{"gname":"University of Sydney","grp_id":"50","rels":[{"rel_title":"Malaria Risk among Internally Mobile Individuals and Heterogeneous Mobility Patterns in Two Hypoendemic Communities: Implications for Malaria Elimination in the Peruvian Amazon.","rel_doi":"10.64898\/2026.06.10.26355294","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355294","rel_abs":"Background: Human mobility is increasingly recognized as a key factor influencing malaria transmission dynamics, particularly in low-transmission settings approaching elimination. This study aimed to assess mobility patterns and their association with malaria risk in two hypoendemic communities in the Peruvian Amazon. Method: A longitudinal study was conducted in the communities of Libertad and Urcomirano (Mazan River basin). Monthly population screenings were combined with weekly active and passive case detection. A total of 678 individuals were enrolled. Mobility patterns were assessed through structured questionnaires, and social network analysis was used to characterize travel connections. Log-binomial regression analysis was applied to identify risk factors associated with malaria infection. Result: Internally, mobile individuals in Libertad showed a higher malaria incidence (>32.47 cases per 1,000 person-months) than those in Urcomirano (<10.15 cases per 1,000 person-months). Travel networks were mainly connected to Mazan district and Iquitos city, followed by local streams such as Armas and Arahuana. Mobility was primarily driven by family, administrative and occupational activities. Male sex (PR = 2.15, 95% CI: 1.37 - 3.37) and age [&ge;]15 years (PR = 1.98, 95% CI: 1.24 - 3.19) were significantly associated with malaria infection (p-value < 0.05). Conclusion: Internally mobile populations represent a key high-risk group sustaining malaria transmission in hypoendemic settings. Targeted interventions focusing on mobile individuals should be integrated into malaria elimination strategies in the Peruvian Amazon and similar endemic regions.","rel_num_authors":8,"rel_authors":[{"author_name":"Roberson Ramirez Saavedra","author_inst":"Unidad Especializada de Biotecnologia, Centro de Investigacion de Recursos Naturales de la Amazonia, Universidad Nacional de la Amazonia Peruana, Iquitos, Peru"},{"author_name":"Carlos Acosta","author_inst":"Laboratorio ICEMR-Enfermedades Emergentes, Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredia, "},{"author_name":"Pamela Rodriguez","author_inst":"Laboratorio de Malaria: Parasitos y Vectores, Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredi"},{"author_name":"Luis Cabrera-Sosa","author_inst":"Laboratorio de Malaria: Parasitos y Vectores, Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredi"},{"author_name":"Ananias A. Escalente","author_inst":"Institute for Genomics and Evolutionary Medicine (IGEM), Temple University, Philadelphia, Pennsylvania, USA."},{"author_name":"Joseph M. Vinetz","author_inst":"Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA."},{"author_name":"Katherine Torres","author_inst":"Departamento de Ciencias Celulares y Moleculares, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredia, Lima, Peru."},{"author_name":"Dionicia Gamboa","author_inst":"Departamento de Ciencias Celulares y Moleculares, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredia, Lima, Peru."}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Incremental costs of transitioning from four to eight WHO-recommended antenatal care visits in Uganda: A costing analysis from a societal perspective","rel_doi":"10.64898\/2026.06.10.26355347","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355347","rel_abs":"Background In 2016, the World Health Organization revised its antenatal care (ANC) recommendation from four to eight visits. For low- and middle-income countries like Uganda, where achieving even four visits remains a challenge, this transition has significant cost implications for both the health system and households. This study estimated the incremental costs of adopting the eight-visit model from a societal perspective. Methods The study was conducted in six government health facilities in southwestern Uganda. A micro-costing approach estimated health facility costs (personnel, equipment, consumables, and overhead). Costs incurred at patients end (transport, ultrasound, medical expenses, and time) were collected from 785 women using a questionnaire, with all costs in 2025 USD. Results For an average of 4.3 visits, total cost per woman was $100.1: facility costs $43.7 (43.7%), and patient costs $56.4 (56.3%). Transitioning to eight visits would increase total cost by $57.8 (57.8%), of which $36.4 (63.0%) would fall on households, equivalent to 68.8% of average monthly household income. Total costs would rise by 55.4% ($115.5 to $179.5) at Health Center IVs and 64.3% ($102.3 to $168.1) at Health Center IIIs, with facility costs up 43.4% and 62.9% and patient costs up 61.2% and 65.7%, respectively. Conclusion Transitioning to eight ANC visits would impose a large financial burden on households, with the incremental patient cost equivalent to more than two-thirds of average monthly household income. Equitable implementation requires improving availability of medicines and diagnostics, subsidizing transport, exploring telemedicine or community-based models, and improving efficiency at lower-tier health centers.","rel_num_authors":10,"rel_authors":[{"author_name":"Elly  B Atuhumuza","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Esther C Atukunda","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Angella Musiimenta","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Godfrey R Mugyenyi","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Jessica Haberer","author_inst":"Department of Medicine and Center for Global Health, Massachusetts General Hospital, Boston, Massachusetts, United States of America"},{"author_name":"Celestino Obua","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Mark J Siedner","author_inst":"Department of Medicine and Center for Global Health, Massachusetts General Hospital, Boston, Massachusetts, United States of America"},{"author_name":"Lynn T Matthews","author_inst":"Yale School of Medicine, Yale University, New Haven, Connecticut"},{"author_name":"Vincent Batwala","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Van T Nghiem","author_inst":"University of Alabama at Birmingham, School of Public Health, Department of Health Policy and Organization, AL, USA"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Decoding the Genetic Architecture of Autistic Traits in the Aging Population","rel_doi":"10.64898\/2026.06.10.26355340","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355340","rel_abs":"Autism research has mostly focused on diagnostic frameworks in childhood. However, autistic traits including social skills, communication, attention switching, attention to detail, and imagination may also vary in many undiagnosed individuals beyond childhood, and the genetic architecture of autistic traits in undiagnosed aging adults remains poorly understood. Here, we performed an exome-wide association study of autistic traits in adults aged >=40 from the UK Biobank (n = 161,269) and independently validated key findings in the SPARK cohort (n = 142,357). We identified exome-wide significance at 17q21.31, represented by a lead variant associated with social skills (rs199533, beta = 0.081, P = 2.04e-11). In addition, we identified an independent signal for communication (rs12632110, beta = 0.042, P = 3.07e-12) and two independent signals for attention switching (rs690733, beta = 0.046, P = 4.26e-12; rs2164272, beta = -0.047, P = 1.73e-12). Gene-based analyses further implicated loss-of-function variation in ZSCAN2 (beta = 1.00, P = 2.44e-6), which was associated with communication differences. Enrichment analyses revealed preferential expression of implicated genes in the cerebral cortex, while phenotypic and neuroimaging analyses linked those variants to cortical brain structure and regional volume. Taken together, these findings delineate the genetic architecture of autistic traits in the aging population and link genetic variation to downstream molecular and neuroanatomical mechanisms.","rel_num_authors":7,"rel_authors":[{"author_name":"Panhui Tian","author_inst":"Peking university"},{"author_name":"Xiaoli Rao","author_inst":"Peking university"},{"author_name":"Yang Sui","author_inst":"University of Washington School of Medicine, Seattle"},{"author_name":"Shilin Gao","author_inst":"Peking University"},{"author_name":"YingYing Meng","author_inst":"Peking university"},{"author_name":"Xu Han","author_inst":"Peking university"},{"author_name":"Tianyun Wang","author_inst":"Peking University"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Vascular Phenotyping in Parkinson's Disease: Diabetes Mellitus Operationalizes a Microvascular Metabolic Syndrome Cluster Across PPMI Diagnostic Cohorts","rel_doi":"10.64898\/2026.06.09.26355285","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355285","rel_abs":"Background: Diabetes mellitus elevates Parkinson's disease (PD) risk, via hypothesized cerebrovascular mediation. Whether the diabetes\/prediabetes vascular-risk phenotype concentrates in cardiometabolic risk or macrovascular events across prodromal and clinically diagnosed PD remains unresolved. Objectives: To quantify the vascular-risk burden associated with diabetes\/prediabetes across the PPMI diagnostic cohorts to test whether this association differs by cohort. Methods: Cross-sectional analysis of 413 PPMI participants (76 healthy controls, 145 prodromal PD, 192 clinically diagnosed PD) examined diabetes\/prediabetes (n = 73) and seven vascular risk factors. The Vascular Burden Score (0 to 7) was a priori partitioned into microvascular and macrovascular sub-scores. Modified Poisson regression estimated adjusted prevalence ratios (aPR), adjusted for age, sex, and body mass index. A cohort-by-diabetes interaction tested cross-cohort consistency. Sensitivity analyses incorporated nigral diffusion tensor imaging (PD-risk biomarker) and FreeSurfer white matter hypointensity volume (cerebrovascular marker). Results: Diabetes\/prediabetes elevated Vascular Burden Score ({beta} = 0.53, 95% CI 0.29 to 0.77, p < 0.001) versus non-diabetic participants, with a non-significant cohort-by-diabetes interaction (F = 0.29, p = 0.747). Three microvascular factors survived false discovery rate correction: obesity (aPR 2.28), hypertension (aPR 1.60), and hyperlipidemia (aPR 1.45). Macrovascular events showed no diabetic amplification ({beta} = -0.06, p = 0.25). In the imaging-phenotyped subset, Vascular Burden Score components contributed classifier variance distinct from nigral microstructure. Conclusions: Diabetes\/prediabetes operationalize a microvascular cluster stable across prodromal and idiopathic PD. Cardiometabolic phenotyping may complement established PD-risk biomarkers (dopamine transporter SPECT, nigral diffusion), pending longitudinal validation linking vascular phenotype to dopaminergic markers.","rel_num_authors":5,"rel_authors":[{"author_name":"Alexander Belnavis","author_inst":"Arizona State University"},{"author_name":"Shannon Chiu","author_inst":"Mayo Clinic"},{"author_name":"Kewei Chen","author_inst":"Arizona State University"},{"author_name":"Roland Thorpe","author_inst":"John Hopkins University"},{"author_name":"Edward Ofori","author_inst":"Arizona State University"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Foundation model-based tool for automated ulcerative colitis histology scoring demonstrates non-inferiority to pathologists across multiple scoring indices","rel_doi":"10.64898\/2026.06.09.26355212","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355212","rel_abs":"In clinical trials for ulcerative colitis (UC), pathologists assess disease severity through standardized histological indices, including the Geboes Score, Robarts Histopathology Index (RHI), and Nancy Histologic Index (NHI). Despite strong associations with clinical outcomes, histologic scoring suffers from inter- and intra-reader variability, and consensus criteria for histologic remission remain uncertain. Through a consortium approach, we developed an artificial intelligence-based measurement (AIM) tool for scoring histology in UC mucosal biopsies (AIM-HI UC). This model, trained on a large dataset of UC biopsies (N=10,230), utilizes additive multiple instance learning models leveraging PLUTO, a pathology foundation model, that predict each of the Geboes subgrades, from which the Geboes grade-level score, RHI, and NHI can be calculated. Evaluation of this model on a standalone verification set including clinical trial specimens established algorithm non-inferiority and\/or superiority relative to standard qualified pathologists through comparison of algorithm-consensus and pathologist-consensus agreement metrics (non-inferior if difference >-0.1, superior if difference >0, inclusive of confidence intervals). AIM-HI UC was determined to be non-inferior to pathologists (N=3) for the prediction of all seven Geboes subgrades, grade-level Geboes, RHI, NHI, histologic improvement (GS<3.1), 2A histologic remission (GS<2A.0), and 2B histologic remission (GS<2B.0). AIM-HI UC was superior to pathologists for several Geboes subgrades (GS 0, GS 1, GS 2B, and GS 5), as well as grade-level Geboes, RHI, and positive percent agreement of 2A histologic remission. The model was shown to be greater than 99% repeatable for all histologic scoring metrics examined. Model-derived scores were shown to strongly correlate with canonical histologic features of inflammation, including the proportion of total epithelium that is inflamed (Spearman r=0.83; p<0.01), the proportion of neutrophils localized within crypt epithelium (Spearman r=0.83, p<0.01), and the amount of mucosal area classified as erosion or ulceration (Spearman r=0.80, p<0.01). Overall, these results suggest that AIM-HI UC has the potential to improve consistency of UC histology interpretation, providing a path toward standardization of UC histology scoring in clinical trials.","rel_num_authors":38,"rel_authors":[{"author_name":"Waleed Tahir","author_inst":"PathAI, Inc."},{"author_name":"John Shamshoian","author_inst":"PathAI, Inc."},{"author_name":"John Tauber","author_inst":"PathAI, Inc."},{"author_name":"Lani K Clinton","author_inst":"PathAI, Inc."},{"author_name":"Michael Griffin","author_inst":"PathAI, Inc."},{"author_name":"Chintan Shah","author_inst":"PathAI, Inc."},{"author_name":"Geetika Singh","author_inst":"PathAI, Inc."},{"author_name":"Darren Fahy","author_inst":"PathAI, Inc."},{"author_name":"Kathleen Sucipto","author_inst":"PathAI, Inc."},{"author_name":"Jacqueline Brosnan-Cashman","author_inst":"PathAI, Inc."},{"author_name":"Tara A Altepeter","author_inst":"US Food and Drug Administration"},{"author_name":"Sabyasachi Bhattacharya","author_inst":"AbbVie Bay Area"},{"author_name":"Wallace Crandall","author_inst":"Eli Lilly and Company"},{"author_name":"Chong Duan","author_inst":"Pfizer Research Technology Center"},{"author_name":"Jeremy D Gale","author_inst":"Pfizer Research Technology Center"},{"author_name":"Vandana Gupta","author_inst":"Takeda Pharmaceuticals America Inc"},{"author_name":"Helene Haarmann","author_inst":"Takeda Pharmaceuticals International"},{"author_name":"Noam Harpaz","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Andrea T Hooper","author_inst":"Regeneron Pharmaceuticals, Inc."},{"author_name":"Julie Horowitz","author_inst":"Regeneron Pharmaceuticals Inc."},{"author_name":"Andres Hurtado-Lorenzo","author_inst":"Crohn's and Colitis Foundation"},{"author_name":"Bader E Hussaini","author_inst":"Takeda Pharmaceuticals America Inc"},{"author_name":"Vipul Jairath","author_inst":"Western University Faculty of Health Sciences"},{"author_name":"Autumn Jones","author_inst":"Foundation for the National Institutes of Health"},{"author_name":"Ben Kostiuk","author_inst":"Crohn's and Colitis Foundation"},{"author_name":"Anjli Kukreja","author_inst":"Boehringer Ingelheim Corp USA"},{"author_name":"F. Stephen Laroux","author_inst":"AbbVie Bioresearch Center"},{"author_name":"Trevor Lissoos","author_inst":"Eli Lilly and Company"},{"author_name":"Russell B McBride","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Fedaa Najdawi","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Anil Nayyar","author_inst":"US Food and Drug Administration"},{"author_name":"Mark T Osterman","author_inst":"Bristol Myers Squibb"},{"author_name":"Pratik Panchal","author_inst":"Takeda Pharmaceuticals America Inc"},{"author_name":"Darren Ruane","author_inst":"Janssen Research & Development"},{"author_name":"Simon Travis","author_inst":"University of Oxford Nuffield Department of Medicine"},{"author_name":"Sudha Visvanathan","author_inst":"Boehringer Ingelheim Corp USA"},{"author_name":"Laura Wilson","author_inst":"Kenneth Rainin Foundation"},{"author_name":"Christina Jayson","author_inst":"PathAI, Inc."}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Long-term exposure to PM2.5 components and lipid profiles in WTC Health Program general responders","rel_doi":"10.64898\/2026.06.10.26355272","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355272","rel_abs":"Fine particulate matter (PM2.5) was found to be associated with elevated blood lipids, but fewer studies have examined the associations with specific constituents of PM2.5. We studied the associations between exposure to annual PM2.5 and its 14 constituents, and repeated blood lipid measurements among general responders enrolled in the World Trade Center Health Program between 2003 and 2019 (n = 44,876). We used generalized additive mixed effect models to investigate the single-pollutant associations with repeated measures of blood total cholesterol (TC), high and low-density lipoprotein (HDL-C and LDL-C) levels. We then used linear generalized weighted quantile sum regression with a random intercept for participant ID to account for the clustering of repeated measures and evaluate the combined associations with the component mixture. A decile increase in the mixture of 14 PM2.5 chemical components was associated with 0.375 mg\/dL increase in TC levels (95% confidence Interval (CI): 0.174-0.577) and 0.302 mg\/dL increase in LDL-C (95% CI: 0.063, 0.540). Lead, organic carbon, and iron were major drivers of both associations. Component-specific models also show higher TC and LDL levels associated with interquartile range increases in organic carbon (0.472, 95% CI [0.027, 0.918] and 0.648 95% CI [0.136, 1.160]) and iron exposure (1.081, 95% CI [0.630, 1.532] and 0.748, 95% CI [0.318, 1.178]). In conclusion, we found PM2.5 exposure to be associated with elevated lipid levels. The associations differed by PM2.5 composition, highlighting organic carbon, lead, and iron and major drivers. These findings are highly significant for a population exposed to extreme air pollution event and susceptible to lipid alterations that might trigger cardiovascular events.","rel_num_authors":8,"rel_authors":[{"author_name":"Helena Krasnov","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"pablo knobel","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Leon Hsiao-Hsien Hsu","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Susan Teitelbaum","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Maryann Mclaughlin","author_inst":"Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Allan C. Just","author_inst":"Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island"},{"author_name":"Itai Kloog","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Maayan Yitshak Sade","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Large-scale proteomics and timing of hypertensive disorders of pregnancy","rel_doi":"10.64898\/2026.06.09.26355317","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355317","rel_abs":"Background: Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset. Methods: We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP versus controls (referent) using first-trimester samples from the NuMoM2b-Heart Health Study, a multi-site cohort that followed nulliparous individuals from the first trimester. Associations of proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted. Results: Of 1628 individuals included, 678 had HDP, of which 67% manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP. Pathway enrichment and graphical summary analyses suggested distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic changes leading to cardiac dysfunction in PP HDP. Conclusion: There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.","rel_num_authors":17,"rel_authors":[{"author_name":"Alisse Hauspurg","author_inst":"Alpert Medical School at Brown University"},{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"},{"author_name":"Victoria Pemberton","author_inst":"NHLBI"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Lisa D. Levine","author_inst":"Hospital of the University of Pennsylvania Helen O Dickens Center for Women's Health"},{"author_name":"Angela Ranzini","author_inst":"The MetroHealth System"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Emily Lau","author_inst":"MassGeneral Brigham \/ Harvard Medical School"},{"author_name":"Sadiya S. Khan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Brian Kleiboeker","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Uma M. Reddy","author_inst":"Yale School of Medicine"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Large-scale proteomics and timing of hypertensive disorders of pregnancy","rel_doi":"10.64898\/2026.06.09.26355317","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355317","rel_abs":"Background: Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset. Methods: We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP versus controls (referent) using first-trimester samples from the NuMoM2b-Heart Health Study, a multi-site cohort that followed nulliparous individuals from the first trimester. Associations of proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted. Results: Of 1628 individuals included, 678 had HDP, of which 67% manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP. Pathway enrichment and graphical summary analyses suggested distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic changes leading to cardiac dysfunction in PP HDP. Conclusion: There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.","rel_num_authors":17,"rel_authors":[{"author_name":"Alisse Hauspurg","author_inst":"Alpert Medical School at Brown University"},{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"},{"author_name":"Victoria Pemberton","author_inst":"NHLBI"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Lisa D. Levine","author_inst":"Hospital of the University of Pennsylvania Helen O Dickens Center for Women's Health"},{"author_name":"Angela Ranzini","author_inst":"The MetroHealth System"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Emily Lau","author_inst":"MassGeneral Brigham \/ Harvard Medical School"},{"author_name":"Sadiya S. Khan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Brian Kleiboeker","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Uma M. Reddy","author_inst":"Yale School of Medicine"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Large-scale proteomics and timing of hypertensive disorders of pregnancy","rel_doi":"10.64898\/2026.06.09.26355317","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355317","rel_abs":"Background: Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset. Methods: We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP versus controls (referent) using first-trimester samples from the NuMoM2b-Heart Health Study, a multi-site cohort that followed nulliparous individuals from the first trimester. Associations of proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted. Results: Of 1628 individuals included, 678 had HDP, of which 67% manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP. Pathway enrichment and graphical summary analyses suggested distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic changes leading to cardiac dysfunction in PP HDP. Conclusion: There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.","rel_num_authors":17,"rel_authors":[{"author_name":"Alisse Hauspurg","author_inst":"Alpert Medical School at Brown University"},{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"},{"author_name":"Victoria Pemberton","author_inst":"NHLBI"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Lisa D. Levine","author_inst":"Hospital of the University of Pennsylvania Helen O Dickens Center for Women's Health"},{"author_name":"Angela Ranzini","author_inst":"The MetroHealth System"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Emily Lau","author_inst":"MassGeneral Brigham \/ Harvard Medical School"},{"author_name":"Sadiya S. Khan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Brian Kleiboeker","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Uma M. Reddy","author_inst":"Yale School of Medicine"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Corticospinal tract risk modifies motor recovery after minimally invasive surgery for intracerebral hemorrhage: a secondary analysis of MISTIE-III","rel_doi":"10.64898\/2026.06.10.26354920","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26354920","rel_abs":"Objective: Outcome after surgical hematoma evacuation for intracerebral hemorrhage (ICH) depends on hematoma location. As corticospinal tract (CST) integrity affects motor recovery after stroke, we hypothesized that CST integrity drives heterogeneity in surgical outcomes and investigated this in a secondary analysis of MISTIE-III participants. Methods: Risk of CST injury was categorized into four levels, based on the interaction between the CST, the hematoma, and perihematomal edema (PHE) on automatically segmented stability CT: no risk, PHE infiltration, hematoma infiltration, and complete interruption of the CST. Associations with outcome were tested using multivariable linear regression for motor National Institutes of Health Stroke Scale (NIHSS) at day 180 and ordinal regression for modified Rankin Scale (mRS) at day 365, introducing an interaction term between CST risk and treatment group. Results: Day 180 motor NIHSS was significantly lower for 'no risk' ({beta}:-3.77, [95% confidence interval [CI]: -5.8 to -1.70], p=0.0003) and 'PHE infiltration' ({beta}:-2.3, [95%CI: -3.5 to -1.1]; p=0.0002) vs. 'complete interruption'. Surgery was associated with lower Day 180 motor NIHSS in participants with hematoma infiltration ({beta}:-2.07, [95%CI: -3.8 to -0.4], p=0.016). Compared to complete interruption, 'no risk' (adjusted odds ratio [aOR]:0.27, [95%CI: 0.10 to 0.74], p=0.01) and 'PHE infiltration' (aOR:0.41, [95%CI: 0.23 to 0.74]; p=0.003) were associated with lower odds of unfavorable day 365 mRS. Surgery was associated with lower mRS in participants with no risk (aOR:0.23, [95%CI: 0.05 to 0.97, p=0.045). Interpretation: Increasing CST risk is associated with worse motor recovery (day 180) and disability (day 365). CST risk modifies the effect of the MISTIE-III procedure on motor recovery and disability.","rel_num_authors":11,"rel_authors":[{"author_name":"Olivia N Murray","author_inst":"The University of Manchester"},{"author_name":"David Jenkins","author_inst":"The University of Manchester"},{"author_name":"Nathan Walborn","author_inst":"John Hopkins Medical Institutions"},{"author_name":"Hiren C Patel","author_inst":"Salford Royal NHS Foundation Trust"},{"author_name":"George WJ Harston","author_inst":"Oxford University Hospitals NHS Foundation Trust"},{"author_name":"Timothy F Cootes","author_inst":"University of Manchetser"},{"author_name":"Catharina J.M. Klijn","author_inst":"Radboud University Medical Center"},{"author_name":"Wendy C Ziai","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Daniel F Hanley","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Ulrike Hammerbeck","author_inst":"Kings College London"},{"author_name":"Adrian R Parry-Jones","author_inst":"University of Manchester"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Sequence-encoded H2A.Z nucleosome dynamics control DNA unwrapping and SUV420H1 recognition","rel_doi":"10.64898\/2026.06.10.731474","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731474","rel_abs":"H2A.Z and canonical H2A adopt nearly identical nucleosomal folds, yet their distinct chromatin functions are not captured by static structural analysis. Using fast magic-angle spinning 1H-detected solid-state NMR, we show that H2A.Z possesses enhanced backbone flexibility in the L1 loop and the 2-L2 region (M2) relative to H2A. Chimeric segment-swapping demonstrates that these dynamic signatures are locally sequence-encoded and functionally transplantable. The inherent mobility of the M2 region promotes nucleosomal DNA-end unwrapping and persists when DNA ends are stabilized by linker histone H1 or opened by SUV420H1, indicating that this mobility is intrinsic rather than a passive consequence of DNA detachment. Chemical shift perturbation mapping and catalytic assays further show that SUV420H1 reads this H2A.Z-specific conformational landscape: the M2 region, together with the H2A.Z DS motif, supports variant-selective methyltransferase activity. These findings establish an axis of sequence-dynamics-accessibility-recognition along which local backbone fluctuations serve as physical determinants of epigenetic enzyme specificity.","rel_num_authors":9,"rel_authors":[{"author_name":"Tong Zhang","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Li Huang","author_inst":"Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences."},{"author_name":"Xuanfeng Li","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Bingyan Liu","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Juan Li","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Chaowei Shi","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Shusheng Fu","author_inst":"Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences."},{"author_name":"Zheng Zhou","author_inst":"Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences;University of Chinese Academy of Sciences."