{"gname":"Vanderbilt University","grp_id":"30","rels":[{"rel_title":"Attenuation of typical sex differences in the time-resolved functional connectivity of the fusiform gyrus in autism","rel_doi":"10.64898\/2026.06.02.26354318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354318","rel_abs":"Background Autism is characterized by social-communicative difficulties, with sex differences in symptom presentation. Social functioning is inherently dynamic, however, many neuroimaging studies rely on static, time-averaged approaches that obscure time-varying network interactions, potentially limiting our ability to capture the dynamic processes underlying social cognition. The fusiform gyrus (FFG), central to face and social perception, shows differences in functional connectivity in autism, yet is rarely examined dynamically or as a spatially heterogeneous structure. Here, we investigate the dynamic functional connectivity of FFG subregions in terms of their large-scale network configurations as a function of diagnosis and sex. Methods We applied micro co-activation patterns analysis (CAPs) to resting-state fMRI data from 286 autistic individuals (208:78 males:females) and 228 non-autistic individuals (146:82 males:females), aged 6-30 years, from the EU-AIMS LEAP dataset. CAPs were identified using k-means clustering with FFG as the seed, and connectopic mapping positioned each CAP along the principal connectivity gradient. We quantified CAPs occurrence and further examined dwell time, transition probabilities, and spatial extent, along with associations with social functioning. Results Six CAPs mapped onto distinct FFG subregions along a posterior-anterior axis. A significant sex-by-diagnosis interaction emerged for a default mode network (DMN)-related CAP. Non-autistic females exhibited significantly more frequent occurrences, longer dwell times and distinct transition dynamics compared to males, while no sex difference was observed in autism. The spatial extent of this CAP showed a reversal of typical sex effects. Conclusions Autism is associated with an attenuation and reversal of typical sex differences in the functional configuration and spatial extent of FFG-DMN coupling, indicating that neural signatures of social-cognitive functions are sex-specific and dynamic. These findings suggest that sex is a neurobiologically meaningful dimension of heterogeneity in autism, expressed in dynamic network organization.","rel_num_authors":21,"rel_authors":[{"author_name":"Dorothea Lilli Floris","author_inst":"University of Zurich"},{"author_name":"Luigi F Saccaro","author_inst":"University of Geneva"},{"author_name":"Farnaz Delavari","author_inst":"University of Geneva"},{"author_name":"Dawid Strzelczyk","author_inst":"University of Zurich"},{"author_name":"Bruno Hebling Vieira","author_inst":"University of Zurich"},{"author_name":"Camille Elleaume","author_inst":"University of Zurich"},{"author_name":"Charlotte M. Pretzsch","author_inst":"King's College London Institute of Psychiatry Psychology & Neuroscience"},{"author_name":"Christine Ecker","author_inst":"University Hospital of the Goethe University Frankfurt am Main"},{"author_name":"Tobias Banaschewski","author_inst":"Heidelberg University"},{"author_name":"Rosemary J. Holt","author_inst":"University of Cambridge"},{"author_name":"Simon Baron-Cohen","author_inst":"University of Cambridge"},{"author_name":"Thomas Bourgeron","author_inst":"Institut Pasteur"},{"author_name":"Tony Charman","author_inst":"King's College London Institute of Psychiatry Psychology & Neuroscience"},{"author_name":"Eva Loth","author_inst":"King's College London Institute of Psychiatry Psychology & Neuroscience"},{"author_name":"Declan Murphy","author_inst":"King's College London Institute of Psychiatry Psychology & Neuroscience"},{"author_name":"Jan K. Buitelaar","author_inst":"Radboud University Medical Center"},{"author_name":"Christian Beckmann","author_inst":"Radboud University Medical Center"},{"author_name":"Dimitri Van De Ville","author_inst":"University of Geneva"},{"author_name":"- APEX consortium","author_inst":"-"},{"author_name":"- EU-AIMS LEAP consortium","author_inst":"-"},{"author_name":"Nicolas Langer","author_inst":"University of Zurich"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Neighborhood Deprivation and Racial Disparities in Metastatic Prostate Cancer at Diagnosis: A Population-Based Study in Ohio","rel_doi":"10.64898\/2026.06.02.26354723","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354723","rel_abs":"Background: Prostate cancer survival varies by stage at diagnosis, and Black men experience a disproportionate burden of advanced disease. We examined whether neighborhood deprivation, measured by Area Deprivation Index (ADI), contributes to racial differences in metastatic presentation. Methods: We conducted a population-based study of men diagnosed with prostate cancer in the Ohio Cancer Incidence Surveillance System from 1996 to 2016. The primary endpoint was distant-stage disease at diagnosis. Generalized additive models assessed nonlinear associations of ADI and diagnosis year with metastatic risk. Inverse probability of treatment weighting (IPTW) models estimated odds ratios comparing Black with White men after sequential adjustment for diagnosis year, age, insurance, and ADI. Results: Among 135,095 men, 18,690 were Black and 116,405 were White. Distant-stage disease occurred in 7.0% of Black men and 5.0% of White men. Black men had higher median ADI (60.9 vs. 47.3). Medicaid-insured men had the highest unadjusted odds of metastatic presentation (OR, 4.68; 95% CI, 4.13-5.31), exceeding uninsured men (OR, 2.91; 95% CI, 2.54-3.34). In IPTW models without age adjustment, the odds ratio decreased from 1.54 to 1.24 after adding insurance and ADI. In age-adjusted IPTW models, the odds ratio decreased from 1.79 to 1.41 after adding insurance and ADI. Generalized additive models showed increasing metastatic risk at higher ADI values and after 2008. Conclusions: Neighborhood deprivation and insurance-related access explained part, but not all, of the excess odds of metastatic diagnosis among Black men. Impact: Integrating ADI into cancer surveillance may improve identification of populations at risk for late-stage diagnosis.","rel_num_authors":7,"rel_authors":[{"author_name":"Julia Y Payne","author_inst":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio"},{"author_name":"Stephen Rhodes","author_inst":"Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio"},{"author_name":"Jonathan Shoag","author_inst":"Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio"},{"author_name":"Michael Rothberg","author_inst":"Center for Value-Based Care Research, Primary Care Institute, Cleveland Clinic, Cleveland, Ohio"},{"author_name":"Phuc Le","author_inst":"Center for Value-Based Care Research, Primary Care Institute, Cleveland Clinic, Cleveland, Ohio"},{"author_name":"Jennifer Cullen","author_inst":"Dr. Mary and Ron Neal Cancer Center, Houston Methodist Research Institute, Houston, Texas"},{"author_name":"Holly Hartman","author_inst":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Powassan Virus Seroprevalence in a U.S. Servicemember Population at High Risk for Tick Exposure","rel_doi":"10.64898\/2026.06.02.26354611","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354611","rel_abs":"Powassan virus (POWV) is an emerging tick-borne flavivirus that can cause severe encephalitis in humans. Currently no vaccines or therapeutics are approved to treat POWV. POWV is spread by the deer tick, Ixodes scapularis, which is ubiquitous across the Northeastern United States. To better understand POWV prevalence in high-risk populations, we examined POWV seroprevalence in Cadets at United States Military Academy (USMA) in West Point, New York. Cadets at USMA, located in a heavily wooded area, are at high risk for tick exposure during outdoor military training. 1,051 serum samples from the Cadet class of 2017 were screened for POWV seropositivity using a POWV Envelope (E) DIII ELISA. A seropositivity rate of 1.3% was determined. Several ELISA-positive samples were also able to neutralize both reporter virus particles bearing the POWV E protein and authentic POWV. This study demonstrates populations at risk for tick exposure may have significant seroprevalence of POWV.","rel_num_authors":27,"rel_authors":[{"author_name":"Alexandra L. Tse","author_inst":"Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx NY"},{"author_name":"Zoey Dipasqua","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Joelle El Hamouche","author_inst":"Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx NY"},{"author_name":"Georgia Fallon","author_inst":"Albert Einstein College of Medicine, Department of Biochemistry, Bronx, NY"},{"author_name":"Kira E. Enos","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Griffin C. Horowicz","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Michael J. Rossen","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Wyatt V. Chapman","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"McKenzie N. Daffin","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Kayla A. Kiniry","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Alexis Jankovich","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Joshua S. Choy","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Audrey R. Whitfield","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Beth A. Bachert","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Erik Cazares","author_inst":"United Sates Army Medical Research Institute of Infectious Diseases Viral Immunology Branch, Fort Detrick, MD"},{"author_name":"Gorka Lasso","author_inst":"Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx NY"},{"author_name":"Justin E. Jones","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Stacey L. Bateman","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Daniel Gordon","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Shauna L. Stahlman","author_inst":"Defense Health Agency, Public Health Directorate, Armed Forces Health Surveillance Division, Epidemiology and Analysis Branch, Silver Spring, MD"},{"author_name":"Andrew S. Herbert","author_inst":"United Sates Army Medical Research Institute of Infectious Diseases Viral Immunology Branch, Fort Detrick, MD"},{"author_name":"Catalina Florez","author_inst":"United Sates Army Medical Research Institute of Infectious Diseases Viral Immunology Branch, Fort Detrick, MD"},{"author_name":"Jonathan R. Lai","author_inst":"Albert Einstein College of Medicine, Department of Biochemistry, Bronx, NY"},{"author_name":"Kartik Chandran","author_inst":"Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx NY"},{"author_name":"Kevin J. ODonovan","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Jeremy R. Hershfield","author_inst":"United States Military Academy, Department of Life Sciences, Highland Falls, NY"},{"author_name":"Emily Happy Miller","author_inst":"Albert Einstein College of Medicine, Department of Medicine, Bronx, NY"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Antidepressant desvenlafaxine identified in wastewater promotes transformation and antibiotic resistance risk in Acinetobacter baylyi via metabolic adaptations","rel_doi":"10.64898\/2026.06.02.26353323","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26353323","rel_abs":"Wastewater treatment plants (WWTPs) are known reservoirs of antibiotic resistance genes (ARGs). Non-antibiotic compounds such as antidepressants may further promote ARG acquisition through horizontal gene transfer (HGT). Desvenlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI) listed on the EU Surface Water Watch Lists, is among the most frequently detected antidepressants in WWTP effluents, yet its role in HGT has not been examined. Here, we detected desvenlafaxine at the highest concentrations among four antidepressants monitored across three municipal WWTPs in western New York. Using Acinetobacter baylyi ADP1 as a model recipient in natural transformation assays (n = 6), we found that desvenlafaxine significantly increased transformation frequency at 10 mg\/L (1.74 {+\/-} 0.33-fold) and 50 mg\/L (1.49 {+\/-} 0.19-fold; Padj < 0.05). Effects were independent of reactive oxygen species or membrane permeability stress, consistent with its very low toxicity (IC20 ~1353 mg\/L). Instead, desvenlafaxine induced dose-dependent increases in membrane fluidity and shifts to less negative zeta potentials, suggesting that electrostatic interactions between its cationic amine group and the negatively charged membrane reduce surface repulsion and facilitate plasmid proximity during uptake. Non-targeted proteomics revealed a biphasic response: at 10 mg\/L, competence-associated proteins (PilB, ComM) were upregulated and STRING analysis identified networks linked to membrane transport, transcriptional regulation, and envelope remodeling, while no connected network was recovered at 50 mg\/L. Electron microscopy confirmed higher pili frequency at both doses. Together, these findings reveal an overlooked role of this non-antibiotic pharmaceutical in promoting ARG spread from wastewater environments.","rel_num_authors":6,"rel_authors":[{"author_name":"Najmuj Sakib","author_inst":"Iowa State University"},{"author_name":"Liezel Abaya","author_inst":"University at Buffalo"},{"author_name":"Brandon Ruddell","author_inst":"Iowa State University"},{"author_name":"Diana Aga","author_inst":"University at Buffalo"},{"author_name":"Adina Howe","author_inst":"Iowa State University"},{"author_name":"Laura R Jarboe","author_inst":"Iowa State University"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Low Self-Efficacy and Depression Predict Non-Viral Suppression Among Ugandan Women Living with HIV Using the ACTG Adherence Questionnaire","rel_doi":"10.64898\/2026.06.02.26354671","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354671","rel_abs":"Background Studies show 53 to 74% of women living with HIV experience postpartum ART adherence challenges. Viral load testing is a delayed indicator, highlighting the need for culturally appropriate screening tools to identify at-risk women early. This study examined the association between non-viral suppression and constructs within the AIDS Clinical Trials Group (ACTG) adherence questionnaire among women in Uganda to inform timely, targeted interventions to improve adherence. Methods The ACTG was adapted, and postpartum participants completed ACASI or Provider-Assisted Interviews (PAIs). Self-efficacy, social support, anxiety, depression, viral load, and clinical factors were analysed using mixed-effects logistic models over a 1-year period. Results Of 166 women, 21 completed ACASI and 145 PAIs. 4.2% (7\/166) were not virally suppressed at baseline, and their non-suppression status was consistent throughout one year of follow-up. High self-efficacy scores were associated with 27% lower odds of viral non-suppression (Odds Ratio [OR], 0.73; 95% CI, 0.54, 0.98). High depression scores were associated with 22% higher odds of non-suppression (OR 1.22;95% (1.01,1.49). Other variables, including age, Body Mass Index, duration on ART, marital status, employment, education level, tap water, and travel time from home to clinic, were not associated with viral suppression in the covariate-adjusted analyses. Median self-efficacy and depression scores were 8 (IQR 1,9) and 1.2 (IQR 0,16), respectively. Focused group discussion data showed high acceptability and feasibility of using the ACTG adherence questionnaire in Uganda. Conclusion Lower self-efficacy and higher depression scores on the ACTG adherence questionnaire can help identify Ugandan women at risk of viral non-suppression in HIV programs. Keywords WLHIV, Antiretroviral Therapy, Adherence, Audio Computer Assisted Self Interview, Viral load","rel_num_authors":9,"rel_authors":[{"author_name":"Patience Atuhaire","author_inst":"Makerere University-John Hopkins University Research Collaboration: MU-JHU Care Limited"},{"author_name":"Martin Nabwana","author_inst":"MU-JHU Research Collaboration"},{"author_name":"Juliane Etima","author_inst":"MU-JHU Research Collaboration"},{"author_name":"Jim Aizire","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Taha Taha","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Lynn Atuyambe","author_inst":"Makerere University CHS: Makerere University College of Health Sciences"},{"author_name":"Arthur Owora","author_inst":"Indiana University Bloomington School of Public Health"},{"author_name":"Monica Nolan","author_inst":"MU-JHU Research Collaboration"},{"author_name":"Mary Glenn Fowler","author_inst":"Johns Hopkins University, Department of Pathology and Epidemiology"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Comfort with AI for HIV Prevention Among Cisgender Women in New York City","rel_doi":"10.64898\/2026.06.02.26354471","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354471","rel_abs":"Background: Long-acting pre-exposure prophylaxis (PrEP) expands HIV prevention options for women. However, PrEP impact depends on addressing persistent gaps in awareness, access, and use. Artificial intelligence (AI) tools, including conversational agents, are being explored to advance PrEP uptake, but comfort with AI may influence their impact. Thus, we examined women's comfort with AI and its association with PrEP awareness. Methods: We analyzed self-reported data from women aged [&ge;]18 years in a cross-sectional survey conducted in New York City from August 2023 to August 2024. We performed descriptive analyses, applied latent class analysis to identify AI knowledge\/comfort profiles, and estimated unadjusted and adjusted odds ratios to assess associations between profile membership and PrEP awareness. Results: Among 306 respondents without a diagnosis of HIV who completed AI-related survey items, the median age was 36. Most women identified as Hispanic\/Latina (60%) or Non-Hispanic Black (18%), had not completed college (53%), and spoke only English or were bilingual (81%). Latent class analysis identified four AI knowledge\/comfort profiles that differed by PrEP awareness, race\/ethnicity, borough, prior drug use, and technology utilization. Women with varied AI knowledge, broad AI discomfort, and comfort with clinicians maintaining privacy had lower odds of PrEP awareness (OR: 0.35, 95% CI: 0.16-0.75), but this association did not persist after statistical adjustment. Conclusions: PrEP awareness and AI knowledge were limited, yet many women expressed openness to AI-enabled tools when privacy was assured. AI-enabled HIV prevention tools should prioritize trust, transparency, confidentiality, and the lived contexts of the women they intend to serve.","rel_num_authors":14,"rel_authors":[{"author_name":"Harry Reyes Nieva","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Max Flanagan","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Simian Huang","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Deborah A Theodore","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Amelie Foumena Nkodo","author_inst":"Brown Alpert Medical School, Rhode Island Hospital"},{"author_name":"Melissa Parkinson","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Sarah Hill","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Megan McAndrew","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Jorge A Benitez","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Henry Peralta","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Sylvia Amesty","author_inst":"Department of Medical Humanities and Ethics, Columbia University Irving Medical Center"},{"author_name":"Jason E Zucker","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Magdalena Sobieszczyk","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"},{"author_name":"Delivette Castor","author_inst":"Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Medication-Wide Association Study of Alzheimer's Disease and Related Dementias: Identifying Drug Candidates from Electronic Health Records through Explainable AI","rel_doi":"10.64898\/2026.06.02.26354752","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354752","rel_abs":"Objective: Alzheimer's disease (AD) is a leading cause of death and disability, and treatment options for Alzheimer's disease and related dementias (ADRD) remain limited. We applied a data-driven, mechanism-agnostic Medication-Wide Association Study Plus (MWAS+) framework to identify candidate medications associated with ADRD using longitudinal electronic health record data and explainable artificial intelligence (AI). Methods: We used Veterans Health Administration electronic health record data from January 1999 to May 2022. The initial study population comprised 8,424,715 Veterans aged 65 years or older. Cases were defined by ADRD-related diagnosis codes or ADRD-related medication prescriptions, and controls were free of ADRD diagnosis and ADRD-related medication use. After exclusions and matching on sex, race, age at first encounter, and duration of follow-up, the primary analytic cohort included 505,817 matched case-control pairs (1:1; 1,011,634 Veterans). Longitudinal features were extracted from historical data up to 1 year before the index date and aggregated into 1-year intervals. We developed an upgraded Hybrid Value-Aware Transformer (HVAT 2.0) to jointly learn from longitudinal and nonlongitudinal clinical data while incorporating numerical values associated with clinical concepts, including cumulative medication dose. To enhance interpretability, we applied a medication-specific impact score method to estimate model-derived associations between medication exposure and ADRD risk. Findings: The model demonstrated stable performance across data partitions, with area under the receiver operating characteristic curve values of 0.791 in the training set, 0.772 in the validation set, and 0.775 in the testing set. Metolazone and varenicline were identified as the top 2 candidate medications with negative impact scores, suggesting potentially protective associations with new-onset ADRD. The impact score was -0.196 per unit of cumulative dose for metolazone (1800 mg) and -0.134 per unit for varenicline (280 mg). Although individual-level impact scores varied, most exposed patients had negative scores, including 12,020 of 12,480 metolazone users (96%) and 8,341 of 8,786 varenicline users (95%). Implications: This study demonstrates the feasibility of combining a medication-wide association framework, longitudinal dose-aware modeling, and explainable AI to identify candidate medications for ADRD from real-world electronic health record data. The findings should be interpreted as signals for hypothesis generation rather than evidence of causality. This framework may support prioritization of repurposing candidates for expert review, follow-up cohort validation, and future clinical investigation.","rel_num_authors":11,"rel_authors":[{"author_name":"Yijun Shao","author_inst":"George Washington University, Washington, DC, United States"},{"author_name":"Ying Yin","author_inst":"George Washington University, Washington, DC, United States"},{"author_name":"Yan Cheng","author_inst":"George Washington University, Washington, DC, United States"},{"author_name":"John E. McGeary","author_inst":"Brown University, Providence, RI, United States"},{"author_name":"Tracy H. Taveira","author_inst":"Brown University, Providence, RI, United States"},{"author_name":"Debby W. Tsuang","author_inst":"University of Washington, Seattle, WA, United States"},{"author_name":"Mark W. Logue","author_inst":"Department of Psychiatry and Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"},{"author_name":"Siamack Ayandeh","author_inst":"Washington DC VA Medical Center, Washington, DC, United States"},{"author_name":"Ali Ahmed","author_inst":"Washington DC VA Medical Center, Washington, DC, United States"},{"author_name":"Edward Zamrini","author_inst":"Washington DC VA Medical Center, Washington, DC, United States"},{"author_name":"Qing Zeng-Treitler","author_inst":"George Washington University, Washington, DC, United States"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Lifetime adversity exposure, mood symptoms, and immune mitochondrial bioenergetics","rel_doi":"10.64898\/2026.06.02.26354718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354718","rel_abs":"Despite their prevalence, the pathophysiology of depression and anxiety remains poorly understood. Although adversity is a known risk factor, the mechanisms and biological contexts through which it contributes to mood disorder symptoms remain unclear. Immune and mitochondrial adaptations have both been implicated in mood disorders, suggesting the biological embedding of adversity may involve both systems. However, inconsistencies in the literature remain, partly due to reliance on mixed peripheral blood mononuclear cell (PBMC) populations despite substantial variability in mitochondrial biology across immune cell subtypes. We therefore investigated associations between adversity, mood disorder symptoms, immune cell proportions, and immune cell-specific mitochondrial bioenergetics (enzyme activities and respirometry) in participants from the Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study (n=105, age 18-60, 68% female, 35% with mitochondrial disease). Depressive and anxiety symptoms were positively associated with the monocyte-to-lymphocyte ratio, suggesting a shift toward greater innate relative to adaptive immunity. Associations between mood disorder symptoms and immune cell count were stronger in those exposed to greater early life adversity. Mood disorder symptoms were negatively associated with lymphocyte maximal mitochondrial respiratory capacity (MRC). As expected, the associations between mood disorder symptoms and lymphocyte mitochondrial bioenergetics (enzyme-based MRC and respiratory measurements) were stronger and more consistent among individuals exposed to higher lifetime adversity compared to those with lower lifetime adversity. Overall, these results suggest a complex interplay between adversity, immune cell mitochondrial bioenergetics, and mood disorder symptoms, highlighting immune mitochondrial biology as a potential allostatic pathway linking adversity to psychiatric disorders.","rel_num_authors":11,"rel_authors":[{"author_name":"Cynthia C Liu","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Catherine Kelly","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Anna S Monzel","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Mandakh Bekhbat","author_inst":"Emory University"},{"author_name":"Natalia Bobba-Alves","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Veronica Ramirez","author_inst":"University of California, Irvine"},{"author_name":"George M Slavich","author_inst":"University of California, Irvine"},{"author_name":"Robert-Paul Juster","author_inst":"University of Montreal"},{"author_name":"Steve W Cole","author_inst":"University of California, Los Angeles"},{"author_name":"Martin Picard","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Caroline Trumpff","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Lifetime adversity exposure, mood symptoms, and immune mitochondrial bioenergetics","rel_doi":"10.64898\/2026.06.02.26354718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354718","rel_abs":"Despite their prevalence, the pathophysiology of depression and anxiety remains poorly understood. Although adversity is a known risk factor, the mechanisms and biological contexts through which it contributes to mood disorder symptoms remain unclear. Immune and mitochondrial adaptations have both been implicated in mood disorders, suggesting the biological embedding of adversity may involve both systems. However, inconsistencies in the literature remain, partly due to reliance on mixed peripheral blood mononuclear cell (PBMC) populations despite substantial variability in mitochondrial biology across immune cell subtypes. We therefore investigated associations between adversity, mood disorder symptoms, immune cell proportions, and immune cell-specific mitochondrial bioenergetics (enzyme activities and respirometry) in participants from the Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study (n=105, age 18-60, 68% female, 35% with mitochondrial disease). Depressive and anxiety symptoms were positively associated with the monocyte-to-lymphocyte ratio, suggesting a shift toward greater innate relative to adaptive immunity. Associations between mood disorder symptoms and immune cell count were stronger in those exposed to greater early life adversity. Mood disorder symptoms were negatively associated with lymphocyte maximal mitochondrial respiratory capacity (MRC). As expected, the associations between mood disorder symptoms and lymphocyte mitochondrial bioenergetics (enzyme-based MRC and respiratory measurements) were stronger and more consistent among individuals exposed to higher lifetime adversity compared to those with lower lifetime adversity. Overall, these results suggest a complex interplay between adversity, immune cell mitochondrial bioenergetics, and mood disorder symptoms, highlighting immune mitochondrial biology as a potential allostatic pathway linking adversity to psychiatric disorders.","rel_num_authors":11,"rel_authors":[{"author_name":"Cynthia C Liu","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Catherine Kelly","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Anna S Monzel","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Mandakh Bekhbat","author_inst":"Emory University"},{"author_name":"Natalia Bobba-Alves","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Veronica Ramirez","author_inst":"University of California, Irvine"},{"author_name":"George M Slavich","author_inst":"University of California, Irvine"},{"author_name":"Robert-Paul Juster","author_inst":"University of Montreal"},{"author_name":"Steve W Cole","author_inst":"University of California, Los Angeles"},{"author_name":"Martin Picard","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Caroline Trumpff","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"MealRes-Gate: Forecasting Glucose Dynamics from CGM and Sparse Meal Logs Using Residual-Gated Multimodal Transformer","rel_doi":"10.64898\/2026.06.01.26354646","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354646","rel_abs":"Continuous glucose monitoring (CGM) enables personalized metabolic health support, but forecasting glucose in free-living settings remains challenging because future trajectories depend on both endogenous dynamics and sparsely recorded meals. We developed MealRes-Gate, a multimodal transformer that incorporates meal information as a gated residual refinement to a strong CGM-based backbone. In 1,752 non-diabetic and pre-diabetic adults from the Framingham Heart Study, MealRes-Gate consistently outperformed recurrent, Transformer-based, and GluFormer baselines across 30-, 60-, 90-, and 120-minute horizons. Gains were largest in postprandial, high glucose, and low glucose windows, and extended to clinically relevant postprandial summaries that included peak glucose, time-to-peak, and glucose area under the curve. Ablation analysis showed that engineered CGM features provided the dominant predictive backbone, while explicit meal features contributed smaller but meaningful gains when integrated through the proposed residual-gating mechanism. These results demonstrate that sparse dietary information can improve glucose forecasting without destabilizing prediction, provided it is incorporated through a selective, residual gating mechanism.","rel_num_authors":11,"rel_authors":[{"author_name":"Jung Lee","author_inst":"Boston University"},{"author_name":"Suheng Yao","author_inst":"Boston University"},{"author_name":"Lin Tang","author_inst":"Boston University"},{"author_name":"Xiaowei Yu","author_inst":"Missouri University of Science and Technology"},{"author_name":"Michael Cheney","author_inst":"Boston University"},{"author_name":"Honghuan Lin","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Xuezhou Zhang","author_inst":"Boston University"},{"author_name":"Debarghya Mukherjee","author_inst":"Boston University"},{"author_name":"Maura Walker","author_inst":"Boston University"},{"author_name":"Nicole Spartano","author_inst":"Boston University"},{"author_name":"Huimin Cheng","author_inst":"Boston University"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Oxygen extraction fraction brain charts for human lifespan and application for brain disorders","rel_doi":"10.64898\/2026.06.02.26354684","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354684","rel_abs":"Cerebral oxygen extraction fraction (OEF) reflects the balance between cerebral oxygen delivery and metabolic demand, but its normative evolution across the human lifespan remains unknown. Here we used rapid, non-contrast TRUST MRI to establish a multisite normative model of global cerebral OEF in 2,025 healthy individuals aged 0-93 years from 17 imaging sites. OEF increased from the neonatal period to middle adulthood, followed by a slower rise and plateau in later life, with the fastest change occurring during early development and no significant sex differences. Individual OEF deviation scores were associated with vascular risk burden in healthy adults. Applying the model to 885 patients revealed disease-related OEF alterations, including positive deviations in pediatric obstructive sleep apnea, autoimmune disorders, brain tumors, mild cognitive impairment and dementia. OEF deviation further tracked tumor grade and Ki-67 proliferation. These findings establish lifespan OEF charting as a scalable framework for individualized physiological neuroimaging.","rel_num_authors":51,"rel_authors":[{"author_name":"Zixuan Lin","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Xiang Fan","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Tianyu Gao","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"},{"author_name":"Shuyue Wang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Yiwen Hong","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Yifan Yan","author_inst":"Department of Psychiatry, School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jianpeng Liu","author_inst":"Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yuchuan Fu","author_inst":"The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China"},{"author_name":"Tao Hua","author_inst":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yue Cai","author_inst":"Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China"},{"author_name":"Gaigai Lu","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Ying Qi","author_inst":"Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China"},{"author_name":"Bing Yu","author_inst":"Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China"},{"author_name":"Zhizheng Zhuo","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"},{"author_name":"Jiani Wu","author_inst":"Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Dayong Ge","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Qingyu Xu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Yizhe Hu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Chuhan Xiong","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Weijia Liu","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Runyu Tang","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Qiuping Ding","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Qiongbin Zhu","author_inst":"Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Lisan Zhang","author_inst":"Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Zhicai Chen","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Hongfu Li","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Wei Luo","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Zhidong Cen","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jianzhong Sun","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Minming Zhang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jiawei Liang","author_inst":"Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China"},{"author_name":"Hongxi Zhang","author_inst":"Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China"},{"author_name":"Zhihan Yan","author_inst":"The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China"},{"author_name":"Yixin Emu","author_inst":"MR Scientific Collaboration, United Imaging Healthcare, Shanghai, China"},{"author_name":"Xijing Zhang","author_inst":"MR Scientific Collaboration, United Imaging Healthcare, Shanghai, China"},{"author_name":"Keyan Yu","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Guanxun Cheng","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Yadong Liu","author_inst":"Department of Radiology, Guiqian International General Hospital, Guiyang, China"},{"author_name":"Libo Zhang","author_inst":"Department of Radiology, Third Hospital of Heilongjiang, Beian, China"},{"author_name":"Sven Haller","author_inst":"Centre d'Imagerie Medicale de Cornavin (CIMC), 1201 Geneva, Switzerland"},{"author_name":"James Cole","author_inst":"Department of Computer Science, University College London, London, UK"},{"author_name":"Yuxin Li","author_inst":"Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Chao Wang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Peiyu Huang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Fang Xie","author_inst":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Hanzhang Lu","author_inst":"Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Dan Wu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Tengfei Guo","author_inst":"Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China"},{"author_name":"Xin Xu","author_inst":"Department of Psychiatry, School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Dengrong Jiang","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Yaou Liu","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Oxygen extraction fraction brain charts for human lifespan and application for brain disorders","rel_doi":"10.64898\/2026.06.02.26354684","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354684","rel_abs":"Cerebral oxygen extraction fraction (OEF) reflects the balance between cerebral oxygen delivery and metabolic demand, but its normative evolution across the human lifespan remains unknown. Here we used rapid, non-contrast TRUST MRI to establish a multisite normative model of global cerebral OEF in 2,025 healthy individuals aged 0-93 years from 17 imaging sites. OEF increased from the neonatal period to middle adulthood, followed by a slower rise and plateau in later life, with the fastest change occurring during early development and no significant sex differences. Individual OEF deviation scores were associated with vascular risk