{"gname":"Johns Hopkins University","grp_id":"47","rels":[{"rel_title":"Trans-ancestry genome-wide association meta-analysis of antidepressant response to selective serotonin reuptake inhibitors in clinical studies of depression","rel_doi":"10.64898\/2026.06.03.26354703","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354703","rel_abs":"Antidepressants are widely prescribed for major depressive disorder, yet only one-third of patients achieve remission after initial treatment. Previous genome-wide association studies (GWAS) of clinically assessed antidepressant response combined multiple antidepressant classes, potentially obscuring class-specific effects. This study focused on selective serotonin reuptake inhibitors (SSRIs), often first-line due to better tolerability. Data from 15 cohorts across four ancestries were integrated: European (N = 3887; 11 studies), East Asian (N = 1068; 4), African (N = 277; 1), and Admixed American (N = 250; 1). GWAS of non-remission and percentage improvement were conducted within cohorts, followed by ancestry-specific meta-analyses and trans-ancestry meta-regression. Single nucleotide polymorphism (SNP)-based heritability was estimated in European samples. Polygenic scores were used for leave-one-out prediction and to assess shared genetic architecture with psychiatric traits. Gene-level and gene-set enrichment analyses were also performed. No genome-wide significant variants were identified for either outcome in any ancestry-specific or trans-ancestry analyses. However, trans-ancestry meta-regression yielded eight independent loci with suggestive associations (p < 1 x 10-5) for non-remission and 17 for percentage improvement. Gene-set analyses revealed nominal enrichment of the serotonergic synapse pathway for non-remission. SNP-based heritability estimates were not significantly different from zero for either outcome. Better SSRI response was nominally associated with lower genetic predisposition to major depressive disorder, post-traumatic stress disorder, and schizophrenia. This study represents the largest trans-ancestry GWAS of SSRI response, highlighting emerging biological signals. Limited power emphasises the need for larger and ancestrally diverse cohorts to better characterise the genetic architecture of antidepressant response.","rel_num_authors":36,"rel_authors":[{"author_name":"Ke Hu","author_inst":"King's College London"},{"author_name":"Chris Wai Hang Lo","author_inst":"King's College London"},{"author_name":"Swapnil Awasthi","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Oliver Pain","author_inst":"King's College London"},{"author_name":"Madhurbain Singh","author_inst":"King's College London"},{"author_name":"Yeeun Ahn","author_inst":"Sungkyunkwan University, Samsung Medical Center"},{"author_name":"Katherine J Aitchison","author_inst":"University of Alberta"},{"author_name":"Bernhard T Baune","author_inst":"University of Munster"},{"author_name":"Joanna M Biernacka","author_inst":"Mayo Clinic"},{"author_name":"Guido Bondolfi","author_inst":"University of Geneva"},{"author_name":"Tania Carrillo-Roa","author_inst":"Max Planck Institute of Psychiatry"},{"author_name":"Hong Choi","author_inst":"Samsung Medical Center"},{"author_name":"Darina Czamara","author_inst":"Max Planck Institute of Psychiatry"},{"author_name":"Katharina Domschke","author_inst":"University of Freiburg"},{"author_name":"Chiara Fabbri","author_inst":"University of Bologna"},{"author_name":"Steven P Hamilton","author_inst":"The Permanente Medical Group"},{"author_name":"Marcus Ising","author_inst":"Max Planck Institute of Psychiatry"},{"author_name":"Yoonjeong Jang","author_inst":"Seoul National University"},{"author_name":"Masaki Kato","author_inst":"Kansai Medical University"},{"author_name":"Doh Kwan Kim","author_inst":"Sungkyunkwan University School of Medicine"},{"author_name":"Dongjun Kim","author_inst":"Genoplan"},{"author_name":"Byung-Chul Lee","author_inst":"Genoplan"},{"author_name":"Glyn Lewis","author_inst":"University College London"},{"author_name":"Shinn-Won Lim","author_inst":"Seoul National University Bundang Hospital"},{"author_name":"Yu-Li Liu","author_inst":"National Health Research Institutes"},{"author_name":"Woojae Myung","author_inst":"Seoul National University Bundang Hospital"},{"author_name":"Nader Perroud","author_inst":"University of Geneva"},{"author_name":"Alessandro Serretti","author_inst":"Kore University of Enna"},{"author_name":"Shih-Jen Tsai","author_inst":"National Yang-Ming University"},{"author_name":"Rudolf Uher","author_inst":"Dalhousie University"},{"author_name":"Richard Weinshilboum","author_inst":"Mayo Clinic"},{"author_name":"Hong-Hee Won","author_inst":"Sungkyunkwan University, Samsung Medical Center"},{"author_name":"- Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"Stephan Ripke","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Jonathan Coleman","author_inst":"King's College London"},{"author_name":"Cathryn M Lewis","author_inst":"King's College London"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Trans-ancestry genome-wide association meta-analysis of antidepressant response to selective serotonin reuptake inhibitors in clinical studies of depression","rel_doi":"10.64898\/2026.06.03.26354703","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354703","rel_abs":"Antidepressants are widely prescribed for major depressive disorder, yet only one-third of patients achieve remission after initial treatment. Previous genome-wide association studies (GWAS) of clinically assessed antidepressant response combined multiple antidepressant classes, potentially obscuring class-specific effects. This study focused on selective serotonin reuptake inhibitors (SSRIs), often first-line due to better tolerability. Data from 15 cohorts across four ancestries were integrated: European (N = 3887; 11 studies), East Asian (N = 1068; 4), African (N = 277; 1), and Admixed American (N = 250; 1). GWAS of non-remission and percentage improvement were conducted within cohorts, followed by ancestry-specific meta-analyses and trans-ancestry meta-regression. Single nucleotide polymorphism (SNP)-based heritability was estimated in European samples. Polygenic scores were used for leave-one-out prediction and to assess shared genetic architecture with psychiatric traits. Gene-level and gene-set enrichment analyses were also performed. No genome-wide significant variants were identified for either outcome in any ancestry-specific or trans-ancestry analyses. However, trans-ancestry meta-regression yielded eight independent loci with suggestive associations (p < 1 x 10-5) for non-remission and 17 for percentage improvement. Gene-set analyses revealed nominal enrichment of the serotonergic synapse pathway for non-remission. SNP-based heritability estimates were not significantly different from zero for either outcome. Better SSRI response was nominally associated with lower genetic predisposition to major depressive disorder, post-traumatic stress disorder, and schizophrenia. This study represents the largest trans-ancestry GWAS of SSRI response, highlighting emerging biological signals. Limited power emphasises the need for larger and ancestrally diverse cohorts to better characterise the genetic architecture of antidepressant response.","rel_num_authors":36,"rel_authors":[{"author_name":"Ke Hu","author_inst":"King's College London"},{"author_name":"Chris Wai Hang Lo","author_inst":"King's College London"},{"author_name":"Swapnil Awasthi","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Oliver Pain","author_inst":"King's College London"},{"author_name":"Madhurbain Singh","author_inst":"King's College London"},{"author_name":"Yeeun Ahn","author_inst":"Sungkyunkwan University, Samsung Medical Center"},{"author_name":"Katherine J Aitchison","author_inst":"University of Alberta"},{"author_name":"Bernhard T Baune","author_inst":"University of Munster"},{"author_name":"Joanna M Biernacka","author_inst":"Mayo Clinic"},{"author_name":"Guido Bondolfi","author_inst":"University of Geneva"},{"author_name":"Tania Carrillo-Roa","author_inst":"Max Planck Institute of Psychiatry"},{"author_name":"Hong Choi","author_inst":"Samsung Medical Center"},{"author_name":"Darina Czamara","author_inst":"Max Planck Institute of Psychiatry"},{"author_name":"Katharina Domschke","author_inst":"University of Freiburg"},{"author_name":"Chiara Fabbri","author_inst":"University of Bologna"},{"author_name":"Steven P Hamilton","author_inst":"The Permanente Medical Group"},{"author_name":"Marcus Ising","author_inst":"Max Planck Institute of Psychiatry"},{"author_name":"Yoonjeong Jang","author_inst":"Seoul National University"},{"author_name":"Masaki Kato","author_inst":"Kansai Medical University"},{"author_name":"Doh Kwan Kim","author_inst":"Sungkyunkwan University School of Medicine"},{"author_name":"Dongjun Kim","author_inst":"Genoplan"},{"author_name":"Byung-Chul Lee","author_inst":"Genoplan"},{"author_name":"Glyn Lewis","author_inst":"University College London"},{"author_name":"Shinn-Won Lim","author_inst":"Seoul National University Bundang Hospital"},{"author_name":"Yu-Li Liu","author_inst":"National Health Research Institutes"},{"author_name":"Woojae Myung","author_inst":"Seoul National