},{"author_name":"ShengQi Xiang","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Laboratory adaptation and complete genome assembly of a Beposo, Ghana strain of the human hookworm Necator americanus","rel_doi":"10.64898\/2026.06.10.728644","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.728644","rel_abs":"Laboratory models are invaluable tools for studying parasite biology and pathogenesis, especially for helminth infections. However, the complex life cycles and frequently narrow host specificity of helminths present challenges to maintaining access to critical parasite material in a laboratory setting. This is especially true of Necator americanus, the most common species of hookworm that infects humans globally. Here we report the successful laboratory adaptation of an African strain of N. americanus, originally isolated from infected individuals in Beposo, Ghana. The Beposo strain has been successfully passaged across 9 generations in Golden Syrian hamsters maintained on oral dexamethasone. Differential susceptibility to mebendazole and albendazole was evaluated using an egg hatch assay, and DNA sequencing of the beta-tubulin isotype 1 gene did not identify known resistance-associated mutations in the endemic strain. Sequencing of the mitochondrial COX1 gene revealed that specimens of N. americanus from Ghana, along with reported sequences from Togo, are distinct from those from South America and Asia. Complementary microsatellite-based population analysis revealed substantial genetic variation in the founding parasite population. To further characterize the novel Beposo strain, a draft hybrid genome assembly was generated from genomic DNA extracted from a single adult male worm via an optimized Oxford Nanopore Technologies MinION library preparation approach tailored to low-input sample types. This high-quality assembly, including a complete mitogenome, is 202.8Mb in 950 contigs with an N50 >449 kb. It contains >95% of conserved nematode orthologs in complete single copy and is estimated by homology-based gene prediction to contain 12,804 genes. This study represents the first comprehensive characterization of a strain of N. americanus originating in Africa that has been successfully adapted to a laboratory animal model.","rel_num_authors":14,"rel_authors":[{"author_name":"Lisa M. Harrison","author_inst":"Yale School of Medicine"},{"author_name":"Kaylee  S. Herzog","author_inst":"University of New Mexico - Albuquerque"},{"author_name":"Dickson Osabutey","author_inst":"University of Ghana Noguchi Memorial Institute for Medical Research"},{"author_name":"Mavis Konoma","author_inst":"University of Ghana Noguchi Memorial Institute for Medical Research"},{"author_name":"Emma Allen","author_inst":"Yale University School of Public Health"},{"author_name":"Kelly Hagadorn","author_inst":"Yale University School of Public Health"},{"author_name":"Santosh George","author_inst":"Yale School of Medicine"},{"author_name":"Richard D. Bungiro","author_inst":"Yale University School of Public Health"},{"author_name":"Claudia Gaither","author_inst":"Yale University Department of Ecology and Evolutionary Biology"},{"author_name":"Carol Mariani","author_inst":"Yale University Department of Ecology and Evolutionary Biology"},{"author_name":"Margaret K. Corley","author_inst":"Yale University Department of Ecology and Evolutionary Biology"},{"author_name":"Adalgisa Caccone","author_inst":"Yale University Department of Ecology and Evolutionary Biology"},{"author_name":"Joseph R. Fauver","author_inst":"University of Nebraska Medical Center College of Public Health"},{"author_name":"Michael Cappello","author_inst":"Yale School of Public Health"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Ultralow frequency vaso-oscillations in human cerebral arteries are independent from Mayer waves","rel_doi":"10.64898\/2026.06.09.731141","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731141","rel_abs":"This study tests the hypothesis that vasomotion, an ~ 0.1 Hz oscillation in arteriole diameter, is generated by intrinsic oscillations within the arterioles that perfuse the brain, and not by external drive from systemic blood pressure oscillations (Mayer waves). During cardio-pulmonary bypass that transiently eliminated systemic blood pressure oscillations in 14 patients, we observed that vasomotor oscillations persist with normal amplitudes and frequencies over the one- to three-hour time course of surgery. In contrast, ~ 0.1 Hz oscillations in peripheral blood pressure were predominantly absent. This implies that cerebral arterioles generate their own rhythmic vaso-dynamics, although we cannot discount that vasomotion can phase-lock with ~ 0.1 Hz systemic physiological rhythms in the awake, healthy state. We discuss the impact of this finding on the role of vasomotion in modulating the perfusion of blood and the transport of interstitial fluid in the brain.","rel_num_authors":6,"rel_authors":[{"author_name":"Aiman Alzetani","author_inst":"Department of Thoracic Surgery, Faculty of Medicine, University Hospital Southampton NHS Foundation Trust, SO16 6YD Southampton, UK"},{"author_name":"Jacob Duckworth","author_inst":"Department of Physics, University of California San Diego, La Jolla, CA 92093 USA"},{"author_name":"Anthony A Birch","author_inst":"Department of Medical Physics and Bioengineering, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK"},{"author_name":"David M Simpson","author_inst":"Institute of Sound and Vibration Research, University of Southampton, Southampton, UK"},{"author_name":"David Kleinfeld","author_inst":"University of California San Diego"},{"author_name":"Roxana O Carare","author_inst":"Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A systematic imputation framework for sparse, multimodal space biology datasets: application to retinal imaging and omics from the RR9 mission","rel_doi":"10.64898\/2026.06.09.730965","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730965","rel_abs":"Space biology experiments are expensive, logistically complex, and inherently limited in sample size, resulting in datasets that are frequently incomplete and highly heterogeneous (2). Missing data is a fundamental barrier to building reliable computational models of how the human body responds to spaceflight. This work introduces a systematic framework for addressing missing data through imputation. We developed a validated four-stage framework for imputation specifically designed to preserve biological signal needed for digital twin development, while quantifying trade-offs in downstream analyses. Using retinal imaging and omics data from the NASA RR9 mission as a case study (9), we demonstrate how to diagnose why data is missing(10), select and optimize appropriate imputation strategies (5,10), and rigorously evaluate whether imputed data remains biologically meaningful. A key finding of this work is that while imputation substantially improves the performance of predictive models, it can simultaneously obscure subtle biological patterns; a critical trade-off that researchers must understand before applying these methods (11). This framework provides practical, actionable guidance for space biologists and data scientists working with sparse, multimodal datasets in space biology, and represents a foundational step toward more complete and reliable data-driven models of human physiology in extreme environments.","rel_num_authors":12,"rel_authors":[{"author_name":"Vaishnavi Nagesh","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Lauren Sanders","author_inst":"Colossal Biosciences, Computational Biology, Dallas, Texas, USA"},{"author_name":"Sylvain V. Costes","author_inst":"Trivedi Institute for Space and Global Biomedicine, University of Pittsburgh, PA, USA"},{"author_name":"Pinar Avci","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Ayse Sigit","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Amey Agarwal","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Alireza Haghighi","author_inst":"Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Alavia Batool","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Fathi Karouia","author_inst":"Blue Marble Space Institute of Science, Seattle, Washington, USA"},{"author_name":"Atul M. Chander","author_inst":"Department of Biology, University of Mississippi, Oxford, Mississippi, USA"},{"author_name":"Caleb M. Schmidt","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Jian Gong","author_inst":"School of Computing, University of Wyoming, Laramie, Wyoming, USA"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice","rel_doi":"10.64898\/2026.06.09.731100","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731100","rel_abs":"Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of myelinic nanochannels, narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.","rel_num_authors":14,"rel_authors":[{"author_name":"Alexandra I Mot","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Ying Li","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Payam Dibaj","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Iva D Tzvetanova","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Ulrike C Gerwig","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Tizibt A Bogale","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Sandra Goebbels","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Wiebke M\u00f6bius","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Dwight E Bergles","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Brett M Morrison","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Jeffrey D Rothstein","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Don W Cleveland","author_inst":"Department of Molecular and Cellular Medicine, University of California at San Diego, La Jolla, CA 92093 USA"},{"author_name":"Julia M Edgar","author_inst":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences University of Glasgow, UK"},{"author_name":"Klaus-Armin Nave","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice","rel_doi":"10.64898\/2026.06.09.731100","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731100","rel_abs":"Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of myelinic nanochannels, narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.","rel_num_authors":14,"rel_authors":[{"author_name":"Alexandra I Mot","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Ying Li","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Payam Dibaj","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Iva D Tzvetanova","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Ulrike C Gerwig","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Tizibt A Bogale","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Sandra Goebbels","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Wiebke M\u00f6bius","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Dwight E Bergles","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Brett M Morrison","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Jeffrey D Rothstein","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Don W Cleveland","author_inst":"Department of Molecular and Cellular Medicine, University of California at San Diego, La Jolla, CA 92093 USA"},{"author_name":"Julia M Edgar","author_inst":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences University of Glasgow, UK"},{"author_name":"Klaus-Armin Nave","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A quantitative coordinate system for developmental dynamics","rel_doi":"10.64898\/2026.06.09.730858","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730858","rel_abs":"Quantitative comparison of morphogenesis across individuals remains a fundamental challenge, as developing embryos vary in shape, orientation and developmental tempo. Moreover, real-time three-dimensional imaging generates large, heterogeneous four-dimensional datasets that are difficult to directly align. As a result, developmental variability is typically described qualitatively rather than measured. Here we introduce STERN, a quantitative framework that learns continuous spatiotemporal representations of morphogenesis directly from in vivo 4D imaging data. By embedding embryos into a shared spatiotemporal space, STERN defines a quantitative developmental coordinate system that enables direct comparison of developmental trajectories across individuals without requiring explicit registration or staging. Applied to mouse embryogenesis, STERN reveals that embryos follow conserved developmental trajectories while progressing at distinct temporal rates, providing a quantitative measure of developmental heterochrony. Extending this framework to zebrafish neural crest light-sheet timelapse imaging, we further show that developmental order is preserved across distinct imaging views even with altered anatomical coverage, supporting the generality of the learned representation across vertebrate imaging contexts. Finally, in developing mouse hearts, where morphogenesis proceeds through subtle and continuously evolving structural changes, STERN resolves fine-scale developmental dynamics at minute-scale temporal resolution that are difficult to localize reproducibly using human experts or general-purpose multimodal AI. Together, these results establish a shared quantitative coordinate system for morphogenesis, in which developmental trajectories become directly comparable across individuals and developmental variability becomes a measurable property.","rel_num_authors":7,"rel_authors":[{"author_name":"Jiawei Wang","author_inst":"European Bioinformatics Institute; University of Bath"},{"author_name":"Jinzheng Ren","author_inst":"European Bioinformatics Institute; University of Bath; Australian National University"},{"author_name":"Cora Moore","author_inst":"University of Bath"},{"author_name":"Robert N. Kelsh","author_inst":"University of Bath"},{"author_name":"Katie McDole","author_inst":"MRC Laboratory of Molecular Biology"},{"author_name":"Bianca Dumitrascu","author_inst":"Columbia University"},{"author_name":"John C. Marioni","author_inst":"European Bioinformatics Institute"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Apollo 3: Multi-Species Genome Curation","rel_doi":"10.64898\/2026.06.08.730970","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730970","rel_abs":"We present Apollo 3, a new manual genome annotation tool that integrates with the JBrowse 2 genome browser. Its functionality is inspired by existing manual genome annotation tools such as Apollo, Artemis, and Otter, but uses an updated and more scalable architecture and technology stack. It allows the simultaneous editing of multiple genomes, including the visualization of synteny to inform those annotations. Apollo 3 can be used as a standalone annotation editor, or it can be installed on a server and used collaboratively. We describe the application's design, features, and use cases.","rel_num_authors":24,"rel_authors":[{"author_name":"Garrett J Stevens","author_inst":"University of California, Berkeley"},{"author_name":"Ky\u00f6sti Sutinen","author_inst":"European Bioinformatics Institute"},{"author_name":"Dario Beraldi","author_inst":"University of Glasgow"},{"author_name":"Shashank Budhanuru Ramaraju","author_inst":"European Bioinformatics Institute"},{"author_name":"Colin M Diesh","author_inst":"University of California, Berkeley"},{"author_name":"William Haese-Hill","author_inst":"University of Glasgow"},{"author_name":"Peter Xie","author_inst":"University of California, Berkeley"},{"author_name":"Caroline Bridge","author_inst":"Ontario Institute for Cancer Research"},{"author_name":"Adrien Morison","author_inst":"University of Glasgow"},{"author_name":"Angel Leung","author_inst":"University of California, Berkeley"},{"author_name":"Ulrike B\u00f6hme","author_inst":"University of Liverpool"},{"author_name":"Scott Cain","author_inst":"Pennsylvania State University"},{"author_name":"Nathan Dunn","author_inst":"University of California, Berkeley"},{"author_name":"Toby Hunt","author_inst":"European Bioinformatics Institute"},{"author_name":"Jane E Loveland","author_inst":"European Bioinformatics Institute"},{"author_name":"Adam Frankish","author_inst":"European Bioinformatics Institute"},{"author_name":"Alexie Papanicolau","author_inst":"Western Sydney University"},{"author_name":"Stefano Giorgetti","author_inst":"European Bioinformatics Institute"},{"author_name":"Jon Keatley","author_inst":"European Bioinformatics Institute"},{"author_name":"Bethany Flint","author_inst":"European Bioinformatics Institute"},{"author_name":"Lincoln D Stein","author_inst":"Ontario Institute for Cancer Research"},{"author_name":"Robert Buels","author_inst":"University of California, Berkeley"},{"author_name":"Matt Berriman","author_inst":"University of Glasgow"},{"author_name":"Ian Holmes","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Improving splice site usage prediction with SPLAIRE","rel_doi":"10.64898\/2026.06.08.731019","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.731019","rel_abs":"Alternative splicing, the mechanism by which intronic sequences are excised from pre-mRNAs to produce mature mRNA, affects >95% of human protein-coding genes and is a major driver of human disease states. The spliceosome, a protein-RNA complex responsible for splicing pre-mRNA, identifies candidate splice sites partly through the recognition of characteristic sequence motifs at exon-intron junctions. Deep learning models that predict the presence of splice sites from pre-mRNA sequence have achieved breakthrough performance relative to previous machine-learning techniques, and these models have improved our ability to identify pathogenic genetic variants that alter splicing. We show that, while overall performance measures from these models suggest near-perfect performance, substantial gaps in prediction remain, including the identification of splice sites with low usage rates and tissue-specific splice sites. We leverage one of the largest paired RNA and genotyping datasets used to date to train a novel splicing model optimized for a specific cell type, human airway epithelial cells. We trained a dilated convolutional neural network on data from cultured airway epithelial cells from 100 donors, and showed that this model outperforms current state-of-the-art models on splice site identification and splice site usage quantification, including on multiple tissues not included in the model training data. We present the most comprehensive evaluation of state-of-the-art splicing models published to date, revealing reasonable performance across models for genetic variant effect prediction, along with important performance gaps and insights into directions for future model development.","rel_num_authors":11,"rel_authors":[{"author_name":"Matthew Runyan","author_inst":"The Institute for Experiential AI, Northeastern University, Boston, MA, USA"},{"author_name":"Saumya Gupta","author_inst":"The Institute for Experiential AI, Northeastern University, Boston, MA, USA"},{"author_name":"Yul Leshaem","author_inst":"Channing Division of Network Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"David Geller-McGrath","author_inst":"Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Congjian Liu","author_inst":"Division of Pulmonary and Critical Care Medicine, Brigham \\& Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Aabida Saferali","author_inst":"Channing Division of Network Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Jennifer Dy","author_inst":"Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA"},{"author_name":"Predrag Radivojac","author_inst":"Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA"},{"author_name":"Yohannes Tesfaigzi","author_inst":"Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Peter Castaldi","author_inst":"Channing Division of Network Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Ayan Paul","author_inst":"The Institute for Experiential AI & Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Disparate introduction histories but similar climatic distribution patterns among congeneric invasive anurans","rel_doi":"10.64898\/2026.06.08.730926","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730926","rel_abs":"Commonly shared patterns of introduction and spread into new environmental conditions are often poorly understood, even though a better understanding of invasion history and niche dynamics among closely related invasive species could give practitioners valuable information to prevent and mitigate the impact of biological invasions. For this study, we investigate the invasion history and niche patterns among congeneric invasive species. We synthesize public occurrence data for five invasive alien anurans (Eleutherodactylus coqui, E. planirostris, E. johnstonei, E. antillensis, and E. martinicensis) to reconstruct their historic introductions and evaluate evidence for climatic niche shifts between their native and established non-native ranges. By pairing these data with current and future climate projections, we compare patterns of range shifts under future climate scenarios. Our results highlight different temporal and geographic introduction histories in invasive Eleutherodactylus, but a strong signal of colonizing broader invasive climatic niches, specifically into colder environmental conditions. Under future climate scenarios, suitable habitats for most of the non-native regions are likely to increase, although this increase is restricted under scenarios with high greenhouse gas emissions. Our results reveal that despite different invasion histories, the ability to spread into colder regions may be a conserved trait among the most widespread Eleutherodactylus anurans. This study ultimately shows that commonalities among closely related invasive species can provide clues about their ability to expand into areas with particular abiotic conditions, a pattern likely to be widespread, offering a potentially valuable opportunity to deploy targeted prevention strategies.","rel_num_authors":4,"rel_authors":[{"author_name":"Andrew J Mularo","author_inst":"W.K. Kellogg Biological Station - Michigan State University"},{"author_name":"Jong Yoon Jeon","author_inst":"Purdue University"},{"author_name":"Jackson T Kirkwood","author_inst":"Purdue University"},{"author_name":"Ximena E Bernal","author_inst":"Purdue University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Gene duplication and retrotransposition diversify the antiviral repertoire of macaque IFITM proteins","rel_doi":"10.64898\/2026.06.11.731520","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731520","rel_abs":"Interferon-induced transmembrane (IFITM) proteins are broad-spectrum antiviral restriction factors that inhibit viral entry of diverse enveloped viruses. Comparative genomic studies have revealed extensive lineage-specific diversification of IFITM genes, yet the functional consequences of this diversification remain poorly understood. We previously identified an expanded IFITM repertoire in macaques consisting of the canonical IFITM proteins, IFITM1 and IFITM3, a duplicated IFITM3 paralog (IFITM3A), and two retrotransposed IFITM3-derived genes (IFITM3-R1 and IFITM3-R2). Here, we thoroughly characterized the antiviral activities, intracellular localization, and mechanisms of regulation of canonical and non-canonical macaque IFITMs against vesicular stomatitis virus (VSV), influenza A virus (IAV), Sendai virus, and HIV-1. IFITM3A exhibited enhanced antiviral activity relative to IFITM3, particularly against VSV and HIV-1. Comparative mutational analyses identified amino acid substitutions in IFITM3 that contribute to the enhanced antiviral phenotype of IFITM3A. In contrast, the retrocopy IFITM3-R1 exhibited markedly reduced expression due to lysosome-dependent protein turnover mediated by a PPxY motif and a unique lysine residue (K51). Alteration of these determinants increased IFITM3-R1 expression and selectively enhanced restriction of VSV and IAV. Although several macaque IFITMs reduced HIV-1 infectivity when expressed in producer cells, none significantly inhibited HIV-1 infection in target cells. Furthermore, differential incorporation of IFITMs into HIV-1 virions did not consistently correlate with antiviral activity, indicating that virion incorporation alone is insufficient to explain HIV-1 restriction. Together, these findings demonstrate that gene duplication and retrotransposition have generated a functionally diverse IFITM repertoire in macaques and provide insight into how evolutionary diversification expands innate antiviral defenses in primates.","rel_num_authors":13,"rel_authors":[{"author_name":"Deepthi Kappala","author_inst":"NC State University"},{"author_name":"Alexis Sauer","author_inst":"The Ohio State University"},{"author_name":"Emma Atwood","author_inst":"NC State University"},{"author_name":"Yuexiu Zhang","author_inst":"The Ohio State University"},{"author_name":"Anuja Pimplapure","author_inst":"NC State University"},{"author_name":"Naveen Bektas-Jolly","author_inst":"NC State University"},{"author_name":"Lohitha Gujjari","author_inst":"The Ohio State University"},{"author_name":"Kasturi Chandra","author_inst":"NC State University"},{"author_name":"Yogesh Saini","author_inst":"NC State University"},{"author_name":"Jacob Yount","author_inst":"The Ohio State University"},{"author_name":"Amol Suryawanshi","author_inst":"NC State University"},{"author_name":"Jianrong Li","author_inst":"The Ohio State University"},{"author_name":"Amit Sharma","author_inst":"NC State University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Engineering a Hyper-Adherent E. coli Nissle Probiotic Strain that Reduces Intestinal Carriage of SalmonellaPathogens in Poultry","rel_doi":"10.64898\/2026.06.11.731546","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731546","rel_abs":"Salmonellosis continues to be one of the most important causes of food-borne illness in the U.S. An additional concern with this bacterial pathogen is that infections with multiple-antibiotic-resistant Salmonella strains are becoming untreatable infectious diseases. Poultry meat and eggs are major sources of Salmonella food-borne illness, due to carriage of these bacterial pathogens in the intestinal microbiome of chickens. A food safety priority, as stated by the USDA, is a significant reduction in carriage of pathogenic Salmonella species in poultry which would significantly improve food safety and reduce cases of human salmonellosis contracted from consumption of contaminated poultry. While this goal has been a priority for many years, basic research and animal management efforts have not achieved significant control of Salmonella carriage. This study represents an alternative approach to reduce or eliminate carriage of Salmonella in poultry flocks. We characterized a type 1 fimbrial allele of Salmonella that confers high levels of adherence to various host cells. We then engineered an E. coli Nissle 1917 probiotic strain that expresses this Salmonella adherence factor at high levels. The E. coli Nissle 1917 is used as the scaffold strain for this work since this E. coli strain has received the FDA designation of Generally Regarded As Safe (GRAS) and has been used for many years as a probiotic to treat human intestinal disorders. Our E. coli Nissle strain was engineered to use an in vivo selection system for a plasmid carrying the cloned Salmonella type 1 fimbrial genes, so that the strain can be used as a probiotic without any antibiotic resistance-encoding genes requiring antibiotic selection for maintenance of the desired phenotype. Our probiotic strain displays high levels of adherence to host cells, in fact higher levels of adherence than a Salmonella strain carrying the same type 1 fimbrial genes. We demonstrate that the probiotic strain significantly outcompetes pathogenic Salmonella strains for adherence to tissue culture cells and in vivo experimental challenges revealed that the probiotic strain mediates a significant exclusion of Salmonella from the intestines of broilers, layers, and turkeys.","rel_num_authors":5,"rel_authors":[{"author_name":"M. Aaron Baxter","author_inst":"Grand Valley State University, Department of Biomedical Sciences"},{"author_name":"Kelsey Greenwood","author_inst":"University of Iowa Carver College of Medicine, Department of Microbiology and Immunology"},{"author_name":"Kristi L. Anderson","author_inst":"Iowa State University College of Veterinary Medicine, Department of Biomedical Sciences"},{"author_name":"Steven A. Carlson","author_inst":"Iowa State University College of Veterinary Medicine, Department of Biomedical Sciences"},{"author_name":"Bradley D Jones","author_inst":"University of Iowa Carver College of Medicine, Department of Microbiology and Immunology"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Engineering a Hyper-Adherent E. coli Nissle Probiotic Strain that Reduces Intestinal Carriage of SalmonellaPathogens in Poultry","rel_doi":"10.64898\/2026.06.11.731546","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731546","rel_abs":"Salmonellosis continues to be one of the most important causes of food-borne illness in the U.S. An additional concern with this bacterial pathogen is that infections with multiple-antibiotic-resistant Salmonella strains are becoming untreatable infectious diseases. Poultry meat and eggs are major sources of Salmonella food-borne illness, due to carriage of these bacterial pathogens in the intestinal microbiome of chickens. A food safety priority, as stated by the USDA, is a significant reduction in carriage of pathogenic Salmonella species in poultry which would significantly improve food safety and reduce cases of human salmonellosis contracted from consumption of contaminated poultry. While this goal has been a priority for many years, basic research and animal management efforts have not achieved significant control of Salmonella carriage. This study represents an alternative approach to reduce or eliminate carriage of Salmonella in poultry flocks. We characterized a type 1 fimbrial allele of Salmonella that confers high levels of adherence to various host cells. We then engineered an E. coli Nissle 1917 probiotic strain that expresses this Salmonella adherence factor at high levels. The E. coli Nissle 1917 is used as the scaffold strain for this work since this E. coli strain has received the FDA designation of Generally Regarded As Safe (GRAS) and has been used for many years as a probiotic to treat human intestinal disorders. Our E. coli Nissle strain was engineered to use an in vivo selection system for a plasmid carrying the cloned Salmonella type 1 fimbrial genes, so that the strain can be used as a probiotic without any antibiotic resistance-encoding genes requiring antibiotic selection for maintenance of the desired phenotype. Our probiotic strain displays high levels of adherence to host cells, in fact higher levels of adherence than a Salmonella strain carrying the same type 1 fimbrial genes. We demonstrate that the probiotic strain significantly outcompetes pathogenic Salmonella strains for adherence to tissue culture cells and in vivo experimental challenges revealed that the probiotic strain mediates a significant exclusion of Salmonella from the intestines of broilers, layers, and turkeys.","rel_num_authors":5,"rel_authors":[{"author_name":"M. Aaron Baxter","author_inst":"Grand Valley State University, Department of Biomedical Sciences"},{"author_name":"Kelsey Greenwood","author_inst":"University of Iowa Carver College of Medicine, Department of Microbiology and Immunology"},{"author_name":"Kristi L. Anderson","author_inst":"Iowa State University College of Veterinary Medicine, Department of Biomedical Sciences"},{"author_name":"Steven A. Carlson","author_inst":"Iowa State University College of Veterinary Medicine, Department of Biomedical Sciences"},{"author_name":"Bradley D Jones","author_inst":"University of Iowa Carver College of Medicine, Department of