15), hemoglobin A1C, and lower hemoglobin. Risk factors associated with both ESKD before HF and HF before ESKD were kidney dysfunction, albuminuria, and mineral bone disorder (higher alkaline phosphatase and PTH), inflammation (TNF-?), fibrotic factor (GDF-15), and anemia. Diabetes, CVD, systolic blood pressure, waist circumference, HbA1c, and BNP were more strongly associated when HF preceded ESKD. Conclusions: Both traditional risk factors and novel risk factors associated with inflammation, mineral bone disorder, anemia, diabetes control, albuminuria, worse kidney function, and fibrotic factors are associated with progressive CRS in individuals with CKD. Many of these risk factors are modifiable representing potential areas for intervention.","rel_num_authors":20,"rel_authors":[{"author_name":"Meredith McAdams","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"- CRIC Study Investigators","author_inst":"-"},{"author_name":"Jiang He","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Bernard G Jaar","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Hua He","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Cong Zhao","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Siyi Geng","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Amanda H Anderson","author_inst":"Tulane University"},{"author_name":"Vecihi Batuman","author_inst":"Tulane Medical School"},{"author_name":"Joshua D. Bundy","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Jonathan Taliercio","author_inst":"j.\tDepartment of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic"},{"author_name":"Panduranga Rao","author_inst":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Sarah Schrauben","author_inst":"Hospital of the University of Pennsylvania"},{"author_name":"Milica Djokic","author_inst":"Tulane University School of Medicine"},{"author_name":"Joel Merriman","author_inst":"University at Buffalo Jacobs School of Medicine and Biomedical Sciences"},{"author_name":"Giselle Rodriguez de Sosa","author_inst":"Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM, USA"},{"author_name":"Alan S. Go","author_inst":"Kaiser Permanente Northern California"},{"author_name":"James Lash","author_inst":"University of Illinois Chicago"},{"author_name":"L. Lee Hamm","author_inst":"Tulane University"},{"author_name":"Jing Chen","author_inst":"The University of Texas Southwestern Medical Center"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Risk Factors for Progressive Cardiorenal Syndrome Events in Patients with Chronic Kidney Disease: The CRIC Study","rel_doi":"10.64898\/2026.10.30.26366964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.30.26366964","rel_abs":"Background: Cardiorenal syndrome (CRS) is associated with poor outcomes. Risk factors for progressive CRS are not understood in patients with chronic kidney disease (CKD). Objectives: This study aimed to determine the incidence of progressive CRS and risk factors in individuals with CKD. Methods: Adults with CKD in the Chronic Renal Insufficiency Cohort (CRIC) study excluding those with heart failure (HF) at baseline were included (n = 3,557). We defined progressive CRS as developing HF and end-stage kidney disease (ESKD) within 12 months. ESKD was defined as needing renal replacement therapy or renal transplant. The associations of baseline risk factors with progressive CRS were examined using Cox proportional hazards models. A sensitivity analysis assessed risk factors in those who developed HF before ESKD and vice versa. Results: 161 patients (4.5%) developed progressive CRS. Traditional risk factors [multivariable-adjusted hazard ratios (HR) (95% CI)] associated with progressive CRS in multivariable models included lower education [1.90 (1.28,2.83)], cardiovascular disease [1.53 (1.07,2.18)], lower estimated glomerular filtration rate [0.64 (0.51,0.82)] and higher albumin to creatinine ratio [2.44 (1.98,3.02)]. Novel risk factors associated included higher levels of alkaline phosphatase, brain natriuretic peptide (BNP), tumor necrosis factor alpha (TNF-?), growth differentiation factor 15 (GDF-15), hemoglobin A1C, and lower hemoglobin. Risk factors associated with both ESKD before HF and HF before ESKD were kidney dysfunction, albuminuria, and mineral bone disorder (higher alkaline phosphatase and PTH), inflammation (TNF-?), fibrotic factor (GDF-15), and anemia. Diabetes, CVD, systolic blood pressure, waist circumference, HbA1c, and BNP were more strongly associated when HF preceded ESKD. Conclusions: Both traditional risk factors and novel risk factors associated with inflammation, mineral bone disorder, anemia, diabetes control, albuminuria, worse kidney function, and fibrotic factors are associated with progressive CRS in individuals with CKD. Many of these risk factors are modifiable representing potential areas for intervention.","rel_num_authors":20,"rel_authors":[{"author_name":"Meredith McAdams","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"- CRIC Study Investigators","author_inst":"-"},{"author_name":"Jiang He","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Bernard G Jaar","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Hua He","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Cong Zhao","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Siyi Geng","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Amanda H Anderson","author_inst":"Tulane University"},{"author_name":"Vecihi Batuman","author_inst":"Tulane Medical School"},{"author_name":"Joshua D. Bundy","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Jonathan Taliercio","author_inst":"j.\tDepartment of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic"},{"author_name":"Panduranga Rao","author_inst":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Sarah Schrauben","author_inst":"Hospital of the University of Pennsylvania"},{"author_name":"Milica Djokic","author_inst":"Tulane University School of Medicine"},{"author_name":"Joel Merriman","author_inst":"University at Buffalo Jacobs School of Medicine and Biomedical Sciences"},{"author_name":"Giselle Rodriguez de Sosa","author_inst":"Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM, USA"},{"author_name":"Alan S. Go","author_inst":"Kaiser Permanente Northern California"},{"author_name":"James Lash","author_inst":"University of Illinois Chicago"},{"author_name":"L. Lee Hamm","author_inst":"Tulane University"},{"author_name":"Jing Chen","author_inst":"The University of Texas Southwestern Medical Center"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A Behaviorally Informed Patient-Facing Intervention to Promote Albuminuria Testing in Hypertension: A Mixed-Methods Evaluation of KnowCKD","rel_doi":"10.64898\/2026.11.06.26367454","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367454","rel_abs":"Background: Albuminuria testing to diagnose chronic kidney disease (CKD) and guide blood pressure management is recommended for adults with hypertension but remains underused in part due to suboptimal patient understanding of its importance. Patient facing behavioral interventions have the potential to bridge this gap. We developed and evaluated KnowCKD, a behaviorally informed intervention designed to increase patient awareness of CKD and knowledge and promote albuminuria testing among adults with hypertension. Methods: KnowCKD consisted of an educational infographic and brief, behaviorally informed messages delivered to patients' smartphones during the 5 days leading up to and including a scheduled primary care visit at one academic medical center. Among 57 adults with hypertension without diabetes or recent albuminuria testing, we assessed changes in CKD awareness and knowledge and patient-reported engagement via survey pre- and post- exposure to KnowCKD. Electronic Health Record (EHR)- confirmed albuminuria or proteinuria testing was compared with 182 contemporaneous primary care controls using unmatched and propensity score-matched analysis. A postintervention focus group evaluated participant experiences. Results: After exposure to KnowCKD, recognition that adults with hypertension should undergo urine testing increased from 58% to 95%, knowledge that albuminuria indicates protein in the urine increased from 47% to 95%, and awareness that testing facilitates early CKD detection increased from 55% to 100% (P <0.001 for all). After the primary care visit, 77% of patients reported asking their clinician about urine testing and 65% reported that testing was ordered. EHR-confirmed albuminuria or proteinuria testing occurred in 36.8% of KnowCKD participants versus 11.0% of controls (risk ratio, 3.35 [95% CI, 1.96-5.73]; absolute risk difference, 25.9 percentage points [95% CI, 12.5- 39.2]). The propensity score-matched risk ratio was 2.93 (95% CI, 1.59-5.42). Participants described KnowCKD as timely, understandable, and actionable and emphasized trusted health-system communication for broader implementation. Conclusions: KnowCKD was associated with increased patient awareness of CKD and knowledge, patient engagement, and higher EHR-confirmed albuminuria or proteinuria testing among adults with hypertension. A rigorous evaluation of KnowCKD implementation within routine health-system workflows is warranted as a next step.","rel_num_authors":9,"rel_authors":[{"author_name":"Ivan Villasenor","author_inst":"University of California San Francisco"},{"author_name":"Rahul Biswas","author_inst":"University of California San Francisco"},{"author_name":"Kelechi Okpara","author_inst":"University of Arizona"},{"author_name":"Sharlene Shirali","author_inst":"University of California San Francisco"},{"author_name":"Jiun-Ruey Hu","author_inst":"Pulse Heart Institute"},{"author_name":"Susanne B. Nicholas","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Delphine S. Tuot","author_inst":"University of California San francisco"},{"author_name":"Nicole A. Errett","author_inst":"University of Washington School of Public Health"},{"author_name":"Julio A. Lamprea-Montealegre","author_inst":"University of California San Francisco"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A Behaviorally Informed Patient-Facing Intervention to Promote Albuminuria Testing in Hypertension: A Mixed-Methods Evaluation of KnowCKD","rel_doi":"10.64898\/2026.11.06.26367454","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367454","rel_abs":"Background: Albuminuria testing to diagnose chronic kidney disease (CKD) and guide blood pressure management is recommended for adults with hypertension but remains underused in part due to suboptimal patient understanding of its importance. Patient facing behavioral interventions have the potential to bridge this gap. We developed and evaluated KnowCKD, a behaviorally informed intervention designed to increase patient awareness of CKD and knowledge and promote albuminuria testing among adults with hypertension. Methods: KnowCKD consisted of an educational infographic and brief, behaviorally informed messages delivered to patients' smartphones during the 5 days leading up to and including a scheduled primary care visit at one academic medical center. Among 57 adults with hypertension without diabetes or recent albuminuria testing, we assessed changes in CKD awareness and knowledge and patient-reported engagement via survey pre- and post- exposure to KnowCKD. Electronic Health Record (EHR)- confirmed albuminuria or proteinuria testing was compared with 182 contemporaneous primary care controls using unmatched and propensity score-matched analysis. A postintervention focus group evaluated participant experiences. Results: After exposure to KnowCKD, recognition that adults with hypertension should undergo urine testing increased from 58% to 95%, knowledge that albuminuria indicates protein in the urine increased from 47% to 95%, and awareness that testing facilitates early CKD detection increased from 55% to 100% (P <0.001 for all). After the primary care visit, 77% of patients reported asking their clinician about urine testing and 65% reported that testing was ordered. EHR-confirmed albuminuria or proteinuria testing occurred in 36.8% of KnowCKD participants versus 11.0% of controls (risk ratio, 3.35 [95% CI, 1.96-5.73]; absolute risk difference, 25.9 percentage points [95% CI, 12.5- 39.2]). The propensity score-matched risk ratio was 2.93 (95% CI, 1.59-5.42). Participants described KnowCKD as timely, understandable, and actionable and emphasized trusted health-system communication for broader implementation. Conclusions: KnowCKD was associated with increased patient awareness of CKD and knowledge, patient engagement, and higher EHR-confirmed albuminuria or proteinuria testing among adults with hypertension. A rigorous evaluation of KnowCKD implementation within routine health-system workflows is warranted as a next step.","rel_num_authors":9,"rel_authors":[{"author_name":"Ivan Villasenor","author_inst":"University of California San Francisco"},{"author_name":"Rahul Biswas","author_inst":"University of California San Francisco"},{"author_name":"Kelechi Okpara","author_inst":"University of Arizona"},{"author_name":"Sharlene Shirali","author_inst":"University of California San Francisco"},{"author_name":"Jiun-Ruey Hu","author_inst":"Pulse Heart Institute"},{"author_name":"Susanne B. Nicholas","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Delphine S. Tuot","author_inst":"University of California San francisco"},{"author_name":"Nicole A. Errett","author_inst":"University of Washington School of Public Health"},{"author_name":"Julio A. Lamprea-Montealegre","author_inst":"University of California San Francisco"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Stakeholder perspectives and preferences for long-acting injectables for tuberculosis treatment and prevention: a multi-regional mixed-methods study","rel_doi":"10.64898\/2026.11.06.26367430","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367430","rel_abs":"Objective: To assess stakeholder acceptability of and preferences for long-acting injectables (LAIs) for tuberculosis (TB) treatment and prevention across World Health Organization regions to inform product development and implementation. Methods: We conducted a sequential explanatory mixed-methods study of survey data and qualitative focus group discussions (FGDs). Online surveys assessed perceptions and acceptance of LAIs among two groups: TB programme managers, civil society members and healthcare workers (Survey A), and community members and persons affected by TB (Survey B). Using purposive sampling, survey participants were invited to join FGDs to explore survey findings. Survey data were analysed using descriptive statistics, ordinal logistic regression with stepwise AIC selection, and one-sample proportion tests. FGD transcripts were analysed using modified framework analysis. Findings: Among 310 participants (102 Survey A; 208 Survey B), 83% (n=256) favoured LAIs over standard oral TB treatment. Compared with six months of daily oral treatment, 69% preferred a three-month regimen comprising one month of daily oral treatment followed by four injections per monthly visit for two months, while 80% preferred the corresponding regimen with two injections per visit. For prevention, 79% preferred a single injection over one month of oral treatment. In Survey B, interest varied according to lived TB experience, with FGDs suggesting that previous negative experiences with injectables may have contributed