University Bundang Hospital"},{"author_name":"Nader Perroud","author_inst":"University of Geneva"},{"author_name":"Alessandro Serretti","author_inst":"Kore University of Enna"},{"author_name":"Shih-Jen Tsai","author_inst":"National Yang-Ming University"},{"author_name":"Rudolf Uher","author_inst":"Dalhousie University"},{"author_name":"Richard Weinshilboum","author_inst":"Mayo Clinic"},{"author_name":"Hong-Hee Won","author_inst":"Sungkyunkwan University, Samsung Medical Center"},{"author_name":"- Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"Stephan Ripke","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Jonathan Coleman","author_inst":"King's College London"},{"author_name":"Cathryn M Lewis","author_inst":"King's College London"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Precision Imaging to Evaluate Kaposi Sarcoma (PRIME-KS): protocol for a multicountry novel artificial intelligence-based imaging device","rel_doi":"10.64898\/2026.06.03.26354815","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354815","rel_abs":"Abstract Background: Kaposi sarcoma (KS) is the most common cancer among men in several Eastern African countries, yet treatment monitoring relies on imprecise, time-consuming ruler-based measurements defined by the AIDS Clinical Trial Group (ACTG). This method suffers from inter-observer variability, fails to capture lesion height or true geometric area, and performs poorly on dark skin. SkinScan3D (SS3D) is a portable, low-cost, AI-enabled 3D imaging device that provides objective measurements of KS skin lesion area, height, volume, and color. The Precision Imaging to Evaluate Kaposi Sarcoma (PRIME-KS) study evaluates whether SS3D provides more reproducible and accurate lesion measurements than the standard method, and validates its integration into routine clinical workflows in Kenya and Uganda. Methods: PRIME-KS is a multicountry prospective mixed-methods study with two clinical objectives. Objective 1 is a cross-sectional diagnostic accuracy study comparing SS3D with ruler-based measurement in 50 adults with KS (150 lesions) across sites in Kenya and Uganda. Two clinicians independently measure three lesions per participant using both methods. The primary outcomes are concordance correlation coefficient (CCC) for inter-rater reproducibility, and co-efficient of determination for accuracy. Objective 2 is a non-randomized before-and-after pilot study in 100 patients at three sites, evaluating device usability, acceptability, appropriateness, and feasibility using validated instruments, along with time-and-motion studies and activity-based micro-costing. Prior to these clinical objectives, a formative study used focus group discussions, discrete choice experiments, and human-centered design workshops to refine the SS3D device and protocols with end-user input. Discussion: PRIME-KS will provide the first rigorous evaluation of a 3D imaging device for monitoring KS treatment response in routine clinical settings. If SS3D demonstrates superior reproducibility and clinical utility, it could reduce unnecessary chemotherapy exposure and associated toxicities by enabling earlier, more objective assessment of treatment response. Trial registration: ClinicalTrials.gov NCT06898203, registered 27 March 2025. Pan African Clinical Trials Registry PACTR202603523439856. Keywords Kaposi sarcoma, SkinScan3D, 3D imaging, treatment monitoring, diagnostic accuracy, implementation science, usability, human-centered design, Kenya, Uganda","rel_num_authors":12,"rel_authors":[{"author_name":"Thomas A Odeny","author_inst":"Washington University in St. Louis"},{"author_name":"Harriet Fridah Adhiambo","author_inst":"Washington University in St. Louis"},{"author_name":"Dorothy Mangale","author_inst":"Washington University in St Louis School of Medicine"},{"author_name":"Philippa Kadama Makanga","author_inst":"Infectious Diseases Institute, Makerere University"},{"author_name":"Beryne Odeny","author_inst":"Washington University in St. Louis"},{"author_name":"Fred Okuku","author_inst":"Uganda Cancer Institute"},{"author_name":"Chao Zhou","author_inst":"Washington University in St. Louis"},{"author_name":"Elvin Geng","author_inst":"Washington University In St Louis"},{"author_name":"Joseph Carson","author_inst":"Pensievision, College of Charleston, South Carolina"},{"author_name":"Victor Mudhune","author_inst":"Kenya Medical Research Institute"},{"author_name":"Elizabeth Bukusi","author_inst":"Kenya Medical Research Institute"},{"author_name":"Aggrey Semeere","author_inst":"Infectious Diseases Institute, Makerere University"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Spatiotemporal Dynamics of Human Metapneumovirus and Potential Impact of Respiratory Syncytial Virus Interventions in the United States","rel_doi":"10.64898\/2026.06.01.26354616","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354616","rel_abs":"Human metapneumovirus (HMPV) causes acute lower respiratory infections, primarily affecting young children and older adults, with seasonal outbreaks peaking annually in March or April in the United States and other temperate regions in the Northern hemisphere. However, the factors driving HMPV seasonality in the United States remain poorly understood. We analyzed laboratory-confirmed HMPV cases and age-specific emergency department visits across 10 US regions, fitting an age-stratified dynamic transmission model to assess spatiotemporal patterns and investigate the influence of environmental variables and viral interference from RSV on HMPV transmission rates. We found that models incorporating climate variables into the transmission rate, including vapor pressure, precipitation, potential evapotranspiration, and minimum temperature, could not capture the timing of HMPV activity across all regions. Instead, HMPV timing was associated with RSV activity, with the HMPV transmission rate reduced in the presence of RSV. We showed that, unlike RSV, only models incorporating viral interference could reproduce the biennial pattern of HMPV observed in some regions, characterized by alternating late-small and early-large epidemics. Furthermore, our model successfully reproduced post-COVID-19 HMPV and RSV epidemics and predicted that RSV interventions are not likely to lead to a substantial increase in HMPV activity despite decreasing competition from RSV. Our work unravels the spatiotemporal dynamics of HMPV and its interaction with RSV, informing future seasonal forecasting and intervention strategies for HMPV.","rel_num_authors":6,"rel_authors":[{"author_name":"Ke Li","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Stephanie Perniciaro","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Jiye Kwon","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Nathan D Grubaugh","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Daniel M Weinberger","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Virginia E. Pitzer","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Study Design Indexing in Transition: A Focused Comparison of manual NLM Indexing vs. Transformer-based Automated Models","rel_doi":"10.64898\/2026.06.03.26354854","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354854","rel_abs":"Objectives: Study design indexing of biomedical publications is crucial for evidence retrieval and synthesis. We sought to evaluate the accuracy and suitability of a transformer-based model (TM) for indexing clinical study designs, in comparison to National Library of Medicine (NLM) indexing. However, this is challenging for at least three reasons: First, to date, all automated systems have been trained and evaluated on manual NLM indexing assignments, itself subject to errors. Second, TM's probabilistic predictive scores take into account uncertainty, and can be converted to TRUE\/FALSE assignments in different ways depending on the needs of users, while NLM labels are categorical. Third, our goal (to tag articles only that exhibit a given design) differs from NLM which tags articles that both discuss as well as exhibit that design. Materials and Methods: Therefore, we carried out a limited evaluation of the TM model that focuses only on the articles that received the most confident predictions, that is, the highest scores that are almost certainly TRUE and the lowest scores that are almost certainly FALSE, but which disagreed with NLM assignments. This was performed both for articles published in 2016 (when NLM decisions were manual) and in 2025 (when NLM decisions were automated). To establish ground truth, dual annotators indexed the articles independently, following written definitions, for four prominent study designs--cohort, case-control, cross-sectional, and case report. Results: For three designs (case-control, case report, cross-sectional), the articles having the top 100 predictive TM scores (when NLM failed to assign that design) were judged to exhibit that design in the great majority (86-100%) of cases. Conversely, the articles having the lowest 100 predictive TM scores (when NLM did assign the study design) exhibited the design only in relatively few (0-21%) of cases. The most confident predictions of the TM model were highly accurate and not redundant with automated NLM indexing; the