Microbiology and Immunology"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A common connectome-based neural reference space across affective, autonomic, and wakefulness arousal","rel_doi":"10.64898\/2026.06.08.730730","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730730","rel_abs":"Arousal is often invoked to explain state-dependent variability in attention, emotion, memory, and decision-making. However, the term is used inconsistently, referring variously to affective experience, autonomic activation, and states of wakefulness. The extent to which different operationalizations of arousal reflect a shared neurobiological basis remains unclear, limiting efforts to unify findings across studies. We applied dynamic connectome predictive models to five fMRI datasets spanning naturalistic movie watching, story listening, wakeful rest, and sleep. We derived measures of affective, autonomic, and wakefulness arousal from subjective ratings, pupil dilation, and EEG, respectively. Models trained to predict arousal in one dataset generalized across datasets, indicating that dynamic connectivity captures shared arousal-related dynamics across measures and task contexts. The models also predicted manually scored sleep stages, suggesting that they capture arousal dynamics that extend to the graded fluctuations in arousal during sleep. Decoded arousal dynamics during movie-viewing predicted how well participants later recalled movie events, reproducing classic arousal-dependent memory enhancement effects. Model predictions were supported by overlapping functional connections, including a subset shared across all models. The largest proportion of shared connections was between the salience and somatomotor networks, suggesting that increased coordination between salience detection and action readiness may be a common feature across multiple operationalizations of arousal. Together, these results are consistent with a connectome-based neural reference space for arousal, in which different varieties share a core set of predictive connections. Our findings offer a quantitative framework for integrating arousal-related findings across tasks and modalities.","rel_num_authors":9,"rel_authors":[{"author_name":"Kannon Bhattacharyya","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Judah Huberman-Shlaes","author_inst":"University of Pittsburgh"},{"author_name":"Yulin Tong","author_inst":"University of Chicago"},{"author_name":"Yuxuan Zhu","author_inst":"University of Chicago"},{"author_name":"Jin Ke","author_inst":"Yale University"},{"author_name":"Jadyn S. Park","author_inst":"University of Chicago"},{"author_name":"Anna Corriveau","author_inst":"University of Chicago"},{"author_name":"Monica D. Rosenberg","author_inst":"University of Chicago"},{"author_name":"Yuan Chang Leong","author_inst":"University of Chicago"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A common connectome-based neural reference space across affective, autonomic, and wakefulness arousal","rel_doi":"10.64898\/2026.06.08.730730","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730730","rel_abs":"Arousal is often invoked to explain state-dependent variability in attention, emotion, memory, and decision-making. However, the term is used inconsistently, referring variously to affective experience, autonomic activation, and states of wakefulness. The extent to which different operationalizations of arousal reflect a shared neurobiological basis remains unclear, limiting efforts to unify findings across studies. We applied dynamic connectome predictive models to five fMRI datasets spanning naturalistic movie watching, story listening, wakeful rest, and sleep. We derived measures of affective, autonomic, and wakefulness arousal from subjective ratings, pupil dilation, and EEG, respectively. Models trained to predict arousal in one dataset generalized across datasets, indicating that dynamic connectivity captures shared arousal-related dynamics across measures and task contexts. The models also predicted manually scored sleep stages, suggesting that they capture arousal dynamics that extend to the graded fluctuations in arousal during sleep. Decoded arousal dynamics during movie-viewing predicted how well participants later recalled movie events, reproducing classic arousal-dependent memory enhancement effects. Model predictions were supported by overlapping functional connections, including a subset shared across all models. The largest proportion of shared connections was between the salience and somatomotor networks, suggesting that increased coordination between salience detection and action readiness may be a common feature across multiple operationalizations of arousal. Together, these results are consistent with a connectome-based neural reference space for arousal, in which different varieties share a core set of predictive connections. Our findings offer a quantitative framework for integrating arousal-related findings across tasks and modalities.","rel_num_authors":9,"rel_authors":[{"author_name":"Kannon Bhattacharyya","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Judah Huberman-Shlaes","author_inst":"University of Pittsburgh"},{"author_name":"Yulin Tong","author_inst":"University of Chicago"},{"author_name":"Yuxuan Zhu","author_inst":"University of Chicago"},{"author_name":"Jin Ke","author_inst":"Yale University"},{"author_name":"Jadyn S. Park","author_inst":"University of Chicago"},{"author_name":"Anna Corriveau","author_inst":"University of Chicago"},{"author_name":"Monica D. Rosenberg","author_inst":"University of Chicago"},{"author_name":"Yuan Chang Leong","author_inst":"University of Chicago"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Gestational inhalation of nanoparticles disrupts placental zone structure and induces vascular placentation in rats","rel_doi":"10.64898\/2026.06.08.730946","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730946","rel_abs":"Airborne contaminants represent a significant environmental health concern for vulnerable populations, including pregnant individuals. In particular, maternal inhalation of particulate matter (PM) during pregnancy has been linked to adverse outcomes such as fetal growth restriction (FGR). Increasing evidence identifies placental dysfunction as a mechanism for this condition. Placental efficiency, defined as the ratio of fetal mass to placental mass, is frequently altered in FGR. Many aspects contribute to placental efficiency including surface area available for nutrient and waste exchange and placental vascularization. In this study, we hypothesized that maternal inhalation of ultrafine PM during pregnancy would reduce the size and\/or number of placental structures that are necessary for nutrient transport. Engineered titanium dioxide nanoparticles (nano-TiO2) were used as a proxy for ultrafine PM and pregnant Sprague Dawley rats were exposed via whole-body inhalation to nano-TiO2 aerosols (9.23 +\/- 0.39 mg\/m3) from gestational day (GD) 5 to 19. On GD 20, placentas were collected and processed for histological evaluation. While gestational inhalation of nano-TiO2 did not affect placental weight or efficiency, it reduced decidua and labyrinth zone size. Exposed placentas exhibited compensatory adaptations characterized by increased blood space number and maternal blood space expansion. Together, these findings indicate that inhalation of nanoparticles disrupts placental structure while simultaneously eliciting adaptive vascular responses that may preserve nutrient exchange capacity. By characterizing the effects of PM exposure on placental morphology and structure, this study highlights the placenta as a vulnerable target of inhaled pollutants and provides mechanistic insight into pathways contributing to PM-induced FGR.","rel_num_authors":8,"rel_authors":[{"author_name":"Talia Seymore","author_inst":"Rutgers University"},{"author_name":"Destiny McWilliams","author_inst":"Villanova University"},{"author_name":"Kevin Ozkuyumcu","author_inst":"Rutgers University"},{"author_name":"Pedro Louro","author_inst":"Rutgers University"},{"author_name":"Chelsea Cary","author_inst":"Rutgers University"},{"author_name":"Michael Goedken","author_inst":"Rutgers University"},{"author_name":"Laurie Joseph","author_inst":"Rutgers University"},{"author_name":"Phoebe Stapleton","author_inst":"Rutgers University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Sub-Chronic Chlorpyrifos Exposure Leads to Epigenetic and Sex-Specific Behavioral Changes in Adult Mice","rel_doi":"10.64898\/2026.06.08.730429","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730429","rel_abs":"Chlorpyrifos is a widely used organophosphate pesticide that exerts its primary toxic effect through inhibition of acetylcholinesterase (AChE). Although the acute neurotoxicity of chlorpyrifos is well characterized, the lasting biochemical, behavioral, and epigenetic consequences of sub-chronic exposure remain poorly understood, particularly when considering sex-specific differences. Therefore, we exposed male and female C57BL\/6J mice to either peanut oil (n=19), low chlorpyrifos exposure (1 mg\/kg\/day; n=19), or high chlorpyrifos exposure (10 mg\/kg\/day n=10) repeatedly for 21 days via subcutaneous injection. Blood AChE activity, behavior, and hippocampal DNA methylation were measured across groups. During exposure, AChE activity decreased in both males and females but only returned to baseline after behavioral testing in females exposed to low chlorpyrifos levels. Behavioral tests also revealed a sex-specific phenotype, with females in the low exposure group exhibiting reduced forced swim test immobility and a significant time by exposure interaction in open field habituation. No significant behavioral effects were observed in males. Significant DNA methylation changes were observed at 3,538 CpG sites in male and female mice after high exposure. Sex-specific analyses revealed two female-specific differentially methylated CpGs after high exposure. Pathways enriched for differentially methylated genes included several related to synaptic remodeling, cholinergic synapse, and various endocrine systems. These findings demonstrate that repeated high chlorpyrifos exposure leads to persistent cholinergic disruption and DNA methylation changes. However, the female-specific behavioral changes seen are independent of AChE activity and widespread DNA methylation changes, suggesting additional mechanisms, present only in females, may underlie behavioral sensitivity to chlorpyrifos.","rel_num_authors":10,"rel_authors":[{"author_name":"Alyssa R Daniel","author_inst":"University of Iowa"},{"author_name":"Noah Gernander","author_inst":"University of Iowa"},{"author_name":"Sara Dodge","author_inst":"University of Iowa"},{"author_name":"Cessily Hayes","author_inst":"University of Iowa"},{"author_name":"Emma Simpson-Wade","author_inst":"University of Iowa"},{"author_name":"Emese HC Kovacs","author_inst":"University of Iowa"},{"author_name":"Gibson Dowd","author_inst":"University of Iowa"},{"author_name":"Jared M McLendon","author_inst":"University of Iowa"},{"author_name":"Benjamin Hing","author_inst":"University of Iowa"},{"author_name":"Marie E Gaine","author_inst":"University of Iowa"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Sub-Chronic Chlorpyrifos Exposure Leads to Epigenetic and Sex-Specific Behavioral Changes in Adult Mice","rel_doi":"10.64898\/2026.06.08.730429","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730429","rel_abs":"Chlorpyrifos is a widely used organophosphate pesticide that exerts its primary toxic effect through inhibition of acetylcholinesterase (AChE). Although the acute neurotoxicity of chlorpyrifos is well characterized, the lasting biochemical, behavioral, and epigenetic consequences of sub-chronic exposure remain poorly understood, particularly when considering sex-specific differences. Therefore, we exposed male and female C57BL\/6J mice to either peanut oil (n=19), low chlorpyrifos exposure (1 mg\/kg\/day; n=19), or high chlorpyrifos exposure (10 mg\/kg\/day n=10) repeatedly for 21 days via subcutaneous injection. Blood AChE activity, behavior, and hippocampal DNA methylation were measured across groups. During exposure, AChE activity decreased in both males and females but only returned to baseline after behavioral testing in females exposed to low chlorpyrifos levels. Behavioral tests also revealed a sex-specific phenotype, with females in the low exposure group exhibiting reduced forced swim test immobility and a significant time by exposure interaction in open field habituation. No significant behavioral effects were observed in males. Significant DNA methylation changes were observed at 3,538 CpG sites in male and female mice after high exposure. Sex-specific analyses revealed two female-specific differentially methylated CpGs after high exposure. Pathways enriched for differentially methylated genes included several related to synaptic remodeling, cholinergic synapse, and various endocrine systems. These findings demonstrate that repeated high chlorpyrifos exposure leads to persistent cholinergic disruption and DNA methylation changes. However, the female-specific behavioral changes seen are independent of AChE activity and widespread DNA methylation changes, suggesting additional mechanisms, present only in females, may underlie behavioral sensitivity to chlorpyrifos.","rel_num_authors":10,"rel_authors":[{"author_name":"Alyssa R Daniel","author_inst":"University of Iowa"},{"author_name":"Noah Gernander","author_inst":"University of Iowa"},{"author_name":"Sara Dodge","author_inst":"University of Iowa"},{"author_name":"Cessily Hayes","author_inst":"University of Iowa"},{"author_name":"Emma Simpson-Wade","author_inst":"University of Iowa"},{"author_name":"Emese HC Kovacs","author_inst":"University of Iowa"},{"author_name":"Gibson Dowd","author_inst":"University of Iowa"},{"author_name":"Jared M McLendon","author_inst":"University of Iowa"},{"author_name":"Benjamin Hing","author_inst":"University of Iowa"},{"author_name":"Marie E Gaine","author_inst":"University of Iowa"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"VISUAL EXPERIENCE SHAPES ARM POSITION SENSE IN INTERNAL AND EXTERNAL REFERENCE FRAMES AND ASSOCIATED CORTICAL LOAD","rel_doi":"10.64898\/2026.06.08.730866","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730866","rel_abs":"The ability to accurately perceive arm position is essential for motor control and depends on the integration of proprioceptive and visual information. However, how lifelong visual impairment (VI) affects position sense and its neural correlates remains unclear. We quantified arm position sense and associated cognitive-motor load in right-handed visually impaired (n = 7) and normally sighted (NS; n = 7) individuals using three bilateral arm position matching tasks: joint angle matching (JAM; internal coordinates), hand direction-distance matching (DDM; external coordinates), and mirror direction-distance matching (MDDM; external coordinates kinematically identical to JAM). Cognitive load was assessed using the contingent negative variation (CNV) from EEG recordings. VI participants exhibited reduced accuracy and precision of arm position sense in most conditions, and greater CNV magnitude, particularly in the left parietal cortex. Across both groups, performance was worse and CNV magnitude was greater in the DDM task compared with JAM, whereas JAM and MDDM yielded similar behavioral and neural outcomes. These findings indicate that (i) visual experience enhances arm position sense, and (ii) representing limb position in external coordinates imposes greater cognitive demands than encoding joint-based posture. The similarity between JAM and MDDM suggests that participants preferentially rely on internal representations when task kinematics permit.","rel_num_authors":4,"rel_authors":[{"author_name":"Kyunggeune Oh","author_inst":"Idaho State University"},{"author_name":"Nikhilesh Natraj","author_inst":"University of California San Francisco"},{"author_name":"Lewis A. Wheaton","author_inst":"Georgia Institute of Technology"},{"author_name":"Boris I. Prilutsky","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"STITCH links cellular morphology and gene expression in spatial transcriptomics","rel_doi":"10.64898\/2026.06.07.730714","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730714","rel_abs":"In situ spatial (ISS) sequencing can uncover co-variation between cellular morphology and gene expression in vivo. However, a principled and interpretable mathematical representation of morphology has not yet been applied in this context. In particular, current deep learning-based representations of cell images confound a cell's shape with its size. We present an interpretable representation of cellular boundary contours, based on tangent principal component analysis (TPCA) in a Kendall shape manifold, that captures size-independent contour shape features. This approach successfully recovers shape-perturbing genes in an RNAi screen than a previous metric geometry-based approach. We build on TPCA to develop STITCH (Shape-TranscriptomIc Correlation and Harmonization), an approach to reveal covariation between cell morphology with gene expression in ISS datasets. In a Xenium dataset, STITCH outperforms a deep learning-based approach in both recovering the layered organization of keratinocytes and a spatial gradient in nuclear eccentricity. Across samples in a melanoma CosMx dataset, STITCH reproducibly associates elongated and triangular fibroblasts with proximity to malignant cells and myofibroblast-like transcriptional program. Finally, STITCH independently recovers a known link between mesenchymal-like malignant cell states and increased cell area in two melanoma cohorts. STITCH can thus yield interpretable morphology-transcriptome relationships across cell types, patients, and spatial transcriptomics platforms.","rel_num_authors":8,"rel_authors":[{"author_name":"Shashwat Kumar","author_inst":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Yingxiao Shi","author_inst":"Harvard Medical School, Boston , Massachusetts, US"},{"author_name":"Tuulia Vallius","author_inst":"Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115"},{"author_name":"Chi-Ping Day","author_inst":"National Cancer Institute"},{"author_name":"P.-A. Absil","author_inst":"ICTEAM Institute, UCLouvain, B-1348 Louvain-la-Neuve, Belgium"},{"author_name":"Anuj Srivastava","author_inst":"Data Science and AI Institute, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Sridhar Hannenhalli","author_inst":"Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Vishaka Gopalan","author_inst":"National Cancer Institute"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Pillbox: A Leakage-Aware Foundation-Model Predictor and Lineage-Ceiling Diagnostic for Cancer Drug Response","rel_doi":"10.64898\/2026.06.08.725572","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.725572","rel_abs":"We present Pillbox, a predictor whose pipeline is audited against the six Asiaee leakage modes with the one residual pathway shown by per-fold ablation to be non-load-bearing on hard splits. Our model combines CpGPT methylation embeddings, CLAMP drug embeddings, and per-fold-fit gene-expression principal components which are fused by Feature-wise Linear Modulation (FiLM)-conditioned graph attention on the STRING v12 protein-protein interaction graph. Then we alpha-ensemble the model against a histogram-based gradient boosting regressor baseline. On GDSC GSE68379 (987 cell lines, 375 drugs) across seeds 42, 7, and 123, the ensemble reaches test R-Squared of 0.78, 0.77, and 0.76 on random, histology-blind, and site-blind splits respectively, with cell-aware lifts above the drug-mean floor of +0.054, +0.060, and +0.037. As a quantitative diagnostic for feature-stack saturation we propose the cross-architecture residual correlation, calibrated against a same-architecture-different-initialization control. On histology-blind splits the cross-architecture value of 0.939 falls short of the same-architecture ceiling of 0.974 by approximately 0.03 in residual correlation, a gap we interpret as the headroom available to architecture choice on top of the current foundation-model representation and consistent with the long-established observation that tissue lineage dominates cell-line drug response. We integrated curated mutation, methylation, and drug-target-expression channels, but these do not improve prediction once foundation-model embeddings are in place. Cross-screen validation against PRISM matches the GDSC-to-PRISM measurement reproducibility ceiling within 0.01 Spearman.","rel_num_authors":7,"rel_authors":[{"author_name":"Justin Joon Kim Hill","author_inst":"Quome, Inc"},{"author_name":"Hong Joo Ryoo","author_inst":"Johns Hopkins University"},{"author_name":"Arhant Ghanta","author_inst":"University of California - Berkeley"},{"author_name":"Shwetank Singh","author_inst":"University of California - Berkeley"},{"author_name":"Declan Anders","author_inst":"Ohio State University"},{"author_name":"Eric Jiao","author_inst":"California State University - Fullerton"},{"author_name":"Jooho Jeong","author_inst":"Sungkyunkwan University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Pillbox: A Leakage-Aware Foundation-Model Predictor and Lineage-Ceiling Diagnostic for Cancer Drug Response","rel_doi":"10.64898\/2026.06.08.725572","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.725572","rel_abs":"We present Pillbox, a predictor whose pipeline is audited against the six Asiaee leakage modes with the one residual pathway shown by per-fold ablation to be non-load-bearing on hard splits. Our model combines CpGPT methylation embeddings, CLAMP drug embeddings, and per-fold-fit gene-expression principal components which are fused by Feature-wise Linear Modulation (FiLM)-conditioned graph attention on the STRING v12 protein-protein interaction graph. Then we alpha-ensemble the model against a histogram-based gradient boosting regressor baseline. On GDSC GSE68379 (987 cell lines, 375 drugs) across seeds 42, 7, and 123, the ensemble reaches test R-Squared of 0.78, 0.77, and 0.76 on random, histology-blind, and site-blind splits respectively, with cell-aware lifts above the drug-mean floor of +0.054, +0.060, and +0.037. As a quantitative diagnostic for feature-stack saturation we propose the cross-architecture residual correlation, calibrated against a same-architecture-different-initialization control. On histology-blind splits the cross-architecture value of 0.939 falls short of the same-architecture ceiling of 0.974 by approximately 0.03 in residual correlation, a gap we interpret as the headroom available to architecture choice on top of the current foundation-model representation and consistent with the long-established observation that tissue lineage dominates cell-line drug response. We integrated curated mutation, methylation, and drug-target-expression channels, but these do not improve prediction once foundation-model embeddings are in place. Cross-screen validation against PRISM matches the GDSC-to-PRISM measurement reproducibility ceiling within 0.01 Spearman.","rel_num_authors":7,"rel_authors":[{"author_name":"Justin Joon Kim Hill","author_inst":"Quome, Inc"},{"author_name":"Hong Joo Ryoo","author_inst":"Johns Hopkins University"},{"author_name":"Arhant Ghanta","author_inst":"University of California - Berkeley"},{"author_name":"Shwetank Singh","author_inst":"University of California - Berkeley"},{"author_name":"Declan Anders","author_inst":"Ohio State University"},{"author_name":"Eric Jiao","author_inst":"California State University - Fullerton"},{"author_name":"Jooho Jeong","author_inst":"Sungkyunkwan University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A multi-agent system for spine MRI report generation from multi-sequence imaging","rel_doi":"10.64898\/2026.06.07.730703","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730703","rel_abs":"Spinal pathology is a leading cause of pain and disability worldwide. Spine magnetic resonance imaging (MRI) is central to clinical evaluation, yet its interpretation remains complex and time-consuming, requiring integration of information across multiple imaging sequences and anatomical regions. Despite recent advances in automated MRI analysis, effectively combining multi-sequence data while preserving sequence-specific diagnostic information remains an open challenge. Here we present SpineAgent, a multi-agent framework for spine MRI report generation built upon a multi-sequence foundation model trained on routine clinical data from 32,047 patients and 453,683 MRI series, comprising a total of 13,441,191 MRI slices. To accommodate diverse modalities of sequences, we first pre-train two DINOv3-based encoders separately on T1- and T2-weighted sequences. We then introduce a continual training strategy that learns a synthesizer to embed images of other sequences using the T1 and T2 encoders, producing patient-level embedding that integrates various signals across MRI sequences. Using these embeddings, SpineAgent achieves state-of-the-art performance, with mean 10.8% AUROC improvement across 17 spinal condition-prediction tasks compared to the best competing method, and demonstrates strong generalizability under cross-manufacturer and cross-cohort evaluation. Beyond classification, SpineAgent enables pathology localization by identifying findings-relevant slices and segmenting pathological regions. It also supports multimodal image-report retrieval, providing a solid foundation for scalable and explainable MRI report generation. We further integrate these validated capabilities of SpineAgent into 37 specialized agents for condition diagnosis, pathological-region localization, and clinically-similar-cases retrieval. Finally, we incorporate their outputs as structured tokens within a Medical Report Agent trained end-to-end for report generation. Through both automated metrics and expert evaluation by five radiologists, SpineAgent achieves leading performance in spine MRI report generation. Together, SpineAgent introduces a continual training approach for multi-sequence spine MRI understanding. By decomposing report generation into clinically grounded subtasks addressed by specialized agents, the SpineAgent framework enables accurate, interpretable and generalizable spine MRI reporting across diverse imaging sequences and anatomical regions.","rel_num_authors":15,"rel_authors":[{"author_name":"Zhiping Xiao","author_inst":"University of Washington"},{"author_name":"Junwei Yang","author_inst":"Peking University"},{"author_name":"Gongbo Sun","author_inst":"University of Wisconsin, Madison"},{"author_name":"Han Zhang","author_inst":"University of Washington"},{"author_name":"Hanwen Xu","author_inst":"University of Washington"},{"author_name":"Yi Yao","author_inst":"New York University"},{"author_name":"Zachary D. Miller","author_inst":"University of Washington Medical Center"},{"author_name":"William E. King III","author_inst":"University of Washington Medical Center"},{"author_name":"Mohammed M. Kanani","author_inst":"University of Washington"},{"author_name":"Jalal B. Andre","author_inst":"University of Washington Medical Center"},{"author_name":"Sammy Chu","author_inst":"University of Washington Medical Center"},{"author_name":"Ming Zhang","author_inst":"Peking University"},{"author_name":"Paul E. Kinahan","author_inst":"University of Washington Medical Center"},{"author_name":"Nathan M. Cross","author_inst":"University of Washington Medical Center"},{"author_name":"Sheng Wang","author_inst":"University of Washington"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"GermRL: Alleviating The Germline Bias In Autoregressive Antibody Language Models Through Reinforcement Learning","rel_doi":"10.64898\/2026.06.08.730660","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730660","rel_abs":"Antibodies are powerful therapeutics whose antigen specificity arises from sequence diversity shaped during development. Recently, language models trained on large antibody repertoire datasets have enabled the generation and screening of novel candidates, but these models retain a strong germline bias. As AI adoption increases in therapeutic workflows, it is crucial to develop models that harness the diversity of antibodies necessary for the discovery of mutations that encode desirable properties. Previous work explored the germline bias in masked antibody language models, yet the bias in generative autoregressive language models has not yet been addressed. Here, we present GermRL, a lightweight and modular reinforcement learning (RL) framework capable of alleviating the germline bias in pre-trained antibody autoregressive language models through group relative policy optimization (GRPO). GermRL achieves consistent one-shot generation of antibodies that satisfy specified mutation thresholds from germline while maintaining structural plausibility. Under the lowest and highest mutation thresholds tested (5 and 35 mutations from germline), GermRL scores 0.992 and 0.950 pass@1, respectively, compared to 0.398 and 0.034 for the pre-trained language model. Within GermRL, we introduce a key pair of modifications to GRPO that increase training efficiency by discouraging reward hacking under our antibody application. Furthermore, comparison of RL generated and natural antibody sequences reveals how RL based optimization can explore alternative evolutionary mutational patterns and residue compositional strategies while preserving key global properties of natural antibodies, including identifiable germline assignments, embedding-level similarity and comparable developability profiles. Thus, RL-trained generative models optimized to promote antibody mutations through diversity from germline provide a promising framework for navigating the antibody sequence landscape, enabling exploration of novel yet biologically plausible candidates for therapeutic design.","rel_num_authors":3,"rel_authors":[{"author_name":"Laurent Ludwig","author_inst":"Johns Hopkins University"},{"author_name":"Michael Chungyoun","author_inst":"Johns Hopkins University"},{"author_name":"Jeffrey J Gray","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Machine Learning-Guided Discovery of Bacterial-Selective Membrane-Active Compounds Reveals Mechanistic Bias in Antibiotic Training Datasets","rel_doi":"10.64898\/2026.06.08.730938","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730938","rel_abs":"The rise of antibiotic resistance necessitates the discovery of antibacterial compounds with novel mechanisms of action (MoAs). Recent machine learning approaches have shown promise in antibacterial compound discovery, but often identify derivatives of known antibiotic classes rather than mechanistically novel compounds. Previous approaches applied Tanimoto similarity filters at the end of screening pipelines, but this method has substantial drawbacks: Tanimoto similarity can be misleading in chemical space, and post-hoc filtering does not influence what activity models learn to prioritize. Here, we present a