burden in healthy adults. Applying the model to 885 patients revealed disease-related OEF alterations, including positive deviations in pediatric obstructive sleep apnea, autoimmune disorders, brain tumors, mild cognitive impairment and dementia. OEF deviation further tracked tumor grade and Ki-67 proliferation. These findings establish lifespan OEF charting as a scalable framework for individualized physiological neuroimaging.","rel_num_authors":51,"rel_authors":[{"author_name":"Zixuan Lin","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Xiang Fan","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Tianyu Gao","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"},{"author_name":"Shuyue Wang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Yiwen Hong","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Yifan Yan","author_inst":"Department of Psychiatry, School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jianpeng Liu","author_inst":"Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yuchuan Fu","author_inst":"The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China"},{"author_name":"Tao Hua","author_inst":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yue Cai","author_inst":"Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China"},{"author_name":"Gaigai Lu","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Ying Qi","author_inst":"Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China"},{"author_name":"Bing Yu","author_inst":"Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China"},{"author_name":"Zhizheng Zhuo","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"},{"author_name":"Jiani Wu","author_inst":"Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Dayong Ge","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Qingyu Xu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Yizhe Hu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Chuhan Xiong","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Weijia Liu","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Runyu Tang","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Qiuping Ding","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Qiongbin Zhu","author_inst":"Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Lisan Zhang","author_inst":"Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Zhicai Chen","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Hongfu Li","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Wei Luo","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Zhidong Cen","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jianzhong Sun","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Minming Zhang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jiawei Liang","author_inst":"Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China"},{"author_name":"Hongxi Zhang","author_inst":"Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China"},{"author_name":"Zhihan Yan","author_inst":"The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China"},{"author_name":"Yixin Emu","author_inst":"MR Scientific Collaboration, United Imaging Healthcare, Shanghai, China"},{"author_name":"Xijing Zhang","author_inst":"MR Scientific Collaboration, United Imaging Healthcare, Shanghai, China"},{"author_name":"Keyan Yu","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Guanxun Cheng","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Yadong Liu","author_inst":"Department of Radiology, Guiqian International General Hospital, Guiyang, China"},{"author_name":"Libo Zhang","author_inst":"Department of Radiology, Third Hospital of Heilongjiang, Beian, China"},{"author_name":"Sven Haller","author_inst":"Centre d'Imagerie Medicale de Cornavin (CIMC), 1201 Geneva, Switzerland"},{"author_name":"James Cole","author_inst":"Department of Computer Science, University College London, London, UK"},{"author_name":"Yuxin Li","author_inst":"Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Chao Wang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Peiyu Huang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Fang Xie","author_inst":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Hanzhang Lu","author_inst":"Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Dan Wu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Tengfei Guo","author_inst":"Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China"},{"author_name":"Xin Xu","author_inst":"Department of Psychiatry, School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Dengrong Jiang","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Yaou Liu","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Epigenetic Clock CpGs form Tumor methylation Programs that Predict Survival Across Cancers","rel_doi":"10.64898\/2026.06.01.26354667","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354667","rel_abs":"Epigenetic clocks have been widely evaluated as cancer biomarkers, but findings have been inconsistent across tumor types and clinical endpoints. This inconsistency may reflect a fundamental misspecification: standard clock analyses treat clock CpGs as scalar aging readouts, assuming that tumors shift along the same methylation-aging axis as normal tissue. We tested this assumption across nine TCGA (The Cancer Genome Atlas) cancer types using Horvath clock CpGs. Tumors did not show a consistent mean shift in Horvath age acceleration relative to normal tissue. Instead, they showed an order-of-magnitude increase in age-acceleration variance. Scalar clock summaries also failed as survival biomarkers, producing zero nominal associations after adjustment for age, sex, and stage. We therefore analyzed Horvath clock CpGs as a coordinated methylation system. PCA-derived tumor methylation programs captured 34.9%-50.8% of clock-CpG variance across cancers, and this structure persisted after adjustment for tumor purity, proliferative history, and global methylation instability. This indicates that tumor-associated clock-CpG variation is not random methylation disorder, but is organized along major axes of covariation. In fully adjusted Cox models, tumor methylation programs produced 15 nominal survival associations, four of which remained significant after FDR correction. Survival-associated programs were linked to transcriptional pathway activity, including UPR, EMT, IFN-{gamma} response, and stemness, in directions consistent with their survival effects. These programs also persisted after controlling for tumor-normal differentially methylated regions, indicating that they were not explained by average cancer-associated methylation shifts. External validation in GSE72308 showed that two of three TCGA-nominated BRCA survival associations reproduced in the same protective direction. The dominance of tumor methylation programs over scalar clock summaries shows that the cancer-relevant signal in epigenetic clock CpGs is not methylation age, but coordinated tumor-state structure. In tumors, Horvath's clock CpGs are reorganized into methylation programs that capture survival-relevant and transcriptionally linked cancer biology.","rel_num_authors":5,"rel_authors":[{"author_name":"Pranava Gande","author_inst":"UC San Diego"},{"author_name":"Alfred Kao","author_inst":"UC San Diego"},{"author_name":"Omar Mokhashi","author_inst":"UC San Diego"},{"author_name":"Wei Tse Li","author_inst":"UCSF School of Medicine"},{"author_name":"Weg Ongkeko","author_inst":"VA San Diego Healthcare System"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Epigenetic Clock CpGs form Tumor methylation Programs that Predict Survival Across Cancers","rel_doi":"10.64898\/2026.06.01.26354667","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354667","rel_abs":"Epigenetic clocks have been widely evaluated as cancer biomarkers, but findings have been inconsistent across tumor types and clinical endpoints. This inconsistency may reflect a fundamental misspecification: standard clock analyses treat clock CpGs as scalar aging readouts, assuming that tumors shift along the same methylation-aging axis as normal tissue. We tested this assumption across nine TCGA (The Cancer Genome Atlas) cancer types using Horvath clock CpGs. Tumors did not show a consistent mean shift in Horvath age acceleration relative to normal tissue. Instead, they showed an order-of-magnitude increase in age-acceleration variance. Scalar clock summaries also failed as survival biomarkers, producing zero nominal associations after adjustment for age, sex, and stage. We therefore analyzed Horvath clock CpGs as a coordinated methylation system. PCA-derived tumor methylation programs captured 34.9%-50.8% of clock-CpG variance across cancers, and this structure persisted after adjustment for tumor purity, proliferative history, and global methylation instability. This indicates that tumor-associated clock-CpG variation is not random methylation disorder, but is organized along major axes of covariation. In fully adjusted Cox models, tumor methylation programs produced 15 nominal survival associations, four of which remained significant after FDR correction. Survival-associated programs were linked to transcriptional pathway activity, including UPR, EMT, IFN-{gamma} response, and stemness, in directions consistent with their survival effects. These programs also persisted after controlling for tumor-normal differentially methylated regions, indicating that they were not explained by average cancer-associated methylation shifts. External validation in GSE72308 showed that two of three TCGA-nominated BRCA survival associations reproduced in the same protective direction. The dominance of tumor methylation programs over scalar clock summaries shows that the cancer-relevant signal in epigenetic clock CpGs is not methylation age, but coordinated tumor-state structure. In tumors, Horvath's clock CpGs are reorganized into methylation programs that capture survival-relevant and transcriptionally linked cancer biology.","rel_num_authors":5,"rel_authors":[{"author_name":"Pranava Gande","author_inst":"UC San Diego"},{"author_name":"Alfred Kao","author_inst":"UC San Diego"},{"author_name":"Omar Mokhashi","author_inst":"UC San Diego"},{"author_name":"Wei Tse Li","author_inst":"UCSF School of Medicine"},{"author_name":"Weg Ongkeko","author_inst":"VA San Diego Healthcare System"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Longitudinal Receptive-Expressive Language Profiles in Young Autistic Children","rel_doi":"10.64898\/2026.06.02.26354680","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354680","rel_abs":"Abstract Background & Aims: Language development in autism is heterogeneous and strongly predicts later functioning. The balance between receptive and expressive abilities and their developmental trajectories, however, remains poorly understood. While some autistic children exhibit a relative expressive advantage (ExpAdv), others show receptive advantage (RecAdv) or a balanced profile. Prior studies report inconsistent findings and are often limited by cross-sectional designs and small samples. The present study aimed to (1) describe longitudinal trajectories of receptive and expressive language in autistic and typically developing (TD) children; (2) classify children into ExpAdv, Balanced, and RecAdv profiles across early childhood; and (3) examine the stability and transitions of these profiles over time, including associated clinical features. Methods: We analyzed 1,174 longitudinal time points from 318 autistic children and 294 time points from 108 TD children (1.2-5.8 years) from the Geneva Autism Cohort. Receptive and expressive language were assessed with the Mullen Scales of Early Learning. Receptive-expressive balance was quantified as the ratio of receptive to expressive age equivalent scores, classifying children into ExpAdv, Balanced, and RecAdv profiles using adapted cut-offs. Mixed-effects models examined developmental trajectories, and Sankey diagrams visualized profile transitions. Autism features and adaptive behavior were compared across profiles. Results: Autistic children displayed lower expressive and receptive language than TD peers, with receptive abilities exceeding expressive skills in both groups. Overall, 30-35% of autistic children were classified as ExpAdv at 18-36 months, declining to ~12% by 48-54 months, while Balanced and RecAdv profiles became more prevalent with age. ExpAdv was associated with slower verbal and non-verbal developmental gains. Stability was highest for Balanced and RecAdv profiles (50-60%), whereas ExpAdv often transitioned to Balanced. Autistic children with stable ExpAdv profiles were more often female, less likely to receive early intervention, and showed weaker adaptive communication. Conclusions: Receptive-expressive language profiles in autistic children are dynamic. ExpAdv profile is more frequent in younger autistic children, less stable, and linked to slower verbal and non-verbal development and higher autism severity. Implications: ExpAdv may represent an early marker of autism associated with slower expressive and receptive language growth. Longitudinal monitoring of receptive and expressive skills is essential, as transitions toward Balanced or RecAdv profiles are associated with improved developmental outcomes. Early intervention before age three may facilitate transitions toward Balanced or RecAdv profiles, supporting more favorable language development and long-term outcomes. Keywords: autism; early childhood; longitudinal design; expressive language; receptive language; language profile; early intervention; language gap; discrepant profiles","rel_num_authors":5,"rel_authors":[{"author_name":"Kenza Latreche","author_inst":"University of Geneva"},{"author_name":"Michel Godel","author_inst":"University of Geneva"},{"author_name":"Fiona Journal","author_inst":"University of Geneva"},{"author_name":"Nada Kojovic","author_inst":"University of Geneva"},{"author_name":"Marie Schaer","author_inst":"University of Geneva"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"SARS-CoV-2 BA.3.2.2 is more evasive of neutralization by sera from young children","rel_doi":"10.64898\/2026.06.01.728533","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.728533","rel_abs":"Dominant SARS-CoV-2 variants have most prominently displayed greater evasion of serum neutralizing antibodies than predecessor strains. BA.3.2, a descendant of Omicron BA.3, carrying 43 additional spike mutations, emerged in 2024, and over the last several months its subvariant BA.3.2.2 has slowly increased in prevalence globally. BA.3.2.2 continues to circulate at lower frequency than the genetically and antigenically distant dominant JN.1 subvariants NB.1.8.1 and XFG. However, concerningly, epidemiologic analyses have suggested that a larger proportion of COVID-19 cases in children are caused by BA.3.2.2 compared to adults, raising the possibility that susceptibility to BA.3.2.2 differs across age groups. Since immune imprinting shapes variant-specific anti-SARS-CoV-2 antibody profiles and children born after 2021 primarily were first exposed to Omicron subvariants, we hypothesized that young children may have lower circulating neutralizing antibody titers against BA.3.2.2 than adults. Using pseudovirus neutralization assays, we measured titers against BA.3.2.2 and other SARS-CoV-2 variants in serum or plasma samples from a total of 36 adults ([&ge;]18 years old), school-age children (3-10 years old), and infants\/toddlers (6-28 months old) in the US. We found that both cohorts of children had lower geometric mean titers against BA.3.2.2 than adults, even though all tested age groups had similar titers against dominant strains NB.1.8.1 and XFG. Together, these findings suggest that susceptibility to emerging SARS-CoV-2 variants may diverge across age groups, perhaps as a result of their different exposure histories. Furthermore, these results highlight the importance of SARS-CoV-2 surveillance and the monitoring of immunity against viral variants across age ranges.","rel_num_authors":9,"rel_authors":[{"author_name":"Madeline Wu","author_inst":"Columbia University"},{"author_name":"Hsiang Hong","author_inst":"Columbia University"},{"author_name":"Yicheng Guo","author_inst":"Columbia University"},{"author_name":"Kristin Daniel","author_inst":"Columbia University"},{"author_name":"Ryan Hisner","author_inst":"University of Cape Town"},{"author_name":"Marc C Johnson","author_inst":"University of Missouri"},{"author_name":"Aubree Gordon","author_inst":"University of Michigan"},{"author_name":"David D Ho","author_inst":"Columbia University"},{"author_name":"Ian A Mellis","author_inst":"Columbia University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"TBC1D23-AAVR Interaction Drives Endosome-to-TGN Trafficking Required for rAAV Transduction","rel_doi":"10.64898\/2026.06.02.729721","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729721","rel_abs":"The adeno-associated virus receptor (AAVR; also known as KIAA0319L) is the proteinaceous receptor required for the transduction of multi-serotype adeno-associated viruses (AAVs). While the extracellular polycystic kidney disease (PKD) domains of AAVR directly bind AAV capsids, the function of its C-terminal cytosolic domain (AAVR-C) in governing AAV internalization and intracellular trafficking remains undefined. Using targeted pulldown of AAVR-interacting host proteins with a glutathione S-Transferase (GST)-fused AAVR-C recombinant protein (GST-AAVR-C) as a bait, we identified that TBC1 domain family member 23 (TBC1D23), a specialized intracellular trafficking adaptor and bridging factor, binds AAVR via the AAVR-C and mediates AAV endosome-to-trans-Golgi network (TGN) transport. Biolayer interferometry (BLI) demonstrates nanomolar-affinity binding between AAVR-C and the C-terminal scaffold domain of TBC1D23 (TBC1D23-C). CRISPR-mediated knockout of TBC1D23 severely impairs rAAV transduction across multiple human cell types, including polarized human airway epithelium (HAE). Loss of TBC1D23 disrupts convergence of internalized AAV capsids at the TGN, leading to diminished nuclear import of AAV vectors. Mutational analyses of AAVR-C reveal that its acidic residue cluster is required for TBC1D23 binding and AAV retrograde transport from the endosome to the TGN. Together, these findings define TBC1D23 as a receptor-proximal trafficking module that couples AAV-AAVR engagement to vesicle transport, revealing a missing core regulatory step in AAV retrograde transport that is essential for productive rAAV transduction.","rel_num_authors":9,"rel_authors":[{"author_name":"Xiujuan Zhang","author_inst":"University of Kansas Medical Center"},{"author_name":"Ariful Habib","author_inst":"University of Kansas Medical Center"},{"author_name":"Shane McFarlin","author_inst":"University of Kansas Medical Center"},{"author_name":"Donovan Richart","author_inst":"University of Kansas Medical Center"},{"author_name":"Soo Yeun Park","author_inst":"University of Alabama at Birmingham"},{"author_name":"Fang Cheng","author_inst":"University of Kansas Medical Center"},{"author_name":"Jinxi Wang","author_inst":"University of Kansas Medical Center"},{"author_name":"Ziying Yan","author_inst":"University of Alabama at Birmingham"},{"author_name":"Jianming Qiu","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Reversible inhibition of viral life cycle in response to elevated temperature in a bloom-forming alga","rel_doi":"10.64898\/2026.06.02.729564","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729564","rel_abs":"Ocean warming is expected to reshape microbial interactions and community composition, with profound consequences for marine biogeochemical cycles. Host virus dynamics are central to these processes, yet their response to elevated temperature remains poorly understood. Here, using the bloom-forming alga Gephyrocapsa huxleyi and its specific large dsDNA virus, Emiliania huxleyi virus (EhV), we show that elevated temperature withheld virion production and abolished distinct stages of the viral life cycle. Viral adsorption and early transcription remained active, whereas viral DNA replication and late gene expression were arrested, leading to an intracellular inhibition of infection. Intriguingly, this arrested infection state was reversible following prolonged heatwave conditions. Single-cell analyses revealed that reversibility of infection inhibition occurred both within a small fraction of infected cells and by reinfection by extracellular virions that remained viable during heat exposure in the extracellular milieu. Furthermore, we detected variability in infection inhibition by temperature across several host-virus pairs, suggesting that the effect of temperature is strain-specific. Our findings uncover a temperature-sensitive checkpoint in the viral life cycle, providing a mechanistic framework for understanding how marine heatwaves may reshape virus-driven mortality and carbon cycling in the ocean.","rel_num_authors":5,"rel_authors":[{"author_name":"Assaf Vardi","author_inst":"Weizmann Institute of Science"},{"author_name":"Noa Shima","author_inst":"Weizmann Institute of Science"},{"author_name":"Talia S. Shaler","author_inst":"Weizmann Institute of Science"},{"author_name":"Nir Joffe","author_inst":"Weizmann Institute of Science"},{"author_name":"Daniella Schatz","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Cellular nucleic acid-binding protein (CNBP) dependent cytokine programming shapes host defense against Plasmodium infection","rel_doi":"10.64898\/2026.06.01.729202","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729202","rel_abs":"During blood-stage Plasmodium infection, effective immune control hinges on the IL12{beta}-IFN-{gamma} axis, yet how this pathway is transcriptionally tuned in vivo remains incompletely defined. Innate sensing of parasite-derived ligands by pattern-recognition receptors, including Toll like receptors, in dendritic cells and macrophages induces IL-12{beta} production that drives IFN-{gamma} mediated control of infection. Emerging evidence implicates cellular nucleic acid-binding protein (CNBP), a zinc-finger transcriptional regulator, in control of IL12{beta} gene expression in myeloid cells exposed to bacterial and viral infections. Here, we defined the contribution of CNBP in cytokine-driven immunity to Plasmodium infection including both P. falciparum (the major cause of malaria),as well as P. chabaudi and P. berghei ANKA, two rodent species that model human disease. Upon exposure to Plasmodium-infected erythrocytes, CNBP rapidly translocated to the nucleus in mouse and human dendritic cells, bound  IL12{beta} promoter, and was required for optimal IL12{beta} induction. Genetic ablation of CNBP in mice and siRNA knockdown of CNBP in human monocyte-derived dendritic cells markedly reduced IL12{beta} production and downstream IFN-{gamma} responses, while TNF- and several other innate cytokines were largely unaffected. In vivo, hematopoietic-specific deletion of CNBP (using vav-iCre; Cnbpfl\/fl) resulted in elevated peak parasitemia, impaired parasite clearance, and relapse after initial resolution. Consistent with these outcomes, spleens from mice lacking CNBP in hematopoietic cells exhibited reduced inflammatory remodeling, altered T-cell composition, and transcriptional reprogramming characterized by selective regulation of IL12{beta}-IFN-{gamma} transcripts alongside upregulation of distinct cytotoxic genes. Paradoxically, mice lacking CNBP in hematopoietic cells showed delayed mortality in the lethal infection model, underscoring its context-dependent contributions to host protection and inflammatory pathology. Collectively, these findings position CNBP as a pivotal modulator of the IL12{beta}-IFN-{gamma} axis during malaria, extending its functional repertoire beyond microbial contexts, with potential as a therapeutic target to fine-tune immune responses for enhanced protection with limited immunopathology.","rel_num_authors":7,"rel_authors":[{"author_name":"Romana Rashid","author_inst":"UMass Chan Medical School Department of Medicine: University of Massachusetts Chan Medical School Department of Medicine"},{"author_name":"Leandro de Souza Silva","author_inst":"UMass Chan Medical School Department of Medicine: University of Massachusetts Chan Medical School Department of Medicine"},{"author_name":"Shahid Banday","author_inst":"UMass Chan Medical School MCCB: University of Massachusetts Chan Medical School Department of Molecular Cell and Cancer Biology"},{"author_name":"Daniel  R Caffrey","author_inst":"UMass Chan Medical School Department of Medicine: University of Massachusetts Chan Medical School Department of Medicine"},{"author_name":"Evelyn Kurt-Jones","author_inst":"UMass Chan Medical School Department of Medicine: University of Massachusetts Chan Medical School Department of Medicine"},{"author_name":"Katherine  A Fitzgerald","author_inst":"UMass Chan Medical School Department of Medicine: University of Massachusetts Chan Medical School Department of Medicine"},{"author_name":"Douglas  T Golenbock","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Integrating Histology with Spatial Molecular Programs Using a Multimodal Foundation Model","rel_doi":"10.64898\/2026.06.01.729028","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729028","rel_abs":"Histopathological assessment remains central to cancer diagnosis and stratification, yet its mechanistic interpretation remains limited without molecular context. To address this, we developed SQUALL, a multimodal foundation model integrating histology with spatial molecular programs. For pretraining, we assembled histMol, a large-scale corpus of 1.76 billion paired histology-spatial transcriptomics spots\/bins across 33 tissues and 12 platforms from 3,446 tissue sections. Following pretraining, SQUALL enables transcriptome-wide virtual biomarker profiling, prognostically relevant spatial niches discovery, and integrative disease progression modeling. Leveraging its multimodal embeddings, SQUALL identifies niches associated with tertiary lymphoid structure (TLS) maturation and ovarian cancer relapse, reconstructs molecular trajectories of breast cancer invasion across 325,112 spots, and uncovers underlying transcriptional programs. Applied to whole-slide images from 898 patients, SQUALL outperforms existing pathology foundation models in outcome prediction while enabling interpretable risk stratification. Together, these results establish spatially aligned multimodal pretraining as a new paradigm for extending molecular insights into pathology images.","rel_num_authors":27,"rel_authors":[{"author_name":"Zongxu Zhang","author_inst":"Peking University"},{"author_name":"Bowen Qin","author_inst":"Peking University"},{"author_name":"Yahui Zhao","author_inst":"Chinese Academy of Medical Sciences and Peking Union Medical College"},{"author_name":"Zekun Qi","author_inst":"Peking University"},{"author_name":"Hanlin Xu","author_inst":"Peking University"},{"author_name":"Yunfeng Wang","author_inst":"Peking University"},{"author_name":"Wenjin Zheng","author_inst":"Chinese PLA Medical School"},{"author_name":"Jiateng Dai","author_inst":"Peking University"},{"author_name":"Anxin Chen","author_inst":"Peking University"},{"author_name":"Nachuan Wang","author_inst":"Peking University"},{"author_name":"Lanxi Nie","author_inst":"Peking University"},{"author_name":"Peng Zhang","author_inst":"Peking University"},{"author_name":"Haorui Zhang","author_inst":"Peking University"},{"author_name":"Yanping Zhao","author_inst":"Tsinghua University"},{"author_name":"Tian Xu","author_inst":"Peking University"},{"author_name":"Siyu Lin","author_inst":"Peking University"},{"author_name":"Pengfei Ren","author_inst":"Peking University"},{"author_name":"Zhe Zhang","author_inst":"Seventh Medical Center of Chinese PLA General Hospital"},{"author_name":"Liyan Xue","author_inst":"Chinese Academy of Medical Sciences and Peking Union Medical College"},{"author_name":"Xuemin Xue","author_inst":"Chinese Academy of Medical Sciences and Peking Union Medical College"},{"author_name":"Zhaoyang Yang","author_inst":"Chinese Academy of Medical Sciences and Peking Union Medical College"},{"author_name":"Jiaqi Xu","author_inst":"Chinese Academy of Medical Sciences and Peking Union Medical College"},{"author_name":"Deng Pan","author_inst":"Tsinghua University"},{"author_name":"Cunyu Wang","author_inst":"Peking University"},{"author_name":"Zhihua Liu","author_inst":"Chinese Academy of Medical Sciences and Peking Union Medical College"},{"author_name":"Yuanguang Meng","author_inst":"Seventh Medical Center of Chinese PLA General Hospital"},{"author_name":"Zexian Zeng","author_inst":"Peking University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Metal Coordination Dynamics Governs Selective Epoxidation in Hyoscyamine 6\u03b2-Hydroxylase: Integrated Experimental and Computational Insights","rel_doi":"10.64898\/2026.06.01.729211","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729211","rel_abs":"Iron(II)-and 2-oxoglutarate-dependent (Fe(II)\/2OG) enzymes catalyze a wide range of C-H bond activation and functionalization reactions and play essential roles in biosynthesis and metabolic regulation. Despite extensive mechanistic studies, the principles governing selectivity between canonical hydroxylation and alternative transformations remain incompletely understood. Here, we investigate the catalytic mechanism of hyoscyamine 6{beta}-hydroxylase (H6H), a Fe(II)\/2OG-dependent oxygenase that sequentially catalyzes the 6{beta}-hydroxylation of hyoscyamine followed by 6,7-exo-epoxidation of 6{beta}-hydroxyhyoscyamine to generate scopolamine. Combined molecular dynamics and QM\/MM calculations reveal that an in-line Fe(IV)-oxo intermediate initiates hydrogen atom abstraction from the substrate C7 position. The resulting Fe(III)-OH species subsequently deprotonates the substrate hydroxyl group in a process coupled to substrate coordination to the iron center and an in-line-to-off-line rearrangement of the Fe(III)-OH moiety. This coordination dynamics machinery is further supported by the observed chlorination reactivity on the same substrate. Importantly, this coordination switch favors epoxide formation over hydroxyl rebound, thereby directing the reaction toward selective epoxidation. Further computational analysis of the L290F variant demonstrates that steric constraints imposed by L290 are essential for suppressing hydroxylation, revealing a bidirectional regulatory mechanism governing epoxidation\/hydroxylation selectivity. Whereas iron coordination dynamics promote epoxidation reactivity, precise substrate positioning and protein-derived steric effects suppress the competing hydroxylation pathway. These findings are consistent with available experimental observations and establish metal coordination dynamics as a key determinant of selective C-H functionalization in Fe(II)\/2OG enzymes.","rel_num_authors":12,"rel_authors":[{"author_name":"Jinyan Zhang","author_inst":"State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemist"},{"author_name":"Lian Wu","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shang"},{"author_name":"Siqi Wu","author_inst":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union M"},{"author_name":"Xiao Liu","author_inst":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China"},{"author_name":"Lina Dong","author_inst":"State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemist"},{"author_name":"Eliott S Wenger","author_inst":"Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States"},{"author_name":"Ridao Chen","author_inst":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union M"},{"author_name":"Carsten Krebs","author_inst":"Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States"},{"author_name":"Alexey Silakov","author_inst":"Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States"},{"author_name":"J. Martin Bollinger Jr.","author_inst":"Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States"},{"author_name":"Jiahai Zhou","author_inst":"State Key Laboratory of Microbial Technology, School of Food Science and Pharmaceutical Engineering, Nanjing Nomal University, Nanjing 210023, China"},{"author_name":"Binju Wang","author_inst":"State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemist"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Phosphorylation-dependent regulation of Hsp70 chaperones stimulates client recruitment","rel_doi":"10.64898\/2026.06.01.729190","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729190","rel_abs":"Molecular chaperones of the Hsp70 family play essential roles in maintaining proteostasis, particularly under conditions of cellular stress. Posttranslational modifications of Hsp70, collectively termed the chaperone code, are emerging as critical regulators of chaperone function, yet their mechanistic contributions remain incompletely understood. Here, we investigate the functional significance of a conserved phosphorylation site in Hsp70, corresponding to serine 326 in yeast Ssa1 and serine 329 in human HSPA8. We demonstrate that DNA double-strand break stress increases cellular reliance on Hsp70 activity in yeast, highlighting a role for chaperones in the DNA damage response. Loss of Ssa1 serine 326 phosphorylation impairs multiple Hsp70-dependent functions, including prion sequestration and glucocorticoid receptor maturation, indicating that this modification is required for optimal chaperone activity. Extending these findings to human cells, we show that the homologous HSPA8 serine 329 residue is necessary for efficient clearance of polyglutamine aggregates. Mechanistically, a phospho-deficient HSPA8-S329A mutant exhibits reduced client-binding capacity. Together, our findings identify a conserved phosphorylation event that enhances Hsp70 function by promoting client engagement, providing new insight into how the chaperone code regulates proteostasis across species.","rel_num_authors":6,"rel_authors":[{"author_name":"Yun Chen","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Yu-Yen Wang","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Yun-Li Yew","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Yuan-Teng Chang","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Ting-Yu Liu","author_inst":"National Taiwan University College of Medicine"},{"author_name":"Shu-Chun Teng","author_inst":"National Taiwan University College of Medicine"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"High-order brain interactions distinguish wakefulness, anaesthesia, and recovery induced by deep brain stimulation","rel_doi":"10.64898\/2026.06.01.728390","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.728390","rel_abs":"Understanding how consciousness depends on large-scale brain interactions is key for both the neuroscience of consciousness and clinical translation. However, it requires moving beyond classical pairwise descriptions of functional connectivity, which cannot capture the collective dependencies emerging across multiple brain regions. Here, we use multivariate information theory measures to characterize how higher-order interactions reorganize across states of consciousness. Specifically, we apply O-information to resting-state fMRI data from non-human primates to quantify whether multiregional brain dynamics are dominated by synergistic or redundant information sharing. We analyse two complementary datasets: (i) wakefulness and anaesthesia-induced loss of consciousness using different molecular agents (propofol, sevoflurane, ketamine), and (ii) the recovery of consciousness driven by central thalamic deep brain stimulation during propofol anaesthesia, indexed by behavioural responsiveness. We identify optimal regional subsets whose O-information robustly discriminates conscious from non-responsive states under two complementary optimization polarities. The first captures elevated redundancy in conscious scans that decreases under anaesthesia, providing robust discrimination and placing high-voltage central-thalamus stimulation closer to wakefulness. The second captures a synergy-to-redundancy transition, prominent in multi-anaesthesia conditions but context-dependent across datasets. Discrimination performance depends on interaction order: redundancy-based signatures improve with increasing subset size, whilst synergy-based signatures peak at low orders. Higher-order informational features significantly outperform pairwise functional connectivity, particularly for synergistic signatures which remain invisible to correlations. These findings demonstrate that consciousness is reflected in the reconfiguration of higher-order interaction structures, with distinct informational substrates requiring multivariate characterization beyond pairwise connectivity.","rel_num_authors":9,"rel_authors":[{"author_name":"Rodrigo Cofre","author_inst":"Universite Cote dAzur, INRIA CRONOS Team, Sophia Antipolis, France"},{"author_name":"Camilo Espinosa-Curilem","author_inst":"Information and Decision System Group, Department of Electrical Engineering, Universidad de Chile, Santiago, Chile"},{"author_name":"Lynn Uhrig","author_inst":"Cognitive Neuroimaging Unit, CEA, INSERM, Universite Paris-Saclay, NeuroSpin Center, Gif-sur-Yvette, France"},{"author_name":"Jordie Tasserie","author_inst":"Center for Brain Circuit Therapeutics, Department of Neurology, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Ruben Herzog","author_inst":"Instituto de Fisica Interdisciplinar y Sistemas Complejos (IFISC, UIB-CSIC), Campus UIB, Palma de Mallorca, Spain"},{"author_name":"Marilyn Gatica","author_inst":"Centre for Apprenticeships, Northeastern University London, London, United Kingdom"},{"author_name":"Andrea Luppi","author_inst":"St John's College, University of Cambridge, Cambridge, UK"},{"author_name":"Jorge F. Silva","author_inst":"Information and Decision System Group, Department of Electrical Engineering, Universidad de Chile, Santiago, Chile"},{"author_name":"Bechir Jarraya","author_inst":"Cognitive Neuroimaging Unit, CEA, INSERM, Universite Paris-Saclay, NeuroSpin Center, Gif-sur-Yvette, France"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features","rel_doi":"10.64898\/2026.05.31.729161","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729161","rel_abs":"Cancer arises from extensive genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To systematically chart cancer-intrinsic regulatory programs, we constructed a pan-cancer single-cell transcriptomic and epigenomic atlas encompassing 60 human cell lines representing 16 tissue origins and 20 cancer types, comprising 240,957 single-nucleus RNA-seq and 223,347 single-nucleus ATAC-seq profiles. Integrative analyses revealed extensive pan-cancer cell-state heterogeneity, core