to this variation. Conclusion: Interest in LAIs for TB treatment and prevention was high, but lower among participants with lived TB experience. Product development and implementation should address concerns about injectables and side effects while preserving patient choice and agency.","rel_num_authors":13,"rel_authors":[{"author_name":"Chaelin Kim","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Erin V. McConnell","author_inst":"Treatment Action Group"},{"author_name":"Samuel G. Schumacher","author_inst":"World Health Organization"},{"author_name":"Dennis Falzon","author_inst":"World Health Organization"},{"author_name":"Medea Gegia","author_inst":"World Health Organization"},{"author_name":"Lusiana Aprilawati","author_inst":"Jaringan Peduli TB Indonesia"},{"author_name":"Jimmy Galarza","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Edna Tembo","author_inst":"Coalition of Women Living with HIV and AIDS"},{"author_name":"Lesia Tonkonoh","author_inst":"TB Europe Coalition"},{"author_name":"Gwenan M Knight","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"C Finn McQuaid","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Fuad Mirzayev","author_inst":"World Health Organization"},{"author_name":"Nora West","author_inst":"University of California, San Francisco"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Harmonization of microbiome data in the Environmental influences on Child Health Outcomes (ECHO) Cohort to analyze environmental influences on the child microbiome","rel_doi":"10.64898\/2026.11.06.26367438","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367438","rel_abs":"The human microbiome is critical for health across the life course and may mediate the relationship between early-life exposures and health outcomes. The Environmental influences on Child Health Outcomes (ECHO) Cohort provides a unique opportunity to investigate this relationship in children. Individual cohort sites within the ECHO Cohort collected and sequenced microbiome data prior to the consortium formation. Sequencing data were annotated using a common protocol. We summarized the relationship between participant characteristics and features of the microbiome to understand how ECHO can advance the study of the connection between environmental exposures, the microbiome, and health outcomes. A total of 15,509 high-quality extant microbiome samples were collected from 1,086 pregnancies and 5,701 children from 21 ECHO cohort sites. The observed microbial communities were shaped by body site, participant type (pregnant person, child), age, and sample processing. Children lived in 40 states across the United States; high-quality geolocation data were available for more than 60% of children with gut samples. Assay measures, including PFAS, and were available for more than 1,000 children with gut samples. Extant ECHO microbiome data provide an opportunity to characterize the effect of environmental exposures on the developing human microbiome and the role of these exposures in shaping long-term health.","rel_num_authors":29,"rel_authors":[{"author_name":"Justine W. Debelius","author_inst":"1"},{"author_name":"Shaoming Xiao","author_inst":"2"},{"author_name":"Noel T. Mueller","author_inst":"2"},{"author_name":"Sarah S. Comstock","author_inst":"4"},{"author_name":"Kristen L. McArthur","author_inst":"1"},{"author_name":"Zone Li","author_inst":"1"},{"author_name":"Ekaterina Smirnova","author_inst":"5"},{"author_name":"Vanja Klepac-Ceraj","author_inst":"6"},{"author_name":"Christian Rosas-Salazar","author_inst":"7"},{"author_name":"Cara Wychgram","author_inst":"1"},{"author_name":"Meredith Palmore","author_inst":"1"},{"author_name":"Grier P. Page","author_inst":"8"},{"author_name":"Judy L. Aschner","author_inst":"9"},{"author_name":"Patricia A. Brennan","author_inst":"10"},{"author_name":"Carlos A. Camargo Jr","author_inst":"11"},{"author_name":"Scott Collingwood","author_inst":"12"},{"author_name":"Suman R. Das","author_inst":"13"},{"author_name":"Janice A. Espinola","author_inst":"11"},{"author_name":"James E. Gern","author_inst":"14"},{"author_name":"Tina V. Hartert","author_inst":"7"},{"author_name":"Daniel J. Jackson","author_inst":"14"},{"author_name":"Margaret R. Karagas","author_inst":"16"},{"author_name":"Leslie D. Leve","author_inst":"17"},{"author_name":"Thomas G. O'Connor","author_inst":"18"},{"author_name":"Ryohei Shibata","author_inst":"11"},{"author_name":"Meghan H. Shilts","author_inst":"13"},{"author_name":"Zhaozhong Zhu","author_inst":"11"},{"author_name":"Amii M. Kress","author_inst":"1"},{"author_name":"- ECHO The Echo Cohort Consortium","author_inst":""}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Harmonization of microbiome data in the Environmental influences on Child Health Outcomes (ECHO) Cohort to analyze environmental influences on the child microbiome","rel_doi":"10.64898\/2026.11.06.26367438","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367438","rel_abs":"The human microbiome is critical for health across the life course and may mediate the relationship between early-life exposures and health outcomes. The Environmental influences on Child Health Outcomes (ECHO) Cohort provides a unique opportunity to investigate this relationship in children. Individual cohort sites within the ECHO Cohort collected and sequenced microbiome data prior to the consortium formation. Sequencing data were annotated using a common protocol. We summarized the relationship between participant characteristics and features of the microbiome to understand how ECHO can advance the study of the connection between environmental exposures, the microbiome, and health outcomes. A total of 15,509 high-quality extant microbiome samples were collected from 1,086 pregnancies and 5,701 children from 21 ECHO cohort sites. The observed microbial communities were shaped by body site, participant type (pregnant person, child), age, and sample processing. Children lived in 40 states across the United States; high-quality geolocation data were available for more than 60% of children with gut samples. Assay measures, including PFAS, and were available for more than 1,000 children with gut samples. Extant ECHO microbiome data provide an opportunity to characterize the effect of environmental exposures on the developing human microbiome and the role of these exposures in shaping long-term health.","rel_num_authors":29,"rel_authors":[{"author_name":"Justine W. Debelius","author_inst":"1"},{"author_name":"Shaoming Xiao","author_inst":"2"},{"author_name":"Noel T. Mueller","author_inst":"2"},{"author_name":"Sarah S. Comstock","author_inst":"4"},{"author_name":"Kristen L. McArthur","author_inst":"1"},{"author_name":"Zone Li","author_inst":"1"},{"author_name":"Ekaterina Smirnova","author_inst":"5"},{"author_name":"Vanja Klepac-Ceraj","author_inst":"6"},{"author_name":"Christian Rosas-Salazar","author_inst":"7"},{"author_name":"Cara Wychgram","author_inst":"1"},{"author_name":"Meredith Palmore","author_inst":"1"},{"author_name":"Grier P. Page","author_inst":"8"},{"author_name":"Judy L. Aschner","author_inst":"9"},{"author_name":"Patricia A. Brennan","author_inst":"10"},{"author_name":"Carlos A. Camargo Jr","author_inst":"11"},{"author_name":"Scott Collingwood","author_inst":"12"},{"author_name":"Suman R. Das","author_inst":"13"},{"author_name":"Janice A. Espinola","author_inst":"11"},{"author_name":"James E. Gern","author_inst":"14"},{"author_name":"Tina V. Hartert","author_inst":"7"},{"author_name":"Daniel J. Jackson","author_inst":"14"},{"author_name":"Margaret R. Karagas","author_inst":"16"},{"author_name":"Leslie D. Leve","author_inst":"17"},{"author_name":"Thomas G. O'Connor","author_inst":"18"},{"author_name":"Ryohei Shibata","author_inst":"11"},{"author_name":"Meghan H. Shilts","author_inst":"13"},{"author_name":"Zhaozhong Zhu","author_inst":"11"},{"author_name":"Amii M. Kress","author_inst":"1"},{"author_name":"- ECHO The Echo Cohort Consortium","author_inst":""}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"OPEN: A Community-Informed Metadata Framework for Interoperable Computable Phenotypes","rel_doi":"10.64898\/2026.11.06.26367456","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367456","rel_abs":"Objective: To identify community - prioritized metadata for reporting and sharing computable phenotypes (CPs), develop a cross-library candidate framework, assess alignment between user requirements and library metadata, and test the feasibility of metadata exchange. Materials and Methods: We combined an international, library - led effort by the Open PhEnomics Network (OPEN) consortium with a UK community consensus-building exercise aimed at improving the FAIRness (Findable, Accessible, Interoperable, Reusable) of CPs. The consortium performed a cross-library field comparison and literature review to inform candidate fields, refined through consortium consensus. The community approach was developed through stakeholder interviews, a survey, and workshop, guided by a working group. Community requirements were interpretively mapped to the resulting framework and classified into conformance tiers. Interoperability was tested by manually and programmatically mapping diabetes-related phenotypes across libraries. Results: The library - led process produced 23 candidate fields spanning phenotype description, data\/technical details, and performance domains. Thirteen fields aligned across all five libraries, and 22 fields aligned with published CP library desiderata. Interoperability testing successfully catalogued phenotypes through manual mapping, with API - mediated mapping achieving 63 - 76% metadata field completeness across libraries. A community survey (n=124 respondents) identified six metadata elements with majority support as mandatory: description, coding terminology, phenotype type, version history, unique identifier, and data source. Logic representation and validation requirements were rated as mostly context-dependent. Community - identified priorities showed strong alignment with the OPEN framework, though some requirements were only partially represented. Discussion: Through a consensus - based, community - driven approach, we established a CP framework enabling interoperability across libraries. Conclusion: OPEN provides a credible, community - informed foundation for a FAIR CP metadata standard.","rel_num_authors":12,"rel_authors":[{"author_name":"Jacqueline Honerlaw","author_inst":"VA Boston Healthcare System"},{"author_name":"Jacqueline A L MacArthur","author_inst":"Health Data Research UK"},{"author_name":"Yuk-Lam Ho","author_inst":"VA Boston Healthcare System"},{"author_name":"Srushti Gangireddy","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center"},{"author_name":"Ashley Galloway","author_inst":"VA Boston Healthcare System"},{"author_name":"Katie Hilty","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center"},{"author_name":"Gowtham Rao","author_inst":"Observational Health Data Sciences and Informatics"},{"author_name":"Lang Li","author_inst":"The Ohio State University College of Medicine"},{"author_name":"Azza Shoaibi","author_inst":"Janssen Research and Development"},{"author_name":"Spiros Denaxas","author_inst":"University College London"},{"author_name":"Kelly Cho","author_inst":"VA Boston Healthcare System"},{"author_name":"Wei-Qi Wei","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Multi-Agent Generative Artificial Intelligence for Transfusion Reaction Feature Extraction","rel_doi":"10.64898\/2026.11.06.26367389","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367389","rel_abs":"BACKGROUND: Many transfusion reactions are not reported to hemovigilance systems, and the features needed to recognize them are often documented only in free-text clinical notes. We sought to develop and evaluate an open-source, multi-agent artificial intelligence (AI) pipeline to extract transfusion reaction features defined by the National Healthcare Safety Network (NHSN) Hemovigilance Module from clinical notes. METHODS: We curated 181 features from the NHSN protocol and developed a multi-stage pipeline that extracted features, their timing, and clinical details from free-text notes. Three open-weight large language models (Qwen 3.6-27B, GPT-OSS-120B, and Kimi K3) were applied to 50 notes from expert-written scenarios, published case reports, and MIMIC-IV discharge summaries. Two physicians independently evaluated every model output in a blinded interface. The primary analysis was restricted to feature occurrences with concordant physician assessments. RESULTS: Physicians agreed on 1,201 of 1,343 co-rated feature occurrences (89.4%; Krippendorff's alpha 0.73). Precision was above 0.98 for all models. Sensitivity was 0.774 (95% CI 0.745-0.800) for Kimi K3, 0.636 (0.604-0.667) for GPT-OSS-120B, and 0.624 (0.593-0.655) for Qwen 3.6-27B, and specificity ranged from 0.952 to 0.991. Omissions accounted for more than 94% of false negatives. Timing and clinical details were judged supported or reasonable in more than 92% and 97% of assessments, respectively. Results were consistent across note sources and in analyses including discordant assessments. CONCLUSION: Multi-agent AI pipelines provide a feasible method for extracting transfusion reaction signals from clinical notes with high precision. Our work may have applications in active hemovigilance, reaction classification, and big data research.","rel_num_authors":15,"rel_authors":[{"author_name":"Ayushi Kumari","author_inst":"Amity Institute of Information Technology, Amity University, Noida, Uttar Pradesh, India"},{"author_name":"Jeremy W. Jacobs","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Laura Dilly","author_inst":"Department of Pathology, University of California San Diego, La Jolla, California, USA"},{"author_name":"Aman Anand","author_inst":"School of Computing, Faculty of Arts and Science, Queens University, Kingston, Ontario, Canada"},{"author_name":"Jennifer Woo","author_inst":"Department of Pathology, City of Hope Comprehensive Cancer Center, Irvine, California, USA"},{"author_name":"Yulia Lin","author_inst":"Sunnybrook Health Sciences Center, Toronto, Ontario, Canada"},{"author_name":"Andrew W. Shih","author_inst":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Garrett S. Booth","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Ismail Raslan","author_inst":"Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada"},{"author_name":"Nicole Relke","author_inst":"Medical Affairs, Canadian Blood Services, Toronto, Ontario, Canada"},{"author_name":"Rounak Dubey","author_inst":"Department of Transfusion Medicine, All India Institute of Medical Sciences, Nagpur, India"},{"author_name":"Siddhartha Srivastava","author_inst":"Division of General Internal Medicine, Department of Medicine, Queens University, Kingston, Ontario, Canada"},{"author_name":"Widad Abdulwahab","author_inst":"Sunnybrook Health Sciences Center, Toronto, Ontario, Canada"},{"author_name":"Ruchika Goel","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Sheharyar Raza","author_inst":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Multi-Agent Generative Artificial Intelligence for Transfusion Reaction Feature Extraction","rel_doi":"10.64898\/2026.11.06.26367389","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367389","rel_abs":"BACKGROUND: Many transfusion reactions are not reported to hemovigilance systems, and the features needed to recognize them are often