machine learning pipeline that addresses chemical novelty upfront by employing an XGBoost-based MoA classifier to explicitly prioritize compounds predicted to have mechanisms distinct from known antibiotic classes, combined with graph neural networks for antibacterial activity and toxicity prediction. Applied to the Zinc20 database, our approach successfully identified non-toxic antibacterial compounds structurally distinct from known antibiotics. Notably, the majority of these hits exhibited membrane-targeting activity with selectivity for bacterial cells over mammalian cells, suggesting potential for next-generation membrane-active antibiotics. However, we did not identify compounds with novel protein targets. Systematic analysis revealed that this limitation stems from mechanistic bias in training data rather than model architecture. Specifically, our activity model learned to preferentially score compounds similar to specific groups in the training data, thus overrepresenting certain MoA classes including membrane-active compounds. Even substantial model architecture and training data enhancements did not overcome this constraint. Our findings demonstrate that the primary bottleneck for discovering mechanistically novel antibiotics is the scarcity of diverse, mechanistically-annotated training data. This work provides both a methodological framework for mechanism-aware screening and critical insights into data requirements for genuinely novel antibiotic discovery.","rel_num_authors":9,"rel_authors":[{"author_name":"Connor Chain","author_inst":"Princeton University"},{"author_name":"Soodabeh Ghaffari","author_inst":"University of California, Berkeley"},{"author_name":"Syrine Belakaria","author_inst":"Stanford University"},{"author_name":"Joseph P Sheehan","author_inst":"Princeton University"},{"author_name":"Ido Irani","author_inst":"Princeton University"},{"author_name":"Chi-Yun Wu","author_inst":"Gladstone Institutes"},{"author_name":"Han Kim","author_inst":"Princeton University"},{"author_name":"Barbara E Engelhardt","author_inst":"Stanford University"},{"author_name":"Zemer E Gitai","author_inst":"Princeton University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Machine Learning-Guided Discovery of Bacterial-Selective Membrane-Active Compounds Reveals Mechanistic Bias in Antibiotic Training Datasets","rel_doi":"10.64898\/2026.06.08.730938","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730938","rel_abs":"The rise of antibiotic resistance necessitates the discovery of antibacterial compounds with novel mechanisms of action (MoAs). Recent machine learning approaches have shown promise in antibacterial compound discovery, but often identify derivatives of known antibiotic classes rather than mechanistically novel compounds. Previous approaches applied Tanimoto similarity filters at the end of screening pipelines, but this method has substantial drawbacks: Tanimoto similarity can be misleading in chemical space, and post-hoc filtering does not influence what activity models learn to prioritize. Here, we present a machine learning pipeline that addresses chemical novelty upfront by employing an XGBoost-based MoA classifier to explicitly prioritize compounds predicted to have mechanisms distinct from known antibiotic classes, combined with graph neural networks for antibacterial activity and toxicity prediction. Applied to the Zinc20 database, our approach successfully identified non-toxic antibacterial compounds structurally distinct from known antibiotics. Notably, the majority of these hits exhibited membrane-targeting activity with selectivity for bacterial cells over mammalian cells, suggesting potential for next-generation membrane-active antibiotics. However, we did not identify compounds with novel protein targets. Systematic analysis revealed that this limitation stems from mechanistic bias in training data rather than model architecture. Specifically, our activity model learned to preferentially score compounds similar to specific groups in the training data, thus overrepresenting certain MoA classes including membrane-active compounds. Even substantial model architecture and training data enhancements did not overcome this constraint. Our findings demonstrate that the primary bottleneck for discovering mechanistically novel antibiotics is the scarcity of diverse, mechanistically-annotated training data. This work provides both a methodological framework for mechanism-aware screening and critical insights into data requirements for genuinely novel antibiotic discovery.","rel_num_authors":9,"rel_authors":[{"author_name":"Connor Chain","author_inst":"Princeton University"},{"author_name":"Soodabeh Ghaffari","author_inst":"University of California, Berkeley"},{"author_name":"Syrine Belakaria","author_inst":"Stanford University"},{"author_name":"Joseph P Sheehan","author_inst":"Princeton University"},{"author_name":"Ido Irani","author_inst":"Princeton University"},{"author_name":"Chi-Yun Wu","author_inst":"Gladstone Institutes"},{"author_name":"Han Kim","author_inst":"Princeton University"},{"author_name":"Barbara E Engelhardt","author_inst":"Stanford University"},{"author_name":"Zemer E Gitai","author_inst":"Princeton University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"SPOTTER: Automated Tissue-Barcoding Platform for Spatial Proteomics and Phosphoproteomics","rel_doi":"10.64898\/2026.06.08.730901","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730901","rel_abs":"Spatial proteomics aims to characterize proteome in situ with regional resolution, linking molecular states to tissue architecture and microenvironments. While recent advances have expanded our access to spatially resolved proteomics, major barriers in scalability and throughput remain. Building on our prior SPOT (Spatial Proteomics through On-site Tissue-protein-labeling) framework1, we introduce SPOTTER, a customizable robotic platform that enables automated, micron-scale spatial barcoding directly on intact tissue sections. SPOTTER barcodes proteins by labeling tissue proteins in situ to encode spatial origin across the whole tissue section. This strategy enables unbiased whole-tissue proteome mapping and, for the first time, spatial phosphoproteome profiling from intact sections. Coupled with high-resolution LC-MS\/MS, SPOTTER achieves deep proteome and phosphoproteome coverage while preserving histological integrity. By replacing labor-intensive laser capture microdissection workflows and low-plex antibody arrays, SPOTTER provides a scalable route to high-plex spatial proteomics, resolving spatially distinct regions within a single experiment.","rel_num_authors":8,"rel_authors":[{"author_name":"Yuanwei Xu","author_inst":"Johns Hopkins University"},{"author_name":"Hyeoncheol Park","author_inst":"Johns Hopkins University"},{"author_name":"Jason Li","author_inst":"Independent Researcher"},{"author_name":"Yuehan Liu","author_inst":"Johns Hopkins University"},{"author_name":"T. Mamie Lih","author_inst":"Johns Hopkins University"},{"author_name":"Chengyu Lee","author_inst":"Johns Hopkins University"},{"author_name":"Xingde Li","author_inst":"Johns Hopkins University"},{"author_name":"hui Zhang","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Natural Selection in the Wake of Catastrophe","rel_doi":"10.64898\/2026.06.08.730870","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730870","rel_abs":"Living organisms, from bacteria to humans, are more likely to survive if their traits enhance fitness. In populations well adapted to their environmental niches, natural selection proceeds via rarely beneficial mutations. But when a catastrophe wipes out niche diversity, sudden adaptation often follows. Here, we present a data-validated theory of natural selection in the wake of catastrophe and unveil a simple law that emerges during recovery: the mean fitness relaxes inversely with time, with a prefactor proportional to the number of traits coupled to the post-catastrophe environment. We put our approach to test using experimental fitness landscapes measured following antibiotic administration to E. coli. The resulting mean trait adaptation is not described by gradient ascent on a fitness landscape, instead it follows an algorithm known as Levenberg--Marquardt optimization. Near fitness peaks, evolutionary trajectories are biased against greediness --- from an optimization perspective, post-catastrophic selection is optimistic.","rel_num_authors":6,"rel_authors":[{"author_name":"Jesse Young Lin","author_inst":"University of Chicago"},{"author_name":"Omer Granek","author_inst":"The University of Chicago"},{"author_name":"Joshua Sodicoff","author_inst":"University of Chicago"},{"author_name":"Seppe Kuehn","author_inst":"The University of Chicago"},{"author_name":"David Pincus","author_inst":"University of Chicago"},{"author_name":"Vincenzo Vitelli","author_inst":"University of Chicago"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Modeling Particle Transport In Biomedical Flows Using Implicit Geometry Representations","rel_doi":"10.64898\/2026.06.07.730719","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730719","rel_abs":"Computational analysis of physiological and biomedical systems necessitate efficient geometry representations for high fidelity model predictions, including patient or device specificity. Particle-based Lagrangian computational approaches comprise a valuable approach to gain insights from quantitative velocity and pressure data from computational models. Examples include particle dynamics and transport in human vasculature for diseases such as stroke, thrombosis, and embolisms; and modern targeted drug delivery systems in the vascular network and respiratory airways. However, current particle simulation approaches can bear significant computational expense that scales with both number of particles and background fluid mesh resolution. A significant determinant of this computational expense is the contact resolution between particles and anatomically realistic vessel wall. Here, we develop an efficient particle dynamics model that leverages an implicit representation of real anatomical features using a signed distance field to efficiently resolve particle-wall contact. We outline the underlying algorithmic details, followed by a systematic illustration of performance and accuracy using simplified and analytically defined geometries and flow fields. Subsequently, we present a representative simulation of embolic particles along a human vascular segment where we compare our distance field-based approach against classical wall-contact checks based on assessing particle boundary intersection with triangulated surface mesh. Our approach transforms the underlying Lagrangian contact detection operation into an equivalent Eulerian operation, significantly speeding up bulk particle dynamics computations without significantly impacting accuracy or geometric fidelity.","rel_num_authors":7,"rel_authors":[{"author_name":"J. Scott Malloy","author_inst":"University of Colorado Boulder"},{"author_name":"Sreeparna Majee","author_inst":"University of Colorado Boulder"},{"author_name":"Akshita Sahni","author_inst":"University of Colorado Boulder; Georgia Institute of Technology"},{"author_name":"Ricardo Roopnarinesingh","author_inst":"University of Colorado Boulder"},{"author_name":"Aditya Balu","author_inst":"Iowa State University"},{"author_name":"Adarsh Krishnamurthy","author_inst":"Iowa State University"},{"author_name":"Debanjan Mukherjee","author_inst":"University of Colorado Boulder"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Modeling Particle Transport In Biomedical Flows Using Implicit Geometry Representations","rel_doi":"10.64898\/2026.06.07.730719","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730719","rel_abs":"Computational analysis of physiological and biomedical systems necessitate efficient geometry representations for high fidelity model predictions, including patient or device specificity. Particle-based Lagrangian computational approaches comprise a valuable approach to gain insights from quantitative velocity and pressure data from computational models. Examples include particle dynamics and transport in human vasculature for diseases such as stroke, thrombosis, and embolisms; and modern targeted drug delivery systems in the vascular network and respiratory airways. However, current particle simulation approaches can bear significant computational expense that scales with both number of particles and background fluid mesh resolution. A significant determinant of this computational expense is the contact resolution between particles and anatomically realistic vessel wall. Here, we develop an efficient particle dynamics model that leverages an implicit representation of real anatomical features using a signed distance field to efficiently resolve particle-wall contact. We outline the underlying algorithmic details, followed by a systematic illustration of performance and accuracy using simplified and analytically defined geometries and flow fields. Subsequently, we present a representative simulation of embolic particles along a human vascular segment where we compare our distance field-based approach against classical wall-contact checks based on assessing particle boundary intersection with triangulated surface mesh. Our approach transforms the underlying Lagrangian contact detection operation into an equivalent Eulerian operation, significantly speeding up bulk particle dynamics computations without significantly impacting accuracy or geometric fidelity.","rel_num_authors":7,"rel_authors":[{"author_name":"J. Scott Malloy","author_inst":"University of Colorado Boulder"},{"author_name":"Sreeparna Majee","author_inst":"University of Colorado Boulder"},{"author_name":"Akshita Sahni","author_inst":"University of Colorado Boulder; Georgia Institute of Technology"},{"author_name":"Ricardo Roopnarinesingh","author_inst":"University of Colorado Boulder"},{"author_name":"Aditya Balu","author_inst":"Iowa State University"},{"author_name":"Adarsh Krishnamurthy","author_inst":"Iowa State University"},{"author_name":"Debanjan Mukherjee","author_inst":"University of Colorado Boulder"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"MipSScs: Artificial neural network-based data integration of 2D\/3D single-cell spatial RNA sequence data from virus-infected human cerebral organoids","rel_doi":"10.64898\/2026.06.08.727881","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.727881","rel_abs":"There is interest in the use of recent single-cell spatial transcriptomic technologies to gain biological insights into disease mechanisms. Previously, we characterized the use of herpes simplex virus 1 (HSV-1) induced neuroinflammation in 2D dissociated cells from human cerebral organoids (dcOrgs) to model molecular and transcriptomic readouts associated with Alzheimers disease (AD). In this work, we generated two datasets by using single-cell non-spatial RNA sequencing and single-cell spatial RNA sequencing technologies on HSV-1-infected 2D dcOrgs and HSV-1-infected 3D cerebral organoids (cOrgs). We conducted cell type assignment for the cells in the 2D dcOrgs and 3D cOrgs, by using single-cell non-spatial RNA sequence data from human fetal brains and adult post-mortem brains, to infer the transcriptomic effects of AD-associated in-vitro perturbations through viral infections linked to AD. We evaluated computational and machine learning methods, including the use of multi-layer perceptrons (MLPs), and we used cross-2D\/3D platform comparisons as a benchmark to evaluate the artificial neural network models. In the process, we found that the use of MLPs can lead to high validation rates for assigning cell type identities from 2D and 3D human cerebral organoids to cell types found in human adult post-mortem brain samples. Furthermore, the use of these technologies and systems enabled the identification of pseudotime trajectories and cell clusters associated with the viral transcriptional life cycle. We identified several cell types, including endothelial cells and astrocytes, with significantly more clustered cell-cell nearest neighbor distances in infected 3D cOrgs compared to mock 3D cOrgs. Permutation tests revealed that these differences in nearest neighbor distances are unlikely to be driven by overall structural differences between individual infected 3D cOrgs and mock 3D cOrgs, such as differences in the density of cells. Given that there are more large-scale single-cell non-spatial (2D) RNA sequence datasets that had been generated from human post-mortem brain samples, compared to single-cell spatial (3D) RNA sequence datasets from human post-mortem brain samples, the development of data integration approaches by using artificial neural networks such as MLPs, across 2D and 3D single-cell transcriptomics datasets generated from human post-mortem brain samples and human in-vitro systems such as brain organoids is likely to be critical to gain novel insights into neurodegenerative diseases such as AD.","rel_num_authors":4,"rel_authors":[{"author_name":"Anusha D Doddi","author_inst":"UMass Chan Medical School"},{"author_name":"Pepper Dawes","author_inst":"UMass Chan Medical School"},{"author_name":"Yingleong Chan","author_inst":"UMass Chan Medical School"},{"author_name":"Elaine T Lim","author_inst":"UMass Chan Medical School"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Integration of zebrafish pineal transcriptomes reveals cell type-specific timing","rel_doi":"10.64898\/2026.06.07.728976","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.728976","rel_abs":"The teleost pineal gland is an eye-like photoreceptive organ with a central role in the circadian clock system, primarily through its melatonin-producing photoreceptor cells. However, the functional molecular interactions between pineal photoreceptors, accessory cells predicted to support photoreceptor function, and projecting neurons remain incompletely understood. Here, we integrated single-cell zebrafish pineal transcriptomes with bulk circadian and light-response pineal transcriptomes. Combined analysis of two single-cell datasets identified novel photoreceptor and neuronal subtypes, including parietopsin-expressing cone-like cells and neurons expressing markers of neuronal maturation. Integration with the light-response dataset revealed light inhibition of photoreceptor opsin genes. Integration with circadian transcriptomes from wildtype fish and fish expressing the clock-disrupting dominant-negative CLOCK ({Delta}CLK) in pineal photoreceptors revealed cell-type-specific rhythmicity. Despite comparable expression of {Delta}CLK, photoreceptor subtypes differed in sensitivity to rhythm disruption, with rod-like cells (rods) most severely affected. In neurons, despite the absence of {Delta}CLK expression, rhythm disruption was comparable to that of rods. Moreover, rhythmic neuronal markers and rhythmic photoreceptor markers exhibited a similar circadian pattern, peaking mainly during the early night. These observations suggest that clock function in neurons depend on photoreceptor output. In contrast, accessory cell rhythmic markers were relatively resistant to {Delta}CLK disruption and peaked predominantly around subjective dawn, consistent with partially autonomous clock function. To facilitate comparative analysis of gene expression, rhythmicity and light responsiveness across pineal cell types, we developed the Zebrafish Pineal Transcriptomics Viewer. Our findings reveal a temporally structured and functionally heterogeneous organization of the zebrafish pineal gland.","rel_num_authors":4,"rel_authors":[{"author_name":"Yair Wexler","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Dengfeng Huang","author_inst":"Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China"},{"author_name":"Jun Yan","author_inst":"Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China"},{"author_name":"Yoav Gothilf","author_inst":"Tel Aviv University, Tel Aviv, Israel"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Continuous Strategy Adaptation and Discrete Switching Driven by Environment and Internal State in Meta-Learning","rel_doi":"10.64898\/2026.06.08.729424","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.729424","rel_abs":"Behavioral strategies can change in response to environmental and internal states, either gradually or abruptly, enabling flexible adaptation. Such strategy regulation is central to meta-learning, the ability to learn to learn. Previous studies analyzed temporal or condition-dependent strategy change using models and theories that assume continuous or discrete changes. Here, we analyze the mice's behavior in a two-step decision task using four different approaches: stay-switch choice probability analysis; generalized linear mixed model (GLMM) of choice and reaction time (RT) given preceding task events; fitting a reinforcement learning (RL) model with time-varying meta-parameter by a novel multiple-step particle filtering method; and fitting a finite internal state (FIS) model that produces choice and RT depending on discrete state transition. Together, the stay probability and GLMM analyses reveal that learning progress encourages a shift toward a model-based, value-based learning strategy, accompanied by elevated choice perseveration. More uncertain reward settings or changes in them lead to random, exploratory behavior. Meta-parameter dynamics show faster learning, greater involvement of a model-based strategy, higher choice stochasticity, and more rapid development of choice perseveration with less contribution to the final decision as learning progresses. Exploratory behavior in the face of uncertain reward settings or changes in those settings is underpinned by slower forgetting and greater model-based contribution. FIS modeling discovered a trial-level switch between an optimal value-based learning state and a suboptimal self-repeating state. Meta-parameter dynamics reflect continuous strategy changes, while state transitions capture abrupt, discrete strategy switches. At an intermediate timescale, when reward settings change, two processes interact: mice persist in a self-repeating state, leading to attempts at model-based strategy with incomplete adaptation.","rel_num_authors":3,"rel_authors":[{"author_name":"Jianning Chen","author_inst":"Okinawa Institute of Science and Technology"},{"author_name":"Masakazu Taira","author_inst":"The University of Sydney"},{"author_name":"Kenji Doya","author_inst":"Okinawa Institute of Science and Technology"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Conserved role of EGFR signaling in apoptotic cell recognition and processing across different phagocytes","rel_doi":"10.64898\/2026.06.10.731277","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731277","rel_abs":"Efferocytosis is an essential process that clears dying cells from tissues and prevents inflammation. However, the mechanisms by which apoptotic cells recruit and activate phagocytes remain poorly understood. Here, we show that EGFR signaling is both necessary and sufficient for efficient efferocytosis in two diverse phagocytes: the gonadal sheath cells of C. elegans and the zebrafish microglia. In C. elegans, loss of LET 23 EGFR or its downstream effector MPK 1 ERK in the sheath cells impairs the recognition and degradation of apoptotic germ cells. Germ cells undergoing apoptosis secrete the EGF ligand LIN 3, which promotes their recognition and engulfment. Overexpression of EGF in non apoptotic germ cells is sufficient to trigger their engulfment, indicating that EGF can function as an engulfment signal independently of apoptotic cell death. In zebrafish larvae, pharmacological inhibition of EGFR signaling reduces microglial motility, recognition of apoptotic neurons, and corpse clearance in the optic tectum. Similar to C. elegans, an ectopic source of EGF serves as an attractive cue that promotes microglial recruitment. Our findings suggest that EGFR signaling controls an evolutionarily conserved efferocytosis module that coordinates the recognition and processing of apoptotic corpses in different types of phagocytes.","rel_num_authors":7,"rel_authors":[{"author_name":"Laura Filomena Comi","author_inst":"University of Zurich"},{"author_name":"Simon Berger","author_inst":"University of Zurich"},{"author_name":"Ambra Villani","author_inst":"University of  Zurich"},{"author_name":"Michael Daube","author_inst":"University of Zurich"},{"author_name":"Francesca Peri","author_inst":"University of  Zurich"},{"author_name":"Alex Hajnal","author_inst":"University of Zurich"},{"author_name":"Silvan Spiri","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A Fully Endovascular Neural Interface","rel_doi":"10.64898\/2026.06.07.730604","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730604","rel_abs":"Electrical stimulation of neural circuits is expanding therapeutic strategies to modulate brain, autonomic, and immune functions. Devices delivered endovascularly offer a less invasive alternative to conventional implanted electrodes, while delivering spatio-temporal specificity superior to noninvasive techniques. We demonstrate a fully endovascular sub-1-mm3 implant, utilizing ultrasound for wireless power delivery and data telemetry in a fashion invariant to device orientation. The implant consists of piezoelectric transducers, an energy storage capacitor, an application-specific integrated circuit, and electrodes packaged on a 7-um-thick polyimide scaffold. The implant can be delivered through a microcatheter in a manner analogous to conventional neurovascular stents, and self-expands upon deployment to appose the vessel walls. We demonstrate intravascular stimulation of the autonomic nervous system from the carotid artery, achieving modulation of blood pressure in rabbits. This approach establishes a broadly applicable platform for neural interfaces enabling both stimulation and recording.","rel_num_authors":13,"rel_authors":[{"author_name":"John Stanton","author_inst":"Columbia University"},{"author_name":"Giovanni Talei Franzesi","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Eleonora Spinazzi","author_inst":"Columbia University"},{"author_name":"Jennifer Haupt","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Darren Orbach","author_inst":"Boston Children's Hospital"},{"author_name":"Jonathan Sisti","author_inst":"Columbia University"},{"author_name":"Morgan Jamiel","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Emily Zhang","author_inst":"Columbia University"},{"author_name":"Sean Lavine","author_inst":"Columbia University"},{"author_name":"E. Sander Connolly","author_inst":"Columbia University"},{"author_name":"Elisa Konofagou","author_inst":"ek2191@columbia.edu"},{"author_name":"Ed Boyden","author_inst":"MIT, HHMI"},{"author_name":"Kenneth Shepard","author_inst":"Columbia University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Dietary fructose promotes MASH\/HCC progression through enhanced intestinal HIF-2\u03b1-dependent iron absorption","rel_doi":"10.64898\/2026.06.07.729655","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.729655","rel_abs":"Dietary fructose is a major risk factor driving the progression of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, the underlying fructose-induced nutrient-sensing pathway remains unclear. Here, we report that fructose facilitates iron absorption through the (Ketohexokinase) KHK\/PKM2\/HIF-2 axis, driving MASH and HCC development. Fructose aberrantly stabilizes intestinal HIF-; this effect is abrogated by a KHK inhibitor and genetic Khk deletion. Mechanistically, fructose-induced metabolic reprogramming drives glutamine-dependent oxidative phosphorylation, leading to HIF- stabilization, which is mediated by pyruvate kinase M2 (PKM2). A selective PKM2 inhibitor rescues reduced intestinal HIF- stability in Khk-deficient mice. Furthermore, dietary fructose increases plasma iron levels. Conversely, Khk-deficient mice exhibit spontaneous systemic iron deficiency, characterized by hypochromic anemia. Moreover, Khk deficiency inhibits iron absorption in a HIF-2-dependent manner. Finally, fructose promotes MASH and HCC progression in an iron-dependent manner. This study reveals a unique, therapeutically targetable nutrient-sensing pathway utilized by dietary fructose.","rel_num_authors":7,"rel_authors":[{"author_name":"Robert A. Mitchell","author_inst":"University of Louisville"},{"author_name":"Manman Xu","author_inst":"University of Louisville"},{"author_name":"Elizabeth Hudson","author_inst":"University of Louisville"},{"author_name":"Madison S. Teer","author_inst":"University of Louisville"},{"author_name":"Bradford G. Hill","author_inst":"University of Louisville"},{"author_name":"Craig J. McClain","author_inst":"University of Louisville"},{"author_name":"Ming Song","author_inst":"University of Louisville"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Galectin-3 is Necessary for Selective Cathartocytosis, which Expedites the Development of Proliferative Gastric SPEM","rel_doi":"10.64898\/2026.06.07.729580","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.729580","rel_abs":"The expression and secretion of sulfated colonic-type mucins is a feature of high-risk metaplasias of the gastrointestinal foregut (Barrett's esophagus, type III intestinal metaplasia of the stomach, and pancreatic intraepithelial neoplasia). Galectin-3 is a lectin that preferentially associates with galactose modified by a 3'-O-sulfate relative to its unmodified counterparts and is upregulated as the tissue transitions to high-risk metaplasia, dysplasia, and cancer. Since both galectin-3 and sulfated glycotopes are aberrantly and concurrently overexpressed in high-risk premalignant and malignant tissue transformations, we sought to investigate the role of galectin-3 in the metaplastic reaction. We found that injury induces the expression of Lgals3 at the RNA and protein levels. Unlike cancer cell lines, we show that in vivo galectin-3 colocalized with sulfomucins in zymogenic granules of the gastric chief cell. Utilizing a synchronous, chemically-induced murine model that produces spasmolytic polypeptide expressing metaplasia, we found that galectin-3 facilitates cathartocytosis of the vesicles it resides in, but not organelles lacking LGALS3. Inhibition of cellular downscaling resulted in delayed expression of the metaplastic transcription factor Sox9 as well as proliferation. Here, we present a new role for galectin-3 in promoting the transition from normal, homeostatic tissue to metaplasia and our data suggest that cathartocytosis represents an unconventional secretory pathway for galectin-3, which has been a matter of controversy as galectins are not secreted via canonical pathways.","rel_num_authors":6,"rel_authors":[{"author_name":"Xiaobo Lin","author_inst":"Washington University School of Medicine"},{"author_name":"Xuemei Liu","author_inst":"Washington University School of Medicine"},{"author_name":"Gabriel Nicolazzi","author_inst":"Washington University School of Medicine"},{"author_name":"Annie Pan","author_inst":"Washington