gene-regulatory networks, and a conserved epithelial-mesenchymal transition (EMT) axis that transcends tissue of origin. Copy-number variation analysis identified transcription factor amplification and downstream hyperactivation as key drivers of cancer cell-state reprogramming. To further examine how regulatory programs diverge within a cancer lineage and contribute to clinically divergent outcomes, we performed a focused comparison of cutaneous melanoma with acral melanoma, a rare, UV-independent subtype underrepresented in existing pan-cancer atlases. The comparison uncovered a universal inflammation-suppressive program in acral melanoma and an inflamed regulatory landscape in cutaneous melanoma, with the JAK-STAT pathway and downstream transcriptional responses as central discriminators. Integration of single-cell and bulk datasets across models and patient cohorts further linked in vitro tumor-intrinsic gene regulations with in vivo microenvironmental composition and immunotherapy responses. Together, by extending single-cell multi-omic profiling to rare alongside common cancer subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific gene-regulatory programs that shape cancer cell-state plasticity.","rel_num_authors":9,"rel_authors":[{"author_name":"Zihan Xu","author_inst":"The Rockefeller University"},{"author_name":"Aileen Ugurbil","author_inst":"The Rockefeller University"},{"author_name":"Joshua Kwan","author_inst":"The Rockefeller University"},{"author_name":"Chloe Schaefer","author_inst":"The Rockefeller University"},{"author_name":"Abdulraouf Abdulraouf","author_inst":"The Rockefeller University"},{"author_name":"Ziyu Lu","author_inst":"The Rockefeller University"},{"author_name":"Erting Tang","author_inst":"The University of Chicago"},{"author_name":"Wei Zhou","author_inst":"The Rockefeller University"},{"author_name":"Junyue Cao","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features","rel_doi":"10.64898\/2026.05.31.729161","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729161","rel_abs":"Cancer arises from extensive genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To systematically chart cancer-intrinsic regulatory programs, we constructed a pan-cancer single-cell transcriptomic and epigenomic atlas encompassing 60 human cell lines representing 16 tissue origins and 20 cancer types, comprising 240,957 single-nucleus RNA-seq and 223,347 single-nucleus ATAC-seq profiles. Integrative analyses revealed extensive pan-cancer cell-state heterogeneity, core gene-regulatory networks, and a conserved epithelial-mesenchymal transition (EMT) axis that transcends tissue of origin. Copy-number variation analysis identified transcription factor amplification and downstream hyperactivation as key drivers of cancer cell-state reprogramming. To further examine how regulatory programs diverge within a cancer lineage and contribute to clinically divergent outcomes, we performed a focused comparison of cutaneous melanoma with acral melanoma, a rare, UV-independent subtype underrepresented in existing pan-cancer atlases. The comparison uncovered a universal inflammation-suppressive program in acral melanoma and an inflamed regulatory landscape in cutaneous melanoma, with the JAK-STAT pathway and downstream transcriptional responses as central discriminators. Integration of single-cell and bulk datasets across models and patient cohorts further linked in vitro tumor-intrinsic gene regulations with in vivo microenvironmental composition and immunotherapy responses. Together, by extending single-cell multi-omic profiling to rare alongside common cancer subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific gene-regulatory programs that shape cancer cell-state plasticity.","rel_num_authors":9,"rel_authors":[{"author_name":"Zihan Xu","author_inst":"The Rockefeller University"},{"author_name":"Aileen Ugurbil","author_inst":"The Rockefeller University"},{"author_name":"Joshua Kwan","author_inst":"The Rockefeller University"},{"author_name":"Chloe Schaefer","author_inst":"The Rockefeller University"},{"author_name":"Abdulraouf Abdulraouf","author_inst":"The Rockefeller University"},{"author_name":"Ziyu Lu","author_inst":"The Rockefeller University"},{"author_name":"Erting Tang","author_inst":"The University of Chicago"},{"author_name":"Wei Zhou","author_inst":"The Rockefeller University"},{"author_name":"Junyue Cao","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic \u03bc-\u03b4 opioid receptor heterodimerization","rel_doi":"10.64898\/2026.05.31.729044","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729044","rel_abs":"Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioural deficits through opioid receptor signaling. Pharmacological and genetic analyses reveal a requirement for both - and {delta}-opioid receptors in astrocytes. Chronic stress reduces -{delta} receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased -{delta} heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the -receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic -{delta} opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.","rel_num_authors":28,"rel_authors":[{"author_name":"Yanxia Liang","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Lingjun Wang","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Yajie Li","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Xiaoxue Li","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Yunxiang Sun","author_inst":"School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China;School of Physical Science and Technology, Ningbo Univ"},{"author_name":"Mengli Yang","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Xuzhuo Guo","author_inst":"Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, HFCNS Institute of Artificial Intelligence, Division of Life Sciences and Medici"},{"author_name":"Junxu Mu","author_inst":"Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, HFCNS Institute of Artificial Intelligence, Division of Life Sciences and Medici"},{"author_name":"Chang Xu","author_inst":"College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062, China"},{"author_name":"Rupak Thapa","author_inst":"Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Ye Cheng","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Huiqiang Zhang","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Zecong He","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Shi Yan","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Shuo Yang","author_inst":"State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, G"},{"author_name":"Tsz Hei Fong","author_inst":"State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, G"},{"author_name":"Huiyuan Bai","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Jia Xu","author_inst":"School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China"},{"author_name":"Qi Zhang","author_inst":"National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China"},{"author_name":"Lei Lui","author_inst":"Department of Biochemistry and Molecular Biology School of Basic Medicine, Capital Medical University, Beijing 100069, China"},{"author_name":"Ming Li","author_inst":"State Key Laboratory of Genetic Evolution & Animal Models, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Ch"},{"author_name":"Dongwu Xu","author_inst":"School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China"},{"author_name":"Wujun Geng","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Department of Anesthesiology, Wenzhou Central Hospital, Department of Pai"},{"author_name":"Jianzhong Su","author_inst":"National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China"},{"author_name":"Aihui Tang","author_inst":"Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, HFCNS Institute of Artificial Intelligence, Division of Life Sciences and Medici"},{"author_name":"Chuang Wang","author_inst":"School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China"},{"author_name":"Qiang Zhou","author_inst":"State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, G"},{"author_name":"Xiang Cai","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic \u03bc-\u03b4 opioid receptor heterodimerization","rel_doi":"10.64898\/2026.05.31.729044","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729044","rel_abs":"Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioural deficits through opioid receptor signaling. Pharmacological and genetic analyses reveal a requirement for both - and {delta}-opioid receptors in astrocytes. Chronic stress reduces -{delta} receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased -{delta} heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the -receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic -{delta} opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.","rel_num_authors":28,"rel_authors":[{"author_name":"Yanxia Liang","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Lingjun Wang","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Yajie Li","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Xiaoxue Li","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Yunxiang Sun","author_inst":"School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China;School of Physical Science and Technology, Ningbo Univ"},{"author_name":"Mengli Yang","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Xuzhuo Guo","author_inst":"Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, HFCNS Institute of Artificial Intelligence, Division of Life Sciences and Medici"},{"author_name":"Junxu Mu","author_inst":"Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, HFCNS Institute of Artificial Intelligence, Division of Life Sciences and Medici"},{"author_name":"Chang Xu","author_inst":"College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062, China"},{"author_name":"Rupak Thapa","author_inst":"Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Ye Cheng","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Huiqiang Zhang","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Zecong He","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Shi Yan","author_inst":"Center of Depression, Beijing Institute of Brain Disorders, Advanced Innovation Center for Human Brain Protection, Collaborative Innovation Center for Brain Dis"},{"author_name":"Shuo Yang","author_inst":"State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, G"},{"author_name":"Tsz Hei Fong","author_inst":"State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, G"},{"author_name":"Huiyuan Bai","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"},{"author_name":"Jia Xu","author_inst":"School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China"},{"author_name":"Qi Zhang","author_inst":"National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China"},{"author_name":"Lei Lui","author_inst":"Department of Biochemistry and Molecular Biology School of Basic Medicine, Capital Medical University, Beijing 100069, China"},{"author_name":"Ming Li","author_inst":"State Key Laboratory of Genetic Evolution & Animal Models, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Ch"},{"author_name":"Dongwu Xu","author_inst":"School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China"},{"author_name":"Wujun Geng","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Department of Anesthesiology, Wenzhou Central Hospital, Department of Pai"},{"author_name":"Jianzhong Su","author_inst":"National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China"},{"author_name":"Aihui Tang","author_inst":"Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, HFCNS Institute of Artificial Intelligence, Division of Life Sciences and Medici"},{"author_name":"Chuang Wang","author_inst":"School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China"},{"author_name":"Qiang Zhou","author_inst":"State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, G"},{"author_name":"Xiang Cai","author_inst":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 32"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Visibly Transparent, Near-Infrared Absorbing Nanofluids Enable High-Efficiency and Safe Laser Lithotripsy","rel_doi":"10.64898\/2026.05.31.729132","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729132","rel_abs":"Laser lithotripsy (LL) is the gold standard for urinary stone management yet maximizing ablation efficiency while maintaining procedural safety remains clinically challenging. Here, we present a visibly transparent, near-infrared (NIR)-absorbing ITO@SiO2 nanofluid irrigation strategy that significantly enhances LL efficiency without compromising endoscopic visibility. By spectrally matching the absorption profile of ITO@SiO2 with the clinical Holmium:YAG laser wavelength, ablation efficiency improved by >200% in the bench-top spot treatments and >100% in the hydrogel kidney model. Mechanistic investigations revealed that the enhanced optical absorption of the nanofluid modifies bubble dynamics and synergistically amplifies photothermal\/microexplosion effects and cavitation damage. Importantly, both in-vitro hydrogel and in-vivo porcine kidney models demonstrated a substantial thermal safety margin (maximum temperatures <35 {degrees}C) and excellent acute biocompatibility, with no evidence of thermal tissue injury. Integrating seamlessly into established clinical workflows without requiring stone pretreatment, this strategy offers a highly translatable, safe, and efficient platform for next-generation endoscopic lithotripsy.","rel_num_authors":16,"rel_authors":[{"author_name":"Qingsong Fan","author_inst":"The university of chicago"},{"author_name":"Junqin Chen","author_inst":"Duke University"},{"author_name":"Arpit Mishra","author_inst":"Duke University"},{"author_name":"Megan Bock","author_inst":"Duke University"},{"author_name":"Aaron Stewart","author_inst":"Duke University"},{"author_name":"Catherine Cai","author_inst":"Duke University"},{"author_name":"Judith Dominguez","author_inst":"Duke University"},{"author_name":"Jiadong Liu","author_inst":"The University of Chicago"},{"author_name":"Yuanke Chen","author_inst":"The University of Chicago"},{"author_name":"Ronghui Wu","author_inst":"The University of Chicago"},{"author_name":"Ting-Hsuan Chen","author_inst":"The University of Chicago"},{"author_name":"Jiaoti Huang","author_inst":"Duke University"},{"author_name":"Christine Payne","author_inst":"Duke University"},{"author_name":"Michael Lipkin","author_inst":"Duke University"},{"author_name":"Pei Zhong","author_inst":"Duke University"},{"author_name":"Po-Chun Hsu","author_inst":"University of Chicago"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Spatially confined niches support hypoxia-associated transcriptional plasticity contributing to malignant progression in IDH-mutant gliomas","rel_doi":"10.64898\/2026.05.31.729105","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729105","rel_abs":"Background While hypoxia is a well-established driver of glioblastoma progression, its role in IDH-mutant gliomas, characterized by localized hypoxic microenvironments rather than overt necrosis, remains poorly understood. Here, we investigate how hypoxia and microenvironmental-adaptations shape cellular heterogeneity and transcriptional plasticity in these tumors. Methods We integrated bulk, single-cell, and spatial-transcriptomics datasets from IDH-mutant glioma patients (Astrocytomas and Oligodendrogliomas) to characterize cellular-states and map the localization of hypoxic niches. To uncover tumor microenvironment effects, we established co-culture models using primary IDH-mutant glioma cells with human microglia and astrocytes, maintained under hypoxic and normoxic conditions, followed by bulk RNA-sequencing. Results We identified a hypoxia-associated astrocyte-like (AC-like) program that defines a quiescent, non-cycling population with a distinct transcription factor profile indicative of functional plasticity in IDH-mutant gliomas. These cells harbor glioma stem cell (GSC)-like features and are poised for a quiescent-to-activated (Q-to-A) transition that drives tumor progression. Mechanistically, co-culture models reveal that microglia promote this Q-to-A transition by enhancing HBEGF\/EGFR paracrine signaling. Spatial transcriptomics uncovers the co-localization of hypoxic niches within quiescent AC-like cells, whereby the activated subpopulation forms discrete niches defined by localized HBEGF\/EGFR communication gradients. Notably, tumors exhibiting elevated EGFR-driven activation signatures correlate with higher histological grade and poorer patient survival, implicating the Q-to-A transition as a critical driver of malignant progression. Conclusion Q-to-A transition within the hypoxic niche represents a critical driver of malignant progression in IDH-mutant gliomas, providing a microenvironment-driven mechanism for the transition to higher-grade disease and identifying targetable-vulnerabilities for therapeutic intervention.","rel_num_authors":29,"rel_authors":[{"author_name":"Depro Das","author_inst":"Medical Center, University of Freiburg, Germany"},{"author_name":"Alina Pandele","author_inst":"Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK"},{"author_name":"Vatsal D Jariwala","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Nishita S Ghariwala","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Aso O. Mohammed","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Tonmoy Das","author_inst":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center University of Freiburg, Germany"},{"author_name":"Christopher Krolla","author_inst":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center University of Freiburg, Germany"},{"author_name":"Saif Mukramoon Arosh","author_inst":"Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh"},{"author_name":"Naiem Hossain","author_inst":"Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh"},{"author_name":"Mohammad Al Shhab","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Ismail Hosen","author_inst":"Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh"},{"author_name":"Stuart J. Smith","author_inst":"Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK"},{"author_name":"Juergen Grauvogel","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Ioannis Vasilikos","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Roland Roelz","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Julia Nakgawa","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Rouven Hoefllin","author_inst":"Department of Medicine I, Medical Center University of Freiburg, Germany"},{"author_name":"Itay Tirosh","author_inst":"Broad institute"},{"author_name":"Tareq Juratli","author_inst":"Department of Neurosurgery, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Germany"},{"author_name":"Matthias Schneider","author_inst":"Department of Neurosurgery, University Hospital Bonn, Germany"},{"author_name":"Marco Prinz","author_inst":"University of Freiburg"},{"author_name":"Shawn Hervey-Jumper","author_inst":"University of California San Francisco"},{"author_name":"Ruman Rahman","author_inst":"Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK"},{"author_name":"Melanie Boerries","author_inst":"University of Freiburg"},{"author_name":"Juergen Beck","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Kevin Jospeh","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Geoffroy Andrieux","author_inst":"University Medical Center Freiburg"},{"author_name":"Vidhya Madapusi Ravi","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Sajib Chakraborty","author_inst":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center University of Freiburg, Germany"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Spatially confined niches support hypoxia-associated transcriptional plasticity contributing to malignant progression in IDH-mutant gliomas","rel_doi":"10.64898\/2026.05.31.729105","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729105","rel_abs":"Background While hypoxia is a well-established driver of glioblastoma progression, its role in IDH-mutant gliomas, characterized by localized hypoxic microenvironments rather than overt necrosis, remains poorly understood. Here, we investigate how hypoxia and microenvironmental-adaptations shape cellular heterogeneity and transcriptional plasticity in these tumors. Methods We integrated bulk, single-cell, and spatial-transcriptomics datasets from IDH-mutant glioma patients (Astrocytomas and Oligodendrogliomas) to characterize cellular-states and map the localization of hypoxic niches. To uncover tumor microenvironment effects, we established co-culture models using primary IDH-mutant glioma cells with human microglia and astrocytes, maintained under hypoxic and normoxic conditions, followed by bulk RNA-sequencing. Results We identified a hypoxia-associated astrocyte-like (AC-like) program that defines a quiescent, non-cycling population with a distinct transcription factor profile indicative of functional plasticity in IDH-mutant gliomas. These cells harbor glioma stem cell (GSC)-like features and are poised for a quiescent-to-activated (Q-to-A) transition that drives tumor progression. Mechanistically, co-culture models reveal that microglia promote this Q-to-A transition by enhancing HBEGF\/EGFR paracrine signaling. Spatial transcriptomics uncovers the co-localization of hypoxic niches within quiescent AC-like cells, whereby the activated subpopulation forms discrete niches defined by localized HBEGF\/EGFR communication gradients. Notably, tumors exhibiting elevated EGFR-driven activation signatures correlate with higher histological grade and poorer patient survival, implicating the Q-to-A transition as a critical driver of malignant progression. Conclusion Q-to-A transition within the hypoxic niche represents a critical driver of malignant progression in IDH-mutant gliomas, providing a microenvironment-driven mechanism for the transition to higher-grade disease and identifying targetable-vulnerabilities for therapeutic intervention.","rel_num_authors":29,"rel_authors":[{"author_name":"Depro Das","author_inst":"Medical Center, University of Freiburg, Germany"},{"author_name":"Alina Pandele","author_inst":"Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK"},{"author_name":"Vatsal D Jariwala","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Nishita S Ghariwala","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Aso O. Mohammed","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Tonmoy Das","author_inst":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center University of Freiburg, Germany"},{"author_name":"Christopher Krolla","author_inst":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center University of Freiburg, Germany"},{"author_name":"Saif Mukramoon Arosh","author_inst":"Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh"},{"author_name":"Naiem Hossain","author_inst":"Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh"},{"author_name":"Mohammad Al Shhab","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Ismail Hosen","author_inst":"Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh"},{"author_name":"Stuart J. Smith","author_inst":"Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK"},{"author_name":"Juergen Grauvogel","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Ioannis Vasilikos","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Roland Roelz","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Julia Nakgawa","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Rouven Hoefllin","author_inst":"Department of Medicine I, Medical Center University of Freiburg, Germany"},{"author_name":"Itay Tirosh","author_inst":"Broad institute"},{"author_name":"Tareq Juratli","author_inst":"Department of Neurosurgery, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Germany"},{"author_name":"Matthias Schneider","author_inst":"Department of Neurosurgery, University Hospital Bonn, Germany"},{"author_name":"Marco Prinz","author_inst":"University of Freiburg"},{"author_name":"Shawn Hervey-Jumper","author_inst":"University of California San Francisco"},{"author_name":"Ruman Rahman","author_inst":"Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK"},{"author_name":"Melanie Boerries","author_inst":"University of Freiburg"},{"author_name":"Juergen Beck","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Kevin Jospeh","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Geoffroy Andrieux","author_inst":"University Medical Center Freiburg"},{"author_name":"Vidhya Madapusi Ravi","author_inst":"Department of Neurosurgery, Medical Center University of Freiburg, Germany"},{"author_name":"Sajib Chakraborty","author_inst":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center University of Freiburg, Germany"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"CpG Atlas: A centralized multi-layer database and AI interface for DNA methylation research","rel_doi":"10.64898\/2026.05.30.729020","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.729020","rel_abs":"DNA methylation research has vastly expanded over the past decade, producing a wealth of epigenome-wide association studies, biomarker algorithms such as epigenetic clocks, technical performance analyses, and functional annotations for CpG sites. However, these resources remain fragmented across dozens of databases and supplementary files within manuscripts, forcing researchers to spend time and effort on data cleaning and integration prior to meaningful analyses. No single resource currently unifies this information into a centralized, easy-to-query framework. Here, we present CpG Atlas, a curated relational database that integrates 18 distinct annotation layers encompassing over 1.2 million CpG sites across all four generations of Illumina methylation arrays (HM450K, EPIC v1, EPIC v2, and MSA). Built on a snowflake schema with a canonical probe identifier hub implemented in SQL, CpG Atlas consolidates over 800,000 CpG-trait associations, results from Mendelian randomization analyses, CpG membership across 81 epigenetic clocks, array manifest information, and probe reliability data. It further includes specialized layers such as solo-WCGW, CoRSIVs, PRC2 binding, transposon and retroelement annotations, tissue-specific differentially methylated positions across 17 tissues, and hallmarks of aging and cancer. To maximize utility and ease of use, the database is paired with an interactive web tool and a natural language-to-SQL query interface, enabling users to quickly perform complex multi-dimensional queries. Detailed documentation about every data source and table is also provided, facilitating the identification and interpretation of relevant studies. We demonstrate the utility of CpG Atlas through two case studies: a systematic enrichment analysis revealing distinct functional signatures across 16 epigenetic clocks, and an iterative biomarker discovery workflow for IBD that leverages cross-layer integration. Because it is readily scalable simply by adding or updating tables in the database, CpG Atlas provides a continuously evolving and extensible infrastructure for the epigenetics community that supports collaborative research, interpretable biomarker development, and integrative analyses across the growing landscape of epigenetic data.","rel_num_authors":10,"rel_authors":[{"author_name":"Jenel Fraij Armstrong","author_inst":"Yale University"},{"author_name":"Shawn Wahi","author_inst":"Yale University"},{"author_name":"Daniel Borrus","author_inst":"Yale University"},{"author_name":"Raghav Sehgal","author_inst":"Yale University"},{"author_name":"Syed Rizvi","author_inst":"Yale University"},{"author_name":"Shiyang Zhang","author_inst":"Yale University"},{"author_name":"Macsue Jacques","author_inst":"Monash University"},{"author_name":"Nir Eynon","author_inst":"Monash University"},{"author_name":"David van Dijk","author_inst":"Yale University"},{"author_name":"Albert Higgins-Chen","author_inst":"Yale University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Homeostatic Plasticity Enables Stable, Flexible, and Tunable Assemblies","rel_doi":"10.64898\/2026.05.31.729097","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729097","rel_abs":"Strongly interconnected neuronal populations, called assemblies, dynamically form through synaptic plasticity mechanisms and are thought to be a substrate for memories in the brain. Many assembly formation models use Hebbian excitatory-to-excitatory plasticity, where coordinated activity strengthens recurrent structure. However, these models typically yield binary assembly outcomes: networks with either weak (no assembly) or maximally strong (assembly) connectivity. We consider networks with a combination of Hebbian excitatory-to-excitatory plasticity and inhibitory-to-excitatory synapses with plasticity that homeostatically stabilizes excitatory neuron firing at a target value. When we set excitatory-to-excitatory plasticity to be homeostatically compliant, in that potentiation and depression are balanced at the homeostatic target firing rate, we find a stable continuum of synaptic strengths, and assembly structure is no longer binary. We use a recurrent network of spiking neuron models and an associated mean-field theory to identify this continuum as a line attractor in synaptic weight space. While along the attractor, homeostasis ensures that neuronal firing rates are invariant, the dynamical response properties of the network are quite malleable, with strongly coupled networks having high gain and longer timescale responses. Using our mean-field theory we show how correlated stochastic spiking activity among the excitatory neurons can destroy the line attractor, yet this can be mitigated when correlated inputs are shared across the excitatory and inhibitory neurons. Altogether, we provide an alternative learning framework based on homeostasis, where a tunable and flexible assembly structure is possible.","rel_num_authors":3,"rel_authors":[{"author_name":"Michelle C Miller","author_inst":"University of Chicago"},{"author_name":"Christoph Miehl","author_inst":"University of Chicago"},{"author_name":"Brent Doiron","author_inst":"University of Chicago"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Patient-Derived Air-Liquid Interface Forebrain Organoids Reveal Functional Synaptic Deficits in Schizophrenia","rel_doi":"10.64898\/2026.06.01.729183","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729183","rel_abs":"Schizophrenia (SCZ) is a severe and debilitating neurodevelopmental disorder with lifelong impact on everyday life. Disruptions in synapse functions play a key role in its complex and poorly understood etiological and pathological mechanisms. Here, we investigated both the molecular composition and the spontaneous and stimulated functional properties of synapses in neural organoids from SCZ individuals. Air-liquid interface forebrain organoids (ALI-FOs) were generated from induced pluripotent stem cells (iPSCs) derived from three individuals with SCZ and three healthy controls. At day 170 synaptosomes were enriched and analyzed by data-independent acquisition mass spectrometry to profile the proteome, alongside with TMT-labeled phosphoproteomics both before and after acute KCl-induced depolarization. In parallel, we characterized the PTMome of the surrounding cellular environment, comprising phosphorylation, peptides with free and reversibly modified cysteines, and sialylated N-linked glycopeptides. Functional glutamatergic and GABAergic activity was assessed using calcium imaging to capture spontaneous neuronal signaling. Both conditions exhibited mature synaptic structures, while growth cones were observed only in SCZ-derived ALI-FOs, indicative of ongoing or delayed synaptogenesis. Proteomic analysis of synaptosome preparations revealed 358 differentially regulated proteins between SCZ and controls and 125 phophoproteins with altered phosphorylation, which clustered into three major categories: (1) synaptogenesis and synapse signaling; (2) cytoskeleton and cell junctions; (3) growth cone dynamics and neurite outgrowth. Analysis of the PTMs in the surrounding cellular environment revealed regulation of key regulatory mechanisms in 526 proteins, supporting the synaptic alterations observed. Notably, components of the Wnt signaling pathway were consistently dysregulated across both the synaptosome preparation and the PTMome in SCZ-derived ALIFOs as compared to controls. Depolarization-induced phospho-signaling revealed SCZ-specific response enriched in synaptic vesicle trafficking pathways. Together, these findings provide new insights into early synaptic alterations in SCZ, highlighting changes not only in protein composition, but more in protein regulatory mechanisms underlying synaptic signaling.","rel_num_authors":16,"rel_authors":[{"author_name":"Lucrezia Criscuolo","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark"},{"author_name":"Pia Jensen","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark"},{"author_name":"Helle Bogetofte Barnkob","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark"},{"author_name":"Sissel Ida Schmidt","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark"},{"author_name":"Fadumo A. Mohamed","author_inst":"Department for Veterinary and Animal Science, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Lene Andrup Jakobsen","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark"},{"author_name":"Marie Sejberg Ohlenschlaeger","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark"},{"author_name":"Henriette Reventlow Frederiksen","author_inst":"Department for Veterinary and Animal Science, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Fangyuan Li","author_inst":"Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Elif Bayram","author_inst":"Copenhagen Research Centre for Biological and Precision Psychiatry, Mental Health Centre Copenhagen, Copenhagen University Hospital, Denmark"},{"author_name":"Michael Eriksen Benros","author_inst":"Copenhagen Research Centre for Biological and Precision Psychiatry, Mental Health Centre Copenhagen, Copenhagen University Hospital, Denmark"},{"author_name":"Jonathan Brewer","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark"},{"author_name":"Barbara Lykke Lind","author_inst":"Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Phillip J. Robinson","author_inst":"Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Sydney, Australia."