exception was cohort studies articles, in which both TM and NLM labels showed high error rates of both omission and commission. Discussion and Conclusion: TM may have value for identifying articles exhibiting study designs, which is especially important for clinical decision-making as well as systematic reviews and other evidence syntheses. NLM indexing of cohort studies cannot be regarded as a reliable gold standard for training or evaluation of automated systems, warranting efforts to create a new manually annotated corpus.","rel_num_authors":12,"rel_authors":[{"author_name":"Puranjani Das","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Jodi Schneider","author_inst":"University of Wisconsin-Madison"},{"author_name":"Evan Mayo-Wilson","author_inst":"University of North Carolina Chapel Hill"},{"author_name":"Halil Kilicoglu","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Joe D. Menke","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Dongin Nam","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Kiran Ninan","author_inst":"University of North Carolina Chapel Hill"},{"author_name":"Jean-Pierre Oberste","author_inst":"University of North Carolina Chapel Hill"},{"author_name":"Ang Michael Troy","author_inst":"University of Illinois Chicago"},{"author_name":"Xiangji Ying","author_inst":"University of North Carolina Chapel Hill"},{"author_name":"Arthur W. Holt","author_inst":"University of Illinois Chicago"},{"author_name":"Neil R. Smalheiser","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Contextualizing the Utility of Polygenic Risk Scores using Absolute Risk Models in Diverse Ancestry Populations","rel_doi":"10.64898\/2026.06.03.26354842","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354842","rel_abs":"Polygenic risk scores (PRSs) are emerging as powerful tools for quantifying inherited risk for common diseases and, in some cases, are approaching clinical implementation. A major concern for PRS implementation is their limited accuracy in non-European populations, particularly in those of African ancestry. However, past evaluations have focused on metrics such as relative risk or AUC, which do not capture background risk arising from contextual factors. We introduce a novel measure of variable importance, the conditional average derivative estimator (CADE), to evaluate PRS utility across diverse contexts and populations within absolute risk models that integrate PRSs with other relevant risk factors. We illustrate this framework by integrating PRSs for breast and prostate cancer within age-specific absolute risk models for incidence and mortality fit using individual-level data from the All of Us Research Program with inputs from the National Cancer Institute SEER cancer registry. Our projections show that although the PRSs are known to have the lowest discriminatory accuracy in African Americans (AA), there are contexts in which they provide greater utility, such as for the stratification of prostate cancer risk and mortality, where the CADE values for AA were 2- and 7-fold higher than for European Americans. These findings suggest that conclusions about the limited clinical utility of PRS in non-European populations may be premature and underscore the need to quantify PRS risk-stratification utility at the absolute-risk level, while accounting for disease onset, survival, and broader health and economic factors.","rel_num_authors":6,"rel_authors":[{"author_name":"Fu Martina","author_inst":"Stanford University School of Medicine"},{"author_name":"Linda Kachuri","author_inst":"Stanford University School of Medicine"},{"author_name":"John Witte","author_inst":"Stanford School of Medicine"},{"author_name":"Dezheng Huo","author_inst":"University of Chicago"},{"author_name":"Pradeep Natarajan","author_inst":"Massachusetts General Hospital"},{"author_name":"Nilanjan Chatterjee","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Contextualizing the Utility of Polygenic Risk Scores using Absolute Risk Models in Diverse Ancestry Populations","rel_doi":"10.64898\/2026.06.03.26354842","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354842","rel_abs":"Polygenic risk scores (PRSs) are emerging as powerful tools for quantifying inherited risk for common diseases and, in some cases, are approaching clinical implementation. A major concern for PRS implementation is their limited accuracy in non-European populations, particularly in those of African ancestry. However, past evaluations have focused on metrics such as relative risk or AUC, which do not capture background risk arising from contextual factors. We introduce a novel measure of variable importance, the conditional average derivative estimator (CADE), to evaluate PRS utility across diverse contexts and populations within absolute risk models that integrate PRSs with other relevant risk factors. We illustrate this framework by integrating PRSs for breast and prostate cancer within age-specific absolute risk models for incidence and mortality fit using individual-level data from the All of Us Research Program with inputs from the National Cancer Institute SEER cancer registry. Our projections show that although the PRSs are known to have the lowest discriminatory accuracy in African Americans (AA), there are contexts in which they provide greater utility, such as for the stratification of prostate cancer risk and mortality, where the CADE values for AA were 2- and 7-fold higher than for European Americans. These findings suggest that conclusions about the limited clinical utility of PRS in non-European populations may be premature and underscore the need to quantify PRS risk-stratification utility at the absolute-risk level, while accounting for disease onset, survival, and broader health and economic factors.","rel_num_authors":6,"rel_authors":[{"author_name":"Fu Martina","author_inst":"Stanford University School of Medicine"},{"author_name":"Linda Kachuri","author_inst":"Stanford University School of Medicine"},{"author_name":"John Witte","author_inst":"Stanford School of Medicine"},{"author_name":"Dezheng Huo","author_inst":"University of Chicago"},{"author_name":"Pradeep Natarajan","author_inst":"Massachusetts General Hospital"},{"author_name":"Nilanjan Chatterjee","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Shared epigenetic regulation acting on neuroimmune pathways contributes to the comorbidity between generalized anxiety disorder and COVID-19","rel_doi":"10.64898\/2026.06.03.26354830","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354830","rel_abs":"Background: The biological mechanisms linking generalized anxiety disorder (GAD) and COVID-19 remain poorly understood, despite substantial evidence of their comorbidity. To address this gap, we examined genetic and epigenetic factors underlying their co-occurrence. Methods: In a multi-ancestry sample of 893 participants, we conducted genome-wide and epigenome-wide analyses of GAD and COVID-19 severity. Integrating large-scale genome-wide datasets and information regarding methylation quantitative trait loci, complementary analytic approaches were used to identify regional methylation patterns, assess genetically regulated DNA methylation in blood and brain tissue, and evaluate causal loci shared between GAD and COVID-19. Results: GAD was associated with epigenome-wide significant variation in loci involved in chromatin regulation and synaptic signaling. Conversely, COVID-19-related epigenetic signals were enriched in immune-inflammatory and host-response pathways. Mild COVID-19 was epigenetically related to endothelial-inflammatory signals, while severe COVID-19 was linked to epigenetic changes implicated in myeloid and thrombo-inflammatory pathways. Epigenetic signals shared between GAD and COVID-19 implicated processes related to stress adaptation and tissue homeostasis. Genetically informed analyses identified 60 shared loci, including MAPT, ZFP57, and FBXL18, indicating pleiotropy between GAD and COVID-19 in genetically regulated DNA methylation variation. Brain-specific analyses further highlighted convergence in additional loci (i.e., MICB and HLA-DPB1), suggesting neuroimmune mechanisms underlying GAD-COVID-19 shared methylation patterns. Conclusions: These findings support that GAD and COVID-19 share epigenetic and genetic architecture involving pathways related to vascular integrity, immune function, and cellular adaptation, highlighting a potential neuroimmune basis for their co-occurrence.","rel_num_authors":11,"rel_authors":[{"author_name":"Sefayet Karaca","author_inst":"Yale University"},{"author_name":"Brenda Cabrera Mendoza","author_inst":"Yale University"},{"author_name":"Jun He","author_inst":"Yale University"},{"author_name":"Dan Qiu","author_inst":"Yale University"},{"author_name":"David Davtian","author_inst":"Yale University"},{"author_name":"AnnMarie Lacobelle","author_inst":"Yale University"},{"author_name":"Yaira Z Nunez","author_inst":"Yale University"},{"author_name":"John H Krystal","author_inst":"Yale University"},{"author_name":"Robert H Pietrzak","author_inst":"Yale University"},{"author_name":"Joel Gelernter","author_inst":"Yale Univ. School of Medicine"},{"author_name":"Renato Polimanti","author_inst":"Yale