University School of Medicine"},{"author_name":"Margaret Hua","author_inst":"Washington University School of Medicine"},{"author_name":"Jeffrey Wade Brown","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Dengue virus infection in Aedes aegypti mosquito brains elicits minimal transcriptional response","rel_doi":"10.64898\/2026.06.10.731349","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731349","rel_abs":"Billions of people each year are at risk from infection by dengue, Zika, yellow fever, and chikungunya viruses, which are transmitted by female Aedes aegypti mosquitoes. Mosquitoes themselves are infected by these arboviruses, but how the mosquito nervous system responds to arboviral infection is unknown. We combined whole-mount immunofluorescence with single-head bulk RNA-sequencing to characterize dengue virus (DENV) infection in the brain of Aedes aegypti. DENV productively infects brain cells in a bimodal pattern: individual brains showed either sparse or widespread infection, with no intermediate phenotypes. An infectious blood meal altered thousands of genes, including 64 immunity genes, at 7 days post-feeding (DPF), yet active viral replication in the head did not increase the transcriptional response. Heads with and without detectable DENV showed minimal transcriptional differences, with no induction of canonical immune effectors. Despite productive infection, the mosquito brain tolerates DENV replication with minimal transcriptional response.","rel_num_authors":8,"rel_authors":[{"author_name":"Umberto Palatini","author_inst":"The Rockefeller University"},{"author_name":"St\u00e9phanie Dabo","author_inst":"Institut Pasteur"},{"author_name":"Adriana Rosas-Villegas","author_inst":"The Rockefeller University"},{"author_name":"Yael N. Tsitohay","author_inst":"The Rockefeller university"},{"author_name":"Alexandra E. DeFoe","author_inst":"The Rockefeller University"},{"author_name":"Nadav Shai","author_inst":"The Rockefeller University: Howard Hughes Medical Institute"},{"author_name":"Louis Lambrechts","author_inst":"Institut Pasteur"},{"author_name":"Leslie B. Vosshall","author_inst":"The Rockefeller University; Howard Hughes Medical Institute"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Galectin-8 Modulates Membrane CD44v Localization and Tempers STAT3 Signaling in Gastric Metaplasia","rel_doi":"10.64898\/2026.06.07.729556","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.729556","rel_abs":"Galectin-8 is lectin that binds N-acetyllactosamine moieties with preference towards those with acidic, terminal modifications (3'-O-sialyated, 3'-O-sulfated). As CD44-variants (CD44v) are biomarkers of metaplasia and cancer, a hyaluronic acid receptor that modulates STAT3 signaling, and specifically express 3'-Sialyl-LeA\/X glycotopes, we asked whether galectin-8 play a role in gastric metaplasia. Using a synchronous, chemically induced murine model that produces gastric spasmolytic polypeptide expressing metaplasia (SPEM), we compared Lgals8-\/- mice to congenic wild-type C57BL\/6J mice. We found that galectin-8 was necessary for membrane localization of CD44v on SPEM cells at the base of the glands, suggesting a physical interaction between galectin-8 and CD44v. Metaplastic glands from Lgals8-\/- mice had an increase in nuclear pSTAT3 compared to C57BL\/6J mice, suggesting that galectin-8 restrains CD44 -> STAT3 signaling. These data may explain why low galectin-8 levels is associated with a worse prognosis in gastric cancer.","rel_num_authors":5,"rel_authors":[{"author_name":"Xiaobo Lin","author_inst":"Washington University School of Medicine"},{"author_name":"Xuemei Liu","author_inst":"Washington University School of Medicine"},{"author_name":"Gabriel Nicolazzi","author_inst":"Washington University School of Medicine"},{"author_name":"Yehiel Zick","author_inst":"Weizmann Institute of Science"},{"author_name":"Jeffrey Wade Brown","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Galectin-8 Modulates Membrane CD44v Localization and Tempers STAT3 Signaling in Gastric Metaplasia","rel_doi":"10.64898\/2026.06.07.729556","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.729556","rel_abs":"Galectin-8 is lectin that binds N-acetyllactosamine moieties with preference towards those with acidic, terminal modifications (3'-O-sialyated, 3'-O-sulfated). As CD44-variants (CD44v) are biomarkers of metaplasia and cancer, a hyaluronic acid receptor that modulates STAT3 signaling, and specifically express 3'-Sialyl-LeA\/X glycotopes, we asked whether galectin-8 play a role in gastric metaplasia. Using a synchronous, chemically induced murine model that produces gastric spasmolytic polypeptide expressing metaplasia (SPEM), we compared Lgals8-\/- mice to congenic wild-type C57BL\/6J mice. We found that galectin-8 was necessary for membrane localization of CD44v on SPEM cells at the base of the glands, suggesting a physical interaction between galectin-8 and CD44v. Metaplastic glands from Lgals8-\/- mice had an increase in nuclear pSTAT3 compared to C57BL\/6J mice, suggesting that galectin-8 restrains CD44 -> STAT3 signaling. These data may explain why low galectin-8 levels is associated with a worse prognosis in gastric cancer.","rel_num_authors":5,"rel_authors":[{"author_name":"Xiaobo Lin","author_inst":"Washington University School of Medicine"},{"author_name":"Xuemei Liu","author_inst":"Washington University School of Medicine"},{"author_name":"Gabriel Nicolazzi","author_inst":"Washington University School of Medicine"},{"author_name":"Yehiel Zick","author_inst":"Weizmann Institute of Science"},{"author_name":"Jeffrey Wade Brown","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery","rel_doi":"10.64898\/2026.06.07.730716","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730716","rel_abs":"Commercially available make-on-demand libraries now exceed 100 billion compounds, requiring over 50 years to screen on 2,000 CPU cores using conventional docking. We present two complementary approaches to address this challenge. CombiDOCK, a combinatorial docking framework, enables exhaustive screening at the 100-billion scale within 40 days. MINT-Dock, a generative framework, accelerates navigation of this space by integrating CombiDOCK with Monte Carlo Tree Search. Benchmarked on 46 diverse targets, CombiDOCK matched full-molecule docking accuracy, and MINT-Dock achieved a 4,800-fold enrichment over random selection. Compared with prior billion-scale brute-force campaigns against {sigma}2, VMAT2, and VAChT, prospective CombiDOCK screens of the 100-billion-molecule library yielded higher hit rates and more potent ligands, while MINT-Dock achieved comparable outcomes across single- and multi-target objectives with >20-fold computational cost reductions. Docking-predicted poses of the best VAChT-binding compounds were confirmed by cryo-EM structures. These methods provide exhaustive and generative paths for navigating the trillion-molecule frontier of drug discovery.","rel_num_authors":14,"rel_authors":[{"author_name":"Jianxiang Zhang","author_inst":"The Rockefeller University"},{"author_name":"Chao Yang","author_inst":"The Rockefeller University"},{"author_name":"Yang Zhang","author_inst":"Peking University"},{"author_name":"Xiao Chen","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Brandon Lam","author_inst":"The Rockefeller University"},{"author_name":"Claire Bryant","author_inst":"Yale School of Medicine"},{"author_name":"Shabareesh Pidathala","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Yangzhi Wang","author_inst":"The Rockefeller University; Tri-Institutional PhD Program in Computational Biology and Medicine"},{"author_name":"Yurii Moroz","author_inst":"Enamine Ltd (www.enamine.net); Taras Shevchenko National University of Kyiv; Chemspace LLC (www.chem-space.com)"},{"author_name":"Dmytro Radchenko","author_inst":"Enamine Ltd (www.enamine.net)"},{"author_name":"Assaf Alon","author_inst":"Yale School of Medicine"},{"author_name":"Chia-Hsueh Lee","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Zhe Zhang","author_inst":"Peking University"},{"author_name":"Jiankun Lyu","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery","rel_doi":"10.64898\/2026.06.07.730716","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730716","rel_abs":"Commercially available make-on-demand libraries now exceed 100 billion compounds, requiring over 50 years to screen on 2,000 CPU cores using conventional docking. We present two complementary approaches to address this challenge. CombiDOCK, a combinatorial docking framework, enables exhaustive screening at the 100-billion scale within 40 days. MINT-Dock, a generative framework, accelerates navigation of this space by integrating CombiDOCK with Monte Carlo Tree Search. Benchmarked on 46 diverse targets, CombiDOCK matched full-molecule docking accuracy, and MINT-Dock achieved a 4,800-fold enrichment over random selection. Compared with prior billion-scale brute-force campaigns against {sigma}2, VMAT2, and VAChT, prospective CombiDOCK screens of the 100-billion-molecule library yielded higher hit rates and more potent ligands, while MINT-Dock achieved comparable outcomes across single- and multi-target objectives with >20-fold computational cost reductions. Docking-predicted poses of the best VAChT-binding compounds were confirmed by cryo-EM structures. These methods provide exhaustive and generative paths for navigating the trillion-molecule frontier of drug discovery.","rel_num_authors":14,"rel_authors":[{"author_name":"Jianxiang Zhang","author_inst":"The Rockefeller University"},{"author_name":"Chao Yang","author_inst":"The Rockefeller University"},{"author_name":"Yang Zhang","author_inst":"Peking University"},{"author_name":"Xiao Chen","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Brandon Lam","author_inst":"The Rockefeller University"},{"author_name":"Claire Bryant","author_inst":"Yale School of Medicine"},{"author_name":"Shabareesh Pidathala","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Yangzhi Wang","author_inst":"The Rockefeller University; Tri-Institutional PhD Program in Computational Biology and Medicine"},{"author_name":"Yurii Moroz","author_inst":"Enamine Ltd (www.enamine.net); Taras Shevchenko National University of Kyiv; Chemspace LLC (www.chem-space.com)"},{"author_name":"Dmytro Radchenko","author_inst":"Enamine Ltd (www.enamine.net)"},{"author_name":"Assaf Alon","author_inst":"Yale School of Medicine"},{"author_name":"Chia-Hsueh Lee","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Zhe Zhang","author_inst":"Peking University"},{"author_name":"Jiankun Lyu","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery","rel_doi":"10.64898\/2026.06.07.730716","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730716","rel_abs":"Commercially available make-on-demand libraries now exceed 100 billion compounds, requiring over 50 years to screen on 2,000 CPU cores using conventional docking. We present two complementary approaches to address this challenge. CombiDOCK, a combinatorial docking framework, enables exhaustive screening at the 100-billion scale within 40 days. MINT-Dock, a generative framework, accelerates navigation of this space by integrating CombiDOCK with Monte Carlo Tree Search. Benchmarked on 46 diverse targets, CombiDOCK matched full-molecule docking accuracy, and MINT-Dock achieved a 4,800-fold enrichment over random selection. Compared with prior billion-scale brute-force campaigns against {sigma}2, VMAT2, and VAChT, prospective CombiDOCK screens of the 100-billion-molecule library yielded higher hit rates and more potent ligands, while MINT-Dock achieved comparable outcomes across single- and multi-target objectives with >20-fold computational cost reductions. Docking-predicted poses of the best VAChT-binding compounds were confirmed by cryo-EM structures. These methods provide exhaustive and generative paths for navigating the trillion-molecule frontier of drug discovery.","rel_num_authors":14,"rel_authors":[{"author_name":"Jianxiang Zhang","author_inst":"The Rockefeller University"},{"author_name":"Chao Yang","author_inst":"The Rockefeller University"},{"author_name":"Yang Zhang","author_inst":"Peking University"},{"author_name":"Xiao Chen","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Brandon Lam","author_inst":"The Rockefeller University"},{"author_name":"Claire Bryant","author_inst":"Yale School of Medicine"},{"author_name":"Shabareesh Pidathala","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Yangzhi Wang","author_inst":"The Rockefeller University; Tri-Institutional PhD Program in Computational Biology and Medicine"},{"author_name":"Yurii Moroz","author_inst":"Enamine Ltd (www.enamine.net); Taras Shevchenko National University of Kyiv; Chemspace LLC (www.chem-space.com)"},{"author_name":"Dmytro Radchenko","author_inst":"Enamine Ltd (www.enamine.net)"},{"author_name":"Assaf Alon","author_inst":"Yale School of Medicine"},{"author_name":"Chia-Hsueh Lee","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Zhe Zhang","author_inst":"Peking University"},{"author_name":"Jiankun Lyu","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"An allelic series reveals the genetic requirement for Adnp in cortical neurogenesis and learning behavior","rel_doi":"10.64898\/2026.06.10.731333","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731333","rel_abs":"Transcriptional regulators and chromatin remodellers are among the most important risk gene categories across the genetic landscape of neurodevelopmental disorders (NDDs). The zinc finger and homeodomain transcription factor ADNP is prominently associated with Helsmoortel-Van der Aa Syndrome (HVDAS), which is characterized by intellectual disability and autism spectrum disorder. Heterozygous frameshifting mutations account for the majority of HVDAS mutations, but it remains unclear how HVDAS mutations affect ADNP dosage, and how dosage in turn relates to neurodevelopmental and behavioral phenotypes. Here, we compared an allelic series of Adnp conditional knockouts and germline heterozygotes. Using a conditional allele, we first deleted Adnp throughout the neural tube using Nestin-Cre. At E15.5, cKO brains exhibited altered upper-layer neuron production. However, AdnpNestin cKOs exhibited perinatal lethality, precluding further behavioral characterization. Next, we compared germline heterozygotes (gHets) versus cKOs generated using the Emx1-Cre driver. We found that AdnpDel\/+ and AdnpL822fs6\/+ gHets exhibited cortical hypoplasia that was quantitatively identical, albeit less severe in comparison to AdnpEmx cKOs. In behavioral testing, AdnpEmx cKOs accordingly exhibited the strongest phenotypes, including hallmarks of elevated anxiety. However, both AdnpEmx cKOs and AdnpL822fs6\/+ gHets exhibited remarkably similar sex-specific deficits in learning during Morris Water Maze testing. Taken together, our work suggests that cortical growth and learning represent core phenotypes shared across Adnp mutant models irrespective of dosage. Moreover, since Adnp mutant phenotypes closely correspond with our prior findings in Chd4 mutants, our results collectively suggest that Adnp regulates behavior via the ChAHP chromatin remodelling complex.","rel_num_authors":5,"rel_authors":[{"author_name":"Sarah Larrigan","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Lina Dizon-Mapula","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Iris Lasker","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"David Picketts","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Pierre Mattar","author_inst":"Ottawa Hospital Research Institute"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Tuft dendrite spikes are accompanied by selective input from distinct functional networks","rel_doi":"10.64898\/2026.06.10.731464","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731464","rel_abs":"The tuft dendrites of layer 5 neurons can support regenerative events - dendritic spikes - that have been proposed to coordinate context-specific engagement and plasticity within cortical networks. However, it remains unclear whether tuft spikes are accompanied by input activity with dynamics that could support these network-level functions. To address this, glutamatergic synapses and postsynaptic calcium signals were simultaneously imaged in the tuft dendrites of layer 5 extratelencephalic neurons within the premotor cortex of mice performing a cued directional licking task. Trial-to-trial, the generation of tuft spikes was associated with a multiphasic elevation in synaptic activity spanning hundreds of milliseconds. This activity was highly specific to the dendrite in which a spike was detected, suggesting the concurrent activation of select subnetworks. Synapses that were strongly coupled to the overall population were the most synchronized with tuft spikes and preferentially encoded the transition between the preparation and action epochs of the task. Even among these strongly coupled synapses, increases in activity were largely specific to synapses located on the spiking dendrite. Surprisingly, among synapses with the poorest population coupling, a second population of coactive synapses was discovered that was also associated with tuft spikes and functionally selective for task-outcome. These results suggest that tuft spikes may be particularly driven by inputs from neurons that are both embedded in sparse subnetworks and synchronized through coupling to larger-scale functional networks.","rel_num_authors":7,"rel_authors":[{"author_name":"Jacob Gable","author_inst":"University of Minnesota"},{"author_name":"Zachary L Newman","author_inst":"University of Minnesota"},{"author_name":"Sarah Young","author_inst":"University of Minnesota"},{"author_name":"Jackson Scheib","author_inst":"University of Minnesota"},{"author_name":"Savannah Bliese","author_inst":"University of Minnesota"},{"author_name":"Nicole Miller","author_inst":"University of Minnesota"},{"author_name":"Aaron Kerlin","author_inst":"University of Minnesota"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Cortical Excitation-Inhibition Balance in Autism Varies by Brain Region and Age","rel_doi":"10.64898\/2026.06.10.731403","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731403","rel_abs":"Autism spectrum disorder (ASD) is characterized by differences in social communication and interaction, alongside restricted and repetitive behaviors. The hypothesis that ASD is associated with an altered cortical excitation-inhibition (EI) balance has been the subject of extensive investigations, yet the evidence supporting it remains mixed. A key challenge in testing this hypothesis is that the EI balance also changes substantially during typical maturation, from childhood through adolescence and into early adulthood. We used resting-state magnetoencephalography (MEG) recordings to examine the developmental trajectory of cortical EI alterations, with regional specificity, in a large cross-sectional cohort (N = 172), comprised of 92 typically developing (TD) individuals and 80 individuals diagnosed with ASD, spanning ages 6-32. To that end, functional EI (fEI), derived from critical brain dynamics, was estimated across 500 cortical parcellations in cortical space. Group-averaged fEI maps revealed broadly similar large-scale topographic patterns in the TD and ASD groups when averaged across all ages. When divided by age into childhood (6-12 years, N ASD = 18, N TD = 16), adolescence (13-18 years, N ASD = 27, N TD = 41) and adulthood (19-32 years, N ASD = 28, N TD = 26), we found an overall pattern of increased global fEI in childhood and decreased fEI in adolescence in the ASD group, with no evidence of a difference between groups in fEI in adulthood. Additional parcel-wise regression analyses identified a significant main effect of diagnostic group, independent of age, in the right dorsolateral prefrontal cortex, where TD individuals showed higher fEI than those with ASD across all ages. Furthermore, a significant group-by-age interaction was observed in the left inferior parietal cortex, where we found evidence that fEI increased with age in TD individuals (beta = 0.012, p = 0.006) but no evidence of a similar age-dependent increase in those with ASD (beta = 0.001, p = 0.84), indicating diverging developmental trajectories. Finally, fEI in paracentral and precuneus cortical regions was associated with ASD symptom severity. Together, these findings support a scenario in which EI imbalance, as assessed with fEI, is not globally distributed in ASD, and is not static through development, but is instead expressed through regionally and developmentally specific differences, with implications for understanding the neural substrates of ASD phenotypic heterogeneity.","rel_num_authors":17,"rel_authors":[{"author_name":"Sergio Osorio","author_inst":"Massachusetts General Hospital"},{"author_name":"Jasmine Tan","author_inst":"Massachusetts General Hospital"},{"author_name":"Sheraz Khan","author_inst":"Massachusetts General Hospital"},{"author_name":"Seppo P Ahlfors","author_inst":"Massachusetts General Hospital"},{"author_name":"Fahimeh Mamashli","author_inst":"Massachusetts General Hospital"},{"author_name":"Jussi Alho","author_inst":"Massachusetts General Hospital"},{"author_name":"Robert M Joseph","author_inst":"Boston University"},{"author_name":"Grace Levine","author_inst":"Massachusetts General Hospital"},{"author_name":"Steven Graham","author_inst":"Massachusetts General Hospital"},{"author_name":"Gagan Joshi","author_inst":"Massachusetts General Hospital"},{"author_name":"Zein Nayal","author_inst":"Massachusetts General Hospital"},{"author_name":"Nicole M McGuiggan","author_inst":"Massachusetts General Hospital"},{"author_name":"Ainsley Losh","author_inst":"Massachusetts General Hospital"},{"author_name":"Stephanie Pawlyszyn","author_inst":"Massachusetts General Hospital"},{"author_name":"Nathaniel Mercaldo","author_inst":"Massachusetts General Hospital"},{"author_name":"Matti S Hamalainen","author_inst":"Massachusetts General Hospital"},{"author_name":"Tal Kenet","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A Two-Dimensional Grid-Cell Code for Three-Dimensional Navigation in Freely Flying Bats","rel_doi":"10.64898\/2026.06.10.728358","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.728358","rel_abs":"Animals have evolved to navigate environments with diverse geometries and dimensionalities, yet how neural circuits for spatial navigation support behavior across such varied demands remains unresolved. In two-dimensional environments, grid cells in the medial entorhinal cortex provide a periodic signal for self-location that is thought to arise from underlying toroidal attractor dynamics at the ensemble level. However, during movement in three-dimensional environments, studies have reported a loss of global grid-cell periodicity. Furthermore, it remains unknown whether, at the ensemble level, a toroidal attractor is preserved across species and, if so, how such a two-dimensional code could support navigation in three-dimensional space. Here we performed large-scale, wireless neural recordings from the medial entorhinal cortex of freely flying bats engaged in spontaneous aerial foraging. We find that grid cells exhibit robust periodic firing during structured flight trajectories, and that co-modular grid-cell ensembles show topological signatures consistent with a two-dimensional toroidal manifold. Behavioral analyses of bats navigating in the wild and in the laboratory revealed that individual flight paths are organized along two-dimensional planes of motion, providing a natural substrate for a two-dimensional code. Accordingly, toroidal phase along flights was consistent with plane-wave patterns on the plane of motion, and single-cell firing was well described by a hexagonal lattice on the same plane. Together, these findings reveal a parsimonious solution whereby a two-dimensional neural code aligns with behaviorally relevant subspaces to support navigation in a three-dimensional world.","rel_num_authors":2,"rel_authors":[{"author_name":"Kevin K Qi","author_inst":"UC Berkeley"},{"author_name":"Michael M Yartsev","author_inst":"UC Berkeley"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Functional brain organization is stable within individuals across years","rel_doi":"10.64898\/2026.06.10.731401","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731401","rel_abs":"Brain regions exhibit dynamic yet highly coordinated activity patterns that form large-scale functional networks measurable through resting-state correlations. While their association with fluctuating activity may intuitively suggest functional networks to be temporally transient and dependent on state, a growing body of literature suggests that they are person-specific and stable across days. If truly person-specific, then functional networks should preserve unique characteristics over extended periods. To test this hypothesis, we collected longitudinal precision fMRI data ([&ge;]60 minutes per participant per time point) from 10 healthy young adults across 1-3 year intervals, as well as three adults over 8-13 years. We further replicated findings in the MyConnectome dataset and its 10-year follow-up. Functional network organization--when sufficient per-participant data were collected-- remained largely stable within individuals over prolonged periods of up to 13 years, suggesting that individualized brain organization constitutes persistent features of personal identity that may be supported by homeostatic mechanisms.","rel_num_authors":17,"rel_authors":[{"author_name":"Hyejin J. Lee","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Ally Dworetsky","author_inst":"Washington University School of Medicine"},{"author_name":"Alexis Porter","author_inst":"Northwestern University"},{"author_name":"Sihan Fei","author_inst":"Northwestern University"},{"author_name":"Ashley N. Nielsen","author_inst":"Washington University School of Medicine"},{"author_name":"Benjamin A. Seitzman","author_inst":"Washington University School of Medicine"},{"author_name":"Babatunde Adeyemo","author_inst":"Washington University School of Medicine"},{"author_name":"Patrick G. Bissett","author_inst":"Stanford University"},{"author_name":"Russell A. Poldrack","author_inst":"Stanford University"},{"author_name":"Jessica R. Cohen","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mark D'Esposito","author_inst":"University of California Berkeley"},{"author_name":"Maital Neta","author_inst":"University of Nebraska-Lincoln"},{"author_name":"Nico U.F. Dosenbach","author_inst":"Washington University School of Medicine"},{"author_name":"Steven E. Petersen","author_inst":"Washington University School of Medicine"},{"author_name":"Evan M. Gordon","author_inst":"Washington University School of Medicine"},{"author_name":"Deanna J. Greene","author_inst":"University of California San Diego"},{"author_name":"Caterina Gratton","author_inst":"University of Illinois Urbana-Champaign"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Posterior Periodic Alpha Power as a Neural Marker of Early Biliteracy Skills: The Mediating Role of Rapid Automatized Naming in Chinese-English Bilingual Children","rel_doi":"10.64898\/2026.06.10.731265","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731265","rel_abs":"In school-aged children, resting-state posterior alpha activity has been linked to thalamocortical signal coordination and literacy-related cognition. However, findings are mixed, partly because conventional band power measures conflate oscillatory (periodic) activity with the broadband aperiodic (1\/f) background. We tested Chinese-English bilingual children in Grades 1 to 5 (N = 121; 72 families; mean age = 8.23 years, SD = 0.81) to examine if posterior periodic alpha power (8-12 Hz), isolated from aperiodic components, predicts foundational biliteracy skills (Chinese and English word reading and dictation). We also tested whether Chinese digit rapid automatized naming (CDRAN) mediates these associations. In regression models that accounted for family clustering and controlled for age, socioeconomic status (SES), and aperiodic components (exponent and offset), higher periodic alpha power uniquely predicted better performance on all four literacy outcomes. In structural equation models that accounted for family clustering, periodic alpha power predicted CDRAN ({beta} = .213, p = .011), and CDRAN significantly predicted Chinese word reading ({beta} = .442, p < .001), Chinese dictation ({beta} = .346, p = .003), English word reading ({beta} = .302, p < .001), and English dictation ({beta} = .349, p < .001). Indirect effects via CDRAN were significant for all outcomes. These findings suggest that aperiodic-adjusted periodic alpha power is associated with biliteracy variation across Chinese and English and that its association with biliteracy operates in part through rapid serial naming efficiency.","rel_num_authors":5,"rel_authors":[{"author_name":"Tak Kwan Lam","author_inst":"the Chinese University of Hong Kong"},{"author_name":"Shuting Huo","author_inst":"CUHK"},{"author_name":"Fai Hong, Kelvin Lui","author_inst":"Lingnan University"},{"author_name":"Catherine Mcbride","author_inst":"Purdue University"},{"author_name":"Urs Maurer","author_inst":"CUHK"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Robust semi-supervised scRNA-seq integration from virtual adversarial learning","rel_doi":"10.64898\/2026.06.07.730754","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730754","rel_abs":"Single-cell RNA sequencing integration methods that rely solely on transcriptomic data often struggle to preserve fine-grained distinctions between closely related cell subtypes. As a result, cell populations that are separable in the raw data may become over-mixed after integration, reducing biological resolution and interpretability. Incorporating marker gene information can potentially address these issues; however, the variability and complexity of available marker sets limit their effective application. To address this, we introduce scCRAFT+, a semi-supervised integration model that innovatively incorporates marker gene information through Virtual Adversarial Training (VAT). By jointly optimizing marker-derived supervision and transcriptome-wide representations, VAT enforces local prediction smoothness among transcriptionally similar cells, improving robustness to noisy marker annotations while enhancing both integration quality and cell type auto-annotation. This targeted approach significantly enhances annotation accuracy and robustness, particularly when faced with incomplete or incorrect marker gene sets. Benchmarking shows that scCRAFT+ achieves consistently stronger performance than current unsupervised and supervised integration approaches, resulting in improved integration quality and biologically meaningful sub-cell type auto-annotations.","rel_num_authors":5,"rel_authors":[{"author_name":"Chuan He","author_inst":"Yale University"},{"author_name":"Paraskevas Filippidis","author_inst":"Yale University"},{"author_name":"Jian Xing","author_inst":"Yale University"},{"author_name":"Steven