documented only in free-text clinical notes. We sought to develop and evaluate an open-source, multi-agent artificial intelligence (AI) pipeline to extract transfusion reaction features defined by the National Healthcare Safety Network (NHSN) Hemovigilance Module from clinical notes. METHODS: We curated 181 features from the NHSN protocol and developed a multi-stage pipeline that extracted features, their timing, and clinical details from free-text notes. Three open-weight large language models (Qwen 3.6-27B, GPT-OSS-120B, and Kimi K3) were applied to 50 notes from expert-written scenarios, published case reports, and MIMIC-IV discharge summaries. Two physicians independently evaluated every model output in a blinded interface. The primary analysis was restricted to feature occurrences with concordant physician assessments. RESULTS: Physicians agreed on 1,201 of 1,343 co-rated feature occurrences (89.4%; Krippendorff's alpha 0.73). Precision was above 0.98 for all models. Sensitivity was 0.774 (95% CI 0.745-0.800) for Kimi K3, 0.636 (0.604-0.667) for GPT-OSS-120B, and 0.624 (0.593-0.655) for Qwen 3.6-27B, and specificity ranged from 0.952 to 0.991. Omissions accounted for more than 94% of false negatives. Timing and clinical details were judged supported or reasonable in more than 92% and 97% of assessments, respectively. Results were consistent across note sources and in analyses including discordant assessments. CONCLUSION: Multi-agent AI pipelines provide a feasible method for extracting transfusion reaction signals from clinical notes with high precision. Our work may have applications in active hemovigilance, reaction classification, and big data research.","rel_num_authors":15,"rel_authors":[{"author_name":"Ayushi Kumari","author_inst":"Amity Institute of Information Technology, Amity University, Noida, Uttar Pradesh, India"},{"author_name":"Jeremy W. Jacobs","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Laura Dilly","author_inst":"Department of Pathology, University of California San Diego, La Jolla, California, USA"},{"author_name":"Aman Anand","author_inst":"School of Computing, Faculty of Arts and Science, Queens University, Kingston, Ontario, Canada"},{"author_name":"Jennifer Woo","author_inst":"Department of Pathology, City of Hope Comprehensive Cancer Center, Irvine, California, USA"},{"author_name":"Yulia Lin","author_inst":"Sunnybrook Health Sciences Center, Toronto, Ontario, Canada"},{"author_name":"Andrew W. Shih","author_inst":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Garrett S. Booth","author_inst":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Ismail Raslan","author_inst":"Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada"},{"author_name":"Nicole Relke","author_inst":"Medical Affairs, Canadian Blood Services, Toronto, Ontario, Canada"},{"author_name":"Rounak Dubey","author_inst":"Department of Transfusion Medicine, All India Institute of Medical Sciences, Nagpur, India"},{"author_name":"Siddhartha Srivastava","author_inst":"Division of General Internal Medicine, Department of Medicine, Queens University, Kingston, Ontario, Canada"},{"author_name":"Widad Abdulwahab","author_inst":"Sunnybrook Health Sciences Center, Toronto, Ontario, Canada"},{"author_name":"Ruchika Goel","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Sheharyar Raza","author_inst":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Joint Longitudinal Hazard Modeling Distinguishes Polygenic Effects on Dementia via Premorbid Cognitive Function and Aging-Related Decline","rel_doi":"10.64898\/2026.11.06.26367441","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367441","rel_abs":"Alzheimers disease and related dementias (AD\/ADRD) are clinical disorders characterized by declines in cognitive function to levels at which everyday living is meaningfully impaired. Genetic variants may confer risk for AD\/ADRD by way of steeper rates of aging-related cognitive declines or their association with lower premorbid levels of cognitive function that place individuals closer to a clinically severe threshold of cognitive function. We applied joint longitudinal-hazard models to 26-year data from an ancestrally diverse US sample of N = 11,518 adults to estimate effects of multi-ancestry polygenic indices (PGIs) for a range of established risk factors on dementia hazard and the degree they operate via premorbid cognitive function and longitudinal cognitive decline. APOE e4 and PGIs for ADRD, type 2 diabetes, stroke, LDL cholesterol, and hearing loss operated via rate of change, whereas PGIs for educational attainment, cognitive function, physical activity, BMI, smoking, loneliness, schizophrenia, and externalizing were associated with dementia hazard via premorbid differences in cognitive function. Some results varied by continental ancestry. Our implementation of joint longitudinal-hazard models allowed us to distinguish how different genetic risk factors for AD\/ADRD operate via degenerative processes that might be therapeutically targeted during later life and via premorbid levels of cognitive function that would require intervention earlier in the life course.","rel_num_authors":8,"rel_authors":[{"author_name":"Margaret L Clapp Sullivan","author_inst":"Washington University School of Medicine"},{"author_name":"Javier de la Fuente","author_inst":"The University of Texas at Austin"},{"author_name":"Janie Corley","author_inst":"University of Edinburgh"},{"author_name":"Sarah E Harris","author_inst":"University of Edinburgh"},{"author_name":"Ian J Deary","author_inst":"University of Edinburgh"},{"author_name":"Tom C Russ","author_inst":"University of Edinburgh"},{"author_name":"Simon R Cox","author_inst":"University of Edinburgh"},{"author_name":"Elliot M Tucker-Drob","author_inst":"University of Texas at Austin"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Functional analysis enables reclassification of SCN1A missense variants of uncertain significance in epilepsy","rel_doi":"10.64898\/2026.11.07.26367252","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367252","rel_abs":"SCN1A, the most prominent gene for epilepsy, encodes the pore-forming subunit of the voltage-gated sodium channel, NaV1.1. Loss-of-function variants reduce NaV1.1 activity in inhibitory neurons leading to hyperexcitability; they are associated with a spectrum of epilepsies, from self-limited phenotypes in genetic epilepsy with febrile seizures plus, to the prototypic developmental and epileptic encephalopathy, Dravet syndrome. Thousands of SCN1A missense variants have been identified, but determining pathogenicity using ACMG criteria can be challenging. Currently, 48% of missense SCN1A variants in ClinVar are classified as variants of uncertain significance (VUS). We aimed to provide functional evidence to inform variant classification using a high-throughput automated patch-clamp assay. We validated our assay using 27 true pathogenic SCN1A variants and 25 true benign variants. The results show that 17\/27 true pathogenic variants from patients with Dravet syndrome showed severe reductions in current density, precluding gating analysis. Of the remaining ten true pathogenic variants, seven showed an increased voltage difference between the midpoints of activation and inactivation (V0.5diff). Current density and V0.5diff were combined within a graded Bayesian framework to derive a functional log-likelihood ratio reflecting the magnitude of loss of function. We then applied our validated assay to 16 SCN1A missense variants detected in an Australian cohort: three likely pathogenic, one likely benign and 12 VUSs. These variants occurred in 31 individuals from 16 families with a broad phenotypic spectrum, including four individuals with Dravet syndrome who carried p.Ser243Phe, p.Met973Val or p.Lys1911Glu. All three variants showed loss of function: p.Ser243Phe had reduced current density, whereas p.Met973Val and p.Lys1911Glu had abnormal V0.5diff despite current density within the normal range. Of these 16 variants, ten have combined functional scores consistent with abnormal functional evidence. Combining our functional evidence with ACMG criteria, our findings changed the classification of eight of 16 variants (50%), with six of 12 VUS reclassified as likely pathogenic and two of three likely pathogenic variants upgraded to pathogenic. We show that calibrated automated patch-clamp assays can provide actionable functional data to enable the interpretation and reclassification of SCN1A variants and inform clinical care, allowing therapeutic optimisation and facilitating access to genetic therapies.","rel_num_authors":14,"rel_authors":[{"author_name":"Keerthi Pilli","author_inst":"Victor Chang Cardiac Research Institute"},{"author_name":"Talia J Allan","author_inst":"The University of Melbourne"},{"author_name":"Mark F Bennett","author_inst":"The University of Melbourne"},{"author_name":"Rebekah V Harris","author_inst":"The University of Melbourne"},{"author_name":"Amy L Schneider","author_inst":"The University of Melbourne"},{"author_name":"QianYi Shen","author_inst":"Victor Chang Cardiac Research Institute"},{"author_name":"Joanne G Ma","author_inst":"Victor Chang Cardiac Research Institute"},{"author_name":"Michael S Hildebrand","author_inst":"The University of Melbourne"},{"author_name":"Elizabeth E Palmer","author_inst":"University of New South Wales"},{"author_name":"Alfred L George Jr.","author_inst":"Northwestern University"},{"author_name":"Samuel F Berkovic","author_inst":"The University of Melbourne"},{"author_name":"Jamie I Vandenberg","author_inst":"Victor Chang Cardiac Research Insitute"},{"author_name":"Ingrid E Scheffer","author_inst":"The University of Melbourne"},{"author_name":"Chai-Ann Ng","author_inst":"Victor Chang Cardiac Research Institute"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Longitudinal Investigation of Autonomic Symptoms in Biologically Confirmed (SAA+) Parkinson's Disease","rel_doi":"10.64898\/2026.11.09.26367184","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.09.26367184","rel_abs":"Background Autonomic symptoms are common in Parkinson disease (PD) and impact quality of life, with unclear relationship to motor and cognitive progression. Objective: Characterize five-year progression of autonomic symptoms in early PD and their association with motor and cognitive outcomes. Methods We analyzed data from 874 PD participants and 252 healthy controls (HC) enrolled in Parkinson Progression Markers Initiative (PPMI). Autonomic symptoms were assessed annually over five years using Scales for Outcomes in Parkinson's disease-Autonomic dysfunction (SCOPA-AUT); affected autonomic domains were defined as domain subscore >1. Clinical measures included MDS-UPDRS and Montreal Cognitive Assessment. Generalized estimating equations evaluated longitudinal changes, adjusting for age, sex, medication, and comorbidities. Results: At baseline, 71% of PD participants reported >1 affected autonomic domain, increasing to 85% among 287 PD participants with 5-year follow-up; HCs reporting >1 affected autonomic domain increased from 40% of participants at baseline to 46% among 145 participants with 5-year follow-up. Gastrointestinal and urinary symptoms were most prevalent in PD. Medication use for constipation and urinary dysfunction increased over time in PD. Cardiovascular comorbidities were common and increased in prevalence in both groups. Greater baseline autonomic symptom burden predicted more rapid cognitive, but not motor decline in PD (p=0.002). Conclusion: Autonomic symptoms in PD are common at disease onset, near universal after 5 years, and associated with faster cognitive, but not motor, decline, driven by those with severe symptoms. The high prevalence and impact of autonomic symptoms in early PD highlights the importance of early assessment and management of these symptoms.","rel_num_authors":8,"rel_authors":[{"author_name":"Adeel Ali Memon","author_inst":"University of Vermont, Larner College of Medicine"},{"author_name":"Seung Ho Choi","author_inst":"Department of Biostatistics, College of Public Health, University of Iowa"},{"author_name":"Jie Yin","author_inst":"Department of Biostatistics, College of Public Health, University of Iowa"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, College of Public Health, University of Iowa"},{"author_name":"Chelsea Caspell-Garcia","author_inst":"Department of Biostatistics, College of Public Health, University of Iowa"},{"author_name":"Daniel Weintraub","author_inst":"Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania,"},{"author_name":"Amy W. Amara","author_inst":"Department of Neurology, University of Colorado, Anschutz Medical Campus"},{"author_name":"Marina Picillo","author_inst":"Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Plasma phosphorylated tau species across neurodegenerative and cerebrovascular diseases: An ONDRI study","rel_doi":"10.64898\/2026.11.06.26367445","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367445","rel_abs":"Elevated plasma phosphorylated tau (p-tau) species are proposed as specific biomarkers of Alzheimer's disease (AD) pathology but have also been reported in amyotrophic lateral sclerosis (ALS). Their profile across neurodegenerative and cerebrovascular diseases, as well as their discriminatory value when combined with other plasma biomarkers, remain uncertain. We studied 551 participants (ages 40.1 to 87.1 years; 207 women), comprising 506 patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) multi-site cohort and 45 amyloid-{beta} (A{beta}) PET-negative cognitively unimpaired controls from the Brain-Eye Amyloid Memory study. Ten diagnostic groups were studied: mild cognitive impairment (MCI), AD, Parkinson's disease subdivided into cognitively unimpaired (CU), MCI, and dementia, frontotemporal dementia (FTD), cerebrovascular disease (CVD) subdivided into cognitively unimpaired (CU) and cognitively impaired (CI), ALS, and the control group. Baseline visit plasma measurements included p-tau217, p-tau181, A{beta}42\/40, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Cross-sectional analyses compared biomarker levels as well as p-tau217-based inference of amyloid positivity status across diagnostic groups. Receiver operating characteristic-area under the curve (ROC-AUC) analyses ascertained the discriminatory capacity of these biomarkers and ratio combinations. Within the ALS group, baseline biomarker measures were also tested for association against baseline clinical features as well as longitudinal measures of neuropsychological change. P-tau217, p-tau181, GFAP, and NfL differed across groups (all P < 0.001). Compared to controls, p-tau217 was elevated in AD and ALS, p-tau181 and GFAP only in AD, and NfL in ALS and FTD. Inferred amyloid-{beta}; positivity was more probable in MCI, AD, ALS, and cognitively impaired CVD groups compared to controls (all P < 0.05). The p-tau217 to NfL ratio discriminated ALS from AD with an ROC-AUC of 0.92 (95% CI 0.85-0.97) compared to p-tau217 alone at 0.65 (95% CI 0.52-0.76). No ALS clinical or longitudinal association survived correction for multiple comparisons. Elevated p-tau217 and inferred amyloid-{beta}; positivity in ALS provide further evidence that the assay signal is not necessarily specific for AD pathology. However, the use of p-tau217 in combination with NfL provides improved discriminatory power between ALS and AD, supporting the use of plasma biomarker