University"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Determinants and propagation of velocity uncertainty in 2D phase-contrast MRI","rel_doi":"10.64898\/2026.06.01.26353730","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26353730","rel_abs":"Purpose: To quantify the contributions of signal-to-noise ratio (SNR) and velocity-to-encoding ratio (v\/VENC) to velocity uncertainty in phase-contrast (PC) MRI and to develop a framework for in vivo voxel-wise uncertainty estimation. Methods: Through-plane 2D PC-MRI of the ascending aorta was acquired using multiple velocity encodings (150, 200, 300 cm\/s) and flip angles (0, 5, 15, 20 degrees) to vary v\/VENC and SNR. Voxel-wise SNR and velocity uncertainty maps were generated using empirically calibrated phase-noise modeling. Phase-resolved subject-level analyses were performed to quantify the relative contributions of SNR and |v|\/VENC to percent velocity uncertainty (%unc). Uncertainty was propagated to flow, stroke volume (SV), and cardiac output (CO). Results: Velocity uncertainty varied substantially across the cardiac cycle and depended on both SNR and |v|\/VENC. Across cardiac phases, |v|\/VENC accounted for most explained variance in %unc (partial R2=0.666), while SNR provided a smaller but meaningful contribution (partial R2=0.287; full R2=0.909). Near peak systole, SNR contributed more strongly while overall uncertainty remained low. In contrast, diastolic %unc became unstable as velocity approached zero. These effects were most pronounced at low |v|\/VENC, where higher VENC settings increased uncertainty despite similar SNR. SV uncertainty ranged from 0.27% to 1.07% across VENCxFA protocols. Conclusion: Velocity uncertainty in PC-MRI depends on both SNR and VENC adequacy in a physiologically phase-dependent manner. Relative uncertainty may become inadequate for precise quantification in low-flow applications, such as diastolic regurgitant jets, despite adequate SNR. Spatiotemporal uncertainty mapping provides a framework for uncertainty-aware PC-MRI acquisition and interpretation.","rel_num_authors":7,"rel_authors":[{"author_name":"Ana E Rodriguez-Soto","author_inst":"University of California San Diego"},{"author_name":"Eleanor L. Schuchardt","author_inst":"Rady Childrens Hospital San Diego"},{"author_name":"Hari K Narayan","author_inst":"Rady Childrens Hospital San Diego"},{"author_name":"Beth F Printz","author_inst":"Rady Childrens Hospital San Diego"},{"author_name":"Sanjeet Hegde","author_inst":"Rady Childrens Hospital San Diego"},{"author_name":"Susan R Hopkins","author_inst":"University of California San Diego"},{"author_name":"Francisco Contijoch","author_inst":"University of California San Diego"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Placental molecular subtypes of severe preeclampsia reveal divergent aging trajectories and fetal growth outcomes","rel_doi":"10.64898\/2026.06.02.26354756","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354756","rel_abs":"Severe preeclampsia (sPE) is a major cause of maternal and fetal morbidity worldwide, yet its placental molecular heterogeneity remains poorly defined by current clinical diagnosis. To resolve the molecular architecture of sPE, here we integrated DNA methylation and proteomic profiling from a multi-ethnical cohort of 444 placentas from the Hawaiian Biorepository (HiBR), including 169 sPE cases, matched preterm controls and full-term controls. To address cellular heterogeneity in bulk placental tissue, we developed HOMED (Hierarchically Optimized Methylation Deconvolution), a single-cell-guided hierarchical framework for inferring placental cell-type composition from DNA methylation data. HOMED-adjusted integrative analyses identified extensive subtype-specific alterations involving hypoxia, angiogenesis, immune activation, trophoblast differentiation and metabolic remodeling. Molecular stratification revealed two reproducible sPE subtypes with divergent placental aging trajectories. One subtype exhibited a pre-mature placental state marked by accelerated placental aging, whereas the other displayed slower accelerated placental aging but a substantially increased risk of small-for-gestational-age birth (P = 0.028). These subtypes were independently replicated across six external cohorts and further supported by proteomic signatures achieving a classification accuracy of 0.88. Integrative epigenomic and proteomic analyses linked the growth-restricted subtype to hypoxia-associated glycolytic remodeling, suggesting distinct pathogenic mechanisms underlying clinically diagnosed sPE. Together, our findings redefine severe preeclampsia as a biologically heterogeneous placental disorder composed of molecularly distinct subtypes with divergent aging trajectories and fetal growth outcomes, providing a framework for mechanism-based stratification and precision obstetric medicine.","rel_num_authors":10,"rel_authors":[{"author_name":"Yuheng Du","author_inst":"University of Michigan"},{"author_name":"Paula A Benny","author_inst":"University of Hawaii"},{"author_name":"Shayanki Lahiri","author_inst":"University of Michigan"},{"author_name":"Fadhl M AlAkwaa","author_inst":"University of Michigan"},{"author_name":"Qianhui Huang","author_inst":"University of Michigan"},{"author_name":"Yuansen Liu","author_inst":"Washington University in St. Louis"},{"author_name":"Cameron B Lassiter","author_inst":"University of Hawaii Cancer Center"},{"author_name":"Joshua Astern","author_inst":"University of Hawaii Biorepository, John A. Burns School of Medicine"},{"author_name":"Jonathan Riel","author_inst":"University of Hawaii Biorepository, John A. Burns School of Medicine"},{"author_name":"Lana X Garmire","author_inst":"University of Alabama Birmingham"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Association of cognitive impairment with statin use in coronary artery disease across APO (\u03b5) genotypes in AllofUS","rel_doi":"10.64898\/2026.06.02.26354765","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354765","rel_abs":"BACKGROUND: Coronary artery disease (CAD) and Impaired Cognitive (IC) disease share sociodemographic, genetic, and clinical factors, but the association of IC with statin use in CAD remains unclear. OBJECTIVES: To determine the association between IC and statin use in CAD based on APO (e) genotype, sex, and lipid levels. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective study of AllofUS (AoU) participants with CAD (Age [&ge;]60 yrs) enrolled from 2017 to 2023. We defined CAD as having a history of angina\/myocardial infarction\/chronic ischemic heart disease or having percutaneous coronary intervention\/CABG, and IC defined as mild cognitive impairment or all cause dementia, using ICD\/SNOMED codes. MEASURES: We assessed the association between IC and statin use using logistic regression analysis, while adjusting for clinical factors, sociodemographics, and APO (e) genotypes before and after propensity score matching. We further performed stratified analysis by sex, and APO (e) genotypes. We finally assessed the association between IC and statin users, based magnitude on the change in lipid levels before CAD and after IC (TC: Total cholesterol, LDL: low density lipoprotein, HDL: High Density Lipoprotein). Significance was defined at p < 0.05. RESULTS: The cohort included 22,089 participants with CAD and 1343 with IC. Thirty-nine percent of participants were females, 77% were European, 13% were African American, and 9% were of Admixed American ancestry. The proportion of IC was higher (6.8% vs 3.5%, p<0.001) in statin users (n=17,191) vs non-statin users (n=4,898). IC was significantly associated with statin use (OR:1.70;1.40-2.10, p = 4.9e-7) after adjustment for clinical factors, sociodemographics, and APO (e) genotypes. After propensity-score matching between IC and CAD, we observed an association between IC and statin use (OR:1.55;1.24-1.94, p =1e-4). In stratified analysis, the association between IC and statin use was strongest in the APO e3\/e3 group (OR:2.04;1.53-2.75, p = 1e-6), and in females (OR:2.20;1.60-3.06, p = 2.e-6) compared to males (OR:1.43;1.10-1.90, p = 0.01). We finally observed an increased magnitude of association between IC and statin users having higher HDL increase (> 10 mg\/dl: OR:1.95;1.44-2.66, p=1e-5) as compared to statin users with lesser HDL increase (<=; 10mg\/dl: OR:1.61;1.22-2.15, p=8e-4). CONCLUSION: In the AllofUS cohort, IC was significantly associated with statin use in CAD participants. We observed the strongest association in the APO e3\/e3 group, among females, and with a greater increase in HDL levels in statin users.","rel_num_authors":3,"rel_authors":[{"author_name":"Praveen Hariharan","author_inst":"Brown University"},{"author_name":"Minoo Bagheri","author_inst":"Vanderbilt University"},{"author_name":"Frank Sellke","author_inst":"Brown University"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"Association of cognitive impairment with statin use in coronary artery disease across APO (\u03b5) genotypes in AllofUS","rel_doi":"10.64898\/2026.06.02.26354765","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354765","rel_abs":"BACKGROUND: Coronary artery disease (CAD) and Impaired Cognitive (IC) disease share sociodemographic, genetic, and clinical factors, but the association of IC with statin use in CAD remains unclear. OBJECTIVES: To determine the association between IC and statin use in CAD based on APO (e) genotype, sex, and lipid levels. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective study of AllofUS (AoU) participants with CAD (Age [&ge;]60 yrs) enrolled from 2017 to 2023. We defined CAD as having a history of angina\/myocardial infarction\/chronic ischemic heart disease or having percutaneous coronary intervention\/CABG, and IC defined as mild cognitive impairment or all cause dementia, using ICD\/SNOMED codes. MEASURES: We assessed the association between IC and statin use using logistic regression analysis, while adjusting for clinical factors, sociodemographics, and APO (e) genotypes before and after propensity score matching. We further performed stratified analysis by sex, and APO (e) genotypes. We finally assessed the association between IC and statin users, based magnitude on the change in lipid levels before CAD and after IC (TC: Total cholesterol, LDL: low density lipoprotein, HDL: High Density Lipoprotein). Significance was defined at p < 0.05. RESULTS: The cohort included 22,089 participants with CAD and 1343 with IC. Thirty-nine percent of participants were females, 77% were European, 13% were African American, and 9% were of Admixed American ancestry. The proportion of IC was higher (6.8% vs 3.5%, p<0.001) in statin users (n=17,191) vs non-statin users (n=4,898). IC was significantly associated with statin use (OR:1.70;1.40-2.10, p = 4.9e-7) after adjustment for clinical factors, sociodemographics, and APO (e) genotypes. After propensity-score matching between IC and CAD, we observed an association between IC and statin use (OR:1.55;1.24-1.94, p =1e-4). In stratified analysis, the association between IC and statin use was strongest in the APO e3\/e3 group (OR:2.04;1.53-2.75, p = 1e-6), and in females (OR:2.20;1.60-3.06, p = 2.e-6) compared to males (OR:1.43;1.10-1.90, p = 0.01). We finally observed an increased magnitude of association between IC and statin users having higher HDL increase (> 10 mg\/dl: OR:1.95;1.44-2.66, p=1e-5) as compared to statin users with lesser HDL increase (<=; 10mg\/dl: OR:1.61;1.22-2.15, p=8e-4). CONCLUSION: In the AllofUS cohort, IC was significantly associated with statin use in CAD participants. We observed the strongest association in the APO e3\/e3 group, among females, and with a greater increase in HDL levels in statin users.","rel_num_authors":3,"rel_authors":[{"author_name":"Praveen Hariharan","author_inst":"Brown University"},{"author_name":"Minoo Bagheri","author_inst":"Vanderbilt University"},{"author_name":"Frank Sellke","author_inst":"Brown University"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"TNFRSF13B Common Variants Enhance Antibody-Dependent Complement Activation and Susceptibility to Acute Respiratory Distress Syndrome Following Respiratory Viral Infection","rel_doi":"10.64898\/2026.06.02.26354763","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354763","rel_abs":"Acute respiratory distress syndrome (ARDS) is a devastating complication of respiratory infections; however, the biological mechanisms that initiate its onset are poorly defined. Here we show that TNFRSF13B polymorphisms increase the risk of ARDS following SARS-CoV-2 infection up to 7.4-fold compared to the WT genotype. The increased risk was not due to immune-deficiency or impaired virus neutralization. On the contrary, TNFRSF13B mutant subjects mounted better antibody neutralization compared to subjects with WT TNFRSF13B. However, IgG from subjects expressing TNFRSF13B variants had less sialic acid, terminal galactose, and fucose than IgG from subjects with a WT genotype. Moreover, IgG from TNFRSF13B mutant subjects exhibited increased recruitment of complement factors. Thus, besides well-known actions governing plasma cell differentiation, TNFRSF13B impacts both affinity maturation and effector functions of IgG in ways that independently govern complement activation controlling inflammatory responses known to trigger ARDS.","rel_num_authors":11,"rel_authors":[{"author_name":"Lwar Naing","author_inst":"University of Michigan"},{"author_name":"Mayara G de Mattos Barbosa","author_inst":"Case Western Reserve University"},{"author_name":"Ian P Connell","author_inst":"Case Western Reserve University"},{"author_name":"Jeffrey Chicca","author_inst":"University of Michigan"},{"author_name":"Ziyin Zhao","author_inst":"Case Western Reserve University"},{"author_name":"Nerissa A Reister","author_inst":"University of Michigan"},{"author_name":"Anna Bruchez","author_inst":"Case Western Reserve University"},{"author_name":"Neil Greenspan","author_inst":"Case Western Reserve University"},{"author_name":"Grace McComsey","author_inst":"Case Western Reserve University and University Hospitals Cleveland Medical Center"},{"author_name":"Jeffrey L Platt","author_inst":"Case Western Reserve University and University of Michigan"},{"author_name":"Marilia Cascalho","author_inst":"Case Western Reserve University and University of Michigan"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"AIM-PrEP: AI-Agent Driven Multicenter Intervention to Improve PrEP Adherence and Health Monitoring Among Men Who Have Sex with Men (MSM)-Protocol of A Randomized Controlled Trial","rel_doi":"10.64898\/2026.06.02.26354777","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354777","rel_abs":"Background: Pre-exposure prophylaxis (PrEP) has demonstrated a significant reduction in HIV infections among men who have sex with men (MSM), however, low medication adherence hinders its preventative effectiveness. Traditional approaches, such as health education and face-to-face inquiry (HEF), have demonstrated certain efficacy in improving PrEP adherence. However, these methods are resource-intensive and often plagued by delays, rendering timely and precise interventions challenging. This randomized controlled trial aims to assess the effectiveness of an intervention comprising AI-chatbot for PrEP (PrEP-bot) and Smart pillbox (SPB) (PrEP-bot-SPB) strategy to improve PrEP adherence among MSM compared to HEF.Methods and analysis: A three-arm, multicenter, open-lable RCT will be conducted with Chinese MSM [&ge;]18 years. A total of 300 participants will be recruited through three sources, including hospitals, community-based organizations (CBOs) and peer referral in five cities: Shenzhen, Beijing, Qingdao, Hangzhou and Zhengzhou. After completing baseline survey, participants will be randomized evenly into interventions or control groups: the PrEP-bot group, the PrEP-bot-SPB group, and the HEF control group. Participants in the PrEP-bot group will be granted access to an AI-chatbot agent through WeChat. This agent will: 1) generate personalized PrEP medication plans; 2) provide medication reminders and PrEP-related health check-ups notifications; 3) inquire about missed doses to deliver tailored interventions; 4) answer participant questions about PrEP using guideline-based knowledge. Participants in the PrEP-bot-SPB group will receive both the SPB and the PrEP-bot interventions. SPB could delivers medication reminders. Participants in HEF group will receive a health education pamphlet introducing PrEP and knowledge related to PrEP medication adherence at baseline and face-to-face inquiry every three months. Outcomes will be assessed for both short-term and medium-to-long-term effects. The primary objective is the effectiveness in improving PrEP adherence measured by self-report, Eight-Item Morisky medication adherence scale (MMAS-8) and concentration of Tenofovir in dried blood spots (DBS) (PrEP adherence [&ge;]90%) at 3 months follow-up. Secondary outcomes include: 1) effectiveness in preventing HIV infection measured by HIV-self test (HIVST); 2) effectiveness of PrEP-related health check-ups; 3) the effectiveness, feasibility, acceptability, and user satisfaction with the PrEP-bot; 4) effectiveness in improving PrEP adherence at 6-month, 9-month and 12-month follow-up periods. All participants will receive quarterly follow-up visits during the 12-month study period. Intention-to-treat analysis and per protocol set (PPS) analysis will be used.Results: Recruitment and enrollment of participants began in January 2026 and is currently ongoing.Discussion: This study is expected to establish a novel AI-based intervention model for PrEP, providing innovative strategies for HIV control among MSM populations. If the PrEP-bot is proven non-inferior to HEF, it could offer users real-time, precise, and personalized interventions while simultaneously addressing PrEP-related inquiries and health check-ups reminders. Importantly, this approach would achieve significant reductions in resource requirements for implementation and maintenance and be more cost-effective. With the ongoing advancement of AI technologies, PrEP-bot holds substantial promise for widespread implementation in PrEP adherence, potentially revolutionizing HIV prevention for MSM in China through this innovative intervention modality.Trial registration: ChiCTR2500111280 (Chinese Clinical Trial Registry). Date of registration: 29 October 2025.","rel_num_authors":13,"rel_authors":[{"author_name":"Rongbiao