Kleinstein","author_inst":"Yale School of Medicine"},{"author_name":"Leying Guan","author_inst":"Yale University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Exploratory Assessment of Pulsed-Wave Doppler Representations of Lung Sounds Using Deep Learning: An In-Vitro Phantom Study","rel_doi":"10.64898\/2026.06.09.26353787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26353787","rel_abs":"The increasing availability of portable ultrasound systems motivates exploration of novel approaches to respiratory signal assessment. In this in-vitro study, we investigate whether pulsed-wave (PW) Doppler ultrasound can capture structured spectral patterns from replayed lung sound recordings. Digitized respiratory sounds were replayed through a tissue-mimicking ultrasound phantom, generating 1,478 PW Doppler spectral images from recordings associated with healthy subjects and several externally labeled disease categories. Exploratory classification experiments using a ResNet-18 architecture demonstrated that these Doppler representations contain learnable differences under controlled conditions. These findings motivate further investigation into PW Doppler as a potential representation of respiratory acoustics.","rel_num_authors":5,"rel_authors":[{"author_name":"Ali A Saad","author_inst":"Alumnus of Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Sarah B Murthi","author_inst":"University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD, USA"},{"author_name":"Emad M Boctor","author_inst":"Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"William A Teeter","author_inst":"University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD, USA"},{"author_name":"Nitin Seam","author_inst":"Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Developmental Associations Linking Childhood Trauma and Early Cannabis Use to Adolescent DNA Methylation and Psychotic-Like Experiences","rel_doi":"10.64898\/2026.06.09.26355257","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355257","rel_abs":"Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Giulia Trotta","author_inst":"King's College London"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Isabelle Austin-Zimmerman","author_inst":"King's College London"},{"author_name":"Edoardo Spinazzola","author_inst":"King's College London"},{"author_name":"Lucia Sideli","author_inst":"Lumsa"},{"author_name":"Monica Aas","author_inst":"King's College London"},{"author_name":"Victoria Rodriguez","author_inst":"King's College London"},{"author_name":"Zhikun Li","author_inst":"King's College London"},{"author_name":"Bok Man Leung","author_inst":"King's College London"},{"author_name":"Qiang Li","author_inst":"King's College London"},{"author_name":"Shengmin Zhang","author_inst":"King's College London"},{"author_name":"Pak C Sham","author_inst":"The University of Hong Kong"},{"author_name":"Evangelos Vassos","author_inst":"King's College London"},{"author_name":"Richard Bentall","author_inst":"University of Sheffield"},{"author_name":"Emma M Walker","author_inst":"University of Exeter"},{"author_name":"Emma Dempster","author_inst":"University of Exeter"},{"author_name":"Robin Murray","author_inst":"King's College London"},{"author_name":"Marta Di Forti","author_inst":"King's College London"},{"author_name":"Luis Alameda","author_inst":"King's College London"},{"author_name":"Chloe C.Y Wong","author_inst":"King's College London"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Developmental Associations Linking Childhood Trauma and Early Cannabis Use to Adolescent DNA Methylation and Psychotic-Like Experiences","rel_doi":"10.64898\/2026.06.09.26355257","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355257","rel_abs":"Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Giulia Trotta","author_inst":"King's College London"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Isabelle Austin-Zimmerman","author_inst":"King's College London"},{"author_name":"Edoardo Spinazzola","author_inst":"King's College London"},{"author_name":"Lucia Sideli","author_inst":"Lumsa"},{"author_name":"Monica Aas","author_inst":"King's College London"},{"author_name":"Victoria Rodriguez","author_inst":"King's College London"},{"author_name":"Zhikun Li","author_inst":"King's College London"},{"author_name":"Bok Man Leung","author_inst":"King's College London"},{"author_name":"Qiang Li","author_inst":"King's College London"},{"author_name":"Shengmin Zhang","author_inst":"King's College London"},{"author_name":"Pak C Sham","author_inst":"The University of Hong Kong"},{"author_name":"Evangelos Vassos","author_inst":"King's College London"},{"author_name":"Richard Bentall","author_inst":"University of Sheffield"},{"author_name":"Emma M Walker","author_inst":"University of Exeter"},{"author_name":"Emma Dempster","author_inst":"University of Exeter"},{"author_name":"Robin Murray","author_inst":"King's College London"},{"author_name":"Marta Di Forti","author_inst":"King's College London"},{"author_name":"Luis Alameda","author_inst":"King's College London"},{"author_name":"Chloe C.Y Wong","author_inst":"King's College London"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Estimating COVID-19 Cumulative Incidence from Seroprevalence Surveys accounting for Time-Varying Seroreversion: A Fully Bayesian Methodology","rel_doi":"10.64898\/2026.06.09.26355264","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355264","rel_abs":"Seroprevalence surveys reveal the extent of humoral immunity against pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and under some circumstances represent cumulative incidence of prior infection. However, antibody waning-or seroreversion-biases these estimates by reducing assay sensitivity in a time-varying manner. Because assay sensitivity decays over time, naively using serosurveys can substantially bias estimates of SARS-CoV-2 cumulative incidence and fatality rates. The Bayesian assay-specific, time-varying sensitivity adjustment developed in this paper can reliably correct for this bias and account for the delay between infection and serosurvey. In seroprevalence studies conducted in the United States in 2020, adjusting for time-varying sensitivity increased cumulative incidence by up to 1.4-fold, with an adjustment of 1.08 for a national study. Our estimates contrast with a previously published 2-fold adjustment that did not account for assay design. This suggests that previous analyses overestimated cumulative incidence by applying seroreversion corrections that did not account for assay-specific effects, or underestimated cumulative incidence by not applying seroreversion corrections. These biases imply fatality rate underestimation and overestimation, respectively. Our model provides a framework for design-specific time-varying sensitivity corrections in seroprevalence surveys for other pathogens.","rel_num_authors":8,"rel_authors":[{"author_name":"Nana Owusu-Boaitey","author_inst":"Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA"},{"author_name":"Mark J. Meyer","author_inst":"Department of Mathematics and Statistics, Georgetown University, Washington, DC, USA"},{"author_name":"Daniel Herrera-Esposito","author_inst":"Computational Neuroscience Initiative, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"author_name":"Lucas Bottcher","author_inst":"Department of Computational Science and Philosophy, Frankfurt School of Finance and Management, Frankfurt, Germany"},{"author_name":"Maria Lukz","author_inst":"School of Public Health, University of Maryland, College Park, Maryland, USA"},{"author_name":"Sydney Cook","author_inst":"Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA"},{"author_name":"Michael A. Stoto","author_inst":"Department of Health Management and Policy, Georgetown University, Washington, DC, USA"},{"author_name":"John D. Kraemer","author_inst":"Department of Health Management and Policy, Georgetown University, Washington, DC, USA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Resolving Diagnostic Discordance in Group 2 Pulmonary Hypertension Through Staged Physiologic Testing: Insights From PVDOMICS","rel_doi":"10.64898\/2026.06.04.26354961","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354961","rel_abs":"BackgroundWorld Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing.\n\nMethodsWe studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV\/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield.\n\nResultsAdjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre\/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post\/NonG2 participants, consistent with ventricular interdependence. RV\/LV ratio [&ge;]0.94 reduced discordant Post\/NonG2 classification by 70.5%, and incorporation of PCWP\/cardiac output slope improved physiologic specificity during exercise.\n\nConclusionsGroup 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.\n\nClinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIIn the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart disease\nC_LIO_LIResting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept.\nC_LIO_LIA staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification.\nC_LI\n\nWhat Are the Clinical Implications?O_LIPre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold.\nC_LIO_LIIntermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield.\nC_LIO_LIExercise pulmonary capillary wedge pressure\/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.\nC_LI","rel_num_authors":21,"rel_authors":[{"author_name":"Franz Rischard","author_inst":"The University of Arizona College of Medicine Tucson"},{"author_name":"PVCOMICS Study Group","author_inst":""},{"author_name":"Mateo Mendoza","author_inst":"Cedars-Sinai Health System"},{"author_name":"Michael Insel","author_inst":"University of Arizona"},{"author_name":"Gerald Beck","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Serpil Erzurum","author_inst":"Cleveland Clinic"},{"author_name":"Robert P Frantz","author_inst":"Mayo Clinic"},{"author_name":"J. Emanuel Finet","author_inst":"Cleveland Clinic"},{"author_name":"Paul Hassoun","author_inst":"Johns Hopkins University"},{"author_name":"Anna R. Hemnes","author_inst":"Vanderbilt University"},{"author_name":"Nicholas S. Hill","author_inst":"Tufts University School of Dental Medicine"},{"author_name":"Evelyn M Horn","author_inst":"Weill Cornell Medical College"},{"author_name":"Jane A. Leopold","author_inst":"Brigham and Women's Hospital"},{"author_name":"Stephen C Mathai","author_inst":"Johns Hopkins Medical Institutions, Baltimore, MD"},{"author_name":"Reena Mehra","author_inst":"University of Washington"},{"author_name":"Yogesh N. V. Reddy","author_inst":"Division of Cardiology, Mayo Clinic"},{"author_name":"Erika B. Rosenzweig","author_inst":"Westchester Medical Center"},{"author_name":"David M Systrom","author_inst":"Brigham & Women's Hospital"},{"author_name":"W. H. Wilson Tang","author_inst":"Cleveland Clinic"},{"author_name":"Aaron Waxman","author_inst":"Brigham and Women's Hospital Department of Medicine"},{"author_name":"Barry A Borlaug","author_inst":"Division of Cardiology, Mayo Clinic"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Resolving Diagnostic Discordance in Group 2 Pulmonary Hypertension Through Staged Physiologic Testing: Insights From PVDOMICS","rel_doi":"10.64898\/2026.06.04.26354961","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354961","rel_abs":"BackgroundWorld Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing.\n\nMethodsWe studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV\/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield.\n\nResultsAdjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre\/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post\/NonG2 participants, consistent with ventricular interdependence. RV\/LV ratio [&ge;]0.94 reduced discordant Post\/NonG2 classification by 70.5%, and incorporation of PCWP\/cardiac output slope improved physiologic specificity during exercise.\n\nConclusionsGroup 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.\n\nClinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIIn the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart disease\nC_LIO_LIResting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept.\nC_LIO_LIA staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification.\nC_LI\n\nWhat Are the Clinical Implications?O_LIPre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold.\nC_LIO_LIIntermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield.\nC_LIO_LIExercise pulmonary capillary wedge pressure\/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.\nC_LI","rel_num_authors":21,"rel_authors":[{"author_name":"Franz Rischard","author_inst":"The University of Arizona College of Medicine Tucson"},{"author_name":"PVCOMICS Study Group","author_inst":""},{"author_name":"Mateo Mendoza","author_inst":"Cedars-Sinai Health System"},{"author_name":"Michael Insel","author_inst":"University of Arizona"},{"author_name":"Gerald Beck","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Serpil Erzurum","author_inst":"Cleveland Clinic"},{"author_name":"Robert P Frantz","author_inst":"Mayo Clinic"},{"author_name":"J. Emanuel Finet","author_inst":"Cleveland Clinic"},{"author_name":"Paul Hassoun","author_inst":"Johns Hopkins University"},{"author_name":"Anna R. Hemnes","author_inst":"Vanderbilt University"},{"author_name":"Nicholas S. Hill","author_inst":"Tufts University School of Dental Medicine"},{"author_name":"Evelyn M Horn","author_inst":"Weill Cornell Medical College"},{"author_name":"Jane A. Leopold","author_inst":"Brigham and Women's Hospital"},{"author_name":"Stephen C Mathai","author_inst":"Johns Hopkins Medical Institutions, Baltimore, MD"},{"author_name":"Reena Mehra","author_inst":"University of Washington"},{"author_name":"Yogesh N. V. Reddy","author_inst":"Division of Cardiology, Mayo Clinic"},{"author_name":"Erika B. Rosenzweig","author_inst":"Westchester Medical Center"},{"author_name":"David M Systrom","author_inst":"Brigham & Women's Hospital"},{"author_name":"W. H. Wilson Tang","author_inst":"Cleveland Clinic"},{"author_name":"Aaron Waxman","author_inst":"Brigham and Women's Hospital Department of Medicine"},{"author_name":"Barry A Borlaug","author_inst":"Division of Cardiology, Mayo Clinic"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Trajectories of brain structure and function in young adult carriers of genetic frontotemporal dementia variants","rel_doi":"10.64898\/2026.06.08.26355165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355165","rel_abs":"Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+\/-}SD, 25.9{+\/-}3.2 years), sex (53% female), or number of visits (2.1{+\/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.","rel_num_authors":79,"rel_authors":[{"author_name":"Isis So","author_inst":"Western University"},{"author_name":"Jolina Lombardi","author_inst":"University of California, San Francisco, CA, USA"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"Kristy Coleman","author_inst":"Western University"},{"author_name":"Arabella Bouzigues","author_inst":"University College London"},{"author_name":"Eve Ferry-Bolder","author_inst":"University College London"},{"author_name":"Eva Cullen","author_inst":"University College London"},{"author_name":"Lucy Russell","author_inst":"University College London"},{"author_name":"Phoebe Foster","author_inst":"University College London"},{"author_name":"Sophie Farley","author_inst":"University College London"},{"author_name":"Rhian Convery","author_inst":"University College London"},{"author_name":"John C van Swieten","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Lize C. Jiskoot","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Harro Seelaar","author_inst":"Erasmus MC University Medical Centre"},{"author_name":"Daniela Galimberti","author_inst":"University of Milan"},{"author_name":"Rik Vandenberghe","author_inst":"KU Leuven"},{"author_name":"Robert Laforce Jr.","author_inst":"Laval University"},{"author_name":"Rose Bruffaerts","author_inst":"University of Antwerp"},{"author_name":"Maxime Bertoux","author_inst":"University of Lille"},{"author_name":"Thibaud Lebouvier","author_inst":"University of Lille"},{"author_name":"Eino Solje","author_inst":"University of Eastern Finland"},{"author_name":"Johannes Levin","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Giuseppe di Fede","author_inst":"Fondazione IRCCS Istituto Neurologico Carlo Besta"},{"author_name":"Alexander Thompson","author_inst":"University of Oxford"},{"author_name":"Isabelle Le Ber","author_inst":"Institut du Cerveau"},{"author_name":"Raffaella Lara Migliaccio","author_inst":"Institut du Cerveau"},{"author_name":"Peter Kortvelyessy","author_inst":"Charite Universitatsmedizin Berlin"},{"author_name":"Matthias L. Schroeter","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Giancarlo Logroscino","author_inst":"University of Bari"},{"author_name":"Markus Otto","author_inst":"Martin Luther University Halle-Wittenberg, University clinic"},{"author_name":"Zeljko Uzelac","author_inst":"University of Ulm"},{"author_name":"Ignacio Illan-Gala","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Johanna Kruger","author_inst":"University of Oulu"},{"author_name":"Benedetta Nacmias","author_inst":"University of Florence"},{"author_name":"Alexander Gerhard","author_inst":"University of Manchester"},{"author_name":"Tobias Langheinrich","author_inst":"University of Manchester"},{"author_name":"Simon Ducharme","author_inst":"McGill University"},{"author_name":"Isabel J Santana","author_inst":"University of Coimbra"},{"author_name":"Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Mario Masellis","author_inst":"University of Toronto"},{"author_name":"Alexandre de Mendonca","author_inst":"University of Lisbon"},{"author_name":"James Rowe","author_inst":"University of Cambridge"},{"author_name":"Caroline Graff","author_inst":"Karolinska Institutet"},{"author_name":"Fermin Morenoizco","author_inst":"Hospital Universitario Donostia, San Sebastian"},{"author_name":"Matthis Synofzik","author_inst":"University of Tubingen"},{"author_name":"Barbara Borroni","author_inst":"Universita degli Studi di BRESCIA"},{"author_name":"Raquel Sanchez-Valle","author_inst":"University of Barcelona"},{"author_name":"Danielle Brushaber","author_inst":"Mayo Clinic"},{"author_name":"Ciaran Considine","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kelley Faber","author_inst":"Indiana University"},{"author_name":"Julie Fields","author_inst":"Mayo Clinic"},{"author_name":"Tatiana Foroud","author_inst":"Mayo Clinic"},{"author_name":"Leah K. Forsberg","author_inst":"Mayo Clinic"},{"author_name":"Tania Gendron","author_inst":"Mayo Clinic"},{"author_name":"Daniel Geschwind","author_inst":"UCLA"},{"author_name":"Hilary Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Eric Huang","author_inst":"University of California, San Francisco"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic in Rochester"},{"author_name":"Tyler Kolander","author_inst":"Mayo Clinic"},{"author_name":"Argentina Lario Lago","author_inst":"University of California, San Francisco"},{"author_name":"Shannon B. Lavigne","author_inst":"Mayo Clinic"},{"author_name":"Carly Mester","author_inst":"Mayo Clinic"},{"author_name":"Joie Molden","author_inst":"Indiana University"},{"author_name":"Leonard Petrucelli","author_inst":"Mayo Clinic"},{"author_name":"Rosa Rademakers","author_inst":"University of Antwerp"},{"author_name":"Eliana Marisa Ramos","author_inst":"University of California, Los Angeles"},{"author_name":"Katherine P. Rankin","author_inst":"University of California, San Francisco"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Kristoffer W. Rhoads","author_inst":"University of Pennsylvania"},{"author_name":"Marijne Vandebergh","author_inst":"VIB-UAntwerp Center for Molecular Neurology"},{"author_name":"Sandra Weintraub","author_inst":"Northwestern University"},{"author_name":"Bonnie Wong","author_inst":"Harvard University"},{"author_name":"Bradley Boeve","author_inst":"Mayo Clinic"},{"author_name":"Adam L. Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Howard J. Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Suzee E. Lee","author_inst":"University of California, San Francisco"},{"author_name":"Jonathan D. Rohrer","author_inst":"University College London"},{"author_name":"Elizabeth C. Finger","author_inst":"Western University"},{"author_name":"- Frontotemporal Dementia Prevention Initiative (FPI) Investigators","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Trajectories of brain structure and function in young adult carriers of genetic frontotemporal dementia variants","rel_doi":"10.64898\/2026.06.08.26355165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355165","rel_abs":"Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+\/-}SD, 25.9{+\/-}3.2 years), sex (53% female), or number of visits (2.1{+\/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.","rel_num_authors":79,"rel_authors":[{"author_name":"Isis So","author_inst":"Western University"},{"author_name":"Jolina Lombardi","author_inst":"University of California, San Francisco, CA, USA"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"Kristy Coleman","author_inst":"Western University"},{"author_name":"Arabella Bouzigues","author_inst":"University College London"},{"author_name":"Eve Ferry-Bolder","author_inst":"University College London"},{"author_name":"Eva Cullen","author_inst":"University College London"},{"author_name":"Lucy Russell","author_inst":"University College London"},{"author_name":"Phoebe Foster","author_inst":"University College London"},{"author_name":"Sophie Farley","author_inst":"University College London"},{"author_name":"Rhian Convery","author_inst":"University College London"},{"author_name":"John C van Swieten","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Lize C. Jiskoot","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Harro Seelaar","author_inst":"Erasmus MC University Medical Centre"},{"author_name":"Daniela Galimberti","author_inst":"University of Milan"},{"author_name":"Rik Vandenberghe","author_inst":"KU Leuven"},{"author_name":"Robert Laforce Jr.","author_inst":"Laval University"},{"author_name":"Rose Bruffaerts","author_inst":"University of Antwerp"},{"author_name":"Maxime Bertoux","author_inst":"University of Lille"},{"author_name":"Thibaud Lebouvier","author_inst":"University of Lille"},{"author_name":"Eino Solje","author_inst":"University of Eastern Finland"},{"author_name":"Johannes Levin","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Giuseppe di Fede","author_inst":"Fondazione IRCCS Istituto Neurologico Carlo Besta"},{"author_name":"Alexander Thompson","author_inst":"University of Oxford"},{"author_name":"Isabelle Le Ber","author_inst":"Institut du Cerveau"},{"author_name":"Raffaella Lara Migliaccio","author_inst":"Institut du Cerveau"},{"author_name":"Peter Kortvelyessy","author_inst":"Charite Universitatsmedizin Berlin"},{"author_name":"Matthias L. Schroeter","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Giancarlo Logroscino","author_inst":"University of Bari"},{"author_name":"Markus Otto","author_inst":"Martin Luther University Halle-Wittenberg, University clinic"},{"author_name":"Zeljko Uzelac","author_inst":"University of Ulm"},{"author_name":"Ignacio Illan-Gala","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Johanna Kruger","author_inst":"University of Oulu"},{"author_name":"Benedetta Nacmias","author_inst":"University of Florence"},{"author_name":"Alexander Gerhard","author_inst":"University of Manchester"},{"author_name":"Tobias Langheinrich","author_inst":"University of Manchester"},{"author_name":"Simon Ducharme","author_inst":"McGill University"},{"author_name":"Isabel J Santana","author_inst":"University of Coimbra"},{"author_name":"Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Mario Masellis","author_inst":"University of Toronto"},{"author_name":"Alexandre de Mendonca","author_inst":"University of Lisbon"},{"author_name":"James Rowe","author_inst":"University of Cambridge"},{"author_name":"Caroline Graff","author_inst":"Karolinska Institutet"},{"author_name":"Fermin Morenoizco","author_inst":"Hospital Universitario Donostia, San Sebastian"},{"author_name":"Matthis Synofzik","author_inst":"University of Tubingen"},{"author_name":"Barbara Borroni","author_inst":"Universita degli Studi di BRESCIA"},{"author_name":"Raquel Sanchez-Valle","author_inst":"University of Barcelona"},{"author_name":"Danielle Brushaber","author_inst":"Mayo Clinic"},{"author_name":"Ciaran Considine","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kelley Faber","author_inst":"Indiana University"},{"author_name":"Julie Fields","author_inst":"Mayo Clinic"},{"author_name":"Tatiana Foroud","author_inst":"Mayo Clinic"},{"author_name":"Leah K. Forsberg","author_inst":"Mayo Clinic"},{"author_name":"Tania Gendron","author_inst":"Mayo Clinic"},{"author_name":"Daniel Geschwind","author_inst":"UCLA"},{"author_name":"Hilary Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Eric Huang","author_inst":"University of California, San Francisco"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic in Rochester"},{"author_name":"Tyler Kolander","author_inst":"Mayo Clinic"},{"author_name":"Argentina Lario Lago","author_inst":"University of California, San Francisco"},{"author_name":"Shannon B. Lavigne","author_inst":"Mayo Clinic"},{"author_name":"Carly Mester","author_inst":"Mayo Clinic"},{"author_name":"Joie Molden","author_inst":"Indiana University"},{"author_name":"Leonard Petrucelli","author_inst":"Mayo Clinic"},{"author_name":"Rosa Rademakers","author_inst":"University of Antwerp"},{"author_name":"Eliana Marisa Ramos","author_inst":"University of California, Los Angeles"},{"author_name":"Katherine P. Rankin","author_inst":"University of California, San Francisco"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Kristoffer W. Rhoads","author_inst":"University of Pennsylvania"},{"author_name":"Marijne Vandebergh","author_inst":"VIB-UAntwerp Center for Molecular Neurology"},{"author_name":"Sandra Weintraub","author_inst":"Northwestern University"},{"author_name":"Bonnie Wong","author_inst":"Harvard University"},{"author_name":"Bradley Boeve","author_inst":"Mayo Clinic"},{"author_name":"Adam L. Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Howard J. Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Suzee E. Lee","author_inst":"University of California, San Francisco"},{"author_name":"Jonathan D. Rohrer","author_inst":"University College London"},{"author_name":"Elizabeth C. Finger","author_inst":"Western University"},{"author_name":"- Frontotemporal Dementia Prevention Initiative (FPI) Investigators","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Development of an Open-Access Action Observation Video Library for Upper Limb Motor Rehabilitation","rel_doi":"10.64898\/2026.06.10.26355108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355108","rel_abs":"BackgroundOccupational therapists can improve stroke survivors hand and arm movement and participation in daily activities through action observation (AO). AO involves watching another persons hand or arm complete a movement or task. While research generally supports the use of AO with stroke survivors, there are limited AO videos are available to occupational therapists which makes applying AO challenging.\n\nObjectiveThe purpose of this work is to develop structured and widely accessible tool to support access to AO for stroke survivors, occupational therapists, and researchers.\n\nMethodsTo develop an AO video library for stroke rehabilitation, functional and non-functional upper limb task deficits were first identified through clinical observations and clinician interviews to establish a prioritized list of daily activities. In collaboration with media production specialists, healthy adult volunteers were recruited and filmed performing these tasks from both first-and third-person perspectives. The recorded videos were then systematically edited, enhanced with instructional title slides, and distributed via a public YouTube channel for clinical application and a categorized digital repository for research purposes.\n\nResultsInitial assessments revealed a complete lack of familiarity, awareness, and utilization of AO resources among local occupational therapists, despite high perceived clinical utility. To address this gap, a final library of 150 tasks was established, resulting in the production of 419 finalized, standardized videos featuring six healthy volunteers. For clinical application, these videos were hosted on a free, public YouTube channel organized into 18 functional playlists, while a parallel set was structured into distinct movement categories for research repository storage.\n\nConclusionBy providing a structured and highly accessible tool, this repository enables clinicians, researchers, and caregivers to readily implement evidence-based action observation interventions in both clinical and home settings.","rel_num_authors":3,"rel_authors":[{"author_name":"Medina Madison","author_inst":"Department of Occupational Therapy, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University"},{"author_name":"Lewis A Wheaton","author_inst":"Georgia Tech"},{"author_name":"Veronica Rowe","author_inst":"Department of Occupational Therapy, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response","rel_doi":"10.64898\/2026.06.06.26354980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26354980","rel_abs":"In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapines pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT1A, 5-HT2A and 5-HT4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapines activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.","rel_num_authors":21,"rel_authors":[{"author_name":"Bridget King","author_inst":"King's College London"},{"author_name":"Dara Cannon","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Nicolas A Crossley","author_inst":"Pontificia Universidad Catolica de Chile"},{"author_name":"Alfonso Gonzalez Valderrama","author_inst":"School of Medicine, Finis Terrae University, Santiago, Chile; Dr Jose Horwitz Barack Psychiatric Institute, Santiago Chile"},{"author_name":"Brian Hallahan","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Wi Hoon Jung","author_inst":"Department of Psychology, Gachon University, Gyeonggi-do, Republic of Korea"},{"author_name":"Matthew J. Kempton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"},{"author_name":"Seoyoung Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea."},{"author_name":"Andrew J Lawrence","author_inst":"Institute of Psychiatry, Psychology and Neuroscience; King's College London"},{"author_name":"James H MacCabe","author_inst":"King's College London"},{"author_name":"Colm McDonald","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Cristian Mena","author_inst":"Centro de Interes Nacional para Investigacion e Innovacion en Ninez, Adolescencia, Resiliencia y Adversidad (IINARA), Santiago, Chile; Dr Jose Horwitz Barack Ps"},{"author_name":"Shinichiro Nakajima","author_inst":"Department of Neuropsychiatry, Keio University School of Medicine, Tokyo."