},{"author_name":"Kristine Freude","author_inst":"Department for Veterinary and Animal Science, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Martin R. Larsen","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"A specific computational role for early-life unpredictability, and not lifelong stressful experience, in decision-making under uncertainty.","rel_doi":"10.64898\/2026.06.01.729407","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729407","rel_abs":"It has been shown that early-life adversity (ELA) shapes how individuals learn, remember, and make decisions, yet the precise computations altered by these experiences remain unclear. Here, we combine a structured foraging task with computational modeling to test a recently developed theory for how a particular kind of ELA, early-life unpredictability (ELU), specifically influences choice under uncertainty. Adult participants (N=297) performed a sequential foraging task requiring continuous trade-offs between exploiting depleting resources and exploring alternatives. Subsets also completed assessments of early-life unpredictability (QUIC) and for trauma symptoms arising from lifelong stressors (PCL). We fit participants' behavior with a Bayesian learning-and-planning model in which uncertainty modulates the valuation of leaving a current resource patch. Critically, the subjective influence of local uncertainty was allowed to vary freely between participants. Consistent with theoretical proposals, computational model fits and mediation analyses revealed a robust indirect pathway: ELU predicted increased discounting in the face of uncertainty, which in turn predicted greater overharvesting. This pattern was consistent across environmental conditions, indicating that early-life unpredictability primarily influences behavior through a general influence on uncertainty processing. Importantly, although PCL scores were also correlated with uncertainty adaptation, these effects were fully accounted for by shared variance with ELU, offering a clear dissociation between developmental unpredictability and lifelong traumatic experience. Together, our results show that early-life unpredictability causes long-lasting changes in decision-making by amplifying the subjective experience of uncertainty.","rel_num_authors":10,"rel_authors":[{"author_name":"Yifan Zhang","author_inst":"UC Irvine"},{"author_name":"Yifei Chen","author_inst":"Princeton University"},{"author_name":"X Roger Chen","author_inst":"UC Irvine"},{"author_name":"Nora C Harhen","author_inst":"New York University"},{"author_name":"Laura Glynn","author_inst":"Chapman University"},{"author_name":"Elysia Davis","author_inst":"University of Denver"},{"author_name":"Tallie Z Baram","author_inst":"UC Irvine"},{"author_name":"Victoria B Risbrough","author_inst":"University of California San Diego"},{"author_name":"Daniel A Stout","author_inst":"University of California San Diego"},{"author_name":"Aaron M Bornstein","author_inst":"University of California, Irvine"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Systematic Engineering of Intra-Articular Drug Release Profiles Reveals a Key Determinant of Disease-Modifying Efficacy in Post-Traumatic Osteoarthritis","rel_doi":"10.64898\/2026.05.30.728894","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728894","rel_abs":"Post-traumatic osteoarthritis (PTOA) is a progressive joint disease for which no disease-modifying osteoarthritis drugs (DMOADs) have been approved. Although injectable drug delivery systems can prolong therapeutic retention within the joint, it remains unclear whether local drug release kinetics influence disease-modifying efficacy. Here, we developed a modular platform of injectable supramolecular hydrogels using biocompatible, generally recognized as safe (GRAS) amphiphilic molecules and systematically engineered a range of degradation and drug release profiles. Using the cathepsin-K inhibitor L-006235 as a model DMOAD, we generated hydrogels with distinct release kinetics and evaluated their therapeutic performance in PTOA. Hydrogels exhibiting slower degradation and more sustained drug release like Sucrose Stearate (SS hydrogel) showed prolonged intra-articular retention and improved therapeutic outcomes. In a destabilization of the medial meniscus (DMM) mouse model, sustained-release formulations significantly reduced cartilage degeneration, preserved aggrecan expression, improved joint histopathology, and enabled effective monthly dosing. In contrast, formulations with faster degradation and release kinetics required more frequent administration to achieve comparable benefits. To our knowledge, this is the first study to establish local drug release kinetics as a critical determinant of disease-modifying efficacy in PTOA. This work provides one of the clearest demonstrations to date that engineering intra-articular release kinetics, rather than merely prolonging residence time, can improve disease-modifying outcomes. Our findings establish local release kinetics as a key design parameter for osteoarthritis therapeutics and highlight the potential of tunable supramolecular hydrogels for long-acting drug delivery.","rel_num_authors":22,"rel_authors":[{"author_name":"Jingjing Gao","author_inst":"University of Massachusetts Amherst"},{"author_name":"Nutan Bhingaradiya","author_inst":"Brigham and Womens Hospital"},{"author_name":"Ziting Judy Xia","author_inst":"University of Massachusetts Amherst"},{"author_name":"Ryan Yip","author_inst":"Brigham and Womens Hospital"},{"author_name":"Eli Weldon","author_inst":"Brigham and Womens Hospital"},{"author_name":"Chilan Bou Chosson Leite","author_inst":"Brigham and Womens Hospital"},{"author_name":"Nishkal Dhiraj Pisal","author_inst":"Brigham and Womens Hospital"},{"author_name":"Swetharajan Gunasekar","author_inst":"Brigham and Womens Hospital"},{"author_name":"Pranav Chandrasekar","author_inst":"Brigham and Womens Hospital"},{"author_name":"Paula Oliva Ribas","author_inst":"Brigham and Womens Hospital"},{"author_name":"Mahima Dewani","author_inst":"Brigham and Womens Hospital"},{"author_name":"Christopher Jiang","author_inst":"Brigham and Womens Hospital"},{"author_name":"Gopinathan Janarthanan","author_inst":"New York University Abu Dhabi"},{"author_name":"Alexandra Dolliver","author_inst":"Brigham and Womens Hospital"},{"author_name":"Chu Wai Chun Rachel","author_inst":"Brigham and Womens Hospital"},{"author_name":"Gunjan Malik","author_inst":"Brigham and Womens Hospital"},{"author_name":"Sohyung Lee","author_inst":"Brigham and Women's Hospital"},{"author_name":"Ranit Dutta","author_inst":"Brigham and Women's Hospital"},{"author_name":"Sanjairaj Vijayavenkataraman","author_inst":"New York University Abu Dhabi"},{"author_name":"Jeffrey M Karp","author_inst":"Brigham and Womens Hospital"},{"author_name":"Joerg Ermann","author_inst":"Brigham and Women's Hospital"},{"author_name":"Nitin Joshi","author_inst":"Brigham and Women's Hospital"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Coupled intracellular redox and extracellular respiration sensing for quantitative oxidative stress profiling","rel_doi":"10.64898\/2026.05.30.727573","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.727573","rel_abs":"Abstract Quantitative assessment of cellular oxidative stress requires simultaneous measurement of intracellular redox state and extracellular respiratory activity, yet integrated sensing approaches remain limited. Here, we present a dual fluorescent sensing platform combining a genetically encoded redox biosensor (roGFP2-Tsa2{Delta}CR) with an optical oxygen sensor embedded in microwell plates for parallel, noninvasive quantification of intracellular reactive oxygen species (ROS) and oxygen consumption rates (OCR) in industrial yeast systems. The roGFP2-based sensor was stably expressed in Saccharomyces cerevisiae (S. cerevisiae) and Yarrowia lipolytica (Y. lipolytica), enabling dynamic monitoring of oxidative stress at population, single cell, and subcellular levels, while oxygen-sensitive films provided real-time respiration measurements. Using this platform, we identified distinct redox respiration phenotypes between the two yeasts. Crabtree-positive S. cerevisiae exhibited low OCR and mitochondrial ROS during glucose cultivation, whereas growth on glycerol increased OCR and mitochondrial ROS by ~2.5-fold and 12%, respectively. In contrast, the obligate respiratory yeast Y. lipolytica displayed 3-fold higher OCR and 16% lower mitochondrial ROS than respiring S. cerevisiae, indicating differences in respiratory oxidative burden. Antimycin A treatment reduced OCR by 60% in respiring S. cerevisiae while increasing mitochondrial ROS by 35%, whereas Y. lipolytica showed greater resistance to respiratory and oxidative perturbations. By integrating intracellular redox sensing with extracellular oxygen measurements, this platform enables quantitative coupling of redox state and respiration in living cells. The approach provides a scalable framework for evaluating cellular fitness, stress tolerance, and metabolic state in biomanufacturing and synthetic biology. Keywords: Reactive oxygen species, genetically encoded sensor, dissolved oxygen sensor, and biomanufacturing","rel_num_authors":5,"rel_authors":[{"author_name":"Shirin Parvin","author_inst":"Department of Electrical and Computer Engineering, Iowa State University"},{"author_name":"Deon Ploessl","author_inst":"Department of Chemical and Biological Engineering, Iowa State University"},{"author_name":"Zheyuan Zhang","author_inst":"Department of Electrical and Computer Engineering, Iowa State University"},{"author_name":"Zengyi Shao","author_inst":"Department of Chemical and Biological Engineering, Iowa State University"},{"author_name":"Meng Lu","author_inst":"Department of Electrical and Computer Engineering, and Department of Mechanical Engineering, Iowa State University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"A phage-encoded small RNA that mimics chimeric guide to inhibit CRISPR-Cas9","rel_doi":"10.64898\/2026.06.03.729762","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729762","rel_abs":"CRISPR Cas9 relies on a dual crRNA-tracrRNA guide, yet whether RNA based anti CRISPRs exist for this system has remained unknown. Here we identify a phage encoded small non coding RNA, rAcrIIA1, that adopts an unexpected chimeric crRNA-tracrRNA architecture, faithfully recapitulating the entire single guide RNA (sgRNA) of Cas9. Cryo EM structures of the Cas9-rAcrIIA1 binary complex and the Cas9-rAcrIIA1-DNA ternary complex reveal that rAcrIIA1 engages Cas9 nearly identically to the native sgRNA, competitively blocking crRNA and tracrRNA loading and thereby abolishing DNA interference. Strikingly, beyond its natural inhibitory function, rAcrIIA1 is fully reprogrammable: with variable guide sequences, it directs Cas9 for sequence specific DNA cleavage with efficiency comparable to the canonical sgRNA, and it activates trans cleavage more potently. Thus, rAcrIIA1 provides the first experimentally validated, mechanistically resolved RNA based inhibitor of CRISPR Cas9, reveals a distinct anti CRISPR mechanism through complete sgRNA mimicry, and serves as a versatile bifunctional scaffold for genome editing and diagnostics.","rel_num_authors":7,"rel_authors":[{"author_name":"Ying Chen","author_inst":"Xiamen University"},{"author_name":"Peng Zhao","author_inst":"Peking University"},{"author_name":"Chenmin Guo","author_inst":"Xiamen University"},{"author_name":"Dandan Chen","author_inst":"Peking University"},{"author_name":"Caihong Yun","author_inst":"Peking University"},{"author_name":"Jiyun Chen","author_inst":"Xiamen University"},{"author_name":"Liang Liu","author_inst":"Xiamen University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"The COPI coatomer influences LDL receptor activity, hepatic lipid storage, and apoB secretion","rel_doi":"10.64898\/2026.05.30.728950","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728950","rel_abs":"Background: Decreased hepatic removal of low density lipoproteins (LDL) and increased apolipoprotein B (apoB) production cause hypercholesterolemia, a major causal risk factor of atherosclerotic cardiovascular disease (ASCVD). By a genome-wide siRNA screen, we previously identified subunits of the Coat protein I (COPI) complex to limit LDL uptake into Huh-7 hepatocarcinoma cells. Methods: These findings were validated by targeted in vitro experiments as well as genetic association studies in humans and three mouse models with mutated or disrupted COPI genes. Results: Silencing of COPA, COPB1, COPB2, ARCN1, COPG1, and COPZ1 in Huh-7 cells resulted in decreased uptake of LDL and aberrant glycosylation and altered cell surface abundance of the LDL receptor (LDLR) as well as increased apoB secretion and cellular lipid storage. Single nucleotide polymorphisms of ARCN1 were associated with lower ARCN1 expression and higher levels of LDL-cholesterol (LDL-C). Rare variants of COPA and COPG1 were enriched among patients with LDL-C > 5 mmol\/L. Patients and mice carrying other rare immunopathogenic missense variants of COPA and COPG1 did not present with elevated plasma levels of LDL-C, while hepatic knockdown of murine Copg1 increased the concentrations of non-HDL-cholesterol in plasma and triglycerides in the liver. Conclusions: The COPI coatomer regulates LDLR activity and apoB secretion as well as lipid content of liver cells. Loss of function of some variants of COPI genes are associated with higher LDL-C levels.","rel_num_authors":30,"rel_authors":[{"author_name":"Grigorios Panteloglou","author_inst":"University & University Hospital Zurich"},{"author_name":"Jerome Robert","author_inst":"University Hospital of Zurich"},{"author_name":"Marieke Smit","author_inst":"University of Groningen, University Medical Center Groningen"},{"author_name":"Nicolette Huijkman","author_inst":"University of Groningen, University Medical Center Groningen"},{"author_name":"Niels J Kloosterhuis","author_inst":"University Medical Center Groningen"},{"author_name":"Christopher S Law","author_inst":"University of California San Francisco"},{"author_name":"Brian Woods","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Alaa Othman","author_inst":"ETH Zurich"},{"author_name":"Marcus E. Kleber","author_inst":"Universitatsklinikum Mannheim"},{"author_name":"Graciela Delgado","author_inst":"University of Heidelberg"},{"author_name":"Patrizia Maria Tarugi","author_inst":"Orto Botanico Universita di Modena e Reggio Emilia"},{"author_name":"Museer A. Lone","author_inst":"University Hospital Zurich"},{"author_name":"Justina Clarinda Wolters","author_inst":"University Medical Center Groningen"},{"author_name":"Antoine Rimbert","author_inst":"University of Nantes"},{"author_name":"Anja Kerksiek","author_inst":"University Hospital of Bonn"},{"author_name":"Dieter Luetjohann","author_inst":"University Hospital of Bonn"},{"author_name":"Lucia Rohrer","author_inst":"University Hospital of Zurich"},{"author_name":"Paolo Zanoni","author_inst":"University of Zurich"},{"author_name":"Sofia Kakava","author_inst":"University of Zurich"},{"author_name":"Stephanie Haeusler","author_inst":"University Hospital of Zurich"},{"author_name":"Eveline Schlumpf","author_inst":"University of Zurich and University Hospital Zurich"},{"author_name":"Marta Futema","author_inst":"St. George's University of London"},{"author_name":"Steve E Humphries","author_inst":"British Heart Foundation Laboratories, University College of London"},{"author_name":"Janet Chou","author_inst":"Boston Childrens Hospital"},{"author_name":"Winfried Maerz","author_inst":"SYNLAB Holding Deutschland GmbH"},{"author_name":"Raif S Geha","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Anthony K Shum","author_inst":"University of California San Francisco"},{"author_name":"Jan Albert K Kuivenhoven","author_inst":"University of Groningen, University Medical Center Groningen"},{"author_name":"Bart van de Sluis","author_inst":"University Medical Center Groningen"},{"author_name":"Arnold von Eckardstein","author_inst":"University of Zurich"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Slow Oscillations Gate Interictal Spikes Across the Human Thalamocortical-Epileptogenic Network","rel_doi":"10.64898\/2026.05.30.728961","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728961","rel_abs":"Background: Slow oscillations (SOs; 0.5-1.5 Hz), a hallmark of non-rapid eye movement (NREM) sleep, are associated with a marked amplification of interictal epileptiform spike (IIS) activity in focal epilepsy. However, the network-level organization of this effect across the thalamocortical-epileptogenic system, and whether IIS-permissive SOs can be predicted from pre-onset brain states, remain unclear. Methods: We analyzed simultaneous scalp EEG and stereo-EEG (SEEG) recordings from 6 patients with drug-resistant focal epilepsy across 24 full-day recording days, sampling prefrontal cortex (PFC), thalamus, and seizure onset zone (SOZ). SO-IIS coupling was characterized across vigilance states using peri-event and phase-based analyses, with a gamma-based validation step to reduce contamination by IIS-related slow potentials. Pre-onset phase-amplitude coupling (PAC) was compared between IIS-permissive and non-permissive SOs. Results: SO-IIS coupling was observed across all regions, with the strongest and most temporally precise pre-trough IIS clustering in the SOZ (peak 4.4% in NREM), exceeding PFC (1.7%) and thalamic coupling. Thalamic coupling was preserved across wakefulness and NREM and was significant in 7\/11 nuclei, with nucleus-specific phase preferences. SO morphological features, particularly up-slope and peak-to-peak amplitude at PFC contacts, predicted IIS occurrence in the SOZ. Pre-onset PAC differed significantly between permissive and non-permissive SOs across regions. Conclusions: SO-IIS coupling is a distributed, network-level phenomenon with region- and state-specific characteristics, and pre-onset PAC provides a predictive signature of IIS-permissive brain states. These findings support the feasibility of developing personalized, closed-loop neuromodulatory strategies targeting SO-gated IIS suppression in focal epilepsy. Keywords: Slow oscillations; Interictal epileptiform spikes; Focal epilepsy; Closed-loop neuromodulation; Phase-amplitude coupling","rel_num_authors":6,"rel_authors":[{"author_name":"Mahmoud Alipour","author_inst":"University of Chicago"},{"author_name":"Wim van Drongelen","author_inst":"University of Chicago"},{"author_name":"Douglas R. Nordli Jr.","author_inst":"University of Chicago"},{"author_name":"Joel Voss","author_inst":"University of Chicago"},{"author_name":"Kenneth Lee","author_inst":"University of Chicago"},{"author_name":"David Satzer","author_inst":"University of Chicago"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Spatiotemporal Cascade of AP1\/CCA1-TOC1 Module Gates Stem Development","rel_doi":"10.64898\/2026.05.30.728956","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728956","rel_abs":"Stem development is crucial in plant vertical architecture and overall crop improvement. The molecular mechanisms underlying the initiation and circadian growth of stem remain still enigmatic. Here, we demonstrate that APETALA1 (AP1) spatially initiates circadian stem growth through a noncell-autonomous role of TIMING OF CAB EXPRESSION1 (TOC1) emanating from the floral meristem to inflorescence meristem in Arabidopsis thaliana. Mechanistically, AP1 interacts with and recruits CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) to associate TOC1. Dynamic AP1-CCA1 complex formation is crucial for maintaining circadian rhythmicity and expression of TOC1. Tissue-specific expression of TOC1 in floral meristems rescues the developmental defects of toc1 mutants at both functional and transcriptional levels. Furthermore, TOC1 directly activates the circadian expression of pectin methylesterase gene family, which is critical for its role in stem development. AP1 homologs regulate circadian stem elongation and plant height in wheat and rice, underscoring the conserved mechanism across species. Our findings uncovered a spatiotemporal regulatory cascade gating stem development and identified candidate genes for crop improvement.","rel_num_authors":17,"rel_authors":[{"author_name":"Jiahui Xu","author_inst":"Hebei Normal University"},{"author_name":"Jiahong Qi","author_inst":"Hebei Normal University"},{"author_name":"Yufeng Yang","author_inst":"Hebei Normal University"},{"author_name":"Chuan Jiang","author_inst":"Hebei Normal University"},{"author_name":"Pedro Garcia-Caparros","author_inst":"University of Almeria"},{"author_name":"Yichao Zheng","author_inst":"Hebei Normal University"},{"author_name":"Mei Jin","author_inst":"Hebei Normal University"},{"author_name":"Qingyu Guo","author_inst":"Hebei Normal University"},{"author_name":"Dan Zhao","author_inst":"Hengshui University"},{"author_name":"Lin Guo","author_inst":"Hebei Normal University"},{"author_name":"Yunzhen Li","author_inst":"Huazhong Agricultural University"},{"author_name":"Xiaoli Fan","author_inst":"Chengdu Institute of Biology, Chinese Academy of Sciences"},{"author_name":"Yuehui He","author_inst":"Peking University"},{"author_name":"Xiaodong Xu","author_inst":"Henan University"},{"author_name":"Qiguang Xie","author_inst":"Henan University"},{"author_name":"Xigang Liu","author_inst":"Hebei Normal University"},{"author_name":"Hao Zhang","author_inst":"Hebei Normal University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"RE-1 silencing transcription factor is reduced in endometriosis and uterine deletion in mice alters progesterone responsiveness","rel_doi":"10.64898\/2026.05.30.728827","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728827","rel_abs":"Endometriosis is a steroid-dependent gynecologic disease characterized by progesterone (P4) resistance, subfertility\/infertility, and pelvic pain; however, the molecular mechanisms underlying impaired P4 responsiveness in endometriosis tissue are not fully understood. RE-1 silencing transcription factor (REST), a transcriptional regulator implicated in steroid hormone signaling, has emerged as a potential mediator of P4 responsiveness. Here, we investigated the role of REST in endometriosis using human tissues and a uterine-specific Rest conditional knockout mouse model. Immunohistochemical analysis of eutopic endometrium and ectopic lesions from patients with endometriosis revealed significantly reduced nuclear REST expression compared with control endometrium, suggesting loss of functional REST in disease. To assess the physiological consequences of REST deficiency, uterine-specific Rest knockout (Rest d\/d) mice were generated. Rest d\/d females exhibited progressive subfertility and hyper-estrogenic uterine tissue characteristics that displayed a blunted responsiveness to P4 treatment. Loss of Rest selectively altered expression of P4-responsive genes associated with endometriosis pathology, despite preserved P4 receptor expression. Following induction of experimental endometriosis, female mice that developed endometriotic-like lesions using Rest-deficient donor tissue developed significantly larger lesions that were less responsive to P4 treatment compared to lesions induced using control tissue. Mechanical sensitivity was modestly increased in mice receiving Rest-deficient tissue, whereas vaginal hyperalgesia was unaffected. These findings identify loss of nuclear REST as a feature of endometriosis and support a role of REST in subfertility, lesion progression, and blunted response to P4. REST may represent a novel molecular contributor to altered P4 responsiveness and a potential therapeutic target in endometriosis.","rel_num_authors":10,"rel_authors":[{"author_name":"Paige M Minchella","author_inst":"University of Kansas Medical Center"},{"author_name":"Ayushi Vashisht","author_inst":"University of Kansas Medical Center"},{"author_name":"Riley Peterson","author_inst":"University of Kansas Medical Center"},{"author_name":"Amanda Graham","author_inst":"University of Kansas Medical Center"},{"author_name":"Sumedha Gunewardena","author_inst":"University of Kansas Medical Center"},{"author_name":"Wei Cui","author_inst":"University of Kansas Medical Center"},{"author_name":"Austin Findley","author_inst":"University of Kansas Medical Center"},{"author_name":"Julie A Christianson","author_inst":"University of Kansas Medical Center"},{"author_name":"Vargheese Chennathukuzhi","author_inst":"University of Kansas University Medical Center"},{"author_name":"Warren B Nothnick","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"A hERG Blocker Facilitates K+ Channel Current by Agonizing Pore Opening while Blocking","rel_doi":"10.64898\/2026.05.30.728541","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728541","rel_abs":"Many drugs that block voltage-gated K+ channels encoded by the human Ether-a-go-go-Related Gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically-approved hERG blockers including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism undergirds facilitation. We focus on nifekalant, a Class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblock of these open-yet-blocked channels results in supranormal hERG current. We develop rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generate atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements reveal that agonism-while-blocking undergirds nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.","rel_num_authors":11,"rel_authors":[{"author_name":"Steffen S. Docken","author_inst":"The Kirby Institute"},{"author_name":"Matthew J. Marquis","author_inst":"University of California, Davis"},{"author_name":"Khoa Ngo","author_inst":"University of California, Davis"},{"author_name":"Yuumu Wada","author_inst":"Tokushima Bunri University"},{"author_name":"Satomi Kita","author_inst":"Tokushima Bunri University"},{"author_name":"Vladimir Yarov-Yarovoy","author_inst":"University of California, Davis"},{"author_name":"Colleen E. Clancy","author_inst":"University of California, Davis"},{"author_name":"Igor V. Vorobyov","author_inst":"University of California, Davis"},{"author_name":"Timothy J. Lewis","author_inst":"University of California, Davis"},{"author_name":"Kazuharu Furutani","author_inst":"Tokushima Bunri University"},{"author_name":"Jon T. Sack","author_inst":"University of California, Davis"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"SciCore-Omics: a tri-modal foundation model unifying histology, spatial transcriptomics and language for spatial biology","rel_doi":"10.64898\/2026.05.30.728937","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728937","rel_abs":"Histomorphology and spatial transcriptomics capture complementary aspects of tissue biology, but their relationships remain difficult to extract, align, and interpret at scale. Existing foundation models typically connect histology, omics, or language only pairwise, which limits their capacity to jointly infer molecular states, decode spatial tissue organization, and generate biologically grounded explanations. Here, we show SciCore-Omics, the first tri-modal foundation model linking histology images, spatial transcriptomics, and biological language. We constructed a spatially paired image-gene-text dataset comprising 151,182 spots across multiple tissues and performed a three-stage progressive training of SciCore-Omics on this dataset. Across gene expression prediction and spatial domain recognition, SciCore-Omics achieved 23.6-80.9% relative gains in task-specific metrics over the strongest external baselines. It further showed robust zero-shot generalization in histopathology classification, outperforming GPT-5 by 6.16 percentage points in mean accuracy across four benchmarks. Expert evaluation in 10 breast cancer cases confirmed its H&E-only case-level molecular reasoning capability. Together, our method demonstrates that a tri-modal framework can effectively bridge histomorphology and molecular state, providing a more general and interpretable foundation model for computational pathology and omics analysis.","rel_num_authors":12,"rel_authors":[{"author_name":"Xinyu Xiao","author_inst":"Chinese Academy of Medical Sciences & Peking Union Medical College"},{"author_name":"Yunfei Li","author_inst":"School of Intelligence Science and Technology, Nanjing University"},{"author_name":"Zheni Zeng","author_inst":"School of Intelligence Science and Technology, Nanjing University"},{"author_name":"Yukun Yan","author_inst":"Department of Computer Science and Technology, Tsinghua University"},{"author_name":"Zhiyuan Liu","author_inst":"Department of Computer Science and Technology, Tsinghua University"},{"author_name":"Zhenghao Liu","author_inst":"School of Computer Science and Engineering, Northeastern University"},{"author_name":"Yujia Xiang","author_inst":"School of Life Sciences, Tsinghua University"},{"author_name":"Zhenbang Ye","author_inst":"Peking Union Medical College"},{"author_name":"Jianming Ying","author_inst":"Peking Union Medical College"},{"author_name":"Yang Li","author_inst":"The State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing)"},{"author_name":"Linhai Xie","author_inst":"The State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing)"},{"author_name":"Fuchu He","author_inst":"The State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing)"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Conformational flexibility of soybean lipoxygenase is coupled to crystal solvent content in serial crystallography","rel_doi":"10.64898\/2026.05.30.729005","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.729005","rel_abs":"Serial femtosecond crystallography (SFX) is increasingly employed to determine protein structures and study conformational dynamics under physiological conditions, but the effects of sample preparation and delivery on crystallized macromolecules remain poorly understood. Here, we report the analysis of soybean lipoxygenase-1 (SLO) microcrystals collected by SFX at the Linac Coherent Light Source. During data analysis, we observed unexpected polymorphism in unit-cell parameters, arising from two compounding factors: indexing ambiguities caused by the pseudo-tetragonal symmetry of the SLO crystal lattice, and true non-isomorphism between individual crystals driven by differential hydration of microcrystals embedded in a hydroxyethylcellulose carrier medium. By combining unit-cell clustering with systematic reindexing, we resolved two distinct polymorphs and determined independent structures from a single experiment. Although the two structures show little difference in the average atomic coordinates (average all-atom RMSD of 0.34 [A]), an approximately 8.5% difference in crystal solvent content produces measurable differences in crystal contacts and conformational flexibility. The more hydrated (large-cell) polymorph exhibits greater inter-domain flexibility and harmonic disorder in hydrophobic core residues belonging to the catalytic network of the enzyme. In the dehydrated (small-cell) polymorph, these same residues adopt discrete alternative conformations resolvable in the electron density. Our results demonstrate that sample delivery conditions in serial crystallography can significantly modulate the apparent conformational landscape of crystallized proteins, with direct implications for the interpretation of protein dynamics from SFX data.","rel_num_authors":27,"rel_authors":[{"author_name":"Alexander M Wolff","author_inst":"University of California, Merced"},{"author_name":"Daniel W Paley","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Iris D Young","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Alexander Deary","author_inst":"University of California, Merced"},{"author_name":"Vidya Ganapati","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Jack Hirschman","author_inst":"SLAC National Accelerator Laboratory"},{"author_name":"Azeem Horani","author_inst":"University of California, Merced"},{"author_name":"Randy Lemons","author_inst":"SLAC National Accelerator Laboratory"},{"author_name":"Stella Lisova","author_inst":"SLAC National Accelerator Laboratory"},{"author_name":"Ralph L McAnelly","author_inst":"University of California, Merced"},{"author_name":"Dondis Moreland","author_inst":"University of California, Merced"},{"author_name":"Sandra T.M. Mous","author_inst":"SLAC National Accelerator Laboratory"},{"author_name":"Amanda Ohler","author_inst":"East Carolina University"},{"author_name":"Joshua M Rodriguez","author_inst":"University of California, Merced"},{"author_name":"Silvia Russi","author_inst":"SLAC National Accelerator Laboratory"},{"author_name":"Raymond G. Sierra","author_inst":"SLAC National Accelerator Laboratory"},{"author_name":"Daniel Mariusz Tcho\u0144","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Jan Paulo T. Zaragoza","author_inst":"University of California, Berkeley"},{"author_name":"Sergio Carbajo","author_inst":"University of California, Los Angeles"},{"author_name":"Alec H. Follmer","author_inst":"University of California, Davis"},{"author_name":"Judith P Klinman","author_inst":"University of California, Berkeley"},{"author_name":"Adam R Offenbacher","author_inst":"East Carolina University"},{"author_name":"Fr\u00e9d\u00e9ric Poitevin","author_inst":"SLAC National Accelerator Laboratory"},{"author_name":"Nicholas K Sauter","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Mark A Wilson","author_inst":"University of Nebraska, Lincoln"},{"author_name":"Aaron S brewster","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Michael C Thompson","author_inst":"University of California, Merced"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"The structural basis for LRRK2's activation and autoinhibition","rel_doi":"10.64898\/2026.05.31.729085","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729085","rel_abs":"Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-EM, biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C\/G\/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the GDP-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.","rel_num_authors":19,"rel_authors":[{"author_name":"Amalia Villagran Suarez","author_inst":"UC San Diego"},{"author_name":"Kathryn S Hatch","author_inst":"Weill Cornell Medicine"},{"author_name":"Tatyana Bodrug","author_inst":"Weill Cornell Medicine"},{"author_name":"Wei Gai","author_inst":"Weill Cornell Medicine"},{"author_name":"Katherine J Surridge","author_inst":"Weill Cornell Medicine"},{"author_name":"Elizabeth Moussikhina","author_inst":"Weill Cornell Medicine"},{"author_name":"Kendrick HV Nguyen","author_inst":"Weill Cornell Medicine"},{"author_name":"Marta Sanz-Murillo","author_inst":"CNIO"},{"author_name":"Robert Callahan","author_inst":"Weill Cornell Medicine"},{"author_name":"Erica Xiong","author_inst":"University of Pennsylvania"},{"author_name":"Delisa Ramos","author_inst":"UC San Diego"},{"author_name":"Lawrence Zhu","author_inst":"UCSF"},{"author_name":"Verena Dederer","author_inst":"Goethe University"},{"author_name":"Sebastian Mathea","author_inst":"Goethe University Frankfurt am Main"},{"author_name":"Janet H Iwasa","author_inst":"University of Utah"},{"author_name":"Stefan Knapp","author_inst":"Goethe-University Frankfurt"},{"author_name":"Kevan Shokat","author_inst":"University of California San Francisco"},{"author_name":"Samara L Reck-Peterson","author_inst":"Weill Cornell Medicine"},{"author_name":"Andres E Leschziner","author_inst":"Weill Cornell Medicine"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"The structural basis for LRRK2's activation and autoinhibition","rel_doi":"10.64898\/2026.05.31.729085","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.729085","rel_abs":"Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-EM, biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C\/G\/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the GDP-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.","rel_num_authors":19,"rel_authors":[{"author_name":"Amalia Villagran Suarez","author_inst":"UC San Diego"},{"author_name":"Kathryn S Hatch","author_inst":"Weill Cornell Medicine"},{"author_name":"Tatyana Bodrug","author_inst":"Weill Cornell Medicine"},{"author_name":"Wei Gai","author_inst":"Weill Cornell Medicine"},{"author_name":"Katherine J Surridge","author_inst":"Weill Cornell Medicine"},{"author_name":"Elizabeth Moussikhina","author_inst":"Weill Cornell Medicine"},{"author_name":"Kendrick HV Nguyen","author_inst":"Weill Cornell Medicine"},{"author_name":"Marta Sanz-Murillo","author_inst":"CNIO"},{"author_name":"Robert Callahan","author_inst":"Weill Cornell Medicine"},{"author_name":"Erica Xiong","author_inst":"University of Pennsylvania"},{"author_name":"Delisa Ramos","author_inst":"UC San Diego"},{"author_name":"Lawrence Zhu","author_inst":"UCSF"},{"author_name":"Verena Dederer","author_inst":"Goethe University"},{"author_name":"Sebastian Mathea","author_inst":"Goethe University Frankfurt am Main"},{"author_name":"Janet H Iwasa","author_inst":"University of Utah"},{"author_name":"Stefan Knapp","author_inst":"Goethe-University Frankfurt"},{"author_name":"Kevan Shokat","author_inst":"University of California San Francisco"},{"author_name":"Samara L Reck-Peterson","author_inst":"Weill Cornell Medicine"},{"author_name":"Andres E Leschziner","author_inst":"Weill Cornell Medicine"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Astrocytic \u03bc-\u03b4 opioid receptor heterodimers mediate the antidepressant effects of ketamine's metabolite","rel_doi":"10.64898\/2026.05.31.727553","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.31.727553","rel_abs":"A deeper understanding of the targets and mechanisms of fast-acting antidepressants, exemplified by ketamine, remains indispensable for better therapeutic strategies and understanding depression. Beyond the canonical neuron-centric NMDAR inhibition hypothesis, brain opioid system and glia-mediated processes are increasingly implicated in ketamine's antidepressant efficacy, yet their precise contributions remain poorly understood. Here, we demonstrate that one major metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), selectively targets mu-delta opioid receptor heterodimers ( mu-delta-ORs) on astrocytes. By promoting the formation and\/or stabilization of mu-delta-ORs, HNK engages Gs-coupled signaling, elevates intracellular cAMP, phosphorylates CREB (p-CREB) levels and Ca 2+ dynamics in astrocytes, and consequently restores key astrocytic proteins and functions in depression models. Disrupting mu-delta-OR assembly or Gs signaling abolishes HNK-mediated antidepressant responses both in vitro and in vivo. Collectively, astrocytic opioid receptor heterodimers are critical to antidepressant responses and HNK may serve as a prototype compound for targeting astrocyte dysfunction across a wide range of brain disorders.","rel_num_authors":17,"rel_authors":[{"author_name":"Shuo Yang","author_inst":"Peking University Shenzhen Graduate School"},{"author_name":"Ling Jun Wang","author_inst":"Oujiang Laboratory"},{"author_name":"Yunxiang Sun","author_inst":"Ningbo University"},{"author_name":"Xiaoyan Ma","author_inst":"Peking University Shenzhen Graduate School"},{"author_name":"Yi Rong","author_inst":"Peking University Shenzhen Graduate School"},{"author_name":"Tsz Hei Fong","author_inst":"Peking University"},{"author_name":"Tianxiang Li","author_inst":"Peking University Shenzhen Graduate School"},{"author_name":"Di Deng","author_inst":"Peking University Shenzhen Graduate School"},{"author_name":"Xiao-Xue Li","author_inst":"Oujiang Laboratory"},{"author_name":"Zhaoxiang Zhang","author_inst":"Peking University Shenzhen Graduate School"},{"author_name":"Yan-Xia Liang","author_inst":"Oujiang Laboratory"},{"author_name":"Xianzhang Bu","author_inst":"Sun Yat-sen University"},{"author_name":"Tao Peng","author_inst":"Peking University Shenzhen Graduate School"},{"author_name":"Huan Xu","author_inst":"Ningbo University"},{"author_name":"Chuang Wang","author_inst":"Ningbo University"},{"author_name":"Xiang Cai","author_inst":"Oujiang Laboratory"},{"author_name":"qiang zhou","author_inst":"Peking University Shenzhen Graduate School"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Protein-state dysregulation and sex-specific neurodevelopmental signatures in schizophrenia forebrain organoids","rel_doi":"10.64898\/2026.06.01.729221","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729221","rel_abs":"Schizophrenia is highly heritable, yet the molecular mechanisms linking genetic risk to abnormal human brain development remain poorly understood. To address this, we generated dorsal forebrain organoids from 17 individuals with idiopathic schizophrenia and 17 age- and sex-matched controls and profiled them across multiple molecular layers, including single-nucleus transcriptomics, quantitative proteomics, metabolomics and deep post-translational modification (PTM) analysis. The organoids reproducibly modelled early cortical development and showed largely similar cellular composition between schizophrenia and control groups. Surprisingly, transcriptomic differences were relatively limited, with the strongest cell-type-specific changes observed in Cajal-Retzius neurons. In contrast, proteomic and particularly PTM-level analyses revealed widespread molecular disruption affecting pathways involved in neuronal migration, neurite development, synaptic function, protein kinase signalling, extracellular matrix organisation and lipid metabolism. Many of the earliest disease-associated changes emerged at the level of protein phosphorylation, consistent with altered neuronal maturation and neurite dynamics. At later developmental stages, schizophrenia organoids showed reduced abundance of synaptic proteins, fewer synaptic puncta and evidence of dysregulated retinoic acid and YAP1 signalling. Notably, most disease-associated alterations occurred independently of changes in transcript or protein abundance, indicating that key aspects of schizophrenia biology are encoded in protein state rather than expression level. These findings identify sex-specific dysregulation of protein state as a major molecular feature of schizophrenia and demonstrate the value of multi-layer proteomic approaches for uncovering disease mechanisms missed by transcriptomics alone.","rel_num_authors":20,"rel_authors":[{"author_name":"Helle Bogetofte","author_inst":"University of Southern Denmark"},{"author_name":"Sissel Ida Schmidt","author_inst":"University of Southern Denmark"},{"author_name":"Sofie Blomberg Elmkvist","author_inst":"University of Southern Denmark"},{"author_name":"Marie Sejberg Oehlenschlaeger","author_inst":"University of Southern Denmark"},{"author_name":"Pia Jensen","author_inst":"University of Southern Denmark"},{"author_name":"Fadumo Abdullahi Mohamed","author_inst":"University of Copenhagen"},{"author_name":"anne With Mikkelsen","author_inst":"University of Southern Denmark"},{"author_name":"Elif Bayram","author_inst":"University of Copenhagen"},{"author_name":"Jesper Havelund","author_inst":"University of Southern