Zeng","author_inst":"Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, China"},{"author_name":"Zhonglin Zuo","author_inst":"Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, China"},{"author_name":"Haihang Yu","author_inst":"Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, China"},{"author_name":"Yujing Jin","author_inst":"Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, China"},{"author_name":"Yingxin Wang","author_inst":"Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, China"},{"author_name":"Hui Lv","author_inst":"Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, China"},{"author_name":"Guoyong Wang","author_inst":"Institute for AIDS Control and Prevention, Shandong Provincial Center for Disease Control and Prevention, Jinan 250014, China"},{"author_name":"Na Zhang","author_inst":"Institute for AIDS Control and Prevention, Shandong Provincial Center for Disease Control and Prevention, Jinan 250014, China"},{"author_name":"Haifeng He","author_inst":"Ai Zhi Aid and Mutual Assistance Srevice Center, Zhengzhou, China"},{"author_name":"Xiaojie Huang","author_inst":"Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Xingliang Zhang","author_inst":"Hangzhou Center for Disease Control and Prevention, Hangzhou, China"},{"author_name":"Qiru Su","author_inst":"Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, China"},{"author_name":"Junjie Xu","author_inst":"Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, China"}],"rel_date":"2026-06-04","rel_site":"medrxiv"},{"rel_title":"R-loop Prediction Reveals Generalization Limits of DNA Foundation Models Beyond Regulatory Genomics","rel_doi":"10.64898\/2026.06.01.729367","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729367","rel_abs":"DNA foundation models are increasingly proposed as general-purpose representations for genomic prediction and design, yet their evaluation remains largely centered on conventional regulatory tasks. This leaves a critical question unresolved: do DNA foundation models generalize to sequence biology beyond conventional gene regulation? To answer this question, we introduce RloopBench, a systematic benchmark for R-loop-forming sequence prediction as a biophysically distinct, genome-stability-associated task. We compare rule-based methods, task-specific models, classical sequence encodings, and foundation model representations across in-distribution, cross-platform, consensus-level, and cross-species evaluations. Foundation models achieve strong performance when positive and negative sequences are compositionally separable, but this advantage does not consistently transfer to cross-platform and cross-species settings, where they are often comparable to classical k-mer representations. Unexpectedly, a one-hot classifier baseline shows the strongest overall sensitivity to R-loop-forming sequences, exceeding more complex models across several generalization tests. Rule-based and task-specific models also exhibit limited transfer outside their original training regimes. Performance is further shaped by sequence properties, negative-control design, experimental platform, and species-specific genomic context. Together, RloopBench establishes genome-stability-associated sequence prediction as a complementary direction for DNA foundation model development and evaluation, while underscoring that simple sequence encodings remain necessary baselines for assessing model generalization beyond conventional regulatory tasks.","rel_num_authors":3,"rel_authors":[{"author_name":"Yafan Zhang","author_inst":"North Carolina State University"},{"author_name":"Arunkumar Ganesan","author_inst":"University of New Mexico"},{"author_name":"Xingcheng Lin","author_inst":"North Carolina State University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Interstitium-mimicking porous alveolar membranes enable physiologic aerosol transport and distinct acute-chronic lung injury responses","rel_doi":"10.64898\/2026.06.01.729429","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729429","rel_abs":"Barrier membranes govern transport and mechanochemical coupling in lung-on-chip systems but typically exhibit low open porosity, limited pore interconnectivity, and diffusion distances exceeding native thin septal regions. An interstitium-mimicking, alveolus-shaped poly caprolactone membrane is developed using dual-templated nonsolvent-induced phase separation followed by controlled enzymatic pore enlargement. The resulting architecture achieves ~40% total porosity with 97% pore interconnectivity and incorporates a locally thinned dome region. This structure sustains cyclic deformation while increasing oxygen diffusivity fivefold compared with conventional Transwell membranes under both acellular and epithelial-endothelial co-culture conditions. Integrated into an air-liquid interface platform, the membrane enables direct aerosol deposition and quantitative interrogation of cross-barrier mass transfer. Using carbonaceous nanoscale particulate matter as a model inhaled aerosol, controlled exposure induces dose-dependent oxidative, inflammatory, and genotoxic responses. Matched cumulative dose studies reveal distinct biological trajectories: acute high-dose exposure produces rapid cytotoxic stress and barrier disruption, whereas chronic low-dose exposure preserves viability yet promotes sustained DNA repair and genome-maintenance programs. Compartment-resolved analysis and therapeutic intervention further demonstrate the platform utility for spatial and translational interrogation of lung injury. By restoring physiologically relevant diffusion distance, interconnectivity, and strain responsiveness, the interstitium-mimicking membrane advances lung-on-chip design toward functional replication of alveolar transport dynamics for studying lung injury and barrier dysfunction.","rel_num_authors":12,"rel_authors":[{"author_name":"Jaewon Choi","author_inst":"Carnegie Mellon University"},{"author_name":"Sheng Zhang","author_inst":"Carnegie Mellon University"},{"author_name":"Abbas Jalili","author_inst":"Carnegie Mellon University"},{"author_name":"August Kohls","author_inst":"Carnegie Mellon University"},{"author_name":"Woo-Youl Maeng","author_inst":"Northwestern University"},{"author_name":"Sikandar Azam","author_inst":"The Pennsylvania State University"},{"author_name":"Wu Liu","author_inst":"Carnegie Mellon University"},{"author_name":"Barbie Varghese","author_inst":"Carnegie Mellon University"},{"author_name":"Yixin Zhao","author_inst":"Carnegie Mellon University"},{"author_name":"Xi Ren","author_inst":"Carnegie Mellon University"},{"author_name":"Shimin Liu","author_inst":"The Pennsylvania State University"},{"author_name":"Si-Yang Zheng","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Structural analysis of de novo designed binders targeting the closed state of HSP90","rel_doi":"10.64898\/2026.06.03.729966","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729966","rel_abs":"Heat shock protein 90 (HSP90) assists protein folding and maturation of many important signaling proteins. In various diseases, HSP90 clients contribute to aberrant signaling, and HSP90 inhibition is being explored as a potential therapeutic approach. Commonly researched HSP90 inhibitors target the ATP-binding pocket, thereby disrupting the ATP-induced closure of HSP90. Drugs disrupting the HSP90 ATPase cycle by targeting the closed state of the chaperone have not been developed. Here, we present de novo design and selection of protein binders interacting exclusively with the closed state HSP90. Two such binders, H2 and H4, were identified that feature a similar fold and comparable affinities for HSP90 but display different binding kinetics. The structures of the HSP90 complexes with H2 and H4 were determined by cryo-EM single particle analysis, and they revealed high accuracy of the BindCraft predictions. H2 and H4 compete with p23 at one but not both symmetrical p23 binding sites on HSP90. H2 expressed in HEK293T cells moderately elevated expression of HSP70 and had no effect on the HSP90 level, suggesting muted heat shock response. Overall, this study demonstrates that the de novo binders represent novel and promising tools to probe the potential utility of HSP90 inhibition by targeting its closed state.","rel_num_authors":4,"rel_authors":[{"author_name":"Dhiraj Srivastava","author_inst":"University of Iowa"},{"author_name":"Sneha Singh","author_inst":"University of Iowa"},{"author_name":"Kimberly Boyd","author_inst":"University of Iowa"},{"author_name":"Nikolai O. Artemyev","author_inst":"University of Iowa"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"A designed overlapping variant immunogen pool elicits broad sarbecovirus neutralization","rel_doi":"10.64898\/2026.06.03.729821","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729821","rel_abs":"A central problem in achieving vaccine-based protection against viral infections is eliciting antibodies that are resilient to viral variation. Successive waves of SARS-CoV-2 infection during the COVID19 pandemic were driven by variants that acquired resistance to neutralizing antibodies elicited by prior SARS-CoV-2 variants. To the extent that serum neutralization breadth occurs in individuals