},{"author_name":"Andrew Papale","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Samira Raminfard","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Deepak Sarpal","author_inst":"University of Pittsburgh"},{"author_name":"Hyejin Sim","author_inst":"Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea."},{"author_name":"Giulia Tronchin","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Lauri Tuominen","author_inst":"University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada"},{"author_name":"Euitae Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College o"},{"author_name":"Alice Egerton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response","rel_doi":"10.64898\/2026.06.06.26354980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26354980","rel_abs":"In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapines pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT1A, 5-HT2A and 5-HT4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapines activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.","rel_num_authors":21,"rel_authors":[{"author_name":"Bridget King","author_inst":"King's College London"},{"author_name":"Dara Cannon","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Nicolas A Crossley","author_inst":"Pontificia Universidad Catolica de Chile"},{"author_name":"Alfonso Gonzalez Valderrama","author_inst":"School of Medicine, Finis Terrae University, Santiago, Chile; Dr Jose Horwitz Barack Psychiatric Institute, Santiago Chile"},{"author_name":"Brian Hallahan","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Wi Hoon Jung","author_inst":"Department of Psychology, Gachon University, Gyeonggi-do, Republic of Korea"},{"author_name":"Matthew J. Kempton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"},{"author_name":"Seoyoung Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea."},{"author_name":"Andrew J Lawrence","author_inst":"Institute of Psychiatry, Psychology and Neuroscience; King's College London"},{"author_name":"James H MacCabe","author_inst":"King's College London"},{"author_name":"Colm McDonald","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Cristian Mena","author_inst":"Centro de Interes Nacional para Investigacion e Innovacion en Ninez, Adolescencia, Resiliencia y Adversidad (IINARA), Santiago, Chile; Dr Jose Horwitz Barack Ps"},{"author_name":"Shinichiro Nakajima","author_inst":"Department of Neuropsychiatry, Keio University School of Medicine, Tokyo."},{"author_name":"Andrew Papale","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Samira Raminfard","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Deepak Sarpal","author_inst":"University of Pittsburgh"},{"author_name":"Hyejin Sim","author_inst":"Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea."},{"author_name":"Giulia Tronchin","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Lauri Tuominen","author_inst":"University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada"},{"author_name":"Euitae Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College o"},{"author_name":"Alice Egerton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Age-specific burden of medically attended respiratory virus disease in high-income countries: a scoping review and meta-analysis","rel_doi":"10.64898\/2026.06.09.26354660","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26354660","rel_abs":"IntroductionRespiratory infections are a leading cause of morbidity. Newly available vaccines to prevent respiratory syncytial virus (RSV) disease and encouraging clinical progress on vaccines for human metapneumovirus (hMPV) and parainfluenza (PIV) could reduce the disease burden beyond existing influenza and SARS-CoV-2 immunisation programs. However, evidence on the contribution of these viruses to respiratory disease burden across the lifespan remains limited.\n\nMethodsWe reviewed studies from 01\/2002-11\/2025 reporting age-stratified, medically attended cases of influenza, and at least one of RSV, hMPV, or PIV, in high-income countries, excluding periods substantially overlapping with the COVID-19 pandemic. Using only studies that tested for all four viruses, we estimated the age-specific proportion of cases that were non-influenza (total across RSV, hMPV and PIV) compared to influenza using a mixed-effects logistic regression model.\n\nResultsFollowing exclusions and screening, 61 studies were included in the primary analysis comprising >500,000 detections of the four viruses. We found that a substantial proportion of medically attended respiratory illness in infants and young children was due to PIV, hMPV and RSV, rather than influenza, with a non-influenza virus proportion of 90.2% (95% CI 85.9-93.2%) in young infants aged 0-6 months. The converse was true for school-aged children, with a non-influenza virus proportion of 34.8% (95% CI 26.5-44.2%) in children aged 5-18 years. In adults aged 65+ years, non-influenza causes of medically attended disease were common at 60.2% (95% CI 50.0-69.5%). Restricting to studies reporting hospitalised cases (n=19) produced broadly similar age-specific trends in relative virus burden contributions.\n\nDiscussionWe highlight the significant burden of medically attended illness due to PIV, hMPV and RSV across ages, particularly in infant and preschool-aged children and older adults, supporting the need for effective vaccines targeting this burden.","rel_num_authors":7,"rel_authors":[{"author_name":"Muskaan Gupta","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Hordur Zoega","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Isaac J Stopard","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Bette Liu","author_inst":"National Centre for Immunisation Research and Surveillance (NCIRS), Sydney, Australia"},{"author_name":"Kristine Macartney","author_inst":"National Centre for Immunisation Research and Surveillance (NCIRS), Sydney, Australia"},{"author_name":"James G Wood","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Alexandra B Hogan","author_inst":"School of Population Health, UNSW Sydney"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32x10-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27x10-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50x10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43x10-237) and opioid use disorder (rg=1.01, P=4.40x10-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32x10-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27x10-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50x10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43x10-237) and opioid use disorder (rg=1.01, P=4.40x10-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32x10-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27x10-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50x10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43x10-237) and opioid use disorder (rg=1.01, P=4.40x10-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32x10-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27x10-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50x10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43x10-237) and opioid use disorder (rg=1.01, P=4.40x10-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV","rel_doi":"10.64898\/2026.06.08.26355202","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355202","rel_abs":"People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1{beta}, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4 T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.","rel_num_authors":28,"rel_authors":[{"author_name":"Ryan Chung","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Namratha Shivani Chalasani","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Alton S. Barbehenn","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Erik Lundgren","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sonia Savur","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sayane Shome","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Caroline H. Sheikhzadeh","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sannidhi Sarvadhavabhatla","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Maria Sophia Donaire","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Vivian Pae","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Xiuping Chu","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Daniel Winder","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Colin T Maguire","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Senay Topal","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Anuradha Ganesan","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Joseph M. Yabes","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Derek T. Larson","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Tahaniyat Lalani","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Evan C. Ewers","author_inst":"Tripler Army Medical Center, Honolulu, HI"},{"author_name":"Rhonda E. Colombo","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Eli Dugan","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Ujjwal Rathore","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Alexander Marson","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Brian K. Agan","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Jeff Alan Tomalka","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Rafick-Pierre Sekaly","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Nilah M. Loannidis","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Sulggi A. Lee","author_inst":"University of California San Francisco, San Francisco, CA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV","rel_doi":"10.64898\/2026.06.08.26355202","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355202","rel_abs":"People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1{beta}, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4 T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.","rel_num_authors":28,"rel_authors":[{"author_name":"Ryan Chung","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Namratha Shivani Chalasani","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Alton S. Barbehenn","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Erik Lundgren","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sonia Savur","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sayane Shome","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Caroline H. Sheikhzadeh","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sannidhi Sarvadhavabhatla","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Maria Sophia Donaire","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Vivian Pae","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Xiuping Chu","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Daniel Winder","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Colin T Maguire","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Senay Topal","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Anuradha Ganesan","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Joseph M. Yabes","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Derek T. Larson","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Tahaniyat Lalani","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Evan C. Ewers","author_inst":"Tripler Army Medical Center, Honolulu, HI"},{"author_name":"Rhonda E. Colombo","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Eli Dugan","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Ujjwal Rathore","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Alexander Marson","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Brian K. Agan","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Jeff Alan Tomalka","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Rafick-Pierre Sekaly","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Nilah M. Loannidis","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Sulggi A. Lee","author_inst":"University of California San Francisco, San Francisco, CA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Efficacy of the PragmaVAC Manual Negative Pressure Wound Therapy Device to Treat Acute Traumatic Wounds in a Conflict Setting: A Retrospective Cohort Study from Gaza","rel_doi":"10.64898\/2026.06.04.26354740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354740","rel_abs":"Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage\/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.","rel_num_authors":7,"rel_authors":[{"author_name":"Ibrahim Ramadan","author_inst":"Indonesian Hospital, Gaza, State of Palestine"},{"author_name":"Mahmoud Hariri","author_inst":"West Hertforshire NHS Trust"},{"author_name":"Omar Shalakhti","author_inst":"Rush University School of Medicine"},{"author_name":"Jude Alawa","author_inst":"Hospital for Special Surgery"},{"author_name":"Amandine Godier-Furnemont","author_inst":"University of California at San Francisco"},{"author_name":"Abd Al-Rahman Traboulsi","author_inst":"MassGeneral Brigham"},{"author_name":"HANI MOWAFI","author_inst":"Yale University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Efficacy of the PragmaVAC Manual Negative Pressure Wound Therapy Device to Treat Acute Traumatic Wounds in a Conflict Setting: A Retrospective Cohort Study from Gaza","rel_doi":"10.64898\/2026.06.04.26354740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354740","rel_abs":"Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage\/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.","rel_num_authors":7,"rel_authors":[{"author_name":"Ibrahim Ramadan","author_inst":"Indonesian Hospital, Gaza, State of Palestine"},{"author_name":"Mahmoud Hariri","author_inst":"West Hertforshire NHS Trust"},{"author_name":"Omar Shalakhti","author_inst":"Rush University School of Medicine"},{"author_name":"Jude Alawa","author_inst":"Hospital for Special Surgery"},{"author_name":"Amandine Godier-Furnemont","author_inst":"University of California at San Francisco"},{"author_name":"Abd Al-Rahman Traboulsi","author_inst":"MassGeneral Brigham"},{"author_name":"HANI MOWAFI","author_inst":"Yale University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Recognition and Treatment of Primary Aldosteronism in the Updated Guideline Era","rel_doi":"10.64898\/2026.06.08.26355219","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355219","rel_abs":"BackgroundPrimary aldosteronism (PA) is increasingly recognized as a common cause of hypertension. The 2025 Endocrine Society guideline introduced a simplified diagnostic framework, but its real-world clinical implications remain unclear.\n\nMethodsWe conducted a multicenter retrospective cohort study of hypertensive patients undergoing PA testing in Taiwan. PA was defined biochemically according to the 2025 Endocrine Society criteria. Multivariable logistic regression identified factors associated with PA diagnosis and aldosterone-targeted therapy. Among patients with suppressed renin ([&le;]1 ng\/mL\/h), restricted cubic splines evaluated the adjusted association between renin and PA probability.\n\nResultsAmong 18,766 patients undergoing PA testing, 6,760 (36.0%) met diagnostic criteria for PA. PA was associated with older age, female sex, lower potassium, resistant hypertension, and a higher antihypertensive medication burden. Among patients with suppressed renin, lower renin remained significantly associated with higher adjusted PA probability. However, only 39.0% of patients with PA received aldosterone-targeted therapy, including 28.2% who received mineralocorticoid receptor antagonist therapy within 6 months and 9.4% who underwent adrenalectomy during follow-up. Lower renin, higher aldosterone, lower potassium, and resistant hypertension were associated with aldosterone-targeted therapy, while younger patients with fewer comorbidities were more likely to undergo adrenalectomy.\n\nConclusionsUsing the updated diagnostic framework, PA was highly prevalent among hypertensive patients undergoing PA testing. Nevertheless, many patients who met these biochemical criteria did not receive aldosterone-targeted therapy in routine care. These findings highlight the potential treatment implications of broader PA recognition and support the development of practical pathways to guide MRA therapy, adrenalectomy referral, and individualized management.","rel_num_authors":12,"rel_authors":[{"author_name":"Cheng-Hsuan Tsai","author_inst":"National Taiwan University Hospital Cardiovascular Center"},{"author_name":"Yu-Ching Chang","author_inst":"National Taiwan University Hospital"},{"author_name":"Chin-Chen Chang","author_inst":"National Taiwan University Hospital"},{"author_name":"Wan-Chen Wu","author_inst":"National Taiwan University Hospital"},{"author_name":"Yi-Yao Chang","author_inst":"Far Eastern Memorial Hospital Library"},{"author_name":"Uei-Lin Chen","author_inst":"National Taiwan University Hospital"},{"author_name":"Bo-Ching Lee","author_inst":"National Taiwan University"},{"author_name":"Chi-Sheng Hung","author_inst":"National Taiwan University Hospital and College of  Medicine"},{"author_name":"Kuo-How Huang","author_inst":"National Taiwan University Hospital Department of Urology"},{"author_name":"Jeff S. Chueh","author_inst":"National Taiwan University, College of Medicine"},{"author_name":"Vin-Cent Wu","author_inst":"College of Medicine, National Taiwan University"},{"author_name":"Yen-Hung Lin","author_inst":"National Taiwan University Hospital"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Identifying Clinical Diagnostic Trajectories Associated With Suicide Death Using Temporal Sequence Mining of Linked Claims and Mortality Data","rel_doi":"10.64898\/2026.06.08.26355231","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355231","rel_abs":"Background: Most approaches to suicide risk assessment consider clinical conditions as independent risk factors, potentially overlooking prognostic information in the order in which conditions accumulate. We applied temporal sequence mining to linked claims and mortality data to identify ordered clinical diagnostic trajectories associated with suicide death. Results: The cohort included 3 647 059 insured Maryland residents aged 10 years or older with available claims records in the Maryland Suicide Data Warehouse from January 1, 2016, to December 31, 2020, among whom 768 suicide deaths were ascertained through medical examiner linkage. Sequential pattern mining of ICD-10-CM diagnoses grouped into Clinical Classifications Software Refined categories identified 89 221 candidate sequences, of which 1 816 remained significantly associated with suicide death in time-varying Cox models. Adjusted hazard ratios (AHRs) ranged from 2.4 to 134.1. Two-thirds of significant trajectories ended in physical conditions, and approximately half crossed from psychiatric to physical endpoints. Among suicide decedents, 62% were exposed to at least 1 significant sequence (median, 16 per case); median sequence duration was 18.7 months, and median time from completion to death was 13.1 months. In landmark analyses, among patients with depression who later developed suicidal ideation (n = 26 356), the path through anxiety, then anemia, was associated with higher risk (AHR, 4.6; 95% CI, 2.2-9.5), whereas the anxiety-only path was not (AHR, 1.3; 95% CI, 0.8-2.1). Among patients with anxiety who later developed hypertension (n = 149 215), the path through history of self-harm was associated with higher risk (AHR, 32.0; 95% CI, 16.6-61.6). Associations were generally consistent across sex and age. Conclusions: Temporal ordering of clinical conditions may carry prognostic information for suicide death. Clinical trajectories incorporating physical illness within psychiatric sequences identified higher-risk groups. These findings suggest that opportunities for risk detection may extend beyond psychiatric settings and that suicide risk signals may be fragmented across care settings and not apparent within isolated encounters.","rel_num_authors":7,"rel_authors":[{"author_name":"Anas Belouali","author_inst":"Georgetown University"},{"author_name":"Christopher Kitchen","author_inst":"Department of Health Policy and Management, Center for Population Health Information Technology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD,"},{"author_name":"Emily Haroz","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Harold Lehmann","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Paul S. Nestadt","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Holly C. Wilcox","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Hadi Kharrazi","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Health Policy and Management, Center for Population"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Alzheimer's disease neuroimaging signature aids identification of cognitive impairment in older adults with early-onset epilepsy","rel_doi":"10.64898\/2026.06.05.26354952","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354952","rel_abs":"Background and ObjectivesOlder adults with epilepsy are at increased risk for Alzheimers disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy.\n\nMethodsParticipants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset ([&ge;]55 years at seizure onset) epilepsy); 362 from the Alzheimers Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers ({beta}-amyloid 42\/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE.\n\nResultsParticipants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls ({beta}= -0.43, padj<0.001), reflecting reduced thickness\/volume in AD-vulnerable regions. This effect was stronger among early-onset ({beta}= -0.57) versus late-onset ({beta}= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL ({beta}= -0.30, padj=0.050), memory performance ({beta}= 0.30, padj=0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction padj=0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p=0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age.\n\nDiscussionAD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.","rel_num_authors":22,"rel_authors":[{"author_name":"McKenna Williams","author_inst":"University of California San Diego"},{"author_name":"Kayela Arrotta","author_inst":"Cleveland Clinic"},{"author_name":"Katherine J. Bangen","author_inst":"University of California San Diego"},{"author_name":"Anny Reyes","author_inst":"Cleveland Clinic"},{"author_name":"Alena Stasenko","author_inst":"University of California San Diego"},{"author_name":"Ifrah Zawar","author_inst":"University of Virginia School of Medicine"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Irene Wang","author_inst":"Cleveland Clinic"},{"author_name":"Wanyong Shin","author_inst":"Cleveland Clinic"},{"author_name":"Ting-Yu Su","author_inst":"Cleveland Clinic"},{"author_name":"Jerry J. Shih","author_inst":"University of California San Diego"},{"author_name":"Nikdokht Farid","author_inst":"University of California San Diego"},{"author_name":"Jaideep Kapur","author_inst":"University of Virginia School of Medicine"},{"author_name":"Aaron F. Struck","author_inst":"Washington University in St. Louis"},{"author_name":"Lynn M. Bekris","author_inst":"University of Washington"},{"author_name":"Lisa Ferguson","author_inst":"Cleveland Clinic"},{"author_name":"Dace N. Almane","author_inst":"Cleveland Clinic"},{"author_name":"Jana E. Jones","author_inst":"Cleveland Clinic"},{"author_name":"Bruce P. Hermann","author_inst":"University of Wisconsin Madison"},{"author_name":"Robyn M. Busch","author_inst":"Cleveland Clinic"},{"author_name":"Carrie R. McDonald","author_inst":"University of California San Diego"},{"author_name":"- for the Alzheimer's Disease Neuroimaging Initiative*","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Alzheimer's disease neuroimaging signature aids identification of cognitive impairment in older adults with early-onset epilepsy","rel_doi":"10.64898\/2026.06.05.26354952","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354952","rel_abs":"Background and ObjectivesOlder adults with epilepsy are at increased risk for Alzheimers disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy.\n\nMethodsParticipants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset ([&ge;]55 years at seizure onset) epilepsy); 362 from the Alzheimers Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers ({beta}-amyloid 42\/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE.\n\nResultsParticipants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls ({beta}= -0.43, padj<0.001), reflecting reduced thickness\/volume in AD-vulnerable regions. This effect was stronger among early-onset ({beta}= -0.57) versus late-onset ({beta}= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL ({beta}= -0.30, padj=0.050), memory performance ({beta}= 0.30, padj=0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction padj=0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p=0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age.\n\nDiscussionAD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.","rel_num_authors":22,"rel_authors":[{"author_name":"McKenna Williams","author_inst":"University of California San Diego"},{"author_name":"Kayela Arrotta","author_inst":"Cleveland Clinic"},{"author_name":"Katherine J. Bangen","author_inst":"University of California San Diego"},{"author_name":"Anny Reyes","author_inst":"Cleveland Clinic"},{"author_name":"Alena Stasenko","author_inst":"University of California San Diego"},{"author_name":"Ifrah Zawar","author_inst":"University of Virginia School of Medicine"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Irene Wang","author_inst":"Cleveland Clinic"},{"author_name":"Wanyong Shin","author_inst":"Cleveland Clinic"},{"author_name":"Ting-Yu Su","author_inst":"Cleveland Clinic"},{"author_name":"Jerry J. Shih","author_inst":"University of California San Diego"},{"author_name":"Nikdokht Farid","author_inst":"University of California San Diego"},{"author_name":"Jaideep Kapur","author_inst":"University of Virginia School of Medicine"},{"author_name":"Aaron F. Struck","author_inst":"Washington University in St. Louis"},{"author_name":"Lynn M. Bekris","author_inst":"University of Washington"},{"author_name":"Lisa Ferguson","author_inst":"Cleveland Clinic"},{"author_name":"Dace N. Almane","author_inst":"Cleveland Clinic"},{"author_name":"Jana E. Jones","author_inst":"Cleveland Clinic"},{"author_name":"Bruce P. Hermann","author_inst":"University of Wisconsin Madison"},{"author_name":"Robyn M. Busch","author_inst":"Cleveland Clinic"},{"author_name":"Carrie R. McDonald","author_inst":"University of California San Diego"},{"author_name":"- for the Alzheimer's Disease Neuroimaging Initiative*","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Daily symptom monitoring is sustainable over months: retention, not compliance, is the primary barrier to long-duration digital tracking","rel_doi":"10.64898\/2026.06.08.26355180","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355180","rel_abs":"Ecological momentary assessment (EMA) enables real-time, longitudinal measurement of symptoms and behavior via smartphones, yet nearly all feasibility evidence comes from protocols lasting one to two weeks, far shorter than the timescales over which chronic diseases fluctuate and clinical decisions unfold. Whether daily compliance can be sustained over months, or whether it decays as short-protocol trends predict, is unknown. Here, 214 participants (173 with pain, 41 healthy controls) completed a 4-month (122-day) EMA protocol via the Soma smartphone app, generating 26,907 check-ins. Half the sample completed the full protocol without a two-week lapse. Aggregate compliance appeared moderate (50%), but this conflated two distinct phenomena: when recomputed over each participant's active period, compliance rose to 71%, with 91% achieving moderate-to-high adherence, and remained stable across all 17 study weeks. Pain status predicted earlier disengagement but not lower compliance among those who remained; after adjustment for differential retention, group differences disappeared. To our knowledge, this is the longest continuous daily EMA evaluation in a clinical population. It suggests the primary barrier to long-duration EMA is not declining motivation among active participants but concentrated early disengagement, with direct implications for the design of digital health protocols, decentralized trials, and remote symptom monitoring.","rel_num_authors":4,"rel_authors":[{"author_name":"Chloe Z Gunsilius","author_inst":"Brown University"},{"author_name":"Pangzhongyuan Pei","author_inst":"Brown University"},{"author_name":"Alexios Carayannopoulos","author_inst":"Brown University Health"},{"author_name":"Frederike H. Petzschner","author_inst":"Brown University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Burden of Chronic Kidney Disease in China, 1990-2021: Findings from the 2021 Global Burden of Disease Study","rel_doi":"10.64898\/2026.06.06.26355056","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355056","rel_abs":"IntroductionTo investigate the epidemiological characteristics of chronic kidney diseases (CKD) in China in 2021 and its trends between 1990 and 2021, in the context of significant population growth and lifestyle changes over the past 30 years that have likely influenced the CKD spectrum.\n\nMethodsData on CKD prevalence, mortality, disability-adjusted life-years (DALY), and risk factors were obtained from the Global Burden of Disease Study 2021. The estimated decadal percentage changes were calculated to evaluate changes in trends in prevalence, mortality and disease burden.\n\nResultsIn 2021, an estimated 118.4 (95% UI 109.4 to 127.5) million people in China were affected by CKD, contributing to 204 230 (95% UI 164 736 to 246 372) deaths and 6.13 (95% UI 5.18 to 7.21) million DALY. Although CKD due to diabetes mellitus and hypertension accounted for less than a quarter of all cases, they were responsible for over 90% of CKD-related deaths. Over the past three decades, CKD mortality and DALY rates have steadily increased, although the prevalence has stabilized in the last decade. Diabetes mellitus type 2 and hypertension have emerged as key drivers of CKD burden in China.