Denmark"},{"author_name":"Matias Ryding","author_inst":"University of Southern Denmark"},{"author_name":"Lucrezia Criscuolo","author_inst":"University of Southern Denmark"},{"author_name":"Lene A Johansen","author_inst":"University of Southern Denmark"},{"author_name":"Arkadiusz Nawrocki","author_inst":"University of Southern Denmark"},{"author_name":"Philip J Robinson","author_inst":"University of Sydney"},{"author_name":"Madeline A Lancaster","author_inst":"MRC Laboratory of Molecular Biology"},{"author_name":"Jonathan Brewer","author_inst":"University of Southern Denmark"},{"author_name":"Nils J Faergeman","author_inst":"University of Southern Denmark"},{"author_name":"Michael Eriksen Benros","author_inst":"University of Copenhagen"},{"author_name":"Kristine K Freude","author_inst":"University of Copenhagen"},{"author_name":"Martin R Larsen","author_inst":"University of Southern Denmark"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Mono-ADP-ribosylation-driven immunosuppression and cross-resistance to therapy through cancer cell intrinsic and extrinsic mechanisms","rel_doi":"10.64898\/2026.06.01.729331","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729331","rel_abs":"Mono-ADP-ribosylation (MARylation) is emerging as an important regulator of anti-cancer immunity and immunosuppressive tumor microenvironment (TME). Our previous studies showed that PARP11, one of several enzymes that facilitate MARylation, regulates the activities of intratumoral cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). Here, we demonstrate that stimuli such as adenosine, epinephrine, or glucagon-like peptide-1 (GLP1) induced PARP11 in cancer cells. Upregulation of PARP11 in cancer cells led to PARP11-mediated MARylation, ubiquitination, and accelerated degradation of MHC-I through the autophagy-lysosomal pathway. Induction of PARP11 protected cancer cells from killing by specific CTLs and stimulated tumor growth and progression. Genetic ablation of PARP11 attenuated MHC-I MARylation, ubiquitination, and interaction with autophagy receptors. Pharmacologic inhibition of PARP11 in pancreatic ductal adenocarcinoma (PDAC) cells restored their MHC-I levels, sensitized them to killing by CTLs, inhibited tumor growth, and impeded their initial resistance to chemotherapy and their acquired resistance to targeted therapy with RAS inhibitors. Moreover, inhibition of PARP11 prevented hyperprogressive disease in a mouse melanoma model treated with immune checkpoint inhibitors (ICBs), suggesting that PARP11 is a major therapeutically actionable driver of immunosuppression in tumors.","rel_num_authors":18,"rel_authors":[{"author_name":"Yuchen Sun","author_inst":"Univ. of Pennsylvania"},{"author_name":"Yingying Tang","author_inst":"Univ of Pennsylvania"},{"author_name":"Vivek T. Singh","author_inst":"Univ of Pennsylvania"},{"author_name":"Agnes Holczbauer","author_inst":"Univ. of Pennsylvania"},{"author_name":"Raghavendra Basavaraja","author_inst":"Univ. of Pennsylvania"},{"author_name":"Quoc Thang Bui","author_inst":"Univ. of Pennsylvania"},{"author_name":"Jeong-Hwa Lee","author_inst":"Univ. of Pennsylvania"},{"author_name":"Runnan Gao","author_inst":"Univ of Pennsylvania"},{"author_name":"A. Cole Edwards","author_inst":"Univ of Pennsylvania"},{"author_name":"Wei Guo","author_inst":"University of Pennsylvania"},{"author_name":"J. Alan Diehl","author_inst":"Case Western Reserve University"},{"author_name":"Yi Fan","author_inst":"Univ of Pennsylvania"},{"author_name":"Constantinos Koumenis","author_inst":"Univ of Pennsylvania"},{"author_name":"Timour Baslan","author_inst":"Univ of Pennsylvania"},{"author_name":"Ben Stanger","author_inst":"University of Pennsylvania"},{"author_name":"Michael S Cohen","author_inst":"Oregon Health and Science University"},{"author_name":"Vladimir Spiegelman","author_inst":"Pennsylvania State University College of Medicine"},{"author_name":"Serge Fuchs","author_inst":"University of Pennsylvania"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Mono-ADP-ribosylation-driven immunosuppression and cross-resistance to therapy through cancer cell intrinsic and extrinsic mechanisms","rel_doi":"10.64898\/2026.06.01.729331","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729331","rel_abs":"Mono-ADP-ribosylation (MARylation) is emerging as an important regulator of anti-cancer immunity and immunosuppressive tumor microenvironment (TME). Our previous studies showed that PARP11, one of several enzymes that facilitate MARylation, regulates the activities of intratumoral cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). Here, we demonstrate that stimuli such as adenosine, epinephrine, or glucagon-like peptide-1 (GLP1) induced PARP11 in cancer cells. Upregulation of PARP11 in cancer cells led to PARP11-mediated MARylation, ubiquitination, and accelerated degradation of MHC-I through the autophagy-lysosomal pathway. Induction of PARP11 protected cancer cells from killing by specific CTLs and stimulated tumor growth and progression. Genetic ablation of PARP11 attenuated MHC-I MARylation, ubiquitination, and interaction with autophagy receptors. Pharmacologic inhibition of PARP11 in pancreatic ductal adenocarcinoma (PDAC) cells restored their MHC-I levels, sensitized them to killing by CTLs, inhibited tumor growth, and impeded their initial resistance to chemotherapy and their acquired resistance to targeted therapy with RAS inhibitors. Moreover, inhibition of PARP11 prevented hyperprogressive disease in a mouse melanoma model treated with immune checkpoint inhibitors (ICBs), suggesting that PARP11 is a major therapeutically actionable driver of immunosuppression in tumors.","rel_num_authors":18,"rel_authors":[{"author_name":"Yuchen Sun","author_inst":"Univ. of Pennsylvania"},{"author_name":"Yingying Tang","author_inst":"Univ of Pennsylvania"},{"author_name":"Vivek T. Singh","author_inst":"Univ of Pennsylvania"},{"author_name":"Agnes Holczbauer","author_inst":"Univ. of Pennsylvania"},{"author_name":"Raghavendra Basavaraja","author_inst":"Univ. of Pennsylvania"},{"author_name":"Quoc Thang Bui","author_inst":"Univ. of Pennsylvania"},{"author_name":"Jeong-Hwa Lee","author_inst":"Univ. of Pennsylvania"},{"author_name":"Runnan Gao","author_inst":"Univ of Pennsylvania"},{"author_name":"A. Cole Edwards","author_inst":"Univ of Pennsylvania"},{"author_name":"Wei Guo","author_inst":"University of Pennsylvania"},{"author_name":"J. Alan Diehl","author_inst":"Case Western Reserve University"},{"author_name":"Yi Fan","author_inst":"Univ of Pennsylvania"},{"author_name":"Constantinos Koumenis","author_inst":"Univ of Pennsylvania"},{"author_name":"Timour Baslan","author_inst":"Univ of Pennsylvania"},{"author_name":"Ben Stanger","author_inst":"University of Pennsylvania"},{"author_name":"Michael S Cohen","author_inst":"Oregon Health and Science University"},{"author_name":"Vladimir Spiegelman","author_inst":"Pennsylvania State University College of Medicine"},{"author_name":"Serge Fuchs","author_inst":"University of Pennsylvania"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"EZH2 Serine 21 Phosphorylation Restrains Compact-State PRC2 Activation and H3K27me3 Propagation","rel_doi":"10.64898\/2026.06.02.729660","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729660","rel_abs":"Polycomb Repressive Complex 2 (PRC2) propagates H3K27me3 through EED-dependent allosteric activation, yet how cells modulate the magnitude of this positive-feedback response remains poorly understood. Here, we identify phosphorylation of EZH2 serine 21 as a post-translational mechanism that attenuates PRC2 allosteric responsiveness. Prior structural studies have established that activator-bound PRC2 adopts both compact and extended active conformations. Using cryo-EM classification of wild-type and phospho-null EZH2 S21A PRC2 complexes, we find that the phospho-null EZH2 S21A substitution changes the distribution of particles across these pre-existing states, shifting PRC2 from a predominantly extended conformation to one enriched for the compact, allosterically activated conformation. Consistent with this structural transition, EZH2 S21A increases basal PRC2 activity, lowers the EC50 for H3K27me3-dependent stimulation, and accelerates H3K27me3 accumulation on peptide and nucleosome substrates. Disruption of the EED-EZH2 interface suppresses the S21A gain-of-activity phenotype, indicating that S21 phosphorylation constrains PRC2 by limiting productive EED-EZH2 allosteric coupling. In mesenchymal stem cells, loss of this phosphorylation-dependent restraint broadens H3K27me3 domains, reduces canonical PRC1 enrichment at high-occupancy Polycomb target loci, misregulates lineage-associated transcriptional programs, and impairs differentiation. These findings identify EZH2 S21 phosphorylation as a molecular rheostat that limits compact-state PRC2 activation, constrains H3K27me3 spreading, and preserves Polycomb-dependent developmental competence.","rel_num_authors":7,"rel_authors":[{"author_name":"Andrew Q. Rashoff","author_inst":"University of Wisconsin-Madison"},{"author_name":"Mark Matyas","author_inst":"University of Colorado Boulder"},{"author_name":"Elizabeth G. Porter","author_inst":"Washington University in Saint Louis"},{"author_name":"Ryen Hazzard","author_inst":"University of Wisconsin-Madison"},{"author_name":"Benjamin A. Garcia","author_inst":"Washington University in Saint Louis"},{"author_name":"Vignesh Kasinath","author_inst":"University of Colorado Boulder"},{"author_name":"Peter W Lewis","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Polynucleotide Phosphorylase Stops Replication Restart by Degrading the RNA within R-loops during Replication-Transcription Conflicts","rel_doi":"10.64898\/2026.06.02.729377","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729377","rel_abs":"DNA replication and transcription machineries function simultaneously, on the same template, leading to conflicts between the two. During conflicts, the nascent mRNAs can hybridize to their template strands, generating RNA:DNA hybrids, which reside within nucleic acid structures known as R-loops. Accumulation of R-loops can lead to severe replication fork stalling, eventually leading to cell death. In bacteria, there are well-known replication restart mechanisms that should rescue these stalled replication forks, and yet, during conflicts, this process is inhibited. Additionally, in vitro work has shown that RNA:DNA hybrids are substrates for replication restart. Here, we discovered that the highly conserved exonuclease Polynucleotide Phosphorylase (PNPase in Bacillus subtilis) prevents replication restart from RNA:DNA hybrids, specifically at regions of severe conflicts where R-loops accumulate. Our in vitro data show that PNPase binds RNA:DNA hybrids and digests the RNA in these structures. Consistently, we found that in vivo, PNPase binds to conflict regions and reduces R-loop levels. To our knowledge, the only other class of enzymes known to digest the RNA from hybrids are RNases H. Our findings identify PNPase as a new enzyme that can perform a similar function. Importantly, our data show that PNPase inhibits replication restart from R-loops and its absence allows for replication restart from conflict regions. We also observed that PNPase activity reduces mutations, suggesting that replication restart from RNA:DNA hybrids is highly mutagenic. We propose that PNPase acts as a safeguard against mutagenic replication restart from RNA:DNA hybrids within R-loops by digesting the RNA which could re-initiate replication.","rel_num_authors":4,"rel_authors":[{"author_name":"Oyku Sensoy","author_inst":"Department of Biochemistry, Vanderbilt University School of Medicine. Nashville, TN 37232, USA"},{"author_name":"Juan Carvajal-Garcia","author_inst":"Department of Biochemistry, Vanderbilt University School of Medicine. Nashville, TN 37232, USA"},{"author_name":"Shahin Boumi","author_inst":"Department of Biochemistry, Vanderbilt University School of Medicine. Nashville, TN 37232, USA"},{"author_name":"Houra Merrikh","author_inst":"Department of Biochemistry, Vanderbilt University School of Medicine. Nashville, TN 37232, USA"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"From eye anatomy to navigation: a biologically accurate model of bees polarisation vision","rel_doi":"10.64898\/2026.06.01.729196","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729196","rel_abs":"Skylight polarisation patterns provide a critical navigational cue for many insects. Bees perceive these patterns through specialised ommatidia in the dorsal rim area of their compound eyes, enabling them to estimate the suns direction and navigate between food sources and the hive. Although polarisation-based navigation has been extensively studied behaviourally, computational models that link DRA anatomy with navigational performance are lacking. Here, we simulate polarisation vision in honeybees (Apis mellifera) and bumblebees (Bombus terrestris) using real sky polarisation images to capture biologically relevant skylight properties. Our biologically grounded simulation incorporates species-specific DRA anatomy, including ommatidial optical axis directions, photoreceptor receptive fields, and microvillar orientations. We evaluate navigational accuracy and consistency across sun elevations under two distinct, potentially complementary navigational models: the matched filter, which requires scanning across body orientations to identify the solar axis, and the vector-sum model, which generates instantaneous sun azimuth estimates from a single body orientation, making it independent of active scanning. Matched filter errors in estimating solar axis are below 5{degrees} across most sun elevations and in both species. Absolute errors in the vector-sum model are lower for honeybees than bumblebees (median ~10{degrees} and ~30{degrees}, respectively), reflecting differences in DRA anatomy, particularly viewing direction and microvillar arrangement. Both models allow stable course control across most sun elevations in both species, yet the matched filter, being limited to solar axis alignment, only enables positive or negative phototaxis. Overall, this work provides a mechanistic and comparative framework based on realistic DRA anatomy to study polarisation-based navigation, generating testable predictions for insect navigation under natural sky conditions.","rel_num_authors":8,"rel_authors":[{"author_name":"Georgios Kolyfetis","author_inst":"University of Konstanz: Universitat Konstanz"},{"author_name":"Evripidis Gkanias","author_inst":"Lunds Universitet"},{"author_name":"Athil Althaf Aliyam Veetil Zynudheen","author_inst":"Bielefeld University: Universitat Bielefeld"},{"author_name":"Vun Wen Jie","author_inst":"Stockholm University: Stockholms Universitet"},{"author_name":"C Giovanni Galizia","author_inst":"University of Konstanz: Universitat Konstanz"},{"author_name":"Emily Baird","author_inst":"Stockholm University: Stockholms Universitet"},{"author_name":"Barbara Webb","author_inst":"The University of Edinburgh"},{"author_name":"James Foster","author_inst":"University of Konstanz: Universitat Konstanz"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"PAD2 knockout reduces myelin protein aggregates, modulates neuroinflammation and protects motor neurons, axons and neuromuscular junction in a SOD1-ALS mouse model","rel_doi":"10.64898\/2026.05.30.729013","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.729013","rel_abs":"Background: Dysregulated peptidyl deiminase 2 (PAD2) and aberrant protein citrullination (PC), a posttranslational modification (PTM), are involved in various inflammatory and neurodegenerative diseases. We previously showed in transgenic mice and postmortem human tissues that PC and PAD2 are altered in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neurons loss, paralysis, and death. Herein, we investigated the role of PAD2 in ALS by PAD2 knockout in a SOD1-ALS mouse model. Methods: To investigate the role of PAD2-induced citrullination in ALS pathogenesis, we generated PAD2 knockout (PAD2KO) in SOD1G93A ALS mouse model and investigated the consequent modulation on the neuropathology and clinical symptoms, using molecular biology techniques such as qPCR, Western blotting, confocal microscopy, and electron microscopy. Additionally, we identified C3 as being citrullinated in human ALS using ionFinder. Results: Our results show that PAD2KO blocked the increased PC and reduced myelin basic protein (MBP) aggregates in the ALS model. PAD2KO also improved motor neuron survival and the integrity of myelin, axons, and neuromuscular junctions, and reduced microgliosis in the white matter and C3 protein levels in astrocytes. Clinically, data from monitoring the body weight changes suggests that PAD2KO modulates the course of the disease in the ALS mouse model, accelerating the onset while slowing the progression after the onset, and modestly extending the survival of male mice. Conclusion: These results show that PAD2 is responsible for the increased PC in ALS and PC contributes to neuroinflammation and degeneration of motor neurons and myelinated axons. The modest modulation of the disease phenotype suggests that the role of PC in ALS is complex, involving altered PC in numerous proteins and in multiple cell types. Future studies are needed to investigate how PC modulates individual protein functions in various cell types to understand the contribution of PC to ALS pathogenesis. Keywords: PAD2 knockout, protein citrullination, neurodegeneration, deimination, neurodegenerative diseases, myelin degeneration, protein aggregation","rel_num_authors":5,"rel_authors":[{"author_name":"Issa O Yusuf","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Rogerio L.A. Silva","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"George G Amoako","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Paul R Thompson","author_inst":"UMass Chan Medical School"},{"author_name":"Zuoshang Xu","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"A nanoscale atlas of extracellular vesicles and particles in Drosophila olfactory sensilla","rel_doi":"10.64898\/2026.05.30.728996","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728996","rel_abs":"Extracellular particles, including non-vesicular extracellular particles (NVEPs) and extracellular vesicles (EVs), are emerging as key contributors to sensory signaling, yet their ultrastructural organization within native tissues remains underexplored. Native tissues preserve extracellular particle organization and heterogeneity that are often lost during dissociation. Using cryofixation-based serial block-face scanning electron microscopy, we generated a nanoscale atlas of NVEPs and EVs across 352 Drosophila antennal olfactory sensilla (~70% coverage). Segmentation of more than 7,800 extracellular particles revealed distinct populations differing in morphology, size, electron density, and sensillum-class distribution. Analyses of EV biogenesis identified multivesicular bodies and membrane budding in auxiliary cells. Furthermore, sensilla housing degenerating neurons exhibited marked accumulation of EVs and NVEPs, accompanied by increased auxiliary-cell EV biogenesis. Together, these findings provide a large-scale ultrastructural characterization of extracellular particles in native sensory tissues and establish a foundation for understanding how extracellular particles are distributed, generated, and function during sensory signaling and degeneration.","rel_num_authors":7,"rel_authors":[{"author_name":"Pawel Vijayakumar","author_inst":"UC San Diego"},{"author_name":"Kalyani Cauwenberghs","author_inst":"UC San Diego"},{"author_name":"Muskaan Garg","author_inst":"UC San Diego"},{"author_name":"Jonathan Choy","author_inst":"UC San Diego"},{"author_name":"Shadi Charara","author_inst":"UC San Diego"},{"author_name":"Quintyn McKaughan","author_inst":"UC San Diego"},{"author_name":"Chih-Ying Su","author_inst":"UC San Diego"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Human Genome-Scale Models of Metabolism and Gene Expression Reveal Resource Constraints of Cancer Cell Lines","rel_doi":"10.64898\/2026.05.30.728988","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728988","rel_abs":"Genome-scale metabolic models (M-models) provide mechanistic insight into intracellular metabolism by simulating fluxes subject to nutrient and energy resource constraints. However, they cannot account for a major component of resource allocation, since they do not explicitly account for the cost of producing and maintaining enzymes. Genome-scale models of metabolism and gene expression (ME-Models) address this by including gene expression reactions, but these have only been developed for prokaryotes due to the additional complexity and challenges of modeling eukaryotes. Here, we present the human ME-Model, which encodes transcription, translation, complex formation, and turnover reactions for all enzymes catalyzing metabolic reactions, and couples these processes to constrain metabolic fluxes. We introduce humanME, a Python package to build and analyze human ME-Models. With this, we constructed 16 cancer cell line ME-Models. We found that resource constraints improve growth-rate predictions, and that ME-Model flux predictions are more biologically plausible and efficient. Moreover, transcriptional fluxes recapitulate RNA-Seq expression levels, with discrepancies revealing potential trade-offs involving multiple cellular objectives. Finally, the ME-Model recapitulates the Warburg effect, with increasing growth rate inducing glycolytic shifts, in part due to machinery costs of the electron transport chain. Altogether, we show ME-modeling can mechanistically link gene expression, resource allocation, and metabolism in human cells, substantially expanding the predictive scope of constraint-based models.","rel_num_authors":8,"rel_authors":[{"author_name":"Hratch M Baghdassarian","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Pablo Di Giusto","author_inst":"University of California, San Diego"},{"author_name":"Juan Tibocha-Bonilla","author_inst":"University of California, San Diego"},{"author_name":"Erick Armingol","author_inst":"University of California, San Diego"},{"author_name":"Saratram Gopalakrishnan","author_inst":"University of California, San Diego"},{"author_name":"Leo Dworkin","author_inst":"University of California, San Diego"},{"author_name":"Laurence M Yang","author_inst":"Queen's University"},{"author_name":"Nathan E Lewis","author_inst":"University of California, San Diego"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Primary cilia promote cardiac fibrosis and limit heart function after myocardial infarction","rel_doi":"10.64898\/2026.05.30.728594","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728594","rel_abs":"Cardiomyocytes die and do not regenerate after an injury such as a myocardial infarction (MI), a leading cause of mortality worldwide. Following MI, cardiac fibroblasts (CFs) proliferate and differentiate into myofibroblasts, which then produce increased collagen and extracellular matrix (ECM) leading to fibrosis. Fibrosis can weaken cardiac output via excessive stiffening and interference with electric signal transmission, but can also prevent wall rupture under load. Thus, dampening fibrosis has been investigated as a potential therapeutic intervention. Most mammalian cells possess a single primary cilium involved in intercellular communication. We investigated the role of CF primary cilia in sensing injury signals and initiating fibrotic remodeling. We found that deleting CF cilia reduced fibrosis and improved cardiac output after MI, demonstrating that cilia act as a signaling hub that amplifies the fibrotic response in the injured heart.","rel_num_authors":8,"rel_authors":[{"author_name":"Xinyue Liu","author_inst":"University of Florida"},{"author_name":"Alessandra Norris","author_inst":"Vanderbilt University"},{"author_name":"Ambili Bai Appu","author_inst":"University of Florida"},{"author_name":"Emily Wilson","author_inst":"University of California, San Francisco"},{"author_name":"Hao Zhang","author_inst":"University of California, San Francisco"},{"author_name":"Jeffrey Olgin","author_inst":"University of California, San Francisco"},{"author_name":"Jeremy F. Reiter","author_inst":"University of California, San Francisco"},{"author_name":"Daniel Kopinke","author_inst":"University of Florida"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Primary cilia promote cardiac fibrosis and limit heart function after myocardial infarction","rel_doi":"10.64898\/2026.05.30.728594","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728594","rel_abs":"Cardiomyocytes die and do not regenerate after an injury such as a myocardial infarction (MI), a leading cause of mortality worldwide. Following MI, cardiac fibroblasts (CFs) proliferate and differentiate into myofibroblasts, which then produce increased collagen and extracellular matrix (ECM) leading to fibrosis. Fibrosis can weaken cardiac output via excessive stiffening and interference with electric signal transmission, but can also prevent wall rupture under load. Thus, dampening fibrosis has been investigated as a potential therapeutic intervention. Most mammalian cells possess a single primary cilium involved in intercellular communication. We investigated the role of CF primary cilia in sensing injury signals and initiating fibrotic remodeling. We found that deleting CF cilia reduced fibrosis and improved cardiac output after MI, demonstrating that cilia act as a signaling hub that amplifies the fibrotic response in the injured heart.","rel_num_authors":8,"rel_authors":[{"author_name":"Xinyue Liu","author_inst":"University of Florida"},{"author_name":"Alessandra Norris","author_inst":"Vanderbilt University"},{"author_name":"Ambili Bai Appu","author_inst":"University of Florida"},{"author_name":"Emily Wilson","author_inst":"University of California, San Francisco"},{"author_name":"Hao Zhang","author_inst":"University of California, San Francisco"},{"author_name":"Jeffrey Olgin","author_inst":"University of California, San Francisco"},{"author_name":"Jeremy F. Reiter","author_inst":"University of California, San Francisco"},{"author_name":"Daniel Kopinke","author_inst":"University of Florida"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Short-Term Developmental Trajectories of Dorsal-Ventral Pathways and Their Relationships with First-Grade Learning","rel_doi":"10.64898\/2026.06.02.729623","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729623","rel_abs":"The first year of formal schooling is a year of foundational reading and math learning, and individual differences emerging within this single year predict academic achievement decades later. Yet, how brain changes throughout this critical year relate to individual differences in reading and math learning remains uncharacterized. In this pre-registered study (https:\/\/osf.io\/97ybe), we acquired monthly both behavioral assessments of reading- and math-learning, and diffusion-weighted MRI scans to measure white matter microstructure, across the first-grade year. Behavioral learning trajectories follow either a sigmoid for reading or an inverted-U for math. Month-to-month microstructural changes in the right middle longitudinal fasciculus predicted corresponding changes in math performance, but not in reading. Findings highlight white matter microstructure as a dynamic substrate of early math learning, and reveal a more general principle: rapid changes in white-matter microstructure during the foundational learning window may be associated with distinct academic domains.","rel_num_authors":5,"rel_authors":[{"author_name":"Xueying Ren","author_inst":"Vanderbilt University"},{"author_name":"James R. Booth","author_inst":"Vanderbilt University"},{"author_name":"Gabriele Amorosino","author_inst":"The University of Texas at Austin"},{"author_name":"Franco Pestilli","author_inst":"The University of Texas at Austin"},{"author_name":"Sophia Vinci-Booher","author_inst":"Vanderbilt University"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"A red-emitting, genetically encoded indicator for two-photon voltage recording in vivo","rel_doi":"10.64898\/2026.06.01.726307","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.726307","rel_abs":"Genetically encoded voltage indicators (GEVIs) enable minimally invasive, cell-type-specific optical measurements of neuronal membrane potential with millisecond temporal resolution. Red-shifted GEVIs are especially advantageous because they permit spectral multiplexing with complementary sensors and enable all-optical circuit interrogation in combination with blue-light-activated opsins. Despite these advantages, existing red GEVIs remain poorly suited for in vivo use due to limited performance under two-photon (2P) excitation, the predominant modality for deep-tissue imaging. Here, we introduce VADER1, a red GEVI that overcomes this limitation and enables reliable spike detection in vivo under 2P illumination. Under 2P excitation, VADER1 supports extended voltage imaging with both random-access and resonant-scanning microscopy, enables recordings from neurons as deep as cortical layer 5, and allows dual-color imaging with calcium indicators. By filling a critical spectral gap, VADER1 enables integrated optical measurements of fast electrical activity alongside other neural signals and establishes a foundation for two-photon all-optical electrophysiology.","rel_num_authors":29,"rel_authors":[{"author_name":"Shuyuan Yang","author_inst":"Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA"},{"author_name":"Alex J. McDonald","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Xiaoyu Lu","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Vincent Villette","author_inst":"Institut de Biologie de l'Ecole Normale Superieure (IBENS), Ecole Normale Superieure, CNRS, INSERM, Universite PSL, Paris, France"},{"author_name":"Noura Hakam","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Mario Galdamez","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Tanmayee Torne-Srivastava","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Gregory Foran","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Xiaoyu Dong","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Matthew Shorey","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Nima Bavili","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Shujuan Lai","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Zhuohe Liu","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Haixin Liu","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Tom Maslianitsyna","author_inst":"Wavefront-engineering Microscopy Group, Vision Institute, UMR S968 Inserm, UMR 7210 CNRS, UM 80 Sorbonne University, Paris, France"},{"author_name":"R\u00e9mi Fournel","author_inst":"Wavefront-engineering Microscopy Group, Vision Institute, UMR S968 Inserm, UMR 7210 CNRS, UM 80 Sorbonne University, Paris, France"},{"author_name":"Emiliano Ronzitti","author_inst":"Wavefront-engineering Microscopy Group, Vision Institute, UMR S968 Inserm, UMR 7210 CNRS, UM 80 Sorbonne University, Paris, France"},{"author_name":"Jun Zhu","author_inst":"Department of Neuroscience, University of California, Berkeley, CA, USA"},{"author_name":"Ryan Gregory Natan","author_inst":"Department of Neuroscience, University of California, Berkeley, CA, USA"},{"author_name":"Jonathan Bradley","author_inst":"Institut de Biologie de l'Ecole Normale Superieure (IBENS), Ecole Normale Superieure, CNRS, INSERM, Universite PSL, Paris, France"},{"author_name":"Daniela Gaspar Santos","author_inst":"Institut de Biologie de l'Ecole Normale Superieure (IBENS), Ecole Normale Superieure, CNRS, INSERM, Universite PSL, Paris, France"},{"author_name":"Yu-Yau Y. Shan","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Lindsey F. Ran","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Ming Hu","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Valentina Emiliani","author_inst":"Wavefront-engineering Microscopy Group, Vision Institute, UMR S968 Inserm, UMR 7210 CNRS, UM 80 Sorbonne University, Paris, France"},{"author_name":"Na Ji","author_inst":"Department of Neuroscience, University of California, Berkeley, CA, USA"},{"author_name":"Jacob Reimer","author_inst":"Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Laurent Bourdieu","author_inst":"Institut de Biologie de l'Ecole Normale Superieure (IBENS), Ecole Normale Superieure, CNRS, INSERM, Universite PSL, Paris, France"},{"author_name":"Francois St-Pierre","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-06-03","rel_site":"biorxiv"},{"rel_title":"Multi-pathogen serosurveillance reveals correlated routine vaccination performance, waning tetanus immunity, and diphtheria boosting among children in Zambia","rel_doi":"10.64898\/2026.06.01.26354612","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354612","rel_abs":"Background: Vaccination coverage estimates and case-based surveillance have limitations in evaluating immunization programs. Serosurveillance offers a complementary approach by directly measuring population immunity. We assessed whether serologic analyses across multiple antigens (i.e., measles, diphtheria, tetanus) could provide additional insights into vaccination program performance. Methods: We conducted a matched case-control study among children aged 2- to 10-years-old (n=1286) in Zambia using specimens from the 2016 ZAMPHIA survey. Using previously generated data on measles serostatus, measles seronegative children (i.e., cases) were matched to measles seropositive children (i.e., controls) on sex, age, HIV infection status, and province. Samples were tested for tetanus and diphtheria antitoxin IgG antibodies using commercial enzyme immunoassays. We estimated the odds of tetanus and diphtheria seropositivity by measles serostatus using conditional logistic regression and examined age-specific antibody dynamics. Results: Measles seronegative children had 1.7-fold increased odds (95% credible interval [CrI]: 1.3-2.1) of being tetanus seronegative compared to measles seropositive children. Diphtheria serostatus had no significant association with measles serostatus (odds ratio: 1.3; 95% CrI: 0.9-1.7). Tetanus seroprevalence declined monotonically with age. However, diphtheria seroprevalence initially declined through 5 years of age, then increased again beginning at 6 years of age despite the lack of vaccine booster doses given after the primary series in infancy, potentially from asymptomatic or subclinical infections. Conclusions: Serologic analyses revealed measles serostatus was positively associated with tetanus serostatus (where seropositivity arises only via vaccination and not infection), suggesting children who are measles seronegative are more likely to have missed DTP vaccination. We additionally found that measles serostatus was not associated with diphtheria serostatus, suggesting that antibody responses to diphtheria continue to boost beyond infancy when DTP vaccination is given. Our findings support consideration of DTP booster doses in Zambia to address waning tetanus immunity and further investigation of potential diphtheria carriage and transmission.","rel_num_authors":14,"rel_authors":[{"author_name":"Alyssa N Sbarra","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Simon Mutembo","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Andrea  C N Carcelen","author_inst":"Johns Hopkins University International Vaccine Access Center"},{"author_name":"Christine Prosperi","author_inst":"Johns Hopkins University International Vaccine Access Center"},{"author_name":"William  J. Moss","author_inst":"Johns Hopkins University International Vaccine Access Center"},{"author_name":"Shaun A Truelove","author_inst":"Johns Hopksin Bloomberg School of Public Health"},{"author_name":"Amy K Winter","author_inst":"University of Georgia"},{"author_name":"Innocent C Bwalya","author_inst":"National Health Research and Training Institute"},{"author_name":"Evans Betha","author_inst":"National Health Research and Training Institute"},{"author_name":"Lombe Kampamba","author_inst":"National Health Research and Training Institute"},{"author_name":"Elizabeth Kabeta","author_inst":"National Health Research and Training Institute"},{"author_name":"Gershom Chongwe","author_inst":"National Health Research and Training Institute"},{"author_name":"Amy Wesolowski","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Saki Takahashi","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Baseline Gut Microbiome-Metabolome Signatures Are Associated with Drinking Severity and Reduction Following Dutasteride Treatment in Alcohol Use Disorder","rel_doi":"10.64898\/2026.05.26.26354041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354041","rel_abs":"The gut microbiome has been implicated in alcohol use disorder (AUD), but its relationship to drinking intensity and treatment response remains poorly understood. We conducted a longitudinal multi-omics analysis of stool samples collected at baseline and endpoint (after 12 weeks) from 122 participants enrolled in a double-blind, placebo-controlled trial of dutasteride for AUD. Gut microbiome composition was characterized using 16S rRNA gene sequencing, and fecal metabolites were measured by LC-MS-based metabolomics. At baseline, drinking intensity was associated with increasingly lower microbial richness. Genera in the class Clostridia emerged as key microbial hubs associated with drinking intensity in an age- and sex-dependent manner. Drinking intensity promoted co-enrichment of [Ruminococcus] gnavus group and [Clostridium] inocuum group with amino acid catabolites, as well as the co-depletion of diverse Clostridia taxa and lipid metabolites. Dutasteride treatment and drinking reduction had minimal impact on gut microbiome composition. Random forest models integrating baseline clinical, microbiome, and metabolome data improved the classification of clinically meaningful drinking reduction compared to models using clinical data alone. These findings show that a coupled baseline gut microbiome-metabolome signature is associated with drinking intensity and future treatment response in AUD, highlighting the potential for multi-omics integration to inform precision treatment approaches.","rel_num_authors":10,"rel_authors":[{"author_name":"Liv R. Dedon","author_inst":"Department of Medicine, UConn School of Medicine"},{"author_name":"Darren J. Lee","author_inst":"Department of Medicine, UConn School of Medicine"},{"author_name":"Qingqi Lin","author_inst":"Department of Computer Science and Engineering, University of Connecticut"},{"author_name":"Hanshu Yuan","author_inst":"Department of Medicine, UConn School of Medicine"},{"author_name":"Jinhua Chi","author_inst":"Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University"},{"author_name":"Lingjun Li","author_inst":"Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University"},{"author_name":"Haiwei Gu","author_inst":"Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University"},{"author_name":"Howard Tennen","author_inst":"Department of Public Health Sciences, UConn School of Medicine"},{"author_name":"Jonathan M. Covault","author_inst":"Department of Psychiatry, UConn School of Medicine"},{"author_name":"Yanjiao Zhou","author_inst":"Department of Medicine, UConn School of Medicine"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"One size fits all: A systematic review of the sample types used for the diagnostics of respiratory viruses in children","rel_doi":"10.64898\/2026.06.02.26354258","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354258","rel_abs":"Nasopharyngeal (NP) swabs remain the dominant gold standard for respiratory infection diagnostics. While there has been increased use of alternative sample types since the COVID-19 pandemic, guidance on their use for detecting respiratory viruses is not yet definitive, especially for children. In this systematic review and meta-analysis, we aimed to compare the diagnostic accuracy and tolerability of multiple respiratory specimen types for detecting respiratory viruses in pediatric populations. Searches were conducted on July 17, 2025 in MEDLINE, Embase, Web of Science, and Scopus, with screening and data extraction performed in Covidence. English-language primary research articles published since 2000 comparing respiratory virus detection rates in children, using nucleic acid amplification tests between paired respiratory specimens, were included. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies criteria. We calculated pooled sensitivities and specificities of index specimens: nasopharyngeal aspirates (NPA), mid-turbinate swabs (MT), anterior nasal swabs (ANS), oropharyngeal swabs (OP), and bronchoalveolar lavage fluid (BAL), as compared to the reference, NP swabs, using random-effects modeling, firstly without discrimination by virus. Index specimens were then grouped by sample collection site as nasal, oral, and lower respiratory tract (LRT) specimens for virus-specific analyses. Overall performance and statistical validity were evaluated by hierarchical summary receiver operating characteristic (HSROC) analysis. Data regarding sampling tolerability was also assessed. We screened 2,448 studies and identified 36 publications (total N participants = 10,687) that reported diagnostic test accuracy using paired index-reference data in children. Of these, 18 (total N participants = 4,310) used NP specimens as the reference and were included in the diagnostic test accuracy analysis. Virus-agnostic pooled sensitivity estimates indicated that MT (0.92%) performed most similarly to NP, though sensitivities of ANS (0.79%) and OP (0.70%) were also moderately high for detection of any respiratory virus. BAL sensitivity was the lowest (0.37%). All sample types demonstrated high specificity (0.98%-0.99%). Group estimates and HSROC statistics found that nasal specimens, when grouped, had the highest sensitivity and accuracy for all examined viruses, including for influenza (92%) and RSV (90%). By comparison, oral and LRT specimens performed less well, with more variability, though both showed moderately high sensitivities for RSV (78%, 76%, respectively) and influenza (82%, 80%, respectively), and LRT samples showed high sensitivity for HMPV (82%). Analysis of sample tolerability found that NP swabs consistently ranked as the least comfortable and least preferred, while nasal swabs and saliva both performed well. Datasets for LRT and oral specimens were sparser than for nasal, and this contributed to greater variability, underscoring the need for further diagnostic accuracy studies on alternatives to NP sampling. These data support the viability of nasal and oral alternatives to NP swabs and affirm their application in pediatric care, particularly in outpatient settings. Such alternatives could greatly improve sampling tolerability and increase global access, including in resource-limited settings, to accurate diagnostic methods for respiratory infections.","rel_num_authors":9,"rel_authors":[{"author_name":"Orchid M Allicock","author_inst":"Yale School of Medicine"},{"author_name":"Arushi Dogra","author_inst":"Yale School of Medicine"},{"author_name":"Jacqueline H Cho","author_inst":"Yale School of Medicine"},{"author_name":"Keyner Rojas","author_inst":"Yale School of Medicine"},{"author_name":"Hannah O Hasson","author_inst":"Ben-Gurion University of the Negev"},{"author_name":"Britney Omene","author_inst":"Yale School of Medicine"},{"author_name":"Melissa C Funaro","author_inst":"Harvey Cushing\/John Hay Whitney Medical Library, Yale University"},{"author_name":"Claire S Laxton","author_inst":"Yale School of Medicine"},{"author_name":"Inci S Yildirim","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"A Three-Item Functional Screen for Multimodal Prognostic Triage in Mild Cognitive Impairment: Benchmarking Against Entorhinal Tau PET and Plasma p-tau217","rel_doi":"10.64898\/2026.06.01.26354584","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354584","rel_abs":"Importance: Broadening access to biomarker-informed risk stratification in mild cognitive impairment (MCI) has become even more critical to early assessment in Alzheimer disease given recent developments in regulatory approvals of disease-modifying therapies and advancements of blood-based biomarkers. This requires accessible approaches that can be deployed at scale to better differentiate the disease biology from the clinical progression risk prediction. While entorhinal tau positron emission tomography (PET) can refine near-term prognostic assessment, the cost and logistic burden of imaging limit broad clinical use. Objective: Evaluate whether a brief informant-reported screen derived from the Functional Activities Questionnaire (FAQ) could better stratify scalable biologically anchored prognostic information for 3-year progression from MCI to Alzheimer disease dementia. The primary study was designed around FAQ-derived screens performance relative to entorhinal tau PET standardized uptake value ratio (SUVR), plasma phosphorylated tau 217 (p-tau217) and Mini-Mental State Examination (MMSE) score. Secondary analyses evaluated the stable FAQ-derived screen selected for clinical risk separation, tau and amyloid PET biological context, additional plasma biomarkers, resource-use scenarios and sensitivity analyses around subgroups, calibration, decision-curve, survival, timing, early-progressor exclusions and endpoint-ascertainment IPW. Design, Setting, and Participants: This retrospective secondary progression risk prediction study analyzed 350 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with a baseline clinical diagnosis of MCI at the tau PET anchor visit. All studies were conducted in cohorts with 3-year progression status known. The first primary benchmarking included 157 participants (including 32 progressors) for FAQ with entorhinal tau PET SUVR comparisons and 153 participants (including 31 progressors) for FAQ, entorhinal tau PET SUVR and MMSE comparisons. The second primary benchmarking was derived from a smaller UPENN plasma p-tau217 subset of 66 participants (including 13 progressors). Exposures: The FAQ-derived candidate screens were evaluated by leakage-controlled repeated nested cross-validation. The stable 3-item FAQ-derived screen selected was defined as any informant-reported difficulty in at least one of the three activities comprising finances\/checkbook, shopping and games\/hobbies (\"Locked FAQ Trio\"). The Locked FAQ Trio was compared against both biological and cognitive comparators: entorhinal tau PET SUVR, plasma p-tau217 and MMSE score. Amyloid PET status and Centiloid burden as well as plasma biomarkers paired per same-file plasma such as A{beta}42\/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and a directionally adjusted 4- marker plasma composite were used for biology or exploratory context and not for defining the clinical endpoint. Main Outcomes and Measures: The primary binary endpoint was progression from baseline MCI at the tau PET anchor visit to Alzheimer disease dementia within 3 years. Model performance used the cross-validated area under the receiver operating characteristic curve (AUC), the difference in AUC ({Delta}AUC) was bootstrap 95% confidence intervals (CI) at the participant level with P values adjusted using the Benjamini-Hochberg (BH) procedure. Other measures included Brier scores, calibration summaries, survival discrimination and operating characteristics such as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and screen-positivity prevalence, while decision-curve analyses and resource-use scenarios remained exploratory. Results: A leakage-controlled nested cross-validation selection repeatedly identified a 3-item screen defined as any difficulty in at least one of the three following activities comprising finances\/checkbook, shopping and games\/hobbies (Locked FAQ Trio). In an independent 3-year progression benchmark analysis of base-covariate models, the Locked FAQ Trio showed higher numerical, directional but not statistically significant, discrimination than entorhinal tau PET among 157 participants including 32 progressors (AUC, 0.787 vs 0.780; {Delta}AUC, +0.007; 95% CI, -0.099 to 0.113; BH-adjusted P = 0.926) and was statistically significantly higher than MMSE score (AUC, 0.796 vs 0.637; {Delta}AUC, +0.159; 95% CI, 0.045 to 0.276; BH-adjusted P = 0.029). The Locked FAQ Trio was positive in 37.6% of participants and captured 27 of 32 progressors, showing sensitivity of 84.4%, specificity of 74.4%, PPV of 45.8%, and NPV of 94.9%. Progression within 3 years occurred in 45.8% of screen-positive participants versus 5.1% of screen-negative participants and the corresponding adjusted hazard ratio over full follow-up was 7.46. The screen was also associated with higher entorhinal tau burden and remained consistent across survival, timing-sensitive, amyloid and missingness analyses. A different 3-item FAQ-derived companion screen (\"Companion FAQ Trio\") was evaluated for sensitivity, it was defined as any impairment in at least one of the three activities comprising forms\/papers, shopping and remembering appointments\/medications\/holidays. The Companion FAQ Trio was positive in 54.1% participants and captured 96.9% of progressors, with 36.5% of screen-positive progressing to dementia versus 1.4% of screen-negative. In a second primary benchmark analysis of a smaller matched plasma subset of 66 participants including 13 progressors, plasma p-tau217 showed the highest discrimination (AUC, 0.890) across all single predictors in a base-covariates model, compared with the Locked FAQ Trio (AUC, 0.749) and entorhinal tau PET SUVR (AUC, 0.798). A stratification study of the Locked FAQ Trio combined with p-tau217 showed separation of observed risk, differentiating lower and higher risk of progression per strata. Notably, none (0 of 31) of the participants in the lower risk cohort progressed and 64.3% (9 of 14) of participants in the higher risk cohort progressed. Nevertheless, 37.5% (3 of 8) of participants in the Locked FAQ Trio-negative\/p-tau 217-high cohort progressed. This emphasizes that patients should not be excluded from further biomarker testing when clinical concern remains. Conclusion: A brief 3-item stable FAQ-derived screen was identified as a compelling front-end additional layer to prognostic triage in MCI patients. This Locked FAQ Trio screen demonstrated a higher numerical discrimination than entorhinal tau PET SUVR in 3-year base-covariates prediction risk models. Plasma p-tau217 remained the strongest scalable predictor of progression to dementia in a smaller plasma subset. These findings reinforce that adding a brief functional screen to the staged prognosis assessment triage pathway can help prioritize and contextualize biomarker escalation, offering a scalable, deployable, and low burden solution to expand screening to a broader patient population.","rel_num_authors":2,"rel_authors":[{"author_name":"Juliette Lafille","author_inst":"No Patient Left Behind Inc"},{"author_name":"Frank Provenzano","author_inst":"Columbia University"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Quantifying donor-recipient mismatches using recipient-derived sources of donor DNA","rel_doi":"10.64898\/2026.06.01.26354606","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354606","rel_abs":"Non-HLA donor-recipient (D-R) genetic mismatches contribute to kidney allograft injury and long-term graft loss, but their clinical use is limited by the unavailability of donor DNA after transplantation. We tested whether non-invasively obtained, recipient-derived samples could be used to infer donor genotype and D-R mismatches. Genomic DNA (g-DNA) of 11 unselected kidney transplant recipients and donors underwent whole-exome sequencing (100x). Additional customized probes were added for intronic coverage (300x) of 55 targeted non-HLA genes of reported clinical relevance. Variants identified from sequencing results were compared with plasma cell-free DNA (cfDNA), urine cell-pellet DNA (U-DNA) obtained from the same recipients. Genome-wide-, exonic-, or non-synonymous exonic- mismatches in transmembrane or secreted proteins, and mismatches within target genes were benchmarked using donor g-DNA to generate mismatch scores for each D-R pair. Within each of these genomic scales of mismatch, U-DNA identified D-R mismatches significantly better than the corresponding cfDNA (P<0.001 for each comparison). U-DNA also identified gene-level mismatches in the LIMS1 gene, and correctly inferred established donor-origin risk alleles, including SHROOM3 and APOL1. Our findings demonstrate proof-of-concept that U-DNA in tandem with recipient genome, can non-invasively infer relevant non-HLA loci\/mismatches circumventing the need for the donor genomic DNA.","rel_num_authors":17,"rel_authors":[{"author_name":"Nallakkandi Rajeevan","author_inst":"Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Gabriel Caldato Barsotti","author_inst":"Yale University School of Medicine"},{"author_name":"Ashwani Kumar","author_inst":"Yale School of Medicine"},{"author_name":"Zeguo Sun","author_inst":"Yale School of Medicine"},{"author_name":"Anand Reghuvaran","author_inst":"Yale School of Medicine"},{"author_name":"Irina Tikhonova","author_inst":"Yale School of Medicine"},{"author_name":"E M Tanvir","author_inst":"Yale School of Medicine"},{"author_name":"Niketa Sareen","author_inst":"Yale School of Medicine"},{"author_name":"Ashley Swan","author_inst":"Yale School of Medicine"},{"author_name":"Richard Formica","author_inst":"Yale School of Medicine"},{"author_name":"Caleigh Mandel-Brehm","author_inst":"Yale School of Medicine"},{"author_name":"Arundati Rao","author_inst":"Yale School of Medicine"},{"author_name":"Whitney Besse","author_inst":"Yale School of Medicine"},{"author_name":"Maureen Miller","author_inst":"Yale School of Medicine"},{"author_name":"Laurine Bow","author_inst":"Yale School of Medicine"},{"author_name":"Bony De Kumar","author_inst":"Versiti Blood Research institute"},{"author_name":"Madhav C Menon","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"A Pilot Study of the EMPOWER Music-based Intervention to Reduce Pulmonary Air Trapping in COPD","rel_doi":"10.64898\/2026.05.26.26350616","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26350616","rel_abs":"Rationale: Air trapping in functional areas of the lung is common in chronic obstructive pulmonary disease (COPD). We developed a novel music-based intervention, Engagement of Music for Pulmonary Obstruction With Expiratory Restoration (EMPOWER) aimed at reducing air trapping and functional small airways disease (fSAD) in patients with COPD. Objectives: We conducted a pilot study to assess if air trapping and fSAD in COPD patients are reduced by our targeted EMPOWER music-based singing intervention. Methods: Participants completed four weeks of singing and vocalizing with a board-certified music therapist. Pre- and post-intervention assessments of standard pulmonary function tests (PFTs), and quantitative computed tomography (qCT) lung imaging documented changes in air trapping. Pre- and post-intervention change in psychological and patient-reported outcomes of hope, emotional wellbeing, agency and COPD symptom burden were also obtained. Main Results: All five adult participants with COPD who enrolled completed the study and reported strong interest in continuing with a similar program. Additionally, we observed trends toward improvement in qCT-measured fSAD, six-minute walk distance, and patient-reported symptoms on the COPD Assessment Test. Conclusion: Results of this preliminary study showed improvements in both patient-reported and imaging-indicated respiratory outcomes, suggesting that targeted singing components in music-based interventions such as the EMPOWER intervention may support physiological lung function changes in COPD patients.","rel_num_authors":9,"rel_authors":[{"author_name":"Jasmine Taylor","author_inst":"The University of Kansas Medical Center"},{"author_name":"Jiwoong Choi","author_inst":"University of Kansas Health System"},{"author_name":"Asma Abdolijomoor","author_inst":"University of Kansas Health System"},{"author_name":"Melissa C. Brunkan","author_inst":"University of Oregon"},{"author_name":"Amy L. Wilson","author_inst":"University of Kansas"},{"author_name":"Mario Castro","author_inst":"University of Kansas Health System"},{"author_name":"Nancy Stewart","author_inst":"University of Kansas Health System"},{"author_name":"Deanna Hanson-Abromeit","author_inst":"University of Kansas"},{"author_name":"Rebecca J Lepping","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Climate change is already reshaping schistosomiasis transmission across Africa","rel_doi":"10.64898\/2026.06.01.26354594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354594","rel_abs":"Climate change is shifting infectious disease burdens1-6, but attributing transmission changes remains difficult where interventions and socioeconomic development interact with temperature-dependent signals7-11. Mechanistic models can isolate temperature-dependent signals from non-climatic influences5,12-16 but are often not tested against independent data. Here, we present a validation-first framework using a temperature-dependent R transmission model17 to detect and attribute temperature-mediated climate impacts on schistosomiasis transmission across Africa. First, semi-natural mesocosm experiments confirmed the model's biological constraints, with high temperatures suppressing the host-parasite system above ~33{degrees}C. Next, we established epidemiological relevance in the Lake Victoria Basin using 141,829 longitudinal infection records. Interannual temperature anomalies predicted infection risk, with anthropogenic warming accounting for 17.1% of observed infections relative to a natural-forcing-only counterfactual. Finally, across Africa, the mechanistic R predictor explained prevalence better than correlative climate metrics, even after accounting for intervention and socioeconomic covariates. Applying the validated framework to ensemble climate model simulations and a natural-forcing-only counterfactual (1984-2014) showed that anthropogenic warming increased transmission potential in cooler regions while suppressing it in hotter regions across Africa, a contrast projected to intensify under higher-emissions scenarios by mid-century. Climate impacts are not solely future threats, but present-day forces already reshaping transmission and disease burden.","rel_num_authors":12,"rel_authors":[{"author_name":"Meghan Forstchen","author_inst":"University of Notre Dame"},{"author_name":"Ibrahim Aslan","author_inst":"Stanford University"},{"author_name":"Caroline Bice","author_inst":"University of Notre Dame"},{"author_name":"Heather Buelow","author_inst":"University of Notre Dame"},{"author_name":"Andrew J. Chamberlin","author_inst":"Stanford University"},{"author_name":"Giulio A. De Leo","author_inst":"Stanford University"},{"author_name":"Kristie L. Ebi","author_inst":"University of Washington"},{"author_name":"Nicholas A. Galle","author_inst":"University of Notre Dame"},{"author_name":"Patrick Heffernan","author_inst":"University of Notre Dame"},{"author_name":"Karena H. Nguyen","author_inst":"Georgia Institute of Technology"},{"author_name":"Matthew Sisk","author_inst":"University of Notre Dame"},{"author_name":"Jason R. Rohr","author_inst":"University of Notre Dame"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Trajectories of depressive symptoms across pregnancy and the extended postpartum period and future cardiovascular health.","rel_doi":"10.64898\/2026.05.26.26353833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353833","rel_abs":"Background: Individuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH. Methods: This secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications. Results: A total of 3,934 participants (mean (M) {+\/-} standard deviation (SD) age=27.6{+\/-}5.6 years) met inclusion criteria with a mean follow-up interval of 3.2{+\/-}0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: {beta}=0.06, p<0.01; decreasing severity: {beta}=0.05, p=0.02; increasing severity: {beta}=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24). Discussion: The longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.","rel_num_authors":15,"rel_authors":[{"author_name":"Shannon D Donofry","author_inst":"Rand Corporation"},{"author_name":"Megan Marie McLaughlin","author_inst":"UCSF"},{"author_name":"Emily S Miller","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Neil J. Wimmer","author_inst":"Christiana Care"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Lauren H Theilen","author_inst":"University of Utah Health; Intermountain Healthcare"},{"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":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Caroline E. Rouse","author_inst":"Indiana University"},{"author_name":"Jessica Page","author_inst":"Intermountain Health"},{"author_name":"Kelly Zafman","author_inst":"Penn Medicine"},{"author_name":"Alexandra Berra","author_inst":"MetroHealth Medical Center Department of Obstetrics and Gynecology"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Trajectories of depressive symptoms across pregnancy and the extended postpartum period and future cardiovascular health.","rel_doi":"10.64898\/2026.05.26.26353833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353833","rel_abs":"Background: Individuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH. Methods: This secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications. Results: A total of 3,934 participants (mean (M) {+\/-} standard deviation (SD) age=27.6{+\/-}5.6 years) met inclusion criteria with a mean follow-up interval of 3.2{+\/-}0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: {beta}=0.06, p<0.01; decreasing severity: {beta}=0.05, p=0.02; increasing severity: {beta}=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24). Discussion: The longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.","rel_num_authors":15,"rel_authors":[{"author_name":"Shannon D Donofry","author_inst":"Rand Corporation"},{"author_name":"Megan Marie McLaughlin","author_inst":"UCSF"},{"author_name":"Emily S Miller","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Neil J. Wimmer","author_inst":"Christiana Care"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Lauren H Theilen","author_inst":"University of Utah Health; Intermountain Healthcare"},{"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":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Caroline E. Rouse","author_inst":"Indiana University"},{"author_name":"Jessica Page","author_inst":"Intermountain Health"},{"author_name":"Kelly Zafman","author_inst":"Penn Medicine"},{"author_name":"Alexandra Berra","author_inst":"MetroHealth Medical Center Department of Obstetrics and Gynecology"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Trajectories of depressive symptoms across pregnancy and the extended postpartum period and future cardiovascular health.","rel_doi":"10.64898\/2026.05.26.26353833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353833","rel_abs":"Background: Individuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH. Methods: This secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications. Results: A total of 3,934 participants (mean (M) {+\/-} standard deviation (SD) age=27.6{+\/-}5.6 years) met inclusion criteria with a mean follow-up interval of 3.2{+\/-}0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: {beta}=0.06, p<0.01; decreasing severity: {beta}=0.05, p=0.02; increasing severity: {beta}=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24). Discussion: The longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.","rel_num_authors":15,"rel_authors":[{"author_name":"Shannon D Donofry","author_inst":"Rand Corporation"},{"author_name":"Megan Marie McLaughlin","author_inst":"UCSF"},{"author_name":"Emily S Miller","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Neil J. Wimmer","author_inst":"Christiana Care"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Lauren H Theilen","author_inst":"University of Utah Health; Intermountain Healthcare"},{"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":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Caroline E. Rouse","author_inst":"Indiana University"},{"author_name":"Jessica Page","author_inst":"Intermountain Health"},{"author_name":"Kelly Zafman","author_inst":"Penn Medicine"},{"author_name":"Alexandra Berra","author_inst":"MetroHealth Medical Center Department of Obstetrics and Gynecology"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"High prevalence of soil-transmitted helminth co-infections in persons with tuberculosis in South India","rel_doi":"10.64898\/2026.05.26.26353735","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353735","rel_abs":"Soil-transmitted helminths (STH) are a plausible but under-characterized comorbidity in tuberculosis. In this prospective South Indian cohort, multiplex stool PCR detected STH in 43% of 137 adults with pulmonary tuberculosis and 34% of 230 household contacts. Food insecurity independently predicted co-infection. Current adult deworming gaps warrant evaluation.","rel_num_authors":23,"rel_authors":[{"author_name":"Prakash Babu Narasimhan","author_inst":"Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Komal Jain","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Nonika Rajkumari","author_inst":"Department of Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Madolyn Rose Dauphinais","author_inst":"University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"},{"author_name":"Jasemina R Priyanga","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Sana Shaikh","author_inst":"Section of Infectious Diseases, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA"},{"author_name":"Jainish Uresh Patel","author_inst":"Section of Infectious Diseases, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA"},{"author_name":"Senbagavalli Prakash Babu","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Chelsie Cintron","author_inst":"Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, USA"},{"author_name":"Meagan Karoly","author_inst":"Department of Medicine, Section of Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA"},{"author_name":"Madeline Elizabeth Carwile","author_inst":"Department of Medicine, Section of Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA"},{"author_name":"Anne Fan Liu","author_inst":"Department of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA"},{"author_name":"Kimberly Maloomian","author_inst":"HMX, Harvard Medical School, Boston, Massachusetts, USA"},{"author_name":"Lindsey M Locks","author_inst":"Department of Health Sciences, Boston University College of Health and Rehabilitation Sciences: Sargent College, Boston, Massachusetts, USA"},{"author_name":"Saurabh Mehta","author_inst":"Cornell Joan Klein Jacobs Center for Precision Nutrition and Health, Cornell University, Ithaca, New York, USA"},{"author_name":"Sonali Sarkar","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Urvashi B Singh","author_inst":"Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India"},{"author_name":"Jerrold J Ellner","author_inst":"Center for Emerging Pathogens, Department of Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA"},{"author_name":"Padmini Salgame","author_inst":"Center for Emerging Pathogens, Department of Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA"},{"author_name":"Scott Kirkland Heysell","author_inst":"Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA"},{"author_name":"Natasha S Hochberg","author_inst":"5)\tSection of Infectious Diseases, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA"},{"author_name":"Subitha Lakshminarayanan","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Pranay Sinha","author_inst":"Boston Medical Center"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Risk of progression to pulmonary tuberculosis among household contacts with chest radiographic abnormalities in South Africa","rel_doi":"10.64898\/2026.06.01.26354586","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354586","rel_abs":"Background High-risk subgroups among household contacts of persons with tuberculosis (TB) might benefit from additional interventions. However, the significance of an abnormal baseline chest radiograph (CXR) suggestive of TB, despite negative sputum microbiology, is uncertain. Methods Adults ([&ge;]18 years) with recent household TB exposure were enrolled at three South African sites (April 2021-September 2022). All participants underwent symptom screening, CXR, and sputum Xpert Ultra and MGIT culture. Pulmonary TB diagnosis was microbiologically-confirmed. Participants without prevalent TB were followed for symptomatic incident TB through 12 months. Multivariable logistic regression identified factors associated with abnormal CXR suggestive of TB. Poisson regression estimated adjusted incidence rate ratios (aIRR) with 95% confidence intervals (95%CI). Results Baseline CXR were available for 795\/846 (94.0%) participants without prevalent TB and were abnormal in 157\/795 (19.7%); associated with older age (adjusted odds ratio, aOR=1.04, 95%CI 1.02-1.05); prior TB (aOR=6.39, 95%CI 4.18-9.78); and current smoking (aOR=1.61, 95%CI 1.00-2.62). Symptomatic incident TB developed in 8\/795 (1.0%) participants, including 7\/8 (87.5%) who were asymptomatic and 4\/8 (50.0%) with abnormal CXR at baseline. TB incidence was higher in those with abnormal versus normal CXR (aIRR=4.11, 95%CI 1.29-13.09), but after median 12.1 (IQR 11.1-13.1) months follow-up, 153\/157 (97.5%) had not progressed to incident TB. Conclusions Adult household contacts with CXR abnormalities, but without prevalent TB, had a four-fold higher incidence of TB within one year, compared to those with normal CXR. This additional risk warrants targeted preventive treatment and extended surveillance, but since most remained TB-free, therapeutic TB treatment is not justified.","rel_num_authors":17,"rel_authors":[{"author_name":"Humphrey Mulenga","author_inst":"University of Cape Town"},{"author_name":"Evans Muchiri","author_inst":"University of Cape Town"},{"author_name":"Simon C Mendelsohn","author_inst":"University of Cape Town"},{"author_name":"Stephanus Theron Malherbe","author_inst":"Stellenbosch University"},{"author_name":"Tumelo Moloantoa","author_inst":"University of the Witwatersrand"},{"author_name":"Michele Tameris","author_inst":"University of Cape Town"},{"author_name":"Fernanda Maruri","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Firdows Noor","author_inst":"Stellenbosch University"},{"author_name":"Ravindre Panchia","author_inst":"University of the Witwatersrand"},{"author_name":"Khuthadzo Hlongwane","author_inst":"University of the Witwatersrand"},{"author_name":"Kim Stanley","author_inst":"Stellenbosch University"},{"author_name":"Katie Hadley","author_inst":"University of Cape Town"},{"author_name":"Neil Martinson","author_inst":"University of the Witwatersrand"},{"author_name":"Gerhard Walzl","author_inst":"Stellenbosch University"},{"author_name":"Thomas J. Scriba","author_inst":"University of Cape Town"},{"author_name":"Mark Hatherill","author_inst":"University of Cape Town"},{"author_name":"- RePORT South Africa Study Team","author_inst":"-"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Disruption of CTCF binding by germline non-coding variants in CDKN2B suppress CDKN2A expression and predispose to melanoma","rel_doi":"10.64898\/2026.06.01.26352322","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26352322","rel_abs":"Some melanoma-prone families linked to the 9p21 locus, harboring the established susceptibility gene CDKN2A, lack pathogenic protein-coding variants. Using whole-exome and targeted sequencing, we identified three rare single-nucleotide variants in two melanoma-prone families and one sporadic melanoma case. Variants map to a conserved CTCF-bound region within the first intron of CDKN2B that physically interacts with CDKN2A. Analysis of UK Biobank showed significant enrichment of variants in this region in melanoma cases. Variants result in diminished CTCF binding in vitro. CTCF ChIP-seq in fibroblasts from the carriers of the largest family demonstrated loss of CTCF binding, accompanied by weakened promoter interactions and allele-specific reduction of CDKN2A p16 transcript expression from the variant haplotype. CRISPR-based perturbation of this region and editing of the large family variant into melanocytes resulted in reduced expression of p14 and p16 CDKN2A transcripts. These findings suggest that non-coding regulatory variants function as high-penetrance susceptibility alleles in melanoma families by altering CDKN2A function.","rel_num_authors":35,"rel_authors":[{"author_name":"Jessica L Scales","author_inst":"National Cancer Institute"},{"author_name":"Jayne A Barbour","author_inst":"The University of Hong Kong"},{"author_name":"Alisa M Goldstein","author_inst":"National Cancer Institute"},{"author_name":"Rebecca Hennessey","author_inst":"National Cancer Institute"},{"author_name":"Mai Xu","author_inst":"National Cancer Institute"},{"author_name":"Abigail J Dennis","author_inst":"National Cancer Institute"},{"author_name":"Sophie Papiernik","author_inst":"National Cancer Institute"},{"author_name":"Jung Kim","author_inst":"National Cancer Institute"},{"author_name":"Sudipto Das","author_inst":"National Cancer Institute"},{"author_name":"Haocheng Yang","author_inst":"The University of Hong Kong"},{"author_name":"S. Chul Kwon","author_inst":"The University of Hong Kong"},{"author_name":"Kornelia Gladysz","author_inst":"The University of Hong Kong"},{"author_name":"Rohit Thakur","author_inst":"National Cancer Institute"},{"author_name":"Joshuah Yon","author_inst":"National Cancer Institute"},{"author_name":"Linh Bui-Raborn","author_inst":"National Cancer Institute"},{"author_name":"Douglas R Stewart","author_inst":"National Cancer Institute"},{"author_name":"Raj Chari","author_inst":"Frederick National Laboratory for Cancer Research"},{"author_name":"Paula L Hyland","author_inst":"US Food and Drug Administration"},{"author_name":"Jiyeon Choi","author_inst":"National Cancer Institute"},{"author_name":"Tongwu Zhang","author_inst":"National Cancer Institute"},{"author_name":"Wen Luo","author_inst":"National Cancer Institute"},{"author_name":"Kedest Teferi","author_inst":"National Cancer Institute"},{"author_name":"Thorkell Andresson","author_inst":"National Cancer Institute"},{"author_name":"Xin Li","author_inst":"National Cancer Institute"},{"author_name":"Kristine M Jones","author_inst":"National Cancer Institute"},{"author_name":"Amy Hutchinson","author_inst":"National Cancer Institute"},{"author_name":"Belynda D Hicks","author_inst":"National Cancer Institute"},{"author_name":"W. Ryan Diver","author_inst":"American Cancer Society"},{"author_name":"Adriana Lori","author_inst":"American Cancer Society"},{"author_name":"Steven C Moore","author_inst":"National Cancer Institute"},{"author_name":"Margaret A Tucker","author_inst":"National Cancer Institute"},{"author_name":"Michael R Sargen","author_inst":"National Cancer Institute"},{"author_name":"Kevin M Brown","author_inst":"National Cancer Institute"},{"author_name":"Jason W H Wong","author_inst":"The University of Hong Kong"},{"author_name":"Xiaohong R Yang","author_inst":"National Cancer Institute"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"A Favorable Modifiable Risk Factor Profile Mitigates Polygenic Risk for Alzheimers Disease and Related Dementia","rel_doi":"10.64898\/2026.06.01.26354634","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354634","rel_abs":"Background: A recent Lancet Commission estimated that up to 45% of Alzheimers Disease and Related Dementias (ADRD) cases could be prevented by addressing modifiable lifestyle risk factors. Meanwhile, genome wide association studies (GWAS) have shown that common genetic variants also account for substantial ADRD risk. Whether a favorable lifestyle can offset risk in genetically predisposed individuals remains unclear. Methods: We conducted a retrospective cohort study of 105,886 participants from the All of Us Research Program enrolled between 2018 and 2023. Participants were over age 49, assigned male or female at birth, of European ancestry, and without ADRD at baseline. ADRD diagnoses were identified via electronic health records (EHR). Fourteen potentially modifiable risk factors for ADRD were assessed using surveys, EHR records, and wearable data. Genetic risk was quantified as a polygenic risk score (PRS) based on 81 independent GWAS loci and APOE E4 genotype. Results: Overall, 967 incident ADRD events occurred over a median follow-up of 3.7 years. Ten out of 13 modifiable risk factors were significantly associated with ADRD. When grouped into risk factor profiles, intermediate and unfavorable modifiable risk factor scores were associated with substantially higher ADRD risk (HR 3.07, 95% CI 2.47, 3.83; HR 8.01, 95% CI 6.39, 10.05, respectively) compared to a favorable lifestyle; APOE E4 dosage and polygenic risk score were also independently associated with ADRD risk. Among individuals in the highest polygenic risk group, a favorable lifestyle reduced ADRD risk from HR 18.63 (95% CI 10.25, 33.86) to 1.90 (95% CI 0.94, 3.81), whereas APOE E4 homozygotes remained at elevated risk