with multiple exposures to SARS-CoV-2 antigens, we and others find that it is largely comprised of antibodies that target the variable receptor binding domain (RBD), rather than more conserved spike protein domains. By designing synthetic dimeric RBD immunogens we show that limiting divergence in heterodimeric components favors the generation of cross-reactive B cells and antibodies. We thus devised a vaccine approach based on a two-dose immunization with a pool of five overlapping heterodimeric synthetic RBD variants. Collectively, the RBD heterodimer pool was designed to cover 10% sequence variation and elicited greater antibody cross-reactivity and neutralization breadth than homodimers or heterodimers with highly divergent components. Using an unconventional prospective challenge model in mice, we demonstrate the effectiveness of the RBD heterodimer pool in inducing antibody responses that attenuate infection by future SARS-CoV-2 variants, as well as protection in a challenge model based on a chimeric vesicular stomatitis virus bearing a spike protein from SARS-CoV-1.","rel_num_authors":15,"rel_authors":[{"author_name":"Trinity Zang","author_inst":"The Rockefeller University"},{"author_name":"Viren A Baharani","author_inst":"The Rockefeller University"},{"author_name":"Miranda Aldis","author_inst":"The Rockefeller University"},{"author_name":"Marie Canis","author_inst":"The Rockefeller University"},{"author_name":"Rachel Patejak","author_inst":"The Rockefeller University"},{"author_name":"Edmund Osei Kuffour","author_inst":"The Rockefeller University"},{"author_name":"Hans Heinrich Hoffman","author_inst":"The Rockefeller University"},{"author_name":"Harm van Bakel","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Emilia M Sordillo","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Viviana Simon","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Margaret R MacDonald","author_inst":"The Rockefeller University"},{"author_name":"Charles M Rice","author_inst":"The Rockefeller University"},{"author_name":"Michel C Nussenzweig","author_inst":"The Rockefeller University"},{"author_name":"Theodora Haziionannou","author_inst":"The Rockefeller University"},{"author_name":"Paul D Bieniasz","author_inst":"The Rockefeller University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Epidemiology and phylodynamic analysis of canine distemper virus circulating in Michigan, USA","rel_doi":"10.64898\/2026.06.03.729155","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729155","rel_abs":"Canine distemper virus (CDV) is a highly contagious generalist pathogen that can cause significant mortality in domestic dogs and wild mammals. Due to the fast-evolving nature of CDV and its global spread, epizootic events and the emergence of new strains have been frequently reported. In Michigan, CDV surveillance from 2008 to 2018 was previously reported. Here, we combine and extend these data through 2023 to bring together 16 years of CDV surveillance in wild mammals in Michigan. We also sequenced CDV strains originating from both wildlife and domestic dogs to examine viral evolution across host populations. To facilitate interpretation of these data in both local and global contexts, we developed a Nextstrain workflow for CDV, enabling interactive visualization of viral evolution over time and geographic space. Our data show persistence of CDV in Michigan mammals during the study period and point to temporal, geographic, and host factors associated with CDV occurrence. Phylogenetic analysis using the newly built Nextstrain workflow showed that three CDV lineages, America-3, America-5, and Canada-1, are currently circulating in both wild and domestic animals in Michigan. The Nextstrain workflow enables reproducible, scalable integration of genomic sequencing into local surveillance and provides an updateable platform for ongoing and future surveillance efforts. This study demonstrates the value of coupling wildlife surveillance and diagnostic testing with genomic sequencing to identify lineage turnover and anticipate changes in viral behavior.","rel_num_authors":12,"rel_authors":[{"author_name":"Kota Nakasato","author_inst":"Iowa State University"},{"author_name":"Julie Melotti","author_inst":"Michigan Department of Natural Resources"},{"author_name":"Scott Fitzgerald","author_inst":"Michigan State University"},{"author_name":"Lindsy Hengesbach","author_inst":"Michigan State University"},{"author_name":"Steffanie Anderson","author_inst":"Michigan State University"},{"author_name":"Kayla Conner-Halim","author_inst":"Michigan State University"},{"author_name":"Annabel Wise","author_inst":"Michigan State University"},{"author_name":"Danielle Thompson","author_inst":"Michigan State University"},{"author_name":"Tuddow Thaiwong-Nebelung","author_inst":"Michigan State University"},{"author_name":"Kimberly Dodd","author_inst":"Michigan State University"},{"author_name":"Roger Maes","author_inst":"Michigan State University"},{"author_name":"Scott Sherrill-Mix","author_inst":"Michigan State University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Epidemiology and phylodynamic analysis of canine distemper virus circulating in Michigan, USA","rel_doi":"10.64898\/2026.06.03.729155","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729155","rel_abs":"Canine distemper virus (CDV) is a highly contagious generalist pathogen that can cause significant mortality in domestic dogs and wild mammals. Due to the fast-evolving nature of CDV and its global spread, epizootic events and the emergence of new strains have been frequently reported. In Michigan, CDV surveillance from 2008 to 2018 was previously reported. Here, we combine and extend these data through 2023 to bring together 16 years of CDV surveillance in wild mammals in Michigan. We also sequenced CDV strains originating from both wildlife and domestic dogs to examine viral evolution across host populations. To facilitate interpretation of these data in both local and global contexts, we developed a Nextstrain workflow for CDV, enabling interactive visualization of viral evolution over time and geographic space. Our data show persistence of CDV in Michigan mammals during the study period and point to temporal, geographic, and host factors associated with CDV occurrence. Phylogenetic analysis using the newly built Nextstrain workflow showed that three CDV lineages, America-3, America-5, and Canada-1, are currently circulating in both wild and domestic animals in Michigan. The Nextstrain workflow enables reproducible, scalable integration of genomic sequencing into local surveillance and provides an updateable platform for ongoing and future surveillance efforts. This study demonstrates the value of coupling wildlife surveillance and diagnostic testing with genomic sequencing to identify lineage turnover and anticipate changes in viral behavior.","rel_num_authors":12,"rel_authors":[{"author_name":"Kota Nakasato","author_inst":"Iowa State University"},{"author_name":"Julie Melotti","author_inst":"Michigan Department of Natural Resources"},{"author_name":"Scott Fitzgerald","author_inst":"Michigan State University"},{"author_name":"Lindsy Hengesbach","author_inst":"Michigan State University"},{"author_name":"Steffanie Anderson","author_inst":"Michigan State University"},{"author_name":"Kayla Conner-Halim","author_inst":"Michigan State University"},{"author_name":"Annabel Wise","author_inst":"Michigan State University"},{"author_name":"Danielle Thompson","author_inst":"Michigan State University"},{"author_name":"Tuddow Thaiwong-Nebelung","author_inst":"Michigan State University"},{"author_name":"Kimberly Dodd","author_inst":"Michigan State University"},{"author_name":"Roger Maes","author_inst":"Michigan State University"},{"author_name":"Scott Sherrill-Mix","author_inst":"Michigan State University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"No objective evidence of neuropsychological deficits in people with subjective cognitive changes following COVID-19 infection","rel_doi":"10.64898\/2026.06.03.723612","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.723612","rel_abs":"Background: Among those who develop Long COVID, many experience persistent cognitive 'brain fog'. The degree to which these subjective complaints reflect measurable neuropsychological deficits remains unclear. Prior work suggests that subjective cognitive impairment may be more closely associated with affective symptoms than objective performance. This study examines the relationship between subjective and objective cognitive function in adults with post-COVID cognitive complaints, and assesses the association between self-reported deficits and biological markers of dementia risk and inflammation. Methods: Eighty-six adults with prior COVID-19 infection (mean age 41.5 years) completed neuropsychological testing (MATRICS; CVLT-III) and self-report measures of depression and anxiety (Beck Inventories). Participants were classified as Cases (n=47) if they endorsed worsening memory or concentration since infection or Controls (n=38) if they did not. Objective cognitive impairment was defined as performance <1 SD below normative means on at least one test. APOE-e4 status and soluble CD14 (sCD14) levels were