\n\nConclusionsThe CKD burden in China shows a dual pattern of rising incidence and high mortality from diabetes and hypertension-related chronic kidney disease, alongside persistently high years lived with disability from glomerulonephritis and other causes.","rel_num_authors":5,"rel_authors":[{"author_name":"Mengwei Wang","author_inst":"Shanxi Medical University"},{"author_name":"Taoran Zhao","author_inst":"Shanxi Medical University"},{"author_name":"Heng Wang","author_inst":"The University of Sydney"},{"author_name":"Shulin Hou","author_inst":"Shanxi Medical University"},{"author_name":"Yongqiang Fu","author_inst":"Shanxi Bethune Hospital"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Polypore Mushroom Mycelia for Treatment of Active COVID-19 Infection: A Randomized Clinical Trial","rel_doi":"10.64898\/2026.06.01.26354267","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354267","rel_abs":"Use of fungal mycelia, which has antiviral properties, constitutes a novel strategy for addressing existing and newly emerging viral diseases. We evaluated safety and feasibility of fungal mycelia (Fomitopsis officinalis and Trametes versicolor, FoTv) for treatment of COVID-19 and assessed its antiviral effects and potential to reduce symptoms. In a randomized, double-blind, placebo-controlled, dual site (UCSD\/UCLA medical centers) clinical trial we examined non-hospitalized patients who contracted mild-to-moderate COVID-19 [&le;] 96 hours, and experienced symptom onset [&le;] nine days, before enrollment. FoTv was safe, well-tolerated, and feasible for COVID-19 treatment. Minor differences in biochemical markers were observed between groups (26 FoTv, 24 Placebo). FoTv significantly reduced the number and severity of symptoms, particularly sore throat\/cough, and in vitro SARS-CoV-2 (pseudovirus) cellular infection. In conclusion, FoTv was safe and reduced COVID-19 symptoms and cellular viral infection. Future studies should investigate therapeutic benefits of fungal mycelia for SARS-CoV-2 and other viruses. Clinicaltrials.gov registration:NCT04667247.","rel_num_authors":16,"rel_authors":[{"author_name":"Gordon Saxe MD\/PHD","author_inst":"University of California San Diego"},{"author_name":"Andrew Shubov MD","author_inst":"University of California Los Angeles"},{"author_name":"Christine N Smith PHD","author_inst":"University of California San Diego"},{"author_name":"Shahrokh Golshan PHD","author_inst":"University of California San Diego"},{"author_name":"Tatyana Shekhtman MS","author_inst":"University of California San Diego"},{"author_name":"Stephen Wilson PHD","author_inst":"Botnar Institute of Immune Engineering"},{"author_name":"Daniel Slater MD\/FAAFP","author_inst":"University of California San Diego"},{"author_name":"Zolton J Bair PHD","author_inst":"Fungi Perfecti, LLC"},{"author_name":"Chase Beathard PHD","author_inst":"Fungi Perfecti, LLC"},{"author_name":"Renee A Davis MA","author_inst":"University of Washington"},{"author_name":"Lauray MacElhern MBA","author_inst":"University of California San Diego"},{"author_name":"Lan K Kao DACM","author_inst":"University of California Los Angeles"},{"author_name":"Phoebe Senowitz MEd","author_inst":"University of California San Diego"},{"author_name":"Natalie Gosnell BS","author_inst":"Cornell University"},{"author_name":"David Buchholz PHD","author_inst":"University of California Los Angeles"},{"author_name":"Hector Aguilar-Carreno PHD","author_inst":"University of California Los Angeles"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Aperiodic and oscillatory activity of the human brain during induced emotional states","rel_doi":"10.64898\/2026.06.02.26354146","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354146","rel_abs":"Normal emotional experience depends on dynamic modulation of neural excitability across limbic and prefrontal circuits, yet the spectral markers that reflect these shifts in humans remain incompletely understood. In this study, we combined a validated video-based emotion induction paradigm with stereotactic electroencephalography (SEEG) in 31 patients with drug-resistant epilepsy to investigate how positive and negative affective states modulate oscillatory and aperiodic (asynchronous) neural activity. Using spectral parameterization to dissociate oscillatory power from the aperiodic 1\/f component, we found that emotional valence robustly altered the aperiodic slope in a regionally specific manner: negative valence flattened the slope in thalamus, posterior insula, and posterior cingulate cortex, whereas positive valence produced flattening in dorsolateral prefrontal cortex. Simultaneous oscillatory changes included increased high-frequency activity and decreased alpha\/beta power during negative affect, and reduced alpha power during positive affect, which were elucidated after adjusting for broadband aperiodic spectral shifts. These effects persisted after controlling for audiovisual stimulus or physiological features and were not evident in simultaneously recorded scalp EEG, underscoring their localization to intracranial sites. Together, these results provide the first direct evidence that active induction of emotional states modulates the aperiodic slope of human intracranial field potentials, reflecting valence-dependent shifts in local circuit excitability. The findings highlight the 1\/f slope as a sensitive neural marker of affective brain states and for mood dysregulation.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC=\"FIGDIR\/small\/26354146v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (40K):\norg.highwire.dtl.DTLVardef@1a40ffforg.highwire.dtl.DTLVardef@163765org.highwire.dtl.DTLVardef@8edd79org.highwire.dtl.DTLVardef@16e3f87_HPS_FORMAT_FIGEXP  M_FIG C_FIG HighlightsO_LIEmotional valence modulates broadband neural activity: Using intracranial SEEG recordings, transient emotional states were shown to alter the aperiodic 1\/f slope of human cortical and subcortical spectra in a regionally specific manner.\nC_LIO_LIValence-specific circuit engagement: Negative emotion flattened the 1\/f slope in the thalamus, posterior insula, and posterior cingulate cortex, whereas positive emotion induced similar flattening in the dorsolateral prefrontal cortex.\nC_LIO_LIDistinct oscillatory patterns accompany broadband shifts: Negative affect increased highfrequency activity and suppressed alpha\/beta oscillation in subcortical and midline regions, while positive affect primarily reduced alpha power in the prefrontal cortex.\nC_LIO_LI1\/f slope as a marker of affective state: Findings identify the aperiodic spectral slope as a sensitive index of valence-dependent shifts in local neural excitability and a potential biomarker for mood-related dysregulation.\nC_LI","rel_num_authors":9,"rel_authors":[{"author_name":"Haeorum Park","author_inst":"Washington University in St. Louis"},{"author_name":"Carl Hacker","author_inst":"Emory University School of Medicine"},{"author_name":"Hohyun Cho","author_inst":"University of Alabama at Birmingham"},{"author_name":"Tao Xie","author_inst":"Washington University in St. Louis"},{"author_name":"Alexis Simmons","author_inst":"Washington University in St. Louis"},{"author_name":"Gansheng Tan","author_inst":"Washington University In St Louis"},{"author_name":"Eric C Leuthardt","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Peter Brunner","author_inst":"Washington University In St Louis: Washington University in St Louis"},{"author_name":"Jon Willie","author_inst":"University of Texas at Austin"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Mortality in people with attention-deficit\/hyperactivity disorder (ADHD): Examining how risk is embodied in a pooling of two prospective cohort studies","rel_doi":"10.64898\/2026.06.08.26355148","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355148","rel_abs":"BackgroundNascent findings suggest that people with attention-deficit\/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk.\n\nMethodsWe used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported.\n\nFindingsAt baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive.\n\nInterpretationIn the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group.\n\nFundingThis paper received no direct funding. GDB is supported by the UK Medical Research Council (MR\/P023444\/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the PubMed database (January 1947 to June 2026) using the terms  attention-deficit\/hyperactivity disorder  ,  ADHD,  mortality, and  death with no language or date restrictions. We considered individual studies, systematic reviews, and meta-analyses. The most recent systematic review was published in 2022 and the majority of the eight non-overlapping studies found that ADHD was associated with a raised risk of mortality. Included cohort studies were typically generated from linked administrative health records and therefore insufficiently well characterized to comprehensively test how ADHD was embodied in order to elevate death rates. There was some suggestion of a role for mediation via socioeconomic position and mental illness but lifestyle factors such as obesity, smoking, physical inactivity, and alcohol intake had not been considered. A side-by-side comparison of the magnitude of the relationship of ADHD with conventional risk factors for mortality was also lacking.\n\nAdded value of this studyThis is the first prospective cohort study to systematically and comprehensively test the mechanisms via which ADHD elevates mortality and to contextualize the strength of this relationship against well-established risk factors. Socioeconomic circumstances, physical co-morbidities, and lifestyle factors mediated less than one fifth of the ADHD-death gradient, with the greatest explanatory power apparent for depression and anxiety. The impact of ADHD on mortality risk was commensurate to that apparent for several well-established risk factors for mortality such as poverty, hypertension, and diabetes but somewhat lower than estimates for cigarette smoking and physical inactivity.\n\nImplications of all the available evidenceWhile supporting evidence is required, our findings point to the possibility that modification of physical co-morbidities, lifestyle factors, and mental illness via pharmacological treatment and behavioral intervention may have utility in the avoidance of premature mortality in people with ADHD.","rel_num_authors":5,"rel_authors":[{"author_name":"Haibin Li","author_inst":"Capital Medical University"},{"author_name":"Tamsin Ford","author_inst":"University of Cambridge"},{"author_name":"Varun Warrier","author_inst":"University of Cambridge"},{"author_name":"Steven Bell","author_inst":"UCL"},{"author_name":"George David Batty","author_inst":"University College London"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"STDP-inspired temporal transition modeling for adaptive clinical risk prediction from electronic health records","rel_doi":"10.64898\/2026.06.04.26354919","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354919","rel_abs":"Electronic health record (EHR) prediction models often summarize longitudinal histories as static patient-level features, which may omit potentially informative event ordering. We developed a simplified spike-timing-dependent plasticity (STDP)-inspired framework that represents asynchronous EHR data as sparse, directional transition features. The approach encodes whether one clinical event precedes another within prespecified temporal windows, preserving event identity, directionality, and approximate timing while retaining feature-level interpretability. We evaluated this framework in two retrospective prediction tasks with different temporal scales: incident acute kidney injury (AKI) prediction in 17,351 MIMIC-IV ICU stays and early postoperative recurrence prediction in 713 CUMC patients with pancreatic ductal adenocarcinoma (PDAC). Models were compared with static burden features (demographics, comorbidities, raw lab measurements) and in addition with STDP transitional feature sets using patient-level cross-validation and rolling prediction horizons. In AKI, a calibrated STDP ensemble model showed higher discrimination than static burden alone at the 24-hour decision snapshot for AKI by 72 hours, with AUROC 0.838 versus 0.800, and at 48 hours for near-term AKI prediction, with AUROC 0.868 versus 0.827. In PDAC, STDP transition features modestly improved Day -30 preoperative recurrence prediction, with AUROC 0.611 versus 0.587 and AUPRC 0.323 versus 0.318 for static burden and showed similar performance at Day 0 (7 days before recorded surgery date), with AUROC 0.681 and AUPRC 0.363. Decision-curve and feature analyses suggested that selected temporal transitions were clinically interpretable across renal, inflammatory, hepatobiliary, hematologic, glycemic, and nutritional trajectories. These findings suggest that STDP-inspired transition features may provide a practical, interpretable way to incorporate temporal ordering into EHR-based risk prediction across both acute and longitudinal settings.","rel_num_authors":8,"rel_authors":[{"author_name":"Liyuan Gong","author_inst":"Columbia University"},{"author_name":"Nitish Aswani","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Peter Shahinian","author_inst":"Columbia University"},{"author_name":"Jeong Yun Yang","author_inst":"Columbia University"},{"author_name":"Despina Kontos","author_inst":"Columbia University"},{"author_name":"Gulam Manji","author_inst":"Columbia University"},{"author_name":"Stella Kang","author_inst":"Columbia University"},{"author_name":"Chin Hur","author_inst":"Columbia University"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Neonatal Brain Network Integration Trajectories Predict Neurodevelopment in Congenital Heart","rel_doi":"10.64898\/2026.06.06.26355074","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355074","rel_abs":"Impact statementO_LIIn infants with critical congenital heart disease, perioperative growth in whole-brain network integration was associated with cognitive, language, and motor outcomes in early childhood.\nC_LIO_LIWhite matter injury was associated with slower growth in network integration, whereas cardiac physiology subtype was not associated with network development.\nC_LIO_LIThis study extends prior work by showing that a longitudinal measure of neonatal whole-brain network development, rather than a single imaging timepoint, predicts neurodevelopment across multiple domains.\nC_LIO_LIThese findings identify early network development as a potential biomarker of neurodevelopmental risk and resilience, and support future risk-stratification and intervention studies in this population.\nC_LI\n\nBackgroundInfants with critical congenital heart disease (CHD) are at high risk for abnormal brain development and later neurodevelopmental impairment. We hypothesized that the trajectory of perioperative whole-brain network development would predict neurodevelopmental outcomes in early childhood.\n\nMethodsThis prospective longitudinal cohort of neonates with critical CHD (n = 97) underwent preoperative and\/or postoperative brain MRI with diffusion imaging. Whole-brain network measures were derived from structural connectomes. Neurodevelopment was assessed between 1 and 4 years using the Bayley Scales of Infant and Toddler Development.\n\nResultsWhite matter injury was associated with slower perioperative growth in global efficiency (p = 0.013), a measure of network integration, whereas cardiac physiology was not associated with network development. Infants with greater perioperative increases in global efficiency had higher cognitive (p = 0.001), language (p < 0.001), and motor (p = 0.008) scores. For each 1-standard deviation increase in the trajectory of global efficiency, cognitive scores increased by 8.2 points (95% CI, 3.64-12.78), independent of brain injury and socioeconomic factors.\n\nConclusionIn infants with critical CHD, longitudinal whole-brain network development was associated with neurodevelopment across multiple domains. Early network development may represent a candidate biomarker of neurodevelopmental risk and resilience in this population.","rel_num_authors":7,"rel_authors":[{"author_name":"Lauren Harasymiw","author_inst":"University of California, San Francisco"},{"author_name":"Amy Kuang","author_inst":"University of California, San Francisco"},{"author_name":"Duan Xu","author_inst":"University of California, San Francisco"},{"author_name":"Aaron Scheffler","author_inst":"University of California, San Francisco"},{"author_name":"Elizabeth George","author_inst":"University of California, San Francisco"},{"author_name":"Shabnam Peyvandi","author_inst":"University of California, San Francisco"},{"author_name":"Patrick McQuillen","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Associations between initial treatments for acute low back pain and opioid use disorder and overdose risk in Medicaid patients","rel_doi":"10.64898\/2026.06.05.26355003","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26355003","rel_abs":"IntroductionAcute low back pain is a leading cause of disability worldwide. Clinical guidelines recommend non-pharmacological therapies as first-line treatment and advise caution with opioid prescribing. However pharmacological therapies, including opioids and gabapentinoids, remain commonly used. The comparative risks of subsequent opioid use disorder (OUD) and overdose diagnosis associated with initial treatment modality in large, real-world populations is not well characterized. We estimated the incidence of new-onset OUD and overdose diagnosis among opioid-naive, Medicaid-insured adults with newly diagnosed acute low back pain and estimated the association between initial treatment modalities and subsequent OUD and overdose diagnosis risk.\n\nMethodsWe conducted a retrospective cohort study using Medicaid T-MSIS Analytic files from 25 states (2016-2019). We identified opioid-naive adults with a new diagnosis of acute low back pain who initiated pharmacologic or non-pharmacologic treatment within 1 month of diagnosis. The primary outcome was incident OUD and overdose diagnosis (based on diagnosis codes in claims) during follow-up. Associations between initial treatment modality and OUD and overdose diagnosis risk were estimated using a non-parametric, doubly robust estimator to adjust for measured confounding.\n\nResultsThe cohort included 525,002 opioid-naive adults initiating treatment for low back pain. The cumulative incidence of OUD and overdose diagnosis was 1.5% and 2.4% at 7 and 13 months, respectively. Compared to non-use, use of gabapentinoids during the first month of treatment was associated with the highest relative risk (increasing risk by 130.1%, 95% confidence interval (CI): 117.8%, 142.3%), the second-highest relative risk was estimated for higher-dose opioids, defined as > 50 daily Morphine Milligram Equivalents (MME) (118.1%, 95% CI: 99.2%, 137.0%). Lower-dose, short-duration opioids ([&le;] 50 MME, [&le;] 7 days) were also associated with elevated risk, though substantially smaller in magnitude (20.8%, 95% CI: 13.8%, 27.9%). In contrast, non-pharmacologic, non-interventional therapies were associated with reduced OUD and overdose diagnosis risk, with physical therapy demonstrating the largest relative reduction of 34.0% (95% CI: -40.9%, -27.1%).\n\nDiscussionIn opioid-naive Medicaid patients with acute low back pain, initial non-pharmacologic treatment was associated with reduced OUD and overdose diagnosis risk. Gabapentinoids and opioids were each associated with increased risk; for opioids, the degree of risk increased with higher doses and durations. These results support guideline recommendations favoring non-pharmacologic treatment as first-line therapy and indicate the importance of cautious prescribing when pharmacologic treatment is considered.","rel_num_authors":5,"rel_authors":[{"author_name":"Lisa V Doan","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Anton M Hung","author_inst":"Columbia University"},{"author_name":"Mark Olfson","author_inst":"Columbia University"},{"author_name":"Nicholas T Williams","author_inst":"University of California at Berkeley"},{"author_name":"Kara E Rudolph","author_inst":"Columbia University"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry analysis of POLG variants in Parkinson's disease","rel_doi":"10.64898\/2026.06.07.26354811","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354811","rel_abs":"IntroductionVariants in the polymerase gamma (POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinsons disease (PD); yet, results remain inconclusive.\n\nObjectivesTo investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries.\n\nMethodsWe leveraged multi-ancestry genetic data from the Global Parkinsons Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses.\n\nResultsFive PD cases carried potentially biallelic rare pathogenic\/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic\/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD.\n\nConclusionsPOLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG-related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.","rel_num_authors":14,"rel_authors":[{"author_name":"Yi Wen Tay","author_inst":"University of Malaya, Malaysia"},{"author_name":"Inas Elsayed","author_inst":"University of Gezira, Wad Medani, Sudan"},{"author_name":"Dennis Yeow","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Mikayla James","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Pin-Jui Kung","author_inst":"National Taiwan University Hospital, Taipei, Taiwan"},{"author_name":"Laurel Screven","author_inst":"GP2, Bethesda, USA"},{"author_name":"Allison A. Dilliott","author_inst":"Parkinsons Foundation, NewYork, NY 10018, USA"},{"author_name":"Roy N. Alcalay","author_inst":"Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"Zih-Hua Fang","author_inst":"DataTecnica LLC, Washington, DC 20037, USA"},{"author_name":"Ai Huey Tan","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"- Global Parkinson's Genetics Program (GP2)","author_inst":"-"},{"author_name":"Carolyn M Sue","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Lara M Lange","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Maria Teresa Perinan","author_inst":"Queen Mary University of London, London, United Kingdom"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry analysis of POLG variants in Parkinson's disease","rel_doi":"10.64898\/2026.06.07.26354811","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354811","rel_abs":"IntroductionVariants in the polymerase gamma (POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinsons disease (PD); yet, results remain inconclusive.\n\nObjectivesTo investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries.\n\nMethodsWe leveraged multi-ancestry genetic data from the Global Parkinsons Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses.\n\nResultsFive PD cases carried potentially biallelic rare pathogenic\/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic\/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD.\n\nConclusionsPOLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG-related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.","rel_num_authors":14,"rel_authors":[{"author_name":"Yi Wen Tay","author_inst":"University of Malaya, Malaysia"},{"author_name":"Inas Elsayed","author_inst":"University of Gezira, Wad Medani, Sudan"},{"author_name":"Dennis Yeow","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Mikayla James","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Pin-Jui Kung","author_inst":"National Taiwan University Hospital, Taipei, Taiwan"},{"author_name":"Laurel Screven","author_inst":"GP2, Bethesda, USA"},{"author_name":"Allison A. Dilliott","author_inst":"Parkinsons Foundation, NewYork, NY 10018, USA"},{"author_name":"Roy N. Alcalay","author_inst":"Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"Zih-Hua Fang","author_inst":"DataTecnica LLC, Washington, DC 20037, USA"},{"author_name":"Ai Huey Tan","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"- Global Parkinson's Genetics Program (GP2)","author_inst":"-"},{"author_name":"Carolyn M Sue","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Lara M Lange","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Maria Teresa Perinan","author_inst":"Queen Mary University of London, London, United Kingdom"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Stochastic Morphodynamics of the Human Aorta Across the Lifespan","rel_doi":"10.64898\/2026.06.05.26355015","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26355015","rel_abs":"Biological systems evolve as continuous dynamical processes, but at organ-scale and across human lifespans they are rarely observed longitudinally---population data typically exist instead as sparse, cross-sectional snapshots. Inferring lifespan dynamics from such data requires methods distinct from those used at cellular and tissue scales where dense observations are accessible. We address this problem in the thoracic aorta, where surgical decisions currently rest on static, age- and sex-agnostic diameter thresholds that reduce three-dimensional morphology to a single scalar. Treating normal aortic morphology as a stochastic dynamical system, we pose a continuous-time drift-diffusion process in a two-coordinate state space of normalized surface area (A) and normalized fluctuation in integrated Gaussian curvature [Formula], and fit closed-form solutions of the Fokker-Planck equation by maximum likelihood to a sex-balanced, age-uniform cohort spanning infancy to age 99. Inter-individual variability is treated as a fitted diffusion parameter rather than as residual scatter, which is distinct from prior normative studies that report variability as scatter around a regression line. The framework identifies two growth regimes for aortic size (childhood expansion followed by persistent adult growth, with adult males growing approximately 70% faster than adult females) and a single dynamical regime for aortic shape, with heteroscedastic variability accumulating at a rate comparable to the mean drift over the lifespan. Applied to independent cohorts of acute and chronic thoracic aortic dissections, the multivariate model identifies over 95% as statistical outliers via Mahalanobis distance, consistently outperforming either coordinate alone. The same probabilistic envelope that describes normal aging thus defines a baseline against which disease can be detected, supporting a shift toward dynamic, age- and sex-aware assessment of thoracic aortic pathology.","rel_num_authors":6,"rel_authors":[{"author_name":"Kelly C. Twohig","author_inst":"University of Chicago"},{"author_name":"Michael Mansour","author_inst":"University of Chicago"},{"author_name":"Joseph A. Pugar","author_inst":"University of Chicago"},{"author_name":"Karen Yuan","author_inst":"Northwestern University"},{"author_name":"Luka Pocivavsek","author_inst":"University of Chicago"},{"author_name":"Andrei A. Klishin","author_inst":"University of Hawai'i at Manoa"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Parental educational attainment polygenic scores contribute to phenotypic heterogeneity in offspring with autism","rel_doi":"10.64898\/2026.06.03.26354779","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354779","rel_abs":"Educational attainment-related polygenic scores have been implicated in autism spectrum disorder (ASD), but how parental polygenic scores shape offspring phenotypes remains unclear. Using genotyping and exome-sequencing data from 142,357 individuals (55,252 ASD cases) in a large ASD cohort, we dissected the direct and indirect genetic effects of educational attainment-related polygenic scores on ASD phenotypes. Trio-model analyses showed that parental polygenic scores for educational attainment (PGSEA) were associated with milder core ASD symptoms, including social deficits and repetitive behaviors, predominantly through indirect genetic effects, whereas their associations with comorbidities were driven predominantly by direct genetic effects. PGSEA was also significantly negatively associated with rare variant burden and prenatal factors, although these factors contributed largely independently to most phenotypes. Adjustment for full-scale intelligence quotient (FSIQ) and socioeconomic status (SES) partially attenuated the indirect effects of PGSEA on offspring phenotypes. Finally, higher parental PGSEA was associated with later age at diagnosis in offspring, partly through its protective effects on ASD phenotypes. These findings indicate that indirect genetic effects of parental PGSEA contribute substantially to phenotypic variation in ASD and highlight family-mediated pathways as an important component of ASD heterogeneity.","rel_num_authors":7,"rel_authors":[{"author_name":"Shilin Gao","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Yang Sui","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA."},{"author_name":"Panhui Tian","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Xiaoli Rao","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Chenghao Yan","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Yue Xu","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Tianyun Wang","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Integrated cardiometabolic and nutritional risk profiling identifies pregnancy loss as a marker of systemic metabolic vulnerability","rel_doi":"10.64898\/2026.06.04.26354910","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354910","rel_abs":"BackgroundPregnancy loss has important implications for womens health. Although maternal age is a well-established risk factor, the contribution of routinely measured cardiometabolic and behavioral markers at population-scale remains incompletely characterized.\n\nObjectiveTo examine associations between cardiometabolic, nutritional, and behavioral risk markers and pregnancy loss among U.S. women of reproductive age.\n\nMethodsWe conducted a cross-sectional analysis of 4,842 U.S. women aged 20-44 years with [&ge;]1 pregnancy using the National Health and Nutrition Examination Survey data (2013-2023). Pregnancy loss was defined as [&ge;]1 prior miscarriages. Exposures included body mass index, smoking exposure (cotinine), lipid biomarkers, vitamin D and folate, and a composite cardiometabolic-nutritional risk score. Survey-weighted logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals, with bootstrap resampling for predictor robustness.\n\nResultsThe weighted prevalence of pregnancy loss was 23%. Higher odds of pregnancy loss were associated with increasing age (aOR per year=1.02; 95% CI: 1.00-1.04), Non-Hispanic Black race (aOR=1.32; 95% CI: 1.00-1.74), overweight (aOR=1.56; 95% CI: 1.16-2.11), obesity (aOR=2.06; 95% CI: 1.39-3.05), and smoking (aOR=1.58; 95% CI: 1.19-2.10).\n\nAdverse lipid profiles, particularly elevated triglycerides (aOR=1.83; 95% CI: 1.16-2.90) and high low-density lipoprotein (aOR=2.97; 95% CI: 1.45-6.61), were independently associated with pregnancy loss. Vitamin D\/folate were not stable predictors. Higher composite cardiometabolic-nutritional risk scores were observed among women with pregnancy loss (P=0.026).\n\nConclusionPregnancy loss clustered with adverse cardiometabolic and behavioral risk markers in a nationally representative population. These findings highlight pregnancy loss as a marker of broader metabolic vulnerability supporting the need for longitudinal studies and cardiometabolic profiling to inform preconception care and risk stratification.","rel_num_authors":3,"rel_authors":[{"author_name":"Tanya Agarwal","author_inst":"Rutgers University: Rutgers The State University of New Jersey"},{"author_name":"Janaki  Ramya Namburu","author_inst":"Rutgers University: Rutgers The State University of New Jersey"},{"author_name":"Priyadarshini Kachroo","author_inst":"Rutgers The State University of New Jersey"}],"rel_date":"2026-06-08","rel_site":"medrxiv"}]}