combinations rather than sole reliance on individual plasma biomarkers. Inferred amyloid-{beta}; positivity in cognitively impaired CVD may indicate AD and\/or cerebral amyloid angiopathy co-pathology. Currently available plasma biomarkers should therefore be used as diagnostic complements and interpreted within clinical context rather than as standalone molecular diagnoses.","rel_num_authors":42,"rel_authors":[{"author_name":"Erlan Sanchez","author_inst":"Centre Integre de Traumatologie, CIUSSS-NIM, Montreal, Quebec, Canada; Department of Neuroscience, Universite de Montreal, Montreal, Quebec, Canada; L.C. Campbe"},{"author_name":"Paul Connon","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Maurice Pasternak","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Agessandro Abrahao","author_inst":"ALS Clinic, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Julia Keith","author_inst":"Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Allison A. Dilliott","author_inst":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Ca"},{"author_name":"Andree-Ann Baril","author_inst":"Center for Advanced Research in Sleep Medicine, Research Center of the CIUSSS-NIM, Hopital du Sacre-Coeur de Montreal, Montreal, QC, Canada; Department of Medic"},{"author_name":"Andrew Frank","author_inst":"Bruyere Research Institute, University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Anthony E. Lang","author_inst":"Division of Neurology, Department of Medicine and Medical Sciences, University of Toronto, Toronto, ON, Canada; Edmond J Safra Program in Parkinson's Disease an"},{"author_name":"Bruce G. Pollock","author_inst":"Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry and Department of Pharmacology and Toxicology, University of Toronto, Toro"},{"author_name":"Connie Marras","author_inst":"Edmond J Safra Program in Parkinson's Disease, University Health Network, University of Toronto, Toronto, ON, Canada"},{"author_name":"Corinne E. Fischer","author_inst":"Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada"},{"author_name":"Dallas Seitz","author_inst":"Department of Psychiatry and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada"},{"author_name":"Dar Dowlatshahi","author_inst":"Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada"},{"author_name":"David A. Grimes","author_inst":"Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada; Brain and Mind Research Institute, Ottawa, ON, Canada"},{"author_name":"David F. Tang-Wai","author_inst":"Division of Neurology, Department of Medicine and Medical Sciences, University of Toronto, Toronto, ON, Canada; Krembil Brain Institute, University Health Netwo"},{"author_name":"Demetrios J. Sahlas","author_inst":"Division of Neurology, Department of Medicine, McMaster University, Hamilton, ON, Canada"},{"author_name":"Ekaterina Rogaeva","author_inst":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada"},{"author_name":"Elizabeth Finger","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada"},{"author_name":"Kubra Tan","author_inst":"Institute of Neuroscience and Physiology, University of Gothenburg, Molndal, Sweden"},{"author_name":"Malcolm A. Binns","author_inst":"Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada; Department of Public Health Sciences, University of Toronto, Toronto, ON, Canada"},{"author_name":"Maria C. Tartaglia","author_inst":"Krembil Brain Institute, University Health Network, Toronto, ON, Canada; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto,"},{"author_name":"Michael Borrie","author_inst":"Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine & Dentistry, Western University, London, ON, Canada"},{"author_name":"Morris Freedman","author_inst":"Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada; Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Prog"},{"author_name":"Rafaella A. Goncalves","author_inst":"Gladstone Institutes of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Richard H. Swartz","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Robert A. Hegele","author_inst":"Robarts Research Institute, Western University, London, ON, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, Londo"},{"author_name":"Roger A. Dixon","author_inst":"Department of Psychology, University of Alberta, Edmonton, AB, Canada"},{"author_name":"Saira Saeed Mirza","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Sali M.K. Farhan","author_inst":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Ca"},{"author_name":"Sandra E. Black","author_inst":"Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada; Division of Neuro"},{"author_name":"Sanjeev Kumar","author_inst":"Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Stephen H. Pasternak","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Cognitive Neurology,"},{"author_name":"Tarek K. Rajji","author_inst":"Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Thomas Steeves","author_inst":"Division of Neurology, Nuvance Health Vassar Brothers Medical Center, Poughkeepsie, NY, USA"},{"author_name":"Walter Swardfager","author_inst":"Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada; Department of Pha"},{"author_name":"Henrik Zetterberg","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden;"},{"author_name":"Hlin Kvartsberg","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden;"},{"author_name":"Douglas P. Munoz","author_inst":"Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada"},{"author_name":"Lorne Zinman","author_inst":"ALS Clinic, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Michael J. Strong","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada"},{"author_name":"Mario Masellis","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Plasma phosphorylated tau species across neurodegenerative and cerebrovascular diseases: An ONDRI study","rel_doi":"10.64898\/2026.11.06.26367445","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367445","rel_abs":"Elevated plasma phosphorylated tau (p-tau) species are proposed as specific biomarkers of Alzheimer's disease (AD) pathology but have also been reported in amyotrophic lateral sclerosis (ALS). Their profile across neurodegenerative and cerebrovascular diseases, as well as their discriminatory value when combined with other plasma biomarkers, remain uncertain. We studied 551 participants (ages 40.1 to 87.1 years; 207 women), comprising 506 patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) multi-site cohort and 45 amyloid-{beta} (A{beta}) PET-negative cognitively unimpaired controls from the Brain-Eye Amyloid Memory study. Ten diagnostic groups were studied: mild cognitive impairment (MCI), AD, Parkinson's disease subdivided into cognitively unimpaired (CU), MCI, and dementia, frontotemporal dementia (FTD), cerebrovascular disease (CVD) subdivided into cognitively unimpaired (CU) and cognitively impaired (CI), ALS, and the control group. Baseline visit plasma measurements included p-tau217, p-tau181, A{beta}42\/40, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Cross-sectional analyses compared biomarker levels as well as p-tau217-based inference of amyloid positivity status across diagnostic groups. Receiver operating characteristic-area under the curve (ROC-AUC) analyses ascertained the discriminatory capacity of these biomarkers and ratio combinations. Within the ALS group, baseline biomarker measures were also tested for association against baseline clinical features as well as longitudinal measures of neuropsychological change. P-tau217, p-tau181, GFAP, and NfL differed across groups (all P < 0.001). Compared to controls, p-tau217 was elevated in AD and ALS, p-tau181 and GFAP only in AD, and NfL in ALS and FTD. Inferred amyloid-{beta}; positivity was more probable in MCI, AD, ALS, and cognitively impaired CVD groups compared to controls (all P < 0.05). The p-tau217 to NfL ratio discriminated ALS from AD with an ROC-AUC of 0.92 (95% CI 0.85-0.97) compared to p-tau217 alone at 0.65 (95% CI 0.52-0.76). No ALS clinical or longitudinal association survived correction for multiple comparisons. Elevated p-tau217 and inferred amyloid-{beta}; positivity in ALS provide further evidence that the assay signal is not necessarily specific for AD pathology. However, the use of p-tau217 in combination with NfL provides improved discriminatory power between ALS and AD, supporting the use of plasma biomarker combinations rather than sole reliance on individual plasma biomarkers. Inferred amyloid-{beta}; positivity in cognitively impaired CVD may indicate AD and\/or cerebral amyloid angiopathy co-pathology. Currently available plasma biomarkers should therefore be used as diagnostic complements and interpreted within clinical context rather than as standalone molecular diagnoses.","rel_num_authors":42,"rel_authors":[{"author_name":"Erlan Sanchez","author_inst":"Centre Integre de Traumatologie, CIUSSS-NIM, Montreal, Quebec, Canada; Department of Neuroscience, Universite de Montreal, Montreal, Quebec, Canada; L.C. Campbe"},{"author_name":"Paul Connon","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Maurice Pasternak","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Agessandro Abrahao","author_inst":"ALS Clinic, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Julia Keith","author_inst":"Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Allison A. Dilliott","author_inst":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Ca"},{"author_name":"Andree-Ann Baril","author_inst":"Center for Advanced Research in Sleep Medicine, Research Center of the CIUSSS-NIM, Hopital du Sacre-Coeur de Montreal, Montreal, QC, Canada; Department of Medic"},{"author_name":"Andrew Frank","author_inst":"Bruyere Research Institute, University of Ottawa, Ottawa, ON, Canada"},{"author_name":"Anthony E. Lang","author_inst":"Division of Neurology, Department of Medicine and Medical Sciences, University of Toronto, Toronto, ON, Canada; Edmond J Safra Program in Parkinson's Disease an"},{"author_name":"Bruce G. Pollock","author_inst":"Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry and Department of Pharmacology and Toxicology, University of Toronto, Toro"},{"author_name":"Connie Marras","author_inst":"Edmond J Safra Program in Parkinson's Disease, University Health Network, University of Toronto, Toronto, ON, Canada"},{"author_name":"Corinne E. Fischer","author_inst":"Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada"},{"author_name":"Dallas Seitz","author_inst":"Department of Psychiatry and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada"},{"author_name":"Dar Dowlatshahi","author_inst":"Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada"},{"author_name":"David A. Grimes","author_inst":"Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada; Brain and Mind Research Institute, Ottawa, ON, Canada"},{"author_name":"David F. Tang-Wai","author_inst":"Division of Neurology, Department of Medicine and Medical Sciences, University of Toronto, Toronto, ON, Canada; Krembil Brain Institute, University Health Netwo"},{"author_name":"Demetrios J. Sahlas","author_inst":"Division of Neurology, Department of Medicine, McMaster University, Hamilton, ON, Canada"},{"author_name":"Ekaterina Rogaeva","author_inst":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada"},{"author_name":"Elizabeth Finger","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada"},{"author_name":"Kubra Tan","author_inst":"Institute of Neuroscience and Physiology, University of Gothenburg, Molndal, Sweden"},{"author_name":"Malcolm A. Binns","author_inst":"Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada; Department of Public Health Sciences, University of Toronto, Toronto, ON, Canada"},{"author_name":"Maria C. Tartaglia","author_inst":"Krembil Brain Institute, University Health Network, Toronto, ON, Canada; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto,"},{"author_name":"Michael Borrie","author_inst":"Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine & Dentistry, Western University, London, ON, Canada"},{"author_name":"Morris Freedman","author_inst":"Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada; Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Prog"},{"author_name":"Rafaella A. Goncalves","author_inst":"Gladstone Institutes of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA"},{"author_name":"Richard H. Swartz","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Robert A. Hegele","author_inst":"Robarts Research Institute, Western University, London, ON, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, Londo"},{"author_name":"Roger A. Dixon","author_inst":"Department of Psychology, University of Alberta, Edmonton, AB, Canada"},{"author_name":"Saira Saeed Mirza","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "},{"author_name":"Sali M.K. Farhan","author_inst":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Ca"},{"author_name":"Sandra E. Black","author_inst":"Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada; Division of Neuro"},{"author_name":"Sanjeev Kumar","author_inst":"Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Stephen H. Pasternak","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada; Cognitive Neurology,"},{"author_name":"Tarek K. Rajji","author_inst":"Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Thomas Steeves","author_inst":"Division of Neurology, Nuvance Health Vassar Brothers Medical Center, Poughkeepsie, NY, USA"},{"author_name":"Walter Swardfager","author_inst":"Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada; Department of Pha"},{"author_name":"Henrik Zetterberg","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden;"},{"author_name":"Hlin Kvartsberg","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden;"},{"author_name":"Douglas P. Munoz","author_inst":"Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada"},{"author_name":"Lorne Zinman","author_inst":"ALS Clinic, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada"},{"author_name":"Michael J. Strong","author_inst":"Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada"},{"author_name":"Mario Masellis","author_inst":"L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, "}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Metabolome-wide Association Study of Bronchopulmonary Dysplasia in Extremely Premature Infants","rel_doi":"10.64898\/2026.11.06.26367452","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367452","rel_abs":"Rationale: Untargeted metabolomics may identify novel pathways involved in bronchopulmonary dysplasia (BPD), a poorly understood lung disease in extremely premature infants. Objective: To identify metabolites and pathways altered in infants who develop BPD through a metabolome-wide association study. Methods: We performed untargeted urinary metabolomics in 314 infants (<29 weeks gestational age) at two time points between postnatal days 5-15 and 23-32, with detailed time-series for 28 infants. We compared metabolite levels between infants with and without BPD at 36 weeks postmenstrual age using logistic regression and pathway enrichment analysis. A stratified analysis by nutrition type was performed at 23-32 days. Results: Among the 913 analyzed urinary metabolites, 23 and 68 were nominally associated with BPD between postnatal days 5-15 and 23-32, respectively (p<0.05). We found enrichment in the lactoyl amino acid sub-pathway (5-15 days; p=0.005, q=0.4) and xanthine metabolism and fatty acid metabolism (23-32 days; p[&le;]0.002, q<0.1). Most BPD-differential metabolites were lower in infants with BPD at days 23-32 (OR=7.1, p=2x10-6), with similar patterns among infants receiving parenteral (OR=9.2, p=7x10-7) and full enteral nutrition (OR=6.1, p=0.003). Twenty-four metabolites, including vitamins C, B1, and B6, were lower in infants on parenteral nutrition with BPD at postnatal days 23-32. Discussion: BPD in extremely premature infants was associated with lower levels of vitamin-related metabolites and dysregulation of lactoyl amino acids, xanthine, and fatty acid metabolism. BPD-differential metabolites were lower in infants with BPD during the fourth week of life, potentially related to higher energy demand, metabolic dysregulation, insufficient nutrient availability, and\/or impaired intestinal absorption.","rel_num_authors":6,"rel_authors":[{"author_name":"Thaybeth I. Malave-Mendez","author_inst":"University of California San Francisco"},{"author_name":"Miguel A Guardado","author_inst":"University of California, San Francisco"},{"author_name":"Cheryl Chapin","author_inst":"University of California, San Francsico"},{"author_name":"Ryan D. Hernandez","author_inst":"University of California, San Francisco"},{"author_name":"Phil Ballard","author_inst":"University of California, San Francisco"},{"author_name":"Dara G. Torgerson","author_inst":"University of California, San Francisco"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"Reducing Biosecurity Risks in Informal Poultry Slaughter: A Pilot Intervention Among Mobile Poultry Vendors in Bangladesh","rel_doi":"10.64898\/2026.11.05.26367345","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367345","rel_abs":"Introduction Mobile poultry vending and slaughtering practices in Bangladesh pose potential public health risks due to poor hygiene, unsafe waste disposal, and close human-animal interactions. Limited data exist on these practices and feasible interventions to improve biosecurity among mobile poultry vendors. Methods This mixed-method study was conducted in three phases across four sub-districts in three districts. Phase 1 involved 416 hours of structured observation, 40 in-depth vendor interviews, and 40 informal customer interviews. Phase 2 involved the development and pilot testing of an intervention package, including poultry killing cones, hand sanitizers, disinfectants, and a hygiene pamphlet, with 10 vendors. Phase 3 implemented the intervention among 20 vendors for one month, followed by 94 hours of observation and 17 customer interviews. Result Phase 1 found 1,959 slaughtering events with no use of personal protective equipment; slaughtering occurred in plastic jars (58%), directly on roads (21%), and roadside drains (11%). Seventy percent of vendors reported discarding slaughtering waste directly into the environment, while 78% reported not knowing how poultry diseases could spread to other animals or humans. During Phase 2, 9\/10 vendors considered the killing cone useful, although bicycle users reported challenges related to weight and balance; the cone was subsequently modified. During Phase 3, 294 poultry were observed being slaughtered, with 79% using killing cones. Waste was stored in cone-attached boxes in 97% of cone uses, and vendors used hand sanitizer before eating in 75% of observed instances. Among 17 interviewed customers, 88% recognized the cones role in safer waste disposal and 53% considered it useful overall. Conclusion This study highlights major hygiene and biosecurity gaps and demonstrates that low-cost, targeted interventions may improve biosecurity practices among mobile poultry vendors and reduce opportunities for environmental contamination in informal slaughter settings.","rel_num_authors":8,"rel_authors":[{"author_name":"Md. Musa Baker","author_inst":"International Centre for Diarrhoeal Disease Research Bangladesh"},{"author_name":"Kamal  Ibne Amin Chowdhury","author_inst":"International Centre for Diarrhoeal Disease Research"},{"author_name":"Dalia Yeasmin","author_inst":"International Centre for Diarrhoeal Disease Research"},{"author_name":"Abu-Hena  Mostofa Kamal","author_inst":"Khulna University of Engineering and Technology"},{"author_name":"Mohammad  Tauhidul Islam","author_inst":"International Centre for Diarrhoeal Disease Research Bangladesh"},{"author_name":"Sheikh  Shariful Islam","author_inst":"International Centre for Diarrhoeal Disease Research Bangladesh"},{"author_name":"Ausraful Islam","author_inst":"International Centre for Diarrhoeal Disease Research Bangladesh"},{"author_name":"Md.  Saiful Islam","author_inst":"University of New South Wales"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"A Framework for Variant Filtering to Improve Diagnostic Outcomes in Genome Sequencing","rel_doi":"10.64898\/2026.11.07.26367371","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.07.26367371","rel_abs":"Rare genetic disorders frequently remain undiagnosed despite the use of exome sequencing (ES) and genome sequencing (GS). This study aimed to enhance diagnostic yield by introducing a systematic framework: SMART filtering (Systematic, Multi-step, Automated, Rare variant prioritization Tool), designed to optimize GS analysis, with a particular emphasis on non-coding regions. We retrospectively analyzed 153 cases with previously negative ES and GS results. SMART filtering was applied as a pre-annotation filtering step, integrating conservation metrics, allele frequency thresholds, and splicing prediction scores. Then followed by phenotype-based prioritization and manual review. Application of this framework identified pathogenic or likely pathogenic variants in 4.6% of cases, strong variants of uncertain significance (VUS) in 1.3%, and additional candidate variants in 5.2% of cases. Several deep-intronic variants were confirmed by RNA studies and segregation analyses. The framework enabled efficient prioritization of non-coding and regulatory variants that were overlooked by standard analyses. In conclusion, SMART filtering offers a reproducible and scalable strategy to improve diagnostic yield in GS, particularly in cases where conventional analysis methods fall short. Integrating such frameworks into clinical genomic pipelines can enhance variant interpretability and diagnostic performance, ultimately leading to better patient care outcomes.","rel_num_authors":22,"rel_authors":[{"author_name":"Rivka Birnbaum","author_inst":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"},{"author_name":"Kamila Lee","author_inst":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"},{"author_name":"Yaron Mazor","author_inst":"Geneyx Genomics, Israel"},{"author_name":"Yaara Unger","author_inst":"Geneyx Genomics, Israel"},{"author_name":"Shira Yanovsky-Dagan","author_inst":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"},{"author_name":"Itay Grundwag","author_inst":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel. Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"},{"author_name":"Michal Chalk","author_inst":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"},{"author_name":"Nava Shaul-Lotan","author_inst":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel"},{"author_name":"Lior Greenbaum","author_inst":"The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.  Gray Faculty of Medical and Health Sciences, Tel Aviv University, Te"},{"author_name":"Orit Freireich","author_inst":"The Fuld Family Institute of Medical Genetics and the Eisenberg RnD Authority and Translational Genomics lab, Shaare Zedek Medical Center, Jerusalem, Israel"},{"author_name":"Tehila Klopstock","author_inst":"The Fuld Family Institute of Medical Genetics and the Eisenberg RnD Authority and Translational Genomics lab, Shaare Zedek Medical Center, Jerusalem, Israel"},{"author_name":"Tal Dror","author_inst":"The Fuld Family Institute of Medical Genetics and the Eisenberg RnD Authority and Translational Genomics lab, Shaare Zedek Medical Center, Jerusalem, Israel"},{"author_name":"Meyrav Sebbagh","author_inst":"The Fuld Family Institute of Medical Genetics and the Eisenberg RnD Authority and Translational Genomics lab, Shaare Zedek Medical Center, Jerusalem, Israel"},{"author_name":"Rachel Beeri","author_inst":"The Fuld Family Institute of Medical Genetics and the Eisenberg RnD Authority and Translational Genomics lab, Shaare Zedek Medical Center, Jerusalem, Israel"},{"author_name":"Omer Murik","author_inst":"The Fuld Family Institute of Medical Genetics and the Eisenberg RnD Authority and Translational Genomics lab, Shaare Zedek Medical Center, Jerusalem, Israel"},{"author_name":"Dan Raved","author_inst":"Department of Pediatrics, Assuta Ashdod University Medical Center, Ashdod, Israel. Pediatric Hematology Unit, Assuta Ashdod University Medical Center, Ashdod, I"},{"author_name":"Rachel Rock","author_inst":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Med"},{"author_name":"Ben Pode-Shakked","author_inst":"The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel. Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel"},{"author_name":"Hagit Shani","author_inst":"The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.  Gray Faculty of Medical and Health Sciences, Tel Aviv University, Te"},{"author_name":"Sagi Josefsberg","author_inst":"Genetics Institute, Kaplan Medical Center, Rehovot, Israel"},{"author_name":"Tamar Harel","author_inst":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel.  Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"},{"author_name":"Hagar Mor","author_inst":"Department of Genetics, Hadassah Medical Center, Jerusalem, Israel.\tFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. \tGeneyx Genomics, Is"}],"rel_date":"2026-11-09","rel_site":"medrxiv"},{"rel_title":"ERV-derived dsRNAs induce stress granules that drive neural crest fate to initiate melanoma","rel_doi":"10.64898\/2026.11.06.764901","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764901","rel_abs":"Melanoma arises when melanocytes are oncogenically reprogrammed into neural crest-like cells, but what initiates this switch is unknown. Here we show that endogenous retrovirus (ERV)-derived double stranded RNAs (dsRNAs) induce stress granules (SGs) that drive this fate change. In zebrafish, melanoma progresses through a stage-specific ERV switch: zferv marks precursor cells before crestin activates in tumor cells. Both elements generate dsRNA that triggers eif2ak2-dependent SGs within precursor lesions and through transformation. SGs are tumorigenic as G3BP1 overexpression accelerates melanoma onset, whereas mosaic, melanocyte-specific g3bp1\/2 knockout delays it. Small molecule-mediated inhibition of G3BP1\/2 eliminates precursor lesions and reduces tumor burden. Similarly, blocking dsRNA sensing prevents SG formation and lowers melanoma incidence. Human nevi and melanomas show analogous, stage-specific ERV programs and SG assembly. In human melanoma cells, SGs sequester and translationally repress SOX10-regulating mRNAs, including the tumor suppressor KMT2D. Mosaic knockout of kmt2d in vivo enhances SOX10-driven neural crest reactivation. Thus, an ERV-SG axis establishes an oncogenic translatome that enables melanoma fate, with diagnostic and therapeutic potential.","rel_num_authors":15,"rel_authors":[{"author_name":"Kyle D Drake","author_inst":"Boston Children's Hospital"},{"author_name":"Emily Formato","author_inst":"Boston Children's Hospital"},{"author_name":"Siras Hakobyan","author_inst":"Yerevan Institute of Molecular Biology"},{"author_name":"Rachel A Hongo","author_inst":"Boston Children's Hospital"},{"author_name":"Song Yang","author_inst":"Boston Children's Hospital"},{"author_name":"Jennifer Porat","author_inst":"Boston Children's Hospital"},{"author_name":"Owen Sanborn","author_inst":"Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Anne L Robertson","author_inst":"Boston Children's Hospital"},{"author_name":"Dmitry A Kretov","author_inst":"CHU de Quebec - Universite Laval Research Center"},{"author_name":"Yi Zhou","author_inst":"Boston's Children's Hospital"},{"author_name":"Daniel Cifuentes","author_inst":"Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Manfred Kunz","author_inst":"University of Leipzig Medical Center"},{"author_name":"Hans Binder","author_inst":"Universitat Leipzig"},{"author_name":"Ryan A Flynn","author_inst":"Boston Children's Hospital"},{"author_name":"Leonard I Zon","author_inst":"Boston Children's Hospital"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Sensory experience-induced plasticity of somatostatin interneurons occurs through two-pore potassium (K2P) channels","rel_doi":"10.64898\/2026.11.06.764984","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764984","rel_abs":"GABAergic interneurons (INs) are powerful modulators of plasticity and learning in cortical networks, but plasticity of INs themselves is not well understood. We studied experience-dependent plasticity in somatostatin (SST) INs, which critically regulate dendritic integration, sensory tuning, and plasticity in pyramidal neurons in sensory cortex. Whether SST INs exhibit experience-dependent plasticity, and by what mechanisms, is unknown. We found that 3 days of whisker deprivation strongly downregulated intrinsic excitability of SST INs in L2\/3 of somatosensory cortex, by reducing input resistance. Deprivation also increased mEPSCs onto SST INs. The reduction in intrinsic excitability was caused by an increase in leak potassium current through two-pore K+ (K2P) channels, without changes in HCN, KV1, or KV7 currents, which contribute to plasticity in other IN types and brain areas. Immunohistochemistry showed an increase in TRESK, but not other K2P channels, indicating a novel role for K2P channels in experience-dependent plasticity of interneuron excitability.","rel_num_authors":7,"rel_authors":[{"author_name":"Briana M Bohannon","author_inst":"Berkeley"},{"author_name":"Nellie L Alonso","author_inst":"Berkeley"},{"author_name":"Mackenzie G Walker","author_inst":"Berkeley"},{"author_name":"Michael Wang","author_inst":"Berkeley"},{"author_name":"Katharine Kaimaktchiev","author_inst":"Berkeley"},{"author_name":"Cheryl Yang","author_inst":"Berkeley"},{"author_name":"Daniel Feldman","author_inst":"Berkeley"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"The role of familiarity in grouping decisions of Trinidadian guppies","rel_doi":"10.64898\/2026.11.06.764979","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764979","rel_abs":"Social grouping is widely observed in numerous taxa, providing individuals with a variety of benefits including efficient information exchange and predator protection. However, grouping can also carry costs such as increased competition for resources, which means that individuals must often make decisions regarding joining or leaving a group. These decisions to leave or stay might in turn depend on prior experience with potential groupmates. Past work has shown that many fish distinguish between familiar and unfamiliar conspecifics and use these distinctions in their grouping choices. Trinidadian guppies (Poecilia reticulata), well known for their diversity in shoaling preferences, are an excellent system in which to investigate the role of familiarity in grouping decisions. We examined preferences for familiar individuals following both a 15-day and 55-day cohabitation period in two different guppy populations. Utilizing two binary-choice designs, we found no evidence