assessed. Results: Cases reported higher depression and anxiety symptoms than Controls (both p<0.001), but groups did not differ on objective cognitive performance (p=0.39). Cases were more likely to be APOE-e4 carriers (p=0.01) and had higher sCD14 levels (p=0.01). Neither marker was associated with objective performance. Conclusions: Subjective cognitive complaints following COVID-19 were not accompanied by measurable neuropsychological deficits but were linked to elevated affective symptoms and biological risk markers. Findings highlight a dissociation between perceived and objective cognition and suggest that inflammatory, genetic, and affective factors may shape self-perceived decline. Longitudinal studies are needed to determine whether these markers confer vulnerability to cognitive decline. Keywords: COVID-19; subjective cognitive decline; APOE-e4; neuropsychological assessment, depression\/anxiety, inflammation","rel_num_authors":9,"rel_authors":[{"author_name":"Samantha Abram","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Kaitlyn Dal Bon","author_inst":"Carnegie Mellon University; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Daniel H Mathalon","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Susanna L Fryer","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Sara Song","author_inst":"University of California, San Francisco"},{"author_name":"Zanib Naeem","author_inst":"Veterans Affairs San Francisco Healthcare System"},{"author_name":"Norina Tang","author_inst":"Veterans Affairs San Francisco Healthcare System"},{"author_name":"Lynn Pulliam","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Judith M Ford","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"No objective evidence of neuropsychological deficits in people with subjective cognitive changes following COVID-19 infection","rel_doi":"10.64898\/2026.06.03.723612","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.723612","rel_abs":"Background: Among those who develop Long COVID, many experience persistent cognitive 'brain fog'. The degree to which these subjective complaints reflect measurable neuropsychological deficits remains unclear. Prior work suggests that subjective cognitive impairment may be more closely associated with affective symptoms than objective performance. This study examines the relationship between subjective and objective cognitive function in adults with post-COVID cognitive complaints, and assesses the association between self-reported deficits and biological markers of dementia risk and inflammation. Methods: Eighty-six adults with prior COVID-19 infection (mean age 41.5 years) completed neuropsychological testing (MATRICS; CVLT-III) and self-report measures of depression and anxiety (Beck Inventories). Participants were classified as Cases (n=47) if they endorsed worsening memory or concentration since infection or Controls (n=38) if they did not. Objective cognitive impairment was defined as performance <1 SD below normative means on at least one test. APOE-e4 status and soluble CD14 (sCD14) levels were assessed. Results: Cases reported higher depression and anxiety symptoms than Controls (both p<0.001), but groups did not differ on objective cognitive performance (p=0.39). Cases were more likely to be APOE-e4 carriers (p=0.01) and had higher sCD14 levels (p=0.01). Neither marker was associated with objective performance. Conclusions: Subjective cognitive complaints following COVID-19 were not accompanied by measurable neuropsychological deficits but were linked to elevated affective symptoms and biological risk markers. Findings highlight a dissociation between perceived and objective cognition and suggest that inflammatory, genetic, and affective factors may shape self-perceived decline. Longitudinal studies are needed to determine whether these markers confer vulnerability to cognitive decline. Keywords: COVID-19; subjective cognitive decline; APOE-e4; neuropsychological assessment, depression\/anxiety, inflammation","rel_num_authors":9,"rel_authors":[{"author_name":"Samantha Abram","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Kaitlyn Dal Bon","author_inst":"Carnegie Mellon University; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Daniel H Mathalon","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Susanna L Fryer","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Sara Song","author_inst":"University of California, San Francisco"},{"author_name":"Zanib Naeem","author_inst":"Veterans Affairs San Francisco Healthcare System"},{"author_name":"Norina Tang","author_inst":"Veterans Affairs San Francisco Healthcare System"},{"author_name":"Lynn Pulliam","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"},{"author_name":"Judith M Ford","author_inst":"University of California, San Francisco; Veterans Affairs San Francisco Healthcare System"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Spatial Gene Set Enrichment Analysis with Applications to Spatially Resolved Transcriptomic Data","rel_doi":"10.64898\/2026.06.01.729158","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729158","rel_abs":"Spatially resolved transcriptomics enables the systematic characterization of spatial gene expression variation across tissue sections. Spatially variable genes within the same biological pathway often exhibit similar spatial expression patterns, reflecting shared biological functions and tissue organization. However, existing gene set enrichment analysis methods typically ignore this spatial dependence, which may reduce power to detect spatially organized pathways and limit the interpretability of pathway-level findings. To address this limitation, we propose spaGSE, a Bayesian hierarchical model for spatial pathway enrichment analysis that integrates gene-level summary statistics from spatial expression analysis with predefined gene set annotations. spaGSE models latent spatially variable gene signals through a Gaussian mixture framework and links spatial variation to gene set membership using logistic regression. To support robust and interpretable inference, we impose a spike-and-slab prior on the enrichment coefficient. Through simulation studies and analyses of four public SRT datasets, we show that spaGSE is scalable and achieves higher power while maintaining false positive rate control compared with existing approaches. In real-data applications, spaGSE identifies biologically relevant pathways with coordinated spatial organization across cancer and developmental tissues, demonstrating the value of incorporating spatial information into pathway-level inference for spatial transcriptomics.","rel_num_authors":4,"rel_authors":[{"author_name":"Zizhao Xie","author_inst":"Brown University"},{"author_name":"Yanghong Guo","author_inst":"The University of Texas at Dallas"},{"author_name":"Qiwei Li","author_inst":"The University of Texas at Dallas"},{"author_name":"Ying Ma","author_inst":"Brown University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Depression Severity Modulates the Cognitive Process of Facial Affect Representation: Evidence from a Genetic-Algorithm Face Synthesis Task","rel_doi":"10.64898\/2026.06.01.729421","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729421","rel_abs":"Depression is associated with biased facial emotion processing, yet existing paradigms measure only the recognition of pre-selected stimuli, conflating the process of forming an internal representation with its endpoint product. Here, we used a genetic-algorithm (GA) face synthesis task to disentangle these components. Fifty-seven undergraduates (40 Low Risk, 17 At Risk by Beck Depression Inventory-II) iteratively evolved photorealistic 3D faces to match their internal representations of 13 emotions across seven generations in a 199-dimensional face shape space. We extracted five evolutionary metrics capturing how participants constructed their representations (convergence speed, velocity, stability, range) and the structure they ultimately produced (peak intensity). At Risk participants converged on embarrassment representations significantly faster than Low Risk participants (d = 0.88, p = .001, FDR-corrected, permutation-validated), reaching their template in roughly half the number of generations. Anger representations showed greater evolutionary instability in the At Risk group (d = -0.75, p = .029, permutation-validated). Critically, endpoint face intensities did not differ between groups for any emotion. These results suggest that depression severity is associated with rigid self-conscious emotion schemas and unstable anger representations during face generation, reflecting altered cognitive processes rather than distorted perceptual products. The findings extend cognitive schema theory to the domain of facial affect representation and highlight self-conscious emotions as an underexplored locus of depression-related perceptual bias.","rel_num_authors":2,"rel_authors":[{"author_name":"Bliss Cui","author_inst":"Northeastern University"},{"author_name":"Peter  John Bex","author_inst":"Northeastern University College of Science"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Single-molecule nucleosome spacing coordinates chromatin fiber interactions","rel_doi":"10.64898\/2026.06.