even with a favorable lifestyle (HR 6.52, 95% CI 2.97, 14.33). Conclusions: Our data suggest ADRD risk is driven more by modifiable risk factors and APOE genotype than polygenic risk score. Future genomic informed risk assessments for ADRD should calibrate their findings to accurately identify high risk individuals.","rel_num_authors":8,"rel_authors":[{"author_name":"Clayton O Mansel","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Soniya Mishra","author_inst":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"},{"author_name":"Andrew Craver","author_inst":"Institute for Population and Precision Health, Biological Science Division, The University of Chicago, Chicago, Illinois"},{"author_name":"Sebastian F Salathe","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"John P Thyfault","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Julia A Bauer","author_inst":"Division of Epidemiology and Biostatistics, University of Illinois Chicago School of Public Health, Chicago, IL, USA"},{"author_name":"Diego R Mazzotti","author_inst":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"},{"author_name":"Olivia J Veatch","author_inst":"Department of Psychiatry and Behavioral Sciences & Division of Medical Informatics, University of Kansas Medical Center, Kansas City, KS, USA"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"A Favorable Modifiable Risk Factor Profile Mitigates Polygenic Risk for Alzheimers Disease and Related Dementia","rel_doi":"10.64898\/2026.06.01.26354634","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354634","rel_abs":"Background: A recent Lancet Commission estimated that up to 45% of Alzheimers Disease and Related Dementias (ADRD) cases could be prevented by addressing modifiable lifestyle risk factors. Meanwhile, genome wide association studies (GWAS) have shown that common genetic variants also account for substantial ADRD risk. Whether a favorable lifestyle can offset risk in genetically predisposed individuals remains unclear. Methods: We conducted a retrospective cohort study of 105,886 participants from the All of Us Research Program enrolled between 2018 and 2023. Participants were over age 49, assigned male or female at birth, of European ancestry, and without ADRD at baseline. ADRD diagnoses were identified via electronic health records (EHR). Fourteen potentially modifiable risk factors for ADRD were assessed using surveys, EHR records, and wearable data. Genetic risk was quantified as a polygenic risk score (PRS) based on 81 independent GWAS loci and APOE E4 genotype. Results: Overall, 967 incident ADRD events occurred over a median follow-up of 3.7 years. Ten out of 13 modifiable risk factors were significantly associated with ADRD. When grouped into risk factor profiles, intermediate and unfavorable modifiable risk factor scores were associated with substantially higher ADRD risk (HR 3.07, 95% CI 2.47, 3.83; HR 8.01, 95% CI 6.39, 10.05, respectively) compared to a favorable lifestyle; APOE E4 dosage and polygenic risk score were also independently associated with ADRD risk. Among individuals in the highest polygenic risk group, a favorable lifestyle reduced ADRD risk from HR 18.63 (95% CI 10.25, 33.86) to 1.90 (95% CI 0.94, 3.81), whereas APOE E4 homozygotes remained at elevated risk even with a favorable lifestyle (HR 6.52, 95% CI 2.97, 14.33). Conclusions: Our data suggest ADRD risk is driven more by modifiable risk factors and APOE genotype than polygenic risk score. Future genomic informed risk assessments for ADRD should calibrate their findings to accurately identify high risk individuals.","rel_num_authors":8,"rel_authors":[{"author_name":"Clayton O Mansel","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Soniya Mishra","author_inst":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"},{"author_name":"Andrew Craver","author_inst":"Institute for Population and Precision Health, Biological Science Division, The University of Chicago, Chicago, Illinois"},{"author_name":"Sebastian F Salathe","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"John P Thyfault","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Julia A Bauer","author_inst":"Division of Epidemiology and Biostatistics, University of Illinois Chicago School of Public Health, Chicago, IL, USA"},{"author_name":"Diego R Mazzotti","author_inst":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"},{"author_name":"Olivia J Veatch","author_inst":"Department of Psychiatry and Behavioral Sciences & Division of Medical Informatics, University of Kansas Medical Center, Kansas City, KS, USA"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"A Favorable Modifiable Risk Factor Profile Mitigates Polygenic Risk for Alzheimers Disease and Related Dementia","rel_doi":"10.64898\/2026.06.01.26354634","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354634","rel_abs":"Background: A recent Lancet Commission estimated that up to 45% of Alzheimers Disease and Related Dementias (ADRD) cases could be prevented by addressing modifiable lifestyle risk factors. Meanwhile, genome wide association studies (GWAS) have shown that common genetic variants also account for substantial ADRD risk. Whether a favorable lifestyle can offset risk in genetically predisposed individuals remains unclear. Methods: We conducted a retrospective cohort study of 105,886 participants from the All of Us Research Program enrolled between 2018 and 2023. Participants were over age 49, assigned male or female at birth, of European ancestry, and without ADRD at baseline. ADRD diagnoses were identified via electronic health records (EHR). Fourteen potentially modifiable risk factors for ADRD were assessed using surveys, EHR records, and wearable data. Genetic risk was quantified as a polygenic risk score (PRS) based on 81 independent GWAS loci and APOE E4 genotype. Results: Overall, 967 incident ADRD events occurred over a median follow-up of 3.7 years. Ten out of 13 modifiable risk factors were significantly associated with ADRD. When grouped into risk factor profiles, intermediate and unfavorable modifiable risk factor scores were associated with substantially higher ADRD risk (HR 3.07, 95% CI 2.47, 3.83; HR 8.01, 95% CI 6.39, 10.05, respectively) compared to a favorable lifestyle; APOE E4 dosage and polygenic risk score were also independently associated with ADRD risk. Among individuals in the highest polygenic risk group, a favorable lifestyle reduced ADRD risk from HR 18.63 (95% CI 10.25, 33.86) to 1.90 (95% CI 0.94, 3.81), whereas APOE E4 homozygotes remained at elevated risk even with a favorable lifestyle (HR 6.52, 95% CI 2.97, 14.33). Conclusions: Our data suggest ADRD risk is driven more by modifiable risk factors and APOE genotype than polygenic risk score. Future genomic informed risk assessments for ADRD should calibrate their findings to accurately identify high risk individuals.","rel_num_authors":8,"rel_authors":[{"author_name":"Clayton O Mansel","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Soniya Mishra","author_inst":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"},{"author_name":"Andrew Craver","author_inst":"Institute for Population and Precision Health, Biological Science Division, The University of Chicago, Chicago, Illinois"},{"author_name":"Sebastian F Salathe","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"John P Thyfault","author_inst":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Julia A Bauer","author_inst":"Division of Epidemiology and Biostatistics, University of Illinois Chicago School of Public Health, Chicago, IL, USA"},{"author_name":"Diego R Mazzotti","author_inst":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"},{"author_name":"Olivia J Veatch","author_inst":"Department of Psychiatry and Behavioral Sciences & Division of Medical Informatics, University of Kansas Medical Center, Kansas City, KS, USA"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Contusion Volume is a Cross-cohort Predictor of Delayed Seizures after Traumatic Brain Injury","rel_doi":"10.64898\/2026.06.01.26354621","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354621","rel_abs":"Objective: Predicting specific cognitive, psychiatric, and health-related sequelae in patients after acute traumatic brain injury (TBI) remains an important but challenging clinical problem. Acute phase computed tomography (CT) scans acquired show hemorrhagic contusions, a common type of traumatic pathology. However, whether CT-measured contusions predict long-term sequelae is uncertain. Methods: We established a Screening Cohort of patients with acute TBI who received care at a single TBI Model Systems (TBIMS) inpatient rehabilitation facility. Regions of hemorrhagic contusion and edema were labeled on acute brain CT scans using the fully-automated Brain Lesion Analysis and Segmentation Tool (BLAST-CT). We screened 198 outcome variables at 1-year post-injury for association with acute hemorrhagic contusion volume using the Harrell's Concordance index (C-index), controlling for multiple comparisons using 5,000 outcome permutations. Finally, we tested whether the significant associations in the TBIMS database replicated in acute (Transforming Research and Clinical Knowledge in TBI [TRACK-TBI]) and chronic (Vietnam Head Injury Study [VHIS]) external validation cohorts. Results: The TBIMS Screening Cohort included 345 participants (mean {+\/-} SD age: 55.7 {+\/-} 21.5 years) with median [IQR] contusion volume 2.3 cc [0.1, 14.6]. Among 198 candidate outcome variables, only delayed seizures were significantly associated with acute hemorrhagic contusion volume (C-index = 0.81; PFWE = 0.007). Contusion volume was not significantly associated with commonly-used measures of global functioning like the Glasgow Outcome Scale Extended, (C-index = 0.55; PFWE = 1). Within the screening cohort, 30 ccs was the optimal volume threshold for discriminating patients with versus without delayed seizures (OR 12.6, 95% CI: [4.6, 34.3]). Contusions larger than 30 cc remained significantly associated with delayed seizures in two external cohorts: (TRACK-TBI OR 4.1 [1.5, 11.2]; VHIS OR 3.2 [1.7, 6.2]). Interpretation: Across three cohorts of patients with TBI, CT-derived contusion volume is robustly associated with the development of delayed seizures, in contrast to commonly-used outcomes measuring global functioning. A 30-cc volume threshold can be used to improve epilepsy prediction models and enrich populations for clinical trials.","rel_num_authors":16,"rel_authors":[{"author_name":"Ajitesh Nanda","author_inst":"Brigham and Women's Hospital"},{"author_name":"Xiaoying Sun","author_inst":"University of California, San Diego"},{"author_name":"Frederic L.W.V.J. Schaper","author_inst":"Brigham and Women's Hospital"},{"author_name":"Jennifer A. Kim","author_inst":"Yale School of Medicine"},{"author_name":"Hui Shi","author_inst":"Brigham and Women's Hospital"},{"author_name":"Shira Cohen-Zimerman","author_inst":"Shirley Ryan Ability Lab"},{"author_name":"Amy J. Markowitz","author_inst":"University of California, San Francisco"},{"author_name":"Eric S. Rosenthal","author_inst":"Mass General Brigham"},{"author_name":"Michael D. Fox","author_inst":"Brigham and Women's Hospital"},{"author_name":"Brian L. Edlow","author_inst":"Mass General Brigham"},{"author_name":"Jordan H. Grafman","author_inst":"Feinberg School of Medicine"},{"author_name":"Geoffrey T. Manley","author_inst":"University of California, San Francisco"},{"author_name":"Joseph T. Giacino","author_inst":"Spaulding Rehabilitation Hospital"},{"author_name":"Sonia Jain","author_inst":"University of California, San Diego"},{"author_name":"Yelena G. Bodien","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Samuel B. Snider","author_inst":"Brigham and Women's Hospital"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Contusion Volume is a Cross-cohort Predictor of Delayed Seizures after Traumatic Brain Injury","rel_doi":"10.64898\/2026.06.01.26354621","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354621","rel_abs":"Objective: Predicting specific cognitive, psychiatric, and health-related sequelae in patients after acute traumatic brain injury (TBI) remains an important but challenging clinical problem. Acute phase computed tomography (CT) scans acquired show hemorrhagic contusions, a common type of traumatic pathology. However, whether CT-measured contusions predict long-term sequelae is uncertain. Methods: We established a Screening Cohort of patients with acute TBI who received care at a single TBI Model Systems (TBIMS) inpatient rehabilitation facility. Regions of hemorrhagic contusion and edema were labeled on acute brain CT scans using the fully-automated Brain Lesion Analysis and Segmentation Tool (BLAST-CT). We screened 198 outcome variables at 1-year post-injury for association with acute hemorrhagic contusion volume using the Harrell's Concordance index (C-index), controlling for multiple comparisons using 5,000 outcome permutations. Finally, we tested whether the significant associations in the TBIMS database replicated in acute (Transforming Research and Clinical Knowledge in TBI [TRACK-TBI]) and chronic (Vietnam Head Injury Study [VHIS]) external validation cohorts. Results: The TBIMS Screening Cohort included 345 participants (mean {+\/-} SD age: 55.7 {+\/-} 21.5 years) with median [IQR] contusion volume 2.3 cc [0.1, 14.6]. Among 198 candidate outcome variables, only delayed seizures were significantly associated with acute hemorrhagic contusion volume (C-index = 0.81; PFWE = 0.007). Contusion volume was not significantly associated with commonly-used measures of global functioning like the Glasgow Outcome Scale Extended, (C-index = 0.55; PFWE = 1). Within the screening cohort, 30 ccs was the optimal volume threshold for discriminating patients with versus without delayed seizures (OR 12.6, 95% CI: [4.6, 34.3]). Contusions larger than 30 cc remained significantly associated with delayed seizures in two external cohorts: (TRACK-TBI OR 4.1 [1.5, 11.2]; VHIS OR 3.2 [1.7, 6.2]). Interpretation: Across three cohorts of patients with TBI, CT-derived contusion volume is robustly associated with the development of delayed seizures, in contrast to commonly-used outcomes measuring global functioning. A 30-cc volume threshold can be used to improve epilepsy prediction models and enrich populations for clinical trials.","rel_num_authors":16,"rel_authors":[{"author_name":"Ajitesh Nanda","author_inst":"Brigham and Women's Hospital"},{"author_name":"Xiaoying Sun","author_inst":"University of California, San Diego"},{"author_name":"Frederic L.W.V.J. Schaper","author_inst":"Brigham and Women's Hospital"},{"author_name":"Jennifer A. Kim","author_inst":"Yale School of Medicine"},{"author_name":"Hui Shi","author_inst":"Brigham and Women's Hospital"},{"author_name":"Shira Cohen-Zimerman","author_inst":"Shirley Ryan Ability Lab"},{"author_name":"Amy J. Markowitz","author_inst":"University of California, San Francisco"},{"author_name":"Eric S. Rosenthal","author_inst":"Mass General Brigham"},{"author_name":"Michael D. Fox","author_inst":"Brigham and Women's Hospital"},{"author_name":"Brian L. Edlow","author_inst":"Mass General Brigham"},{"author_name":"Jordan H. Grafman","author_inst":"Feinberg School of Medicine"},{"author_name":"Geoffrey T. Manley","author_inst":"University of California, San Francisco"},{"author_name":"Joseph T. Giacino","author_inst":"Spaulding Rehabilitation Hospital"},{"author_name":"Sonia Jain","author_inst":"University of California, San Diego"},{"author_name":"Yelena G. Bodien","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Samuel B. Snider","author_inst":"Brigham and Women's Hospital"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Contusion Volume is a Cross-cohort Predictor of Delayed Seizures after Traumatic Brain Injury","rel_doi":"10.64898\/2026.06.01.26354621","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354621","rel_abs":"Objective: Predicting specific cognitive, psychiatric, and health-related sequelae in patients after acute traumatic brain injury (TBI) remains an important but challenging clinical problem. Acute phase computed tomography (CT) scans acquired show hemorrhagic contusions, a common type of traumatic pathology. However, whether CT-measured contusions predict long-term sequelae is uncertain. Methods: We established a Screening Cohort of patients with acute TBI who received care at a single TBI Model Systems (TBIMS) inpatient rehabilitation facility. Regions of hemorrhagic contusion and edema were labeled on acute brain CT scans using the fully-automated Brain Lesion Analysis and Segmentation Tool (BLAST-CT). We screened 198 outcome variables at 1-year post-injury for association with acute hemorrhagic contusion volume using the Harrell's Concordance index (C-index), controlling for multiple comparisons using 5,000 outcome permutations. Finally, we tested whether the significant associations in the TBIMS database replicated in acute (Transforming Research and Clinical Knowledge in TBI [TRACK-TBI]) and chronic (Vietnam Head Injury Study [VHIS]) external validation cohorts. Results: The TBIMS Screening Cohort included 345 participants (mean {+\/-} SD age: 55.7 {+\/-} 21.5 years) with median [IQR] contusion volume 2.3 cc [0.1, 14.6]. Among 198 candidate outcome variables, only delayed seizures were significantly associated with acute hemorrhagic contusion volume (C-index = 0.81; PFWE = 0.007). Contusion volume was not significantly associated with commonly-used measures of global functioning like the Glasgow Outcome Scale Extended, (C-index = 0.55; PFWE = 1). Within the screening cohort, 30 ccs was the optimal volume threshold for discriminating patients with versus without delayed seizures (OR 12.6, 95% CI: [4.6, 34.3]). Contusions larger than 30 cc remained significantly associated with delayed seizures in two external cohorts: (TRACK-TBI OR 4.1 [1.5, 11.2]; VHIS OR 3.2 [1.7, 6.2]). Interpretation: Across three cohorts of patients with TBI, CT-derived contusion volume is robustly associated with the development of delayed seizures, in contrast to commonly-used outcomes measuring global functioning. A 30-cc volume threshold can be used to improve epilepsy prediction models and enrich populations for clinical trials.","rel_num_authors":16,"rel_authors":[{"author_name":"Ajitesh Nanda","author_inst":"Brigham and Women's Hospital"},{"author_name":"Xiaoying Sun","author_inst":"University of California, San Diego"},{"author_name":"Frederic L.W.V.J. Schaper","author_inst":"Brigham and Women's Hospital"},{"author_name":"Jennifer A. Kim","author_inst":"Yale School of Medicine"},{"author_name":"Hui Shi","author_inst":"Brigham and Women's Hospital"},{"author_name":"Shira Cohen-Zimerman","author_inst":"Shirley Ryan Ability Lab"},{"author_name":"Amy J. Markowitz","author_inst":"University of California, San Francisco"},{"author_name":"Eric S. Rosenthal","author_inst":"Mass General Brigham"},{"author_name":"Michael D. Fox","author_inst":"Brigham and Women's Hospital"},{"author_name":"Brian L. Edlow","author_inst":"Mass General Brigham"},{"author_name":"Jordan H. Grafman","author_inst":"Feinberg School of Medicine"},{"author_name":"Geoffrey T. Manley","author_inst":"University of California, San Francisco"},{"author_name":"Joseph T. Giacino","author_inst":"Spaulding Rehabilitation Hospital"},{"author_name":"Sonia Jain","author_inst":"University of California, San Diego"},{"author_name":"Yelena G. Bodien","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Samuel B. Snider","author_inst":"Brigham and Women's Hospital"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Contusion Volume is a Cross-cohort Predictor of Delayed Seizures after Traumatic Brain Injury","rel_doi":"10.64898\/2026.06.01.26354621","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354621","rel_abs":"Objective: Predicting specific cognitive, psychiatric, and health-related sequelae in patients after acute traumatic brain injury (TBI) remains an important but challenging clinical problem. Acute phase computed tomography (CT) scans acquired show hemorrhagic contusions, a common type of traumatic pathology. However, whether CT-measured contusions predict long-term sequelae is uncertain. Methods: We established a Screening Cohort of patients with acute TBI who received care at a single TBI Model Systems (TBIMS) inpatient rehabilitation facility. Regions of hemorrhagic contusion and edema were labeled on acute brain CT scans using the fully-automated Brain Lesion Analysis and Segmentation Tool (BLAST-CT). We screened 198 outcome variables at 1-year post-injury for association with acute hemorrhagic contusion volume using the Harrell's Concordance index (C-index), controlling for multiple comparisons using 5,000 outcome permutations. Finally, we tested whether the significant associations in the TBIMS database replicated in acute (Transforming Research and Clinical Knowledge in TBI [TRACK-TBI]) and chronic (Vietnam Head Injury Study [VHIS]) external validation cohorts. Results: The TBIMS Screening Cohort included 345 participants (mean {+\/-} SD age: 55.7 {+\/-} 21.5 years) with median [IQR] contusion volume 2.3 cc [0.1, 14.6]. Among 198 candidate outcome variables, only delayed seizures were significantly associated with acute hemorrhagic contusion volume (C-index = 0.81; PFWE = 0.007). Contusion volume was not significantly associated with commonly-used measures of global functioning like the Glasgow Outcome Scale Extended, (C-index = 0.55; PFWE = 1). Within the screening cohort, 30 ccs was the optimal volume threshold for discriminating patients with versus without delayed seizures (OR 12.6, 95% CI: [4.6, 34.3]). Contusions larger than 30 cc remained significantly associated with delayed seizures in two external cohorts: (TRACK-TBI OR 4.1 [1.5, 11.2]; VHIS OR 3.2 [1.7, 6.2]). Interpretation: Across three cohorts of patients with TBI, CT-derived contusion volume is robustly associated with the development of delayed seizures, in contrast to commonly-used outcomes measuring global functioning. A 30-cc volume threshold can be used to improve epilepsy prediction models and enrich populations for clinical trials.","rel_num_authors":16,"rel_authors":[{"author_name":"Ajitesh Nanda","author_inst":"Brigham and Women's Hospital"},{"author_name":"Xiaoying Sun","author_inst":"University of California, San Diego"},{"author_name":"Frederic L.W.V.J. Schaper","author_inst":"Brigham and Women's Hospital"},{"author_name":"Jennifer A. Kim","author_inst":"Yale School of Medicine"},{"author_name":"Hui Shi","author_inst":"Brigham and Women's Hospital"},{"author_name":"Shira Cohen-Zimerman","author_inst":"Shirley Ryan Ability Lab"},{"author_name":"Amy J. Markowitz","author_inst":"University of California, San Francisco"},{"author_name":"Eric S. Rosenthal","author_inst":"Mass General Brigham"},{"author_name":"Michael D. Fox","author_inst":"Brigham and Women's Hospital"},{"author_name":"Brian L. Edlow","author_inst":"Mass General Brigham"},{"author_name":"Jordan H. Grafman","author_inst":"Feinberg School of Medicine"},{"author_name":"Geoffrey T. Manley","author_inst":"University of California, San Francisco"},{"author_name":"Joseph T. Giacino","author_inst":"Spaulding Rehabilitation Hospital"},{"author_name":"Sonia Jain","author_inst":"University of California, San Diego"},{"author_name":"Yelena G. Bodien","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Samuel B. Snider","author_inst":"Brigham and Women's Hospital"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Temporal Co-Evolution of Clinical Scores and Neuro-Immune Biomarkers in Preterm Infants with Severe Germinal Matrix-Intraventricular Hemorrhage and Post-Hemorrhagic Ventricular Dilation","rel_doi":"10.64898\/2026.06.02.26349284","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26349284","rel_abs":"Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most frequent and severe neurological complications in preterm infants (PT). It triggers an inflammatory response accompanied by neuronal and glial injury and may progress to post-hemorrhagic ventricular dilatation (PHVD), thereby increasing long term disability and cognitive deficits. Nevertheless, the characteristics and evolution of the associated pathology is poorly understood. To assess neuroimmune response and neuropathology induced by GM-IVH, we quantified cytokines, glial activation and neurodegeneration makers in cerebrospinal fluid collected from 12 patients with grades III\/IV GM-IVH and PHVD and 5 controls neonates from the onset of pathology up to 2 months of age. Additionally, to evaluate long-term deficits and behavioral outcomes, we used standard behavioral test including Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 2 years of age. Interestingly, we found that while pathology markers such as ubiquitin carboxy-terminal hydrolase L1 (UCHL1), alpha II spectrin breakdown product 145 (SBDP145) and myelin basic protein (MBP) are elevated in PT, their level decline over time. Furthermore, cytokine profiling identified two divergent temporal trajectories (i.e., diminishing or sustained) that correspond with either neuronal or astrocytic markers. Specifically, diminishing cytokines including IL-6, IL-8, and IP-10 decreased with age and were correlated with neuronal markers such as SBDP145, UCH-L1, and MBP. In contrast, sustained cytokines such as IFN-{gamma}, IL-7, IL-13, and MCP-1 remained elevated or unchanged throughout the study period and were positively correlated with astrocyte reactivity marker GFAP. Notably, sustained cytokines were consistent with worse motor function and behavioral outcome. Together, longitudinal CSF analysis in PT with severe GM-IVH and PHVD identifies a cytokine profile that declines and correlates with neuronal and glial injury markers, and another that remains sustained and correlates with gliosis and adverse neurodevelopmental outcomes. These findings highlight potential CSF biomarkers associated with disease progression and long-term neurological impairment, providing a foundation for future evaluation of candidate therapeutic interventions.","rel_num_authors":7,"rel_authors":[{"author_name":"Sara Bitarafan","author_inst":"Georgia Institute of Technology"},{"author_name":"Angel del Marco","author_inst":"Universidad de Cadiz"},{"author_name":"Isabel Benavente-Fernandez","author_inst":"Universidad de Cadiz"},{"author_name":"Juan Arnaez","author_inst":"Hospital Universitario de Burgos"},{"author_name":"Simon Lubian-Lopez","author_inst":"Puerta del Mar University"},{"author_name":"Levi B. Wood","author_inst":"Georgia Institute of Technology"},{"author_name":"Monica Garcia-Alloza","author_inst":"Universidad de Cadiz"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Autism associated Cntnap2 deletion disrupts vestibular sensory signaling and spatial cognition in mice","rel_doi":"10.64898\/2026.05.28.728446","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728446","rel_abs":"Autism spectrum disorder (ASD) is frequently accompanied by sensory and motor abnormalities, including impaired balance, postural control, and spatial orientation, that are often attributed largely to altered central circuitry. Emerging evidence, however, suggests that peripheral sensory dysfunction can also shape ASD related behavioral phenotypes. Here, we tested whether loss of the ASD associated gene Cntnap2\/Caspr2 alters vestibular signaling in Cntnap2-\/- mice. Developmental transcriptomic analysis showed that Cntnap2 is expressed in vestibular sensory organs and increases during the first postnatal month, coincident with vestibular pathway maturation. Vestibular sensory evoked potentials revealed reduced response amplitudes and prolonged latencies in Cntnap2-\/- mice, indicating impaired peripheral afferent responses to transient linear acceleration. Cntnap2-\/- mice also showed delayed contact righting, reduced ocular counter roll, and increased hindlimb slips and compensatory tail excursions during balance beam walking, whereas rotational vestibulo-ocular reflex gain and phase were preserved. These vestibular and balance abnormalities were accompanied by reduced novel arm preference in the Y maze and severe impairment of Barnes maze acquisition, consistent with impaired spatial learning. Together, these findings identify Cntnap2\/Caspr2 as a regulator of vestibular sensory signaling and support a model in which disrupted peripheral vestibular input, likely acting together with central effects of Cntnap2 loss, contributes to sensorimotor and spatial cognitive phenotypes relevant to ASD.","rel_num_authors":7,"rel_authors":[{"author_name":"Yvette Shu","author_inst":"Johns Hopkins University"},{"author_name":"Yushan Chen","author_inst":"Johns Hopkins University"},{"author_name":"Dyllan Zhou","author_inst":"Johns Hopkins University"},{"author_name":"Xiaoya Deng","author_inst":"Johns Hopkins University"},{"author_name":"Liliana D Florea","author_inst":"Johns Hopkins University"},{"author_name":"Tara Deemyad","author_inst":"Johns Hopkins University"},{"author_name":"Soroush G Sadeghi","author_inst":"Johns Hopkins University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Conditional and marginal SNP-heritability to leverage ancestral and environmental diversity","rel_doi":"10.64898\/2026.05.28.728536","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728536","rel_abs":"SNP-heritability is defined as the fraction of variance of a trait that is explained by the SNPs in a genome-wide association study. Several methodologies have been proposed to estimate this quantity. More recent methods aim to do so with ancestrally diverse datasets and yet obtain a single heritability for an entire dataset, which we refer to as marginal heritability. However, the different underlying subpopulations that compose a genetically diverse dataset might have different environmental and genetic exposures, and thus may have different heritabilities. In order to address this, we propose a conditional SNP-heritability approach that allows to estimate multiple SNP-heritabilities on a dataset corresponding to different ancestral compositions and environmental exposures. We take a careful statistical approach, including estimation of conditional genetic and environmental variances, and calculation of standard errors via a combination of the delta method with bootstrapping. We validate our method via extensive simulations. We then apply it to an ancestrally and socio-economically diverse dataset of 6603 subjects aged around 9 to 11 from the Adolescent Brain Cognitive Development study, and illustrate how the SNP-heritability of intelligence scores can change due to differing extrinsic variances in different socio-economic groups, which coincides with previous work in the literature. This conditional estimation approach can be a valuable tool for understanding differences in risks across subpopulations. Our work here improves on existing methodology and allows us to leverage the heterogeneity of the data to obtain new insights.","rel_num_authors":3,"rel_authors":[{"author_name":"Anubhav Nikunj Singh Sachan","author_inst":"University of California San Diego"},{"author_name":"Armin Schwartzman","author_inst":"University of California, San Diego"},{"author_name":"David Azriel","author_inst":"Techion - Israel Institute of Technology"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Gradients in excitability generate hippocampal waves and shape their interactions with cortex","rel_doi":"10.64898\/2026.05.27.728116","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.27.728116","rel_abs":"Travelling waves are a prominent feature of hippocampal activity, but the mechanisms determining their propagation and influence on the cerebral cortex remain unclear. Using a biophysically-grounded model of neural activity evolving across hippocampal and cortical surfaces, we show that spatial gradients in external in-put or neural excitability are a sufficient mechanism for the emergence of travelling waves along the long axis of the hippocampus. These waves emerge only above a critical gradient threshold, propagate with biologically-plausible velocities and exhibit frequency-dependent reversals in direction across slow and fast theta regimes. When coupled to the cerebral cortex, anterior-to-posterior hippocampal waves selectively reorganise globally synchronous cortical activity into metastable travelling waves, whereas posterior-to-anterior hippocampal waves do not, revealing a directional asymmetry in hippocampal-cortical communication. Conversely, cortical waves aligned with large-scale functional gradients induce structured hippocampal waves, revealing complementary direction specific effects across the two systems. These analyses identify structured excitability gradients as a principle governing wave propagation in the hippocampus and suggest how wave-to-wave interactions may coordinate complex cortical and hippocampal interactions during mnemonic and perceptual processes.","rel_num_authors":5,"rel_authors":[{"author_name":"Anna Behler","author_inst":"The University of Newcastle"},{"author_name":"Richa Phogat","author_inst":"The University of Newcastle"},{"author_name":"David T. Jones","author_inst":"Department of Neurology, Mayo Clinic, Rochester, MN, USA"},{"author_name":"James Shine","author_inst":"The University of Sydney"},{"author_name":"Michael Breakspear","author_inst":"University of Newcastle"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Comparative connectomics reveals stage-specific gap junction rewiring that reshapes avoidance behavior","rel_doi":"10.64898\/2026.05.28.728331","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728331","rel_abs":"Environmental stress can remodel neural circuits, yet how such rewiring generates behavioral adaptation remains poorly understood. The dauer stage of Caenorhabditis elegans provides a unique model to address this question. Here, we investigated how dauer-specific circuit remodeling alters nociceptive behavior. We found that dauers exhibit markedly shorter avoidance durations than adults. Comparative connectomics revealed substantial expansion of gap junctions within the dauer nociceptive circuit. Calcium imaging further showed that dauer neurons exhibit faster and more transient activity dynamics throughout the circuit. Introducing synthetic dauer-specific gap junctions into adults was sufficient to recapitulate dauer-like neuronal activity patterns and significantly shorten avoidance duration. Despite extensive circuit rewiring, however, avoidance initiation remained preserved across developmental stages. Together, our findings demonstrate that the dauer connectome is selectively rewired through gap junction remodeling to tune behavioral persistence while robustly preserving behavioral initiation, revealing how developmental circuit reorganization balances flexibility and stability for survival under stress.","rel_num_authors":6,"rel_authors":[{"author_name":"Daniel T. Choe","author_inst":"SEOUL NATIONAL UNIVERSITY"},{"author_name":"David  H Hall","author_inst":"Yeshiva University Albert Einstein College of Medicine"},{"author_name":"Ken  C.Q. Nguyen","author_inst":"Yeshiva University Albert Einstein College of Medicine"},{"author_name":"Myunghwan Choi","author_inst":"Seoul National University"},{"author_name":"J. Alexander Bae","author_inst":"KAIST"},{"author_name":"Junho Lee","author_inst":"Seoul National University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Clonal dynamics of germinal center refueling by secondary immunization","rel_doi":"10.64898\/2026.05.26.728008","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.728008","rel_abs":"Many vaccine regimens involve delivery of multiple doses to the same anatomical site, such that booster doses frequently encounter germinal centers (GCs) still active from prior immunization. The consequences of this \"GC refueling\" to B cell clonality have not been systematically investigated. Using mouse models of mRNA-LNP vaccination combined with multicolor fate-mapping, longitudinal GC imaging, and immunoglobulin sequencing, we show that refueling triggers clonal burst-type expansion of GC-resident B cells, rather than recruiting local memory, resulting in marked focusing of GCs on the descendants of individual B cells. Refueling with a drifted antigen led to limited but detectable retraining of primary-cohort clones, although most variant-specific responses in this setting arose from newly recruited naive B cells. These findings identify GC refueling as a distinct mode of vaccine response with implications for sequential immunization strategies against rapidly evolving pathogens.","rel_num_authors":10,"rel_authors":[{"author_name":"Luka Mesin","author_inst":"The Rockefeller University"},{"author_name":"Alvaro Hobbs","author_inst":"The Rockefeller University"},{"author_name":"Jin-Jie Shen","author_inst":"The Rockefeller University"},{"author_name":"Juhee Pae","author_inst":"The Rockefeller University"},{"author_name":"Arien Schiepers","author_inst":"The Rockefeller University"},{"author_name":"Nadine Abrahamse","author_inst":"The Rockefeller University"},{"author_name":"Hiromi Muramatsu","author_inst":"University of Pennsylvania"},{"author_name":"Ying K Tam","author_inst":"Acuitas Therapeutics"},{"author_name":"Norbert Pardi","author_inst":"University of Pennsylvania"},{"author_name":"Gabriel D Victora","author_inst":"The Rockefeller University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Utility of the ADAS-Cog as a Cognitive Screening Tool in Older Adults with Epilepsy: A Multicenter Cohort Study","rel_doi":"10.64898\/2026.05.27.26354210","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354210","rel_abs":"ObjectiveCognitive impairment is common among older adults with epilepsy, although efficient screening tools suitable for routine use are lacking. Here we examine, for the first time, the utility of the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) as a screening tool to identify cognitive impairment in older adults with epilepsy.\n\nMethodsParticipants included 83 adults (ages [&ge;] 55) with epilepsy from the Brain, Aging, and Cognition in Epilepsy (BrACE) study and 83 age-, sex-, and education-matched cognitively healthy controls from the Alzheimers Disease Neuroimaging Initiative (ADNI-3). All completed the ADAS-Cog and a comprehensive neuropsychological battery to identify cognitive phenotypes (intact vs impaired). Performance on individual ADAS-Cog items and the total score was assessed, and diagnostic efficiency statistics were determined.\n\nResultsEpilepsy participants (mean age=66.4 years) performed significantly worse across the ADAS-Cog total score and 8 of the 13 individual test items compared to controls. The largest effect sizes were observed on verbal learning and memory tasks, particularly word recall (d=0.87) and delayed word recall (d=1.06). An ADAS-Cog total score of [&ge;]15 yielded optimal diagnostic efficiency (67.5% accuracy, 68.8% sensitivity, 66.7% specificity) for identifying cognitive impairment.