for a familiarity preference in either population, despite observing a high preference to group with conspecifics in both populations. These results suggest that various contextual- and population-level differences may impact familiarity preferences, in turn contributing to the growing body of work on the evolution of social organization and grouping decisions in teleost species and beyond.","rel_num_authors":4,"rel_authors":[{"author_name":"Adithi S Rao","author_inst":"University of Chicago"},{"author_name":"Nina P C Alves","author_inst":"Sao Paulo State University"},{"author_name":"Jon T Sakata","author_inst":"McGill University"},{"author_name":"Simon M Reader","author_inst":"McGill University"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"FACT frees Ubp10 from nucleosome sequestration after rapid H2B deubiquitination","rel_doi":"10.64898\/2026.11.06.765004","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.765004","rel_abs":"Chromatin-modifying enzymes must engage their substrate, act on it and release it, but which step limits their turnover is unclear. Using three-color single-molecule fluorescence, we directly visualized the yeast deubiquitinase Ubp10 removing ubiquitin from H2B on individual nucleosomes. Ubp10 cleaved the mark within seconds of binding, without detectable DNA unwrapping, yet it did not let go: ~80% of nucleosomes remained bound after 45 minutes, and unmodified nucleosomes formed similarly long-lived complexes. Ubp10 turnover is therefore limited by release rather than catalysis. The histone chaperone FACT relieved this bottleneck by accelerating Ubp10-nucleosome dissociation. In living yeast, nuclear depletion of the FACT subunit Spt16 increased the slowly diffusing, chromatin-bound fraction of nucleoplasmic Ubp10. These findings identify FACT-dependent release as a likely mechanism for recycling Ubp10 on chromatin. More broadly, a nucleosome can sequester the enzyme acting on it, making enzyme release a step at which chromatin modification can be controlled.","rel_num_authors":5,"rel_authors":[{"author_name":"Raquel Merino-Urteaga","author_inst":"Johns Hopkins University"},{"author_name":"Jonas Zaehringer","author_inst":"Harvard University"},{"author_name":"Melesse Nune","author_inst":"National Institutes of Health"},{"author_name":"Cynthia Wolberger","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Taekjip Ha","author_inst":"Boston Children's Hospital"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"A Three-View System for CRISPR-Cas12a crRNA Activity Ranking: When to Ensemble, When Context Matters More","rel_doi":"10.64898\/2026.11.07.765023","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.765023","rel_abs":"CRISPR-Cas12a assays require effective crRNA selection, but experimentally screening all possible candidates is costly. We developed TriCasRank, a ranking model that combines sequence features with EasyDesign reference mapping and activity summaries from related training records. Historical summaries were calculated within each training fold to avoid information leakage. In five-fold target-grouped cross-validation using out-of-fold predictions, TriCasRank improved the Spearman correlation from 0.741 for the sequence-only ensemble to 0.821 (paired difference, 0.080; 95% target-group bootstrap interval, 0.072 to 0.090). However, its performance was comparable to that of a strong sequence-plus-mapping XGBoost model (SCC, 0.822; paired difference, -0.001; 95% interval, -0.007 to 0.005). Separate perturbation analyses supported the predictive value of mapping and historical features, although their effect sizes were not directly comparable because they were evaluated using different model configurations. Prediction errors remained larger at the extremes of the activity distribution. Performance also became less stable when template identities were separated between training and evaluation. TriCasRank may therefore be useful for ranking candidates represented within the EasyDesign-derived domain, but evaluation on an independent experimental cohort is still needed.","rel_num_authors":4,"rel_authors":[{"author_name":"Tianze Deng","author_inst":"University of Washington"},{"author_name":"Zibo Lin","author_inst":"Central South University"},{"author_name":"Hoyan Lam","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Shirui Xu","author_inst":"Wenzhou Medical University"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Reversible decrease in swimming motility accompanies emergent \u03b2-lactam antibiotic resistance in Escherichia coli","rel_doi":"10.64898\/2026.11.06.764950","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764950","rel_abs":"Antimicrobial resistance (AMR) threatens global health, food security, and development; however, the evolutionary and molecular pathways that drive AMR remain poorly understood, limiting our ability to advance diagnostics and rapidly detect newly emerging resistance. In this report, we employed laboratory evolution of an environmental Escherichia coli strain (NIST 0056) under B-lactam antibiotic pressure (ampicillin and cephalexin) to specifically investigate the relationship between resistance genotype and motility phenotype. Within 10 passages, populations evolved varying levels of B-lactam resistance (including high-level resistance > 32 ug\/mL) and showed consistent, dose-dependent reductions in swimming motility. Whole-population genome sequencing revealed large deletions in marR, SNPs in efflux pump gene acrB and fumarate reductase gene frdD, and mutations with evidence of amplification in the chromosomal class C B-lactamase gene ampC, collectively linking these efflux-mediated, B-lactam resistance mechanisms to loss of motility. Notably, motility reductions were more pronounced in individual clones than in the mixed populations (p < 0.005, Mann-Whitney; two-tailed test). Following removal of antibiotic pressure, motility was restored and AMR-associated mutations decreased in frequency, suggesting fitness costs associated with resistance. In aggregate, our results demonstrate that reduced swimming motility accompanies specific efflux-driven, B-lactam resistance mechanisms. Further work will investigate if the behavior is generalizable across flagellated Enterobacteriaceae. Because these rapid changes are amenable to high-throughput measurement, swimming motility may offer a tractable physiological metric for AMR detection in environmental surveillance.","rel_num_authors":6,"rel_authors":[{"author_name":"Lisa Stabryla","author_inst":"University of Illinois Chicago"},{"author_name":"William Ackerman","author_inst":"University of Illinois Chicago"},{"author_name":"Jennifer N Dootz","author_inst":"National Institute of Standards and Technology"},{"author_name":"Stephanie  L. Servetas","author_inst":"NIST"},{"author_name":"Scott  A. Jackson","author_inst":"NEST"},{"author_name":"Jason  G. Kralj","author_inst":"NIST"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"41% of Gram-negative bacteria encode a Type Six Secretion System","rel_doi":"10.64898\/2026.11.07.764895","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.07.764895","rel_abs":"The type six secretion system (T6SS) is a highly studied, versatile bacterial nanoweapon that is important in bacterial pathogenesis and evolution. Despite extensive study, its prevalence remains poorly quantified. Analyzing 35,467 representative genomes, we find that approximately 41% of genomes in the average well-sampled Gram-negative genus (more than 30 sampled genomes) encode a T6SS. Further, we show that the distribution of the T6SS is patchy at all taxonomic levels. The uneven distribution we found is consistent with context-dependent selection, repeated evolutionary loss, or greater evolutionary lability. Our dataset provides a foundation for studying the drivers of T6SS distribution, and our pipeline enables similar surveys of other secretion systems, gene clusters, and multi-protein complexes across bacteria.","rel_num_authors":5,"rel_authors":[{"author_name":"Christopher Zhang","author_inst":"Georgia Institute of Technology"},{"author_name":"Hayley Hassler","author_inst":"Georgia Institute of Technology"},{"author_name":"William Ratcliff","author_inst":"Georgia Institute of Technology"},{"author_name":"Lauren Speare","author_inst":"Georgia Institute of Technology"},{"author_name":"Brian K Hammer","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Linking Covariates to State Durations in Dynamic Brain Networks via Hidden Semi-Markov Models","rel_doi":"10.64898\/2026.11.06.764975","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764975","rel_abs":"Hidden semi-Markov models (HSMMs) provide a flexible framework for studying dynamic functional connectivity because they represent brain activity as transitions between latent network states with explicit dwell time distributions. Although dwell times are often associated with behavioral and demographic variables, these associations are typically assessed only after model fitting using indirect group comparisons, limiting formal covariate modeling and the simultaneous inclusion of multiple predictors. In this work, we extend the HSMM framework by introducing covariate-dependent dwell time distributions through a regression-based formulation, allowing expected state duration to vary with subject-level covariates and enabling direct inference on how these factors relate to state persistence. Model parameters are estimated with an expectation-maximization algorithm, and uncertainty in the dwell-time regression coefficients is quantified using a subject-level nonparametric bootstrap. In simulations, the proposed model accurately recovered covariate effects under both shifted-Poisson and Gamma dwell time specifications, with low bias and variability. We applied the method to resting-state fMRI data from 1,000 UK Biobank participants and found that age and sex were associated with dwell times in a subset of brain states. Together, these results show that modeling dwell-time behavior directly provides a more flexible framework for studying individual differences in brain dynamics, revealing not only which states occur, but also how long individuals remain in them.","rel_num_authors":2,"rel_authors":[{"author_name":"Heather Shappell","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Martin Lindquist","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Comparing apples to oranges from photoreceptors to inferior temporal cortex through neural manifolds","rel_doi":"10.64898\/2026.10.30.763101","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.30.763101","rel_abs":"In the neural processing of color, cone photoreceptor outputs are combined over successive stages to form inferior temporal cortex (IT) cells with narrower color tuning and more diverse peak preferences. To understand the benefits of these transformations, we explored the capability of photoreceptor, retinal ganglion cell and IT population responses to distinguish between pairs of natural fruits and vegetables, based solely on their color distributions extracted from hyperspectral images. Simulations with realistic Poisson response variability show that linear separations are possible for many more pairs by IT neurons. Shapes of low-dimensional manifolds extracted from neural population responses explain the improvement.","rel_num_authors":4,"rel_authors":[{"author_name":"Yi Grace Xu","author_inst":"SUNY College of Optometry"},{"author_name":"Akihito Maruya","author_inst":"Zuckerman Institute, Columbia University"},{"author_name":"Bevil Conway","author_inst":"National Eye Institute, National Institutes of Health"},{"author_name":"Qasim Zaidi","author_inst":"State University of New York"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Allele-selective knockdown of mutant DNAJB6 improves molecular features in a primary mouse myotube model of LGMDD1","rel_doi":"10.64898\/2026.11.06.764697","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764697","rel_abs":"Dominant variants in DNAJB6 cause limb-girdle muscular dystrophy D1 (LGMDD1), a progressive myopathy associated with disrupted protein homeostasis. Because complete loss of DNAJB6 is embryonic lethal in mice, we evaluated allele-selective knockdown as a strategy to reduce mutant DNAJB6 while preserving wild-type protein. We generated a knock-in mouse carrying an N-terminal 3xFLAG tag on the wild-type Dnajb6 allele, allowing endogenous wild-type and F90I DNAJB6, the murine equivalent of human F89I, to be measured within the same sample. Flag-LGMDD1 mice recapitulated the functional, myopathological, and biochemical features seen in other LGMDD1 models and in human disease. F90I DNAJB6 was more abundant and degraded more slowly than wild-type DNAJB6, and LGMDD1 muscle and primary myotubes showed altered protein handling at baseline and following proteostatic stress. Comparative proteomic analyses identified DNAJA4 as a candidate marker responsive to pathogenic DNAJB6 activity. A two-stage mismatch screen identified a lead candidate siRNA with 264-fold selectivity for F90I DNAJB6. In primary Flag-LGMDD1 myotubes, this siRNA selectively reduced F90I DNAJB6 and shifted several baseline and stress-dependent molecular abnormalities involving p62, HSP70, DNAJA4, and markers associated with unfolded protein response signaling toward control values. These findings establish cellular proof of concept for allele-selective knockdown in LGMDD1.","rel_num_authors":15,"rel_authors":[{"author_name":"Aliasgar Vohra","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Meade Haller","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"May M Paing","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Alina Bao Lan Dam","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Jil A Daw","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Rocio Bengoechea","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Sara K Pittman","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Ting-Yu Wang","author_inst":"Division of Biology and Biological Engineering, California Institute of Technology"},{"author_name":"Carla M Yuede","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Timothy M Miller","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Heather L True","author_inst":"Department of Cell Biology and Physiology, Washington University School of Medicine"},{"author_name":"Scott Q Harper","author_inst":"Jerry R. Mendell Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children's Hospital"},{"author_name":"Tsui-Fen Chou","author_inst":"Division of Biology and Biological Engineering, California Institute of Technology"},{"author_name":"Conrad C Weihl","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Andrew R Findlay","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Allele-selective knockdown of mutant DNAJB6 improves molecular features in a primary mouse myotube model of LGMDD1","rel_doi":"10.64898\/2026.11.06.764697","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764697","rel_abs":"Dominant variants in DNAJB6 cause limb-girdle muscular dystrophy D1 (LGMDD1), a progressive myopathy associated with disrupted protein homeostasis. Because complete loss of DNAJB6 is embryonic lethal in mice, we evaluated allele-selective knockdown as a strategy to reduce mutant DNAJB6 while preserving wild-type protein. We generated a knock-in mouse carrying an N-terminal 3xFLAG tag on the wild-type Dnajb6 allele, allowing endogenous