\n\nSignificanceThe ADAS-Cog is sensitive to detecting cognitive impairment in older adults with epilepsy and may represent a scalable screening option in this population. Additional comparative studies in older epilepsy populations are needed to determine the sensitivity of this measure to longitudinal change, cross-cultural applicability, and availability across languages.\n\nPlain language summaryCognitive decline is common among older adults with epilepsy, although sufficient evidence supporting the use of screening tools to identify cognitive impairment in this population is lacking. The ADAS-Cog may be a useful screening option in epilepsy research and clinical care, although additional studies are needed to compare it with other cognitive screening tests and to confirm its applicability for clinical care and across cultures and healthcare settings.\n\nKey Points{square} ADAS-Cog, a tool widely used in Alzheimers disease research, was used to detect cognitive impairment in older adults with epilepsy versus healthy controls.\n{square}Largest deficits were in verbal learning and delayed recall, aligning with epilepsy-related memory vulnerability.\n{square}ADAS-Cog was compared with the gold standard, the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE). An ADAS-Cog-13 cutoff [&ge;]15 showed optimal accuracy for IC-CoDE-defined cognitive impairment.\n{square}ADAS-Cog performance reliably distinguished IC-CoDE-impaired from intact participants within the epilepsy cohort.\n{square}These findings support ADAS-Cog as a cognitive screening tool in aging epilepsy populations to identify neurodegenerative vulnerability.","rel_num_authors":13,"rel_authors":[{"author_name":"Bruce  P. Hermann","author_inst":"University of Wisconsin Madison School of Medicine and Public Health"},{"author_name":"Jessica Kania","author_inst":"University of Wisconsin School of Medicine and Public Health"},{"author_name":"Ifrah Zawar","author_inst":"University of Virginia School of Medicine"},{"author_name":"Anny Reyes","author_inst":"Cleveland Clinic"},{"author_name":"Victoria J Williams","author_inst":"University of Wosconsin School of Medicine and Public Health"},{"author_name":"Rani Sarkis","author_inst":"Brigham and Women's Hospiral"},{"author_name":"Vineet Punia Punia","author_inst":"Cleveland Clinic"},{"author_name":"McKenna Williams","author_inst":"University of California-San Diego"},{"author_name":"Lisa Ferguson","author_inst":"Cleveland Clinic"},{"author_name":"kayela Arrotta","author_inst":"Cleveland Clinic"},{"author_name":"Robyn Busch","author_inst":"Cleveland Clinic"},{"author_name":"Jana E Jones","author_inst":"University of Wisconsin School of Medicine and Public Health"},{"author_name":"Carrie McDonald","author_inst":"University of California-San Diego"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Segmental Lung Sound Analysis in Obstructive Lung Diseases Using Electronic Stethoscope; a protocol to establish an acoustic repository","rel_doi":"10.64898\/2026.05.27.26354263","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354263","rel_abs":"IntroductionObstructive lung diseases (OLDs) are responsible for high rates of illness and death worldwide. Inflammation, chronic airflow limitation, and bronchial remodeling occur in OLD and eventually result in the unique respiratory sounds. Despite its subjective and having low reproducibility, still traditional auscultation using a manual stethoscope is the main method used to identify the lung sounds. Nevertheless, the combination of recent advancements in digital stethoscopes and AI (Artificial Intelligence) has permitted the objective measurement of lung sounds. Nevertheless, there is a lack of standardized, region-specific databases for AI training and validation. Even though lung sound classification is an emerging aspect in research and telerehabilitation the lobar wise acoustic pattern is still novel due to lack of prevailing database to train AI models. Identifying this gap this study aims to develop an acoustic repository and analyze the data using segmental lung sounds from patients with OLDs and healthy controls through an electronic stethoscope.\n\nMethods and analysisThis is a cross sectional observational study involving 120 participants (60 OLD patients and 60 healthy controls). Lobar wise acoustic signals will be captured using an electronic stethoscope in healthy and diseases population. The data will be analyzed using Audacity software for annotations and then it will be used for feature extraction and statistical analysis. The acoustic features extracted through Audacity, will include frequency, intensity, pitch, and root mean square (RMS) energy. Repeated measures ANOVA will be applied to compare mean sound intensities across lung segments while Pearson correlation will be used to assess associations with body composition parameters. The data will then be standardized for AI-based diagnostic applications.\n\nEthics and disseminationThe study is being reviewed from the Ethics Review Committee, Faculty of Medicine, University of Peradeniya (2025\/EC\/87) will be sought. Informed consent will be obtained in writing. The dissemination of results will take place through peer-reviewed publications and the creation of a public database containing lung sounds from the region.","rel_num_authors":5,"rel_authors":[{"author_name":"Helani Anuradha","author_inst":"University of Peradeniya Faculty of Allied Health Sciences"},{"author_name":"Duminda Yasaratne","author_inst":"University of Peradeniya"},{"author_name":"Godaliyadda GMRI","author_inst":"University of Peradeniya"},{"author_name":"Ekanayake Parakrama","author_inst":"University of Peradeniya"},{"author_name":"R Severin","author_inst":"University of Illinois Chicago College of Applied Health Sciences"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Nicotine pouch adverts reach ten times more young men than women: targeting and reach on Meta social media platforms in the UK","rel_doi":"10.64898\/2026.05.27.26354221","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354221","rel_abs":"AimsTo examine which demographic groups nicotine pouch advertisers chose to target on social media, and which groups Metas algorithms actually delivered the adverts to.\n\nDesignCross-sectional analysis of advert-level data from the Meta Ad Library.\n\nSettingMeta social media platforms (including Facebook and Instagram) in the UK.\n\nCasesA random sample of 741 nicotine pouch adverts shown in the 12 months up to December 2025, and a comparison sample of 1,125 general adverts. Analyses of reach were restricted to adverts eligible for all genders and adult ages (444 pouch adverts; 674 general).\n\nMeasurementsOutcomes were advertiser-set gender and age-group targeting criteria (i.e., groups eligible to be shown each advert) and estimated advert reach to each group (i.e., number of people who saw each advert). Male-to-female reach ratios within age groups, and reach ratios comparing age groups, were calculated per advert and summarised using geometric means. To assess whether patterns were pouch-specific, comparisons with general adverts were made using ratios of reach ratios (RRR).\n\nFindingsAdvertisers of nicotine pouches targeted a broad sample; most adverts (79.1%; 586\/741) were eligible to be shown to all genders, the remainder were restricted to men only. All were restricted to adults (minimum age 18 years) and most (95.6%; 708\/741) had no upper age limit. Despite this, of pouch adverts eligible to be shown to all adults, adverts were more likely to reach men, particularly among younger men. Among 18-24-year-olds, pouch adverts reached around ten times as many men as women (RR 10.0, 95% CI 8.7-11.5), compared with a slight skew towards women for general adverts (RR 0.81, 95% CI 0.71-0.94), corresponding to an RRR of 12.3 (95% CI 10.0-15.1). Pouch adverts also showed a skew in reach towards younger age groups. Relative to those aged 35-44 years, reach was higher among 18-24-year-olds for nicotine pouch adverts (RR 1.33, 95% CI 1.17-1.51) but much lower for general adverts (RR 0.19, 95% CI 0.17-0.21), corresponding to an RRR of 7.0 (95% CI 6.0- 8.2).\n\nConclusionsNicotine pouch adverts on social media are often eligible to be shown broadly to all demographic groups but are disproportionately delivered to young men.","rel_num_authors":6,"rel_authors":[{"author_name":"Haoxiong Sun","author_inst":"University College London"},{"author_name":"Sarah E Jackson","author_inst":"University College London"},{"author_name":"Leon Xiao","author_inst":"School of Creative Media, City University of Hong Kong, Hong Kong"},{"author_name":"Sharon Cox","author_inst":"University College London"},{"author_name":"Melissa Oldham","author_inst":"University College London"},{"author_name":"Harry Oisin Tattan-Birch","author_inst":"University College London"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Establishing a framework for human dose prediction in anti-tuberculosis drug development","rel_doi":"10.64898\/2026.05.26.26354063","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354063","rel_abs":"RationaleEfficacious dose selection for anti-tuberculosis drugs has traditionally relied on achieving plasma exposures above the minimum inhibitory concentration, but this approach has not consistently aligned with clinical outcomes.\n\nObjectivesWe sought to identify early pharmacokinetic-pharmacodynamic targets most predictive of clinical efficacious dose.\n\nMethodsWe conducted a back-translational, pharmacokinetic-pharmacodynamic simulation-based analysis of 15 anti-tuberculosis drugs. Using pharmacokinetic data from multiple biological matrices and a range of pharmacodynamic metrics, we established candidate exposure-response targets for attainment. We systematically evaluated the predictive accuracy of each target pair against established clinical doses to formulate a decision-making framework linking key drug properties to the most predictive targets.\n\nMeasurements and Main ResultsDepending on the target used, projected clinical doses varied widely--both within and across compounds--highlighting the importance of target selection for dose projection and go\/no-go decisions. In general, targeting cellular lesion-level drug exposures relative to in vivo preclinical potency provided an effective approach for early dose selection. However, for highly penetrating drugs, targeting site-of-action therapeutic exposures in the caseum was more predictive of clinical dose. Based on these findings, we developed a preliminary dose prediction tool that enables drug developers to estimate clinically relevant dose ranges of compounds using in vitro and early in vivo data.\n\nConclusionsThis work establishes and validates a simple, evidence-based framework to standardize early translational decision-making on dose selection of anti-tuberculosis candidates in development.","rel_num_authors":4,"rel_authors":[{"author_name":"Anu Patel","author_inst":"University of California, San Francisco"},{"author_name":"Angela T Li","author_inst":"University of California, San Francisco"},{"author_name":"Bel\u00e9n Solans","author_inst":"University of California, San Francisco"},{"author_name":"Radojka Savic","author_inst":"University of California, San Francisco"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Diabetes, impaired fasting glucose, and cognitive trajectories: a multi-cohort study","rel_doi":"10.64898\/2026.05.26.26354185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354185","rel_abs":"INTRODUCTIONCognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke.\n\nMETHODSData from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis.\n\nRESULTSOver 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline.\n\nDISCUSSIONIn older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.","rel_num_authors":27,"rel_authors":[{"author_name":"Jessica W Lo","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"John D Crawford","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Katherine Samaras","author_inst":"Department of Endocrinology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia"},{"author_name":"Richard B Lipton","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Mindy J Katz","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Carol A Derby","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Pierre-Marie Preux","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Maelenn Guerchet","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Eleonora d'Orsi","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Anna Quialheiro","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Cassiano Ricardo Rech","author_inst":"Federal University of Santa Catarina, Department of Physical Education, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Karen Ritchie","author_inst":"Inserm, Institut de Neurosciences de Montpellier, France"},{"author_name":"Elena Rolandi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Annalisa Davin","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Michele Rossi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Suzana Shahar","author_inst":"Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Norfadilah Rajab","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Nurul Fatin Malek Rivan","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Mary Ganguli","author_inst":"Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Erin Jacobsen","author_inst":"University of Pittsburgh School of Medicine, Department of Psychiatry. Pittsburgh, PA, USA"},{"author_name":"Beth E. Snitz","author_inst":"University of Pittsburgh School of Medicine, Department of Neurology. Pittsburgh, PA, USA"},{"author_name":"Henry Brodaty","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Yen-Ching Chen","author_inst":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Jen-Hau Chen","author_inst":"Department of Geriatrics and Gerontology, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan"},{"author_name":"Matthew Lennon","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Darren M Lipnicki","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Perminder S Sachdev","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Diabetes, impaired fasting glucose, and cognitive trajectories: a multi-cohort study","rel_doi":"10.64898\/2026.05.26.26354185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354185","rel_abs":"INTRODUCTIONCognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke.\n\nMETHODSData from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis.\n\nRESULTSOver 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline.\n\nDISCUSSIONIn older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.","rel_num_authors":27,"rel_authors":[{"author_name":"Jessica W Lo","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"John D Crawford","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Katherine Samaras","author_inst":"Department of Endocrinology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia"},{"author_name":"Richard B Lipton","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Mindy J Katz","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Carol A Derby","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Pierre-Marie Preux","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Maelenn Guerchet","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Eleonora d'Orsi","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Anna Quialheiro","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Cassiano Ricardo Rech","author_inst":"Federal University of Santa Catarina, Department of Physical Education, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Karen Ritchie","author_inst":"Inserm, Institut de Neurosciences de Montpellier, France"},{"author_name":"Elena Rolandi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Annalisa Davin","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Michele Rossi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Suzana Shahar","author_inst":"Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Norfadilah Rajab","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Nurul Fatin Malek Rivan","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Mary Ganguli","author_inst":"Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Erin Jacobsen","author_inst":"University of Pittsburgh School of Medicine, Department of Psychiatry. Pittsburgh, PA, USA"},{"author_name":"Beth E. Snitz","author_inst":"University of Pittsburgh School of Medicine, Department of Neurology. Pittsburgh, PA, USA"},{"author_name":"Henry Brodaty","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Yen-Ching Chen","author_inst":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Jen-Hau Chen","author_inst":"Department of Geriatrics and Gerontology, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan"},{"author_name":"Matthew Lennon","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Darren M Lipnicki","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Perminder S Sachdev","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Diabetes, impaired fasting glucose, and cognitive trajectories: a multi-cohort study","rel_doi":"10.64898\/2026.05.26.26354185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354185","rel_abs":"INTRODUCTIONCognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke.\n\nMETHODSData from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis.\n\nRESULTSOver 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline.\n\nDISCUSSIONIn older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.","rel_num_authors":27,"rel_authors":[{"author_name":"Jessica W Lo","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"John D Crawford","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Katherine Samaras","author_inst":"Department of Endocrinology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia"},{"author_name":"Richard B Lipton","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Mindy J Katz","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Carol A Derby","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Pierre-Marie Preux","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Maelenn Guerchet","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Eleonora d'Orsi","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Anna Quialheiro","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Cassiano Ricardo Rech","author_inst":"Federal University of Santa Catarina, Department of Physical Education, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Karen Ritchie","author_inst":"Inserm, Institut de Neurosciences de Montpellier, France"},{"author_name":"Elena Rolandi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Annalisa Davin","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Michele Rossi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Suzana Shahar","author_inst":"Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Norfadilah Rajab","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Nurul Fatin Malek Rivan","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Mary Ganguli","author_inst":"Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Erin Jacobsen","author_inst":"University of Pittsburgh School of Medicine, Department of Psychiatry. Pittsburgh, PA, USA"},{"author_name":"Beth E. Snitz","author_inst":"University of Pittsburgh School of Medicine, Department of Neurology. Pittsburgh, PA, USA"},{"author_name":"Henry Brodaty","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Yen-Ching Chen","author_inst":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Jen-Hau Chen","author_inst":"Department of Geriatrics and Gerontology, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan"},{"author_name":"Matthew Lennon","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Darren M Lipnicki","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Perminder S Sachdev","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Same household, different choices: variation in health behaviors related to respiratory viruses in Illinois","rel_doi":"10.64898\/2026.05.26.26354179","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354179","rel_abs":"1While SARS-CoV-2 and influenza continue to place a significant burden on population health, within-household differences in decisions towards vaccination and seeking care across these two pathogens, and across sociodemographic groups, remain largely unexplored. By conducting a household-level survey in Illinois, we found that many individuals made inconsistent decisions about vaccination: among all adults, 29% were vaccinated for only one of COVID-19 or influenza, and among those with children in the home, 39% lived with a child whose influenza or COVID-19 vaccination status differed from their own. A higher proportion of adults were vaccinated against COVID-19 compared to influenza, while the opposite was true for those younger than 18 years old. These differences hold even when accounting for disparities in coverage by age, race\/ethnicity, political affiliation, and socioeconomic status. While vaccinated individuals consistently reported wanting to protect themselves or others, those who declined vaccination reported highly hetero-geneous reasons ranging from resource constraints to distrust or misconceptions about vaccination. These differences are even more pronounced for COVID-19, with larger partisan gaps and higher refusal driven by safety concerns, lack of trust, or religious reasons than those who decide not to get the influenza vaccine. In contrast to vaccination, the decision to seek medical care when sick showed opposite sociodemographic trends, that are likely attributable to illness severity. Our findings highlight that closing gaps in COVID-19 and influenza vaccination coverage will require an integrative strategy that accounts for diverse motivations, fears, and barriers to access, while addressing social inequalities common to both diseases.","rel_num_authors":8,"rel_authors":[{"author_name":"Soren L Larsen","author_inst":"University of California, Berkeley"},{"author_name":"Junke Yang","author_inst":"The Ohio State University"},{"author_name":"Erin M Haslett","author_inst":"Emory University"},{"author_name":"Alyssa Anastasi","author_inst":"University of Wisconsin Madison"},{"author_name":"Annika Venegas","author_inst":"University of Illinois at Urbana Champaign"},{"author_name":"Lydia Schieleit","author_inst":"University of Illinois at Urbana Champaign"},{"author_name":"Ayesha Mahmud","author_inst":"University of California, Berkeley"},{"author_name":"Pamela P. Martinez","author_inst":"University of Illinois at Urbana Champaign"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Tobacco Use is Related to Parietal-Hippocampal Connectivity in People at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.05.26.26354136","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354136","rel_abs":"BackgroundTobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship.\n\nMethodsWe used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use.\n\nResultsBrainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR.\n\nConclusionsMore frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.","rel_num_authors":19,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Maxwell J Roeske","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Adam Beermann","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary"},{"author_name":"Carrie E Bearden","author_inst":"UCLA"},{"author_name":"Kristin Cadenhead","author_inst":"Department of Psychiatry, University of California, San Diego"},{"author_name":"Tyrone D Cannon","author_inst":"Department of Psychology and Psychiatry, Yale University"},{"author_name":"Ricardo E Carrion","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Barbara Cornblatt","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Matcheri Keshavan","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Daniel H Mathalon","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Diana O Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill"},{"author_name":"Larry Seidman","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"William S Stone","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Ming T Tsuang","author_inst":"Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles"},{"author_name":"Elaine F Walker","author_inst":"Department of Psychology, Emory University"},{"author_name":"Scott W Woods","author_inst":"Yale University"},{"author_name":"Roscoe O Brady","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Tobacco Use is Related to Parietal-Hippocampal Connectivity in People at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.05.26.26354136","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354136","rel_abs":"BackgroundTobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship.\n\nMethodsWe used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use.\n\nResultsBrainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR.\n\nConclusionsMore frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.","rel_num_authors":19,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Maxwell J Roeske","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Adam Beermann","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary"},{"author_name":"Carrie E Bearden","author_inst":"UCLA"},{"author_name":"Kristin Cadenhead","author_inst":"Department of Psychiatry, University of California, San Diego"},{"author_name":"Tyrone D Cannon","author_inst":"Department of Psychology and Psychiatry, Yale University"},{"author_name":"Ricardo E Carrion","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Barbara Cornblatt","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Matcheri Keshavan","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Daniel H Mathalon","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Diana O Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill"},{"author_name":"Larry Seidman","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"William S Stone","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Ming T Tsuang","author_inst":"Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles"},{"author_name":"Elaine F Walker","author_inst":"Department of Psychology, Emory University"},{"author_name":"Scott W Woods","author_inst":"Yale University"},{"author_name":"Roscoe O Brady","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Tobacco Use is Related to Parietal-Hippocampal Connectivity in People at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.05.26.26354136","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354136","rel_abs":"BackgroundTobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship.\n\nMethodsWe used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use.\n\nResultsBrainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR.\n\nConclusionsMore frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.","rel_num_authors":19,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Maxwell J Roeske","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Adam Beermann","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary"},{"author_name":"Carrie E Bearden","author_inst":"UCLA"},{"author_name":"Kristin Cadenhead","author_inst":"Department of Psychiatry, University of California, San Diego"},{"author_name":"Tyrone D Cannon","author_inst":"Department of Psychology and Psychiatry, Yale University"},{"author_name":"Ricardo E Carrion","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Barbara Cornblatt","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Matcheri Keshavan","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Daniel H Mathalon","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Diana O Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill"},{"author_name":"Larry Seidman","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"William S Stone","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Ming T Tsuang","author_inst":"Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles"},{"author_name":"Elaine F Walker","author_inst":"Department of Psychology, Emory University"},{"author_name":"Scott W Woods","author_inst":"Yale University"},{"author_name":"Roscoe O Brady","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Tobacco Use is Related to Parietal-Hippocampal Connectivity in People at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.05.26.26354136","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354136","rel_abs":"BackgroundTobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship.\n\nMethodsWe used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use.\n\nResultsBrainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR.\n\nConclusionsMore frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.","rel_num_authors":19,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Maxwell J Roeske","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Adam Beermann","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary"},{"author_name":"Carrie E Bearden","author_inst":"UCLA"},{"author_name":"Kristin Cadenhead","author_inst":"Department of Psychiatry, University of California, San Diego"},{"author_name":"Tyrone D Cannon","author_inst":"Department of Psychology and Psychiatry, Yale University"},{"author_name":"Ricardo E Carrion","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Barbara Cornblatt","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Matcheri Keshavan","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Daniel H Mathalon","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Diana O Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill"},{"author_name":"Larry Seidman","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"William S Stone","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Ming T Tsuang","author_inst":"Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles"},{"author_name":"Elaine F Walker","author_inst":"Department of Psychology, Emory University"},{"author_name":"Scott W Woods","author_inst":"Yale University"},{"author_name":"Roscoe O Brady","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Development and Validation of a Machine Learning Model to Predict Prognosis in Patients with Advanced Head and Neck Cancer","rel_doi":"10.64898\/2026.05.27.26354194","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354194","rel_abs":"ImportancePrognostic tools beyond staging are needed to guide treatment and counseling in head and neck squamous cell carcinoma (HNSCC).\n\nObjectiveTo develop and externally validate a machine learning model predicting survival in advanced HNSCC using routinely collected clinical and biomarker data.\n\nDesign, Setting, and ParticipantsRetrospective, multi-institutional cohort study including 2,385 patients with stage III-IV HNSCC diagnosed from 2012-2022 in the University of California Health Data Warehouse (UCHDW). Patients were randomly split into training (n = 1,908) and test (n = 477) sets. Partial external validation used 7,749 patients from the Surveillance, Epidemiology, and End Results (SEER) registry (2010-2020).\n\nExposuresDemographic, tumor, treatment, comorbidity, and biomarker variables recorded at or before diagnosis.\n\nMain Outcomes and MeasuresThe primary outcome was all-cause mortality within 70 months. Cox proportional hazards models included all predictors. Discrimination was assessed with Harrells concordance index (C-index), calibration with predicted vs observed survival, and stratification with Kaplan-Meier curves. A Random Survival Forest (RSF) was trained for benchmarking and interpretability using Shapley Additive exPlanations (SHAP).\n\nResultsAmong 2,385 patients in UCHDW (median age, 63 years; 29.0% mortality), the Cox model achieved a C-index of 0.735 in the internal test set. Risk quartiles showed clear separation on Kaplan-Meier curves (log-rank p < 0.0001). In the SEER cohort (n = 7,749), where only demographic, staging, subsite, and treatment variables were available, the reduced Cox model achieved a C-index of 0.688, with calibration showing modest underestimation of survival in high-risk groups. Age, T stage, Charlson Comorbidity Index, neutrophil-to-lymphocyte ratio, and platelet count were among the strongest predictors, while surgery was associated with improved survival. The RSF achieved a C-index of 0.758 internally, with SHAP highlighting nonlinear effects of albumin, BMI, and inflammatory markers.\n\nConclusions and RelevanceA machine learning model using routine clinical and biomarker data demonstrated good prognostic performance in advanced HNSCC, with partial external validation. Such approaches may support individualized survival estimates, risk stratification, and treatment discussions, but broader validation is required before clinical adoption.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSCan a machine learning model accurately predict prognosis in patients with head and neck cancer utilizing only clinical features and biomarkers?\n\nFindingIn a study of 2,385 patients with advanced HNSCC from the UC Health Data Warehouse, a Cox model incorporating demographics, staging, comorbidities, treatment, and clinical biomarkers showed good internal discrimination (C-index 0.735). In partial external validation using 7,749 SEER patients with only demographic, staging, subsite, and treatment variables, performance remained acceptable (C-index 0.688) with preserved risk stratification.\n\nMeaningMachine learning using clinical data can predict prognosis in head and neck cancer; this tool could be used to provide individualized survival estimates and help guide treatment discussions and risk stratification at diagnosis.","rel_num_authors":7,"rel_authors":[{"author_name":"Kevin Zhang","author_inst":"University of California San Diego"},{"author_name":"Lan Gao","author_inst":"University of California San Diego"},{"author_name":"Daniel John","author_inst":"University of California San Diego"},{"author_name":"Wei Tse Li","author_inst":"University of California, San Francisco"},{"author_name":"Michael Hogarth","author_inst":"University of California San Diego"},{"author_name":"Charles S. Coffey","author_inst":"University of California San Diego"},{"author_name":"Weg M. Ongkeko","author_inst":"University of California San Diego"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Development and Validation of a Machine Learning Model to Predict Prognosis in Patients with Advanced Head and Neck Cancer","rel_doi":"10.64898\/2026.05.27.26354194","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354194","rel_abs":"ImportancePrognostic tools beyond staging are needed to guide treatment and counseling in head and neck squamous cell carcinoma (HNSCC).\n\nObjectiveTo develop and externally validate a machine learning model predicting survival in advanced HNSCC using routinely collected clinical and biomarker data.\n\nDesign, Setting, and ParticipantsRetrospective, multi-institutional cohort study including 2,385 patients with stage III-IV HNSCC diagnosed from 2012-2022 in the University of California Health Data Warehouse (UCHDW). Patients were randomly split into training (n = 1,908) and test (n = 477) sets. Partial external validation used 7,749 patients from the Surveillance, Epidemiology, and End Results (SEER) registry (2010-2020).\n\nExposuresDemographic, tumor, treatment, comorbidity, and biomarker variables recorded at or before diagnosis.\n\nMain Outcomes and MeasuresThe primary outcome was all-cause mortality within 70 months. Cox proportional hazards models included all predictors. Discrimination was assessed with Harrells concordance index (C-index), calibration with predicted vs observed survival, and stratification with Kaplan-Meier curves. A Random Survival Forest (RSF) was trained for benchmarking and interpretability using Shapley Additive exPlanations (SHAP).\n\nResultsAmong 2,385 patients in UCHDW (median age, 63 years; 29.0% mortality), the Cox model achieved a C-index of 0.735 in the internal test set. Risk quartiles showed clear separation on Kaplan-Meier curves (log-rank p < 0.0001). In the SEER cohort (n = 7,749), where only demographic, staging, subsite, and treatment variables were available, the reduced Cox model achieved a C-index of 0.688, with calibration showing modest underestimation of survival in high-risk groups. Age, T stage, Charlson Comorbidity Index, neutrophil-to-lymphocyte ratio, and platelet count were among the strongest predictors, while surgery was associated with improved survival. The RSF achieved a C-index of 0.758 internally, with SHAP highlighting nonlinear effects of albumin, BMI, and inflammatory markers.\n\nConclusions and RelevanceA machine learning model using routine clinical and biomarker data demonstrated good prognostic performance in advanced HNSCC, with partial external validation. Such approaches may support individualized survival estimates, risk stratification, and treatment discussions, but broader validation is required before clinical adoption.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSCan a machine learning model accurately predict prognosis in patients with head and neck cancer utilizing only clinical features and biomarkers?\n\nFindingIn a study of 2,385 patients with advanced HNSCC from the UC Health Data Warehouse, a Cox model incorporating demographics, staging, comorbidities, treatment, and clinical biomarkers showed good internal discrimination (C-index 0.735). In partial external validation using 7,749 SEER patients with only demographic, staging, subsite, and treatment variables, performance remained acceptable (C-index 0.688) with preserved risk stratification.\n\nMeaningMachine learning using clinical data can predict prognosis in head and neck cancer; this tool could be used to provide individualized survival estimates and help guide treatment discussions and risk stratification at diagnosis.","rel_num_authors":7,"rel_authors":[{"author_name":"Kevin Zhang","author_inst":"University of California San Diego"},{"author_name":"Lan Gao","author_inst":"University of California San Diego"},{"author_name":"Daniel John","author_inst":"University of California San Diego"},{"author_name":"Wei Tse Li","author_inst":"University of California, San Francisco"},{"author_name":"Michael Hogarth","author_inst":"University of California San Diego"},{"author_name":"Charles S. Coffey","author_inst":"University of California San Diego"},{"author_name":"Weg M. Ongkeko","author_inst":"University of California San Diego"}],"rel_date":"2026-05-28","rel_site":"medrxiv"}]}