wild-type and F90I DNAJB6, the murine equivalent of human F89I, to be measured within the same sample. Flag-LGMDD1 mice recapitulated the functional, myopathological, and biochemical features seen in other LGMDD1 models and in human disease. F90I DNAJB6 was more abundant and degraded more slowly than wild-type DNAJB6, and LGMDD1 muscle and primary myotubes showed altered protein handling at baseline and following proteostatic stress. Comparative proteomic analyses identified DNAJA4 as a candidate marker responsive to pathogenic DNAJB6 activity. A two-stage mismatch screen identified a lead candidate siRNA with 264-fold selectivity for F90I DNAJB6. In primary Flag-LGMDD1 myotubes, this siRNA selectively reduced F90I DNAJB6 and shifted several baseline and stress-dependent molecular abnormalities involving p62, HSP70, DNAJA4, and markers associated with unfolded protein response signaling toward control values. These findings establish cellular proof of concept for allele-selective knockdown in LGMDD1.","rel_num_authors":15,"rel_authors":[{"author_name":"Aliasgar Vohra","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Meade Haller","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"May M Paing","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Alina Bao Lan Dam","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Jil A Daw","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Rocio Bengoechea","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Sara K Pittman","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Ting-Yu Wang","author_inst":"Division of Biology and Biological Engineering, California Institute of Technology"},{"author_name":"Carla M Yuede","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Timothy M Miller","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Heather L True","author_inst":"Department of Cell Biology and Physiology, Washington University School of Medicine"},{"author_name":"Scott Q Harper","author_inst":"Jerry R. Mendell Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children's Hospital"},{"author_name":"Tsui-Fen Chou","author_inst":"Division of Biology and Biological Engineering, California Institute of Technology"},{"author_name":"Conrad C Weihl","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"},{"author_name":"Andrew R Findlay","author_inst":"Department of Neurology, Neuromuscular Division, Washington University School of Medicine"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Diverse bacteria exhibit superadditive growth on mixed classes of carbon sources","rel_doi":"10.64898\/2026.11.06.764671","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764671","rel_abs":"Heterotrophic bacteria in nature encounter complex mixtures of functionally-distinct carbon sources, yet whether such diversity enhances growth yield across diverse taxa remains unknown. We grew dozens of strains from four phyla on defined mixtures representing five classes of carbon sources. Remarkably, many but not all strains exhibited superadditive growth on a dilute mixture of all 64 compounds--that is, yield exceeding the weighted sum of yields on more concentrated subsets of functionally-similar compounds. Using exometabolomics, pooled genetic screens, and proteomics, we find that superadditive growth is associated with enhanced carbon consumption in the mixed-class medium, combined with reduced dependence on amino acid and nucleotide biosynthesis. Moreover, superadditive growth was predictable from genomes within the tested strain panel and correlated with genomically encoded sugar-over-acid preference. These findings reveal a previously underrecognized axis of physiological variation among heterotrophs and open the door to understanding the biochemical and evolutionary basis of this divergence.","rel_num_authors":12,"rel_authors":[{"author_name":"Elena K Perry","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Ying Wang","author_inst":"Texas A&M University"},{"author_name":"Valentine V Trotter","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Yan Chen","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Markus de Raad","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Suzanne M Kosina","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Rowan Nelson","author_inst":"Boston University"},{"author_name":"Christopher J Petzold","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Daniel Segr\u00e8","author_inst":"Boston University"},{"author_name":"Adam P Arkin","author_inst":"University of California, Berkeley"},{"author_name":"Adam M Deutschbauer","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Trent R Northen","author_inst":"Lawrence Berkeley National Laboratory"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Mitochondrial Dysfunction is Part of a Novel Mechanism for Chemotherapy-Induced Neuropathic Pain","rel_doi":"10.64898\/2026.11.06.764717","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764717","rel_abs":"Chemotherapy-induced peripheral neuropathy (CIPN) is a common, persistent complication of cancer treatment, yet the mechanisms sustaining pain remain unclear. Mitochondrial dysfunction has been implicated in chronic pain, but its role in spinal cord dysfunction after chemotherapy, and whether it can be reversed, is unknown. Here, we show that paclitaxel-induced persistent mechanical allodynia was associated with spinal cord (L1-L6) mitochondrial dysfunction 18 days after the last injection, including reduced oxygen consumption and membrane potential ({Psi}m) in the non-phosphorylated state, ATP-linked respiration, maximal respiration, and electron transfer capacity. Paclitaxel also increased susceptibility to mitochondrial permeability transition pore (mPTP)-induction, lowering calcium retention capacity at 3, 8, and 13 days after the last injection. Acute ex-vivo paclitaxel exposure had a similar effect, and cyclosporin A, an mPTP blocker, significantly reversed it. Consistent with a causal role for mitochondrial impairment, hyperbaric oxygen therapy (HBOT), initiated after allodynia developed, improved oxygen consumption and {Psi}m and progressively enhanced mechanical thresholds. Likewise, intrathecal delivery of healthy mitochondria to the spinal cord attenuated established allodynia in paclitaxel-treated rats and reduced mechanical and thermal hypersensitivity in other pain models, sciatic nerve crush and capsaicin. These findings identify persistent spinal mitochondrial dysfunction and increased mPTP susceptibility as features of CIPN and support mitochondrial protection as a therapeutic strategy for CIPN and other pain conditions.","rel_num_authors":9,"rel_authors":[{"author_name":"Reem Sakas","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Zefat, Israel."},{"author_name":"Saher Abu-Ata","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Zefat, Israel."},{"author_name":"Yara Nakhleh-Francis","author_inst":"Department of Obstetrics and Gynecology, Galilee Medical Center, Nahariya, Israel Haifa, Israel."},{"author_name":"Nasser Abd Elkarim","author_inst":"General Intensive Care Department at Hadassah Ein-Kerem, Jerusalem, Israel"},{"author_name":"Akhilesh Kotiyal","author_inst":"Department of Anesthesiology, Center for Clinical Pharmacology, Washington University in St. Louis, St. Louis, MO, USA."},{"author_name":"Henry Politte","author_inst":"Department of Chemistry, School of Science and Engineering, Saint Louis University, St. Louis, MO, USA."},{"author_name":"Yaseen Awad-Igbaria","author_inst":"Research Institute of Galilee Medical Center"},{"author_name":"Jean F. Soustiel","author_inst":"Department of Neurosurgery, Galilee Medical Center, Nahariya, Israel."},{"author_name":"Eilam Palzur","author_inst":"Azrieli Faculty of Medicine, Bar-Ilan University, Zefat, Israel."}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Ergodic breakdown of brain dynamics under chronnectome complexity across cognitive states and age","rel_doi":"10.64898\/2026.11.06.764964","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764964","rel_abs":"Chronnectome complexity, the extent to which time-varying functional connectivity follows a structured sequence of distinct configurations, contributes to shaping large-scale brain dynamics. However, it remains unclear how this complexity influences the encoding of information that distinguishes resting state and task conditions. In ergodic theory, time averages represent ensemble behavior under ergodicity, which breaks down when dynamics are non-stationary, as when activity moves sequentially between distinct regimes. We hypothesize that this information resides in time-averaged connectivity under lower-complexity conditions but in trajectory geometry under higher-complexity conditions, where brain activity traverses distinct configurations over time, consistent with ergodic breakdown, which we term the \\textit{information migration principle}. We formulate this as dynamics-driven multi-class classification and introduce the Brain Dynamics Classifier (BDC), an interpretable data-driven mechanistic model in which a graph neural network embeds dynamic functional connectivity into a latent space and a neural ordinary differential equation learns the vector field governing trajectories through that space. The proposed model derives two complementary representations within a single learned dynamical system, capturing time-averaged connectivity, which is sufficient under ergodic dynamics, and trajectory geometry, which preserves the temporal organization obscured by averaging under non-ergodic dynamics. Our results show high classification accuracy, $97.4\\%$ for eight conditions in the Human Connectome Project young adult cohort and $92.2\\%$ for four in the aging cohort. To test the information migration principle, we ablated the time-averaged representation and found that trajectory contributions varied with chronnectome complexity, from high for Working Memory to absent for Relational Reasoning, consistent with ergodic breakdown. Including subcortical regions further increased trajectory contributions for affective conditions. In aging, the distinction between higher and lower complexity conditions was preserved, resting-state dynamics became less ergodic with advancing age, and higher fluid intelligence was associated with more ergodic resting-state dynamics.","rel_num_authors":2,"rel_authors":[{"author_name":"Behnam Kazemivash","author_inst":"Albert Einstein College of Medicine"},{"author_name":"David Zhu","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"THiRST: Computer Vision Empowered Three-dimensional High-Resolution Spatial Transcriptomics Analytics","rel_doi":"10.64898\/2026.10.29.762926","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.29.762926","rel_abs":"High-resolution spatial transcriptomics (ST) preserves gene expression within tissue architecture but remains limited to individual two-dimensional (2D) sections, restricting analysis of continuous three-dimensional (3D) structures and cross-section consistency. We present THiRST, a computational framework for reconstructing multi-resolution 3D spatial transcriptomic representations from serial sections. THiRST combines coarse-to-fine morphology-guided registration, spatial matching of ST units, cross-section association of segmented structures, and integration of Visium V2 and high-definition ST. In serial kidney sections, patch-level refinement increased the same-cluster proportions of matched units at adjacent offsets from 63.8% and 65.6% to 70.7% and 70.0%, respectively, while improving expression concordance. The reconstructed correspondences enabled 3D glomerular and object-level expression analysis, with 54.1% of differential genes detected only in 3D. Cross-platform integration further aligned V2 and high-definition measurements in a shared expression space. THiRST demonstrates the feasibility of object-level 3D ST analysis from serial 2D sections and underscores the importance of accurate local registration.","rel_num_authors":10,"rel_authors":[{"author_name":"Junchao Zhu","author_inst":"Vanderbilt University"},{"author_name":"Yu Wang","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Zhengyi Lu","author_inst":"Vanderbilt University"},{"author_name":"Chongyu Qu","author_inst":"Vanderbilt University"},{"author_name":"Yanfan Zhu","author_inst":"Vanderbilt Univeristy"},{"author_name":"Yuechen Yang","author_inst":"Vanderbilt University"},{"author_name":"Shilin Zhao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Haichun Yang","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Yuankai Huo","author_inst":"Vanderbilt University"},{"author_name":"Ruining Deng","author_inst":"Vanderbilt University"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"mFrag: Integrating External DNA Methylation References Improves Lung Cancer Early Detection by Fragmentomics","rel_doi":"10.64898\/2026.10.28.762499","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.28.762499","rel_abs":"Fragmentomics analyzes features of circulating cell-free DNA fragments (e.g., fragment length or end motifs) derived from whole-genome sequencing of liquid biopsy samples (blood or other body fluids), enabling non-invasive early cancer detection. Here we present mFrag, a framework that integrates external methylation reference atlases with fragmentomic features for lung cancer detection. mFrag comprises two complementary methods: mFrag-Weight, which uses DNA methylation information to weight fragmentomic features, and mFrag-Net, which integrates fragmentomic features and external DNA methylation data through neural networks. We average the output probabilities of the two methods to obtain a final prediction score. The mFrag model was trained using 287 individuals at risk for lung cancer. In an independent case-control testing set comprising 385 non-cancer controls and 46 cancers (28 stage I, 12 stage II, and 6 stage III or IV), mFrag outperforms a DELFI-style fragmentomic approach, improving PR-AUC from 0.455 to 0.720 and sensitivity at 99% specificity from 0.043 to 0.478, with ROC-AUC from 0.871 to 0.908. For stage I lung cancer, mFrag raises PR-AUC from 0.314 to 0.558 and ROC-AUC from 0.855 to 0.894. Applied to end 4-mer motif features, mFrag likewise improved over an unweighted baseline, with gains contributed by both mFrag-Weight and mFrag-Net. In summary, mFrag improves the accuracy of fragmentomics-based lung cancer detection through integrating external DNA methylation data and the complementarity of its two component models, without incurring any additional data-generating cost.","rel_num_authors":8,"rel_authors":[{"author_name":"Saishi Cui","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Neeti Swarup","author_inst":"University of California Los Angeles"},{"author_name":"Qianchuan He","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"William Hsu","author_inst":"University of California Los Angeles"},{"author_name":"David Wong","author_inst":"University of California Los Angeles"},{"author_name":"Yingye Zheng","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Robert B Scharpf","author_inst":"Johns Hopkins University"},{"author_name":"Wei Sun","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"mFrag: Integrating External DNA Methylation References Improves Lung Cancer Early Detection by Fragmentomics","rel_doi":"10.64898\/2026.10.28.762499","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.28.762499","rel_abs":"Fragmentomics analyzes features of circulating cell-free DNA fragments (e.g., fragment length or end motifs) derived from whole-genome sequencing of liquid biopsy samples (blood or other body fluids), enabling non-invasive early cancer detection. Here we present mFrag, a framework that integrates external methylation reference atlases with fragmentomic features for lung cancer detection. mFrag comprises two complementary methods: mFrag-Weight, which uses DNA methylation information to weight fragmentomic features, and mFrag-Net, which integrates fragmentomic features and external DNA methylation data through neural networks. We average the output probabilities of the two methods to obtain a final prediction score. The mFrag model was trained using 287 individuals at risk for lung cancer. In an independent case-control testing set comprising 385 non-cancer controls and 46 cancers (28 stage I, 12 stage II, and 6 stage III or IV), mFrag outperforms a DELFI-style fragmentomic approach, improving PR-AUC from 0.455 to 0.720 and sensitivity at 99% specificity from 0.043 to 0.478, with ROC-AUC from 0.871 to 0.908. For stage I lung cancer, mFrag raises PR-AUC from 0.314 to 0.558 and ROC-AUC from 0.855 to 0.894. Applied to end 4-mer motif features, mFrag likewise improved over an unweighted baseline, with gains contributed by both mFrag-Weight and mFrag-Net. In summary, mFrag improves the accuracy of fragmentomics-based lung cancer detection through integrating external DNA methylation data and the complementarity of its two component models, without incurring any additional data-generating cost.","rel_num_authors":8,"rel_authors":[{"author_name":"Saishi Cui","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Neeti Swarup","author_inst":"University of California Los Angeles"},{"author_name":"Qianchuan He","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"William Hsu","author_inst":"University of California Los Angeles"},{"author_name":"David Wong","author_inst":"University of California Los Angeles"},{"author_name":"Yingye Zheng","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Robert B Scharpf","author_inst":"Johns Hopkins University"},{"author_name":"Wei Sun","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"MELD: Mutation Effect Learning through Differential embeddings","rel_doi":"10.64898\/2026.10.29.762727","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.29.762727","rel_abs":"We introduce MELD (Mutation Effect Learning through Differential Embeddings), a compact model for predicting the functional consequences of single nucleotide variants (SNVs) by training directly on the wild-type (WT) versus mutant differential. Interpreting SNVs is central to clinical genomics, yet experimental characterization cannot scale to millions of observed variants. Leading sequence-to-function models (Enformer, Borzoi, AlphaGenome) are trained on absolute genomic tracks and score variants post hoc through in-silico mutagenesis (ISM), so the WT-mutant difference never enters the training loss. MELD instead places the logit difference {Delta}z = zmut - zwt inside the supervised objective. It combines a shared CNN-Transformer encoder, a mutant-specific mutation-mask boost, multiscale mutation-centered pooling, and a learned adaptive amplification factor . On ClinVar (1.57M variants), MELD (1.9M parameters) reached an AUROC of 0.986 versus 0.800 for a same-data, same-backbone ISM baseline, with ablations confirming the contribution of each component. On a shared benchmark, it outperformed frozen foundation models with 3-1,300x more parameters (AUROC 0.967 vs. 0.924 for AlphaGenome and 0.936 for Nucleotide Transformer). With only 50, 000 training variants, it exceeded the ISM baseline trained on all 1.48M (AUROC 0.903 vs. 0.796) variants. On BRCA1 saturation genome editing, frozen MELD achieved a Spearman {rho} of 0.42, above Borzoi (0.40), and ClinVar transfer raised it to 0.45. These results demonstrate that direct differential supervision is a compact, data-efficient alternative to post-hoc ISM scoring with substantially larger pretrained models.","rel_num_authors":4,"rel_authors":[{"author_name":"Aliaa Alajji","author_inst":"Qatar University"},{"author_name":"Raihan Jashil","author_inst":"University of Doha for Science and Technology"},{"author_name":"Raghvendra Mall","author_inst":"Qatar Computing Research Institute"},{"author_name":"Mohamed Elshrif","author_inst":"Qatar Computing Research Institute"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"Ok-k-mer: Selecting k-mer length ensembles for calculating genomic distance","rel_doi":"10.64898\/2026.11.06.764926","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.11.06.764926","rel_abs":"Current methods for computing sequence similarity across large groups of genome sequences tend to do so at the level of k-mers since this is far more efficient than base-by-base alignment. While these methods use default k-mer lengths, recent work shows that the particular choice of k-mer length greatly affects accuracy, and that using multiple values of k can boost accuracy relative to the best single choice of k, particularly when the goal is to estimate genomic distances that reflect true phylogenetic relationships. Here, we introduce Ok-k-mer, a tool to systematically select weighted k-mer length ensembles for pairwise genomic distance estimation, thereby increasing the accuracy of those estimates. Given a phylogenetic tree, Ok-k-mer ranks genome pairs by Jaccard distance across a range of k and uses a progressive search to maximize the Spearman correlation, {rho}, between weighted-average k-mer ranks and branch distances. Across eight Genome Taxonomy Database datasets, Ok-k-mer ensembles improved correlation over standard default k-mer lengths. In the Chlamydiales taxonomy, a three-length ensemble k=(9,17,22) achieved a 23.9% relative improvement over the best single length (k=20) and a 36.7% improvement over a commonly used default of 31-mers. We demonstrate that Ok-k-mer k-mer length ensembles remain stable (i.e. lengths and weights change only moderately) under genome subsampling within a taxonomy but vary across datasets. Ok-k-mer can annotate all subtrees of a phylogeny, which reveals distinct patterns of ensembles reflecting potential differences in genome evolution. Ok-k-mer provides a framework for moving beyond a \"one-k-fits-all\" k-mer analysis, improving genomic distance estimation in the era of massive-scale genomics.","rel_num_authors":2,"rel_authors":[{"author_name":"Stephen Hwang","author_inst":"Johns Hopkins University"},{"author_name":"Ben Langmead","author_inst":"Johns Hopkins University"}],"rel_date":"2026-11-09","rel_site":"biorxiv"},{"rel_title":"On conducting diary-based social contact surveys to inform transmission models of close-contact infections: a systematic review and expert-informed questionnaire","rel_doi":"10.64898\/2026.11.06.26367418","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.06.26367418","rel_abs":"Background: Diary-based social contact surveys are widely used to parameterise transmission models of close-contact infections. However, variation in study design, contact definitions, and questionnaire content limits comparability across studies. These challenges became particularly evident during the COVID-19 pandemic, when rapid and repeated data collection was urgently needed, often without harmonised instruments. To address these challenges, we aimed to develop an expert-informed questionnaire and update the recommendations on conducting diary-based social contact studies previously proposed by Hoang et al. (2019). Methods and findings: We conducted a systematic review of diary-based social contact surveys published between 31 January 2018 and 25 September 2025 using PubMed and the Web of Science Core Collection, extracting information on study design, survey methodology, contact definitions, and survey items from available questionnaires. Methodological quality and reporting were assessed using an adapted AXIS tool, with results summarised for each criterion. In total, we identified 129 studies across 62 countries, with most studies conducted during the COVID-19 pandemic (59.7% in 2021-2022). Retrospective reporting (86.0%) and non-probability sampling (77.5%) were largely adopted and became increasingly common during the pandemic, while non-paper-based data collection rose sharply from 2021 onwards. Across 36 retrievable questionnaires from general-population surveys, we identified 54 survey items. An online assessment involving 26 experts informed the classification of these items according to their perceived importance, resulting in an expert-informed questionnaire comprising 22 core items. Based on our findings, we updated previous recommendations on sampling, survey methods, contact definitions, behavioural change, essential contact information, and data governance. Conclusions: This study provides an expert-informed questionnaire and updated recommendations to support harmonised social contact data collection, improve comparability across studies, and strengthen preparedness for future public health emergencies.","rel_num_authors":19,"rel_authors":[{"author_name":"Neilshan Loedy","author_inst":"Hasselt University and University of Antwerp"},{"author_name":"Giulia Lumia","author_inst":"Hasselt University"},{"author_name":"Laura Di Domenico","author_inst":"Hasselt University"},{"author_name":"Janik Suer","author_inst":"University of Munster"},{"author_name":"Mark Jit","author_inst":"New York University"},{"author_name":"Alessia Melegaro","author_inst":"Bocconi University"},{"author_name":"Sebastian Funk","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Jantien A. Backer","author_inst":"National Institute for Public Health and the Environment"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Daniela Paolotti","author_inst":"ISI Foundation"},{"author_name":"Joeri Verbiest","author_inst":"Hasselt University"},{"author_name":"Oliver Ratmann","author_inst":"Imperial College London"},{"author_name":"Pietro Coletti","author_inst":"Universite catholique de Louvain"},{"author_name":"Shozen Dan","author_inst":"Imperial College London"},{"author_name":"Vittoria Colizza","author_inst":"INSERM"},{"author_name":"Philippe Beutels","author_inst":"University of Antwerp"},{"author_name":"Lander Willem","author_inst":"University of Antwerp"},{"author_name":"Steven Abrams","author_inst":"Hasselt University and University of Antwerp"},{"author_name":"Niel Hens","author_inst":"Hasselt University and University of Antwerp"}],"rel_date":"2026-11-08","rel_site":"medrxiv"},{"rel_title":"Investigating Climate-Driven Disruption of Malaria Transmission Following the 2022 Sindh, Pakistan Floods: An Interrupted Time Series Study","rel_doi":"10.64898\/2026.11.05.26367402","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367402","rel_abs":"Malaria remains a major global public health challenge in developing countries, with climate change intensifying its impact, particularly in vulnerable populations. Rising temperatures can expand the geographic range and local abundance of malaria vectors, Anopheles mosquitoes, which thrive in warm climates, with 25C representing the optimal temperature for malaria transmission. In Pakistan, malaria is primarily spread through P. falciparum and P. vivax. Pakistan is one of the seven countries in the Eastern Mediterranean Region that accounts for 98% of the total malaria burden in the region. Recently, after catastrophic flooding in Pakistan in 2022 and the subsequent increase in malaria incidence, it has become imperative to estimate the climate change-attributed increase in the risk of malaria. In this study, we analyze the time series malaria case incidence data from the province of Sindh, Pakistan, and the climate data to quantify climate-attributed malaria cases in Sindh, Pakistan. We fit a negative binomial generalized linear model (GLM) to monthly case counts with interrupted time series and seasonality terms. The majority of malaria-confirmed infections were Plasmodium Vivax (40-95%) between 2016-2024, followed by Plasmodium falciparum infections. The positivity rate for malaria remained <10% until June 2022, and increased massively after the July 2022 flooding. After accounting for this case momentum, the onset of the 2022 floods was associated with an immediate, independent increase in malaria cases of approximately threefold (IRR 2.985, 95% CI 1.878-4.751, p < 0.001). These findings suggest that post-flooding malaria surveillance and response in flood-affected settings should anticipate not only an acute environmentally driven surge in cases but also a subsequent period of elevated, self-sustaining transmission that may persist well beyond the resolution of the initiating environmental disruption, in this case the flooding.","rel_num_authors":5,"rel_authors":[{"author_name":"Amna Tariq","author_inst":"Stanford University School of Medicine"},{"author_name":"Raheel Allana","author_inst":"Agha Khan University Karachi"},{"author_name":"Sajid Shah","author_inst":"Agha Khan University Karachi"},{"author_name":"Abdul  Momin Kazi","author_inst":"Aga Khan University"},{"author_name":"A. Desiree LaBeaud","author_inst":"Stanford University School of Medicine"}],"rel_date":"2026-11-08","rel_site":"medrxiv"},{"rel_title":"The impact of climate variability on dengue virus case incidence in Sindh, Pakistan: Post-2022 flooding.","rel_doi":"10.64898\/2026.11.05.26367382","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.11.05.26367382","rel_abs":"Dengue virus is spread primarily by the Aedes aegypti and Ae. albopictus mosquitoes is a self-limiting viral disease primarily present in the tropical and subtropical regions of the world. Temperature and rainfall impact vector development, virus replication, and habitat suitability for Ae. aegypti and Ae. albopictus larvae and pupae. Pakistan, located in Southeast Asia, is one country where DENV is endemic and impacts thousands of lives each year. In recent years, Pakistan has been hardly hit by climate change, with heavy rainfalls and flooding recurring each year, with simultaneous surges of dengue virus across the country. In this paper, we analyze the monthly dengue virus disease data from Sindh Pakistan, from 2020-2025 to understand the impacts of flooding, rainfall, and temperature fluctuations on dengue case incidence in the region. We use parametric generalized linear models and the generalized additive model. Our results indicate that monthly confirmed dengue cases exhibit a strong seasonality, with the great majority of cases concentrated in the post-monsoon months (September-November). A 1-month lag in rainfall was associated with a statistically significant increase in dengue incidence (IRR = 1.008, 95% CI: 1.003-1.012, p = 0.002), corresponding to a 0.8% increase in expected case counts per unit (mm) increase in rainfall one month prior. In contrast, neither lagged temperature term reached statistical significance.","rel_num_authors":5,"rel_authors":[{"author_name":"Amna Tariq","author_inst":"Stanford School of Medicine"},{"author_name":"Raheel Allana","author_inst":"Agha Khan University Pakistan"},{"author_name":"Sajid Shah","author_inst":"Agha Khan University Pakistan"},{"author_name":"Momin Kazi","author_inst":"Agha Khan University Pakistan"},{"author_name":"Desiree LaBeaud","author_inst":"Stanford School of Medicine"}],"rel_date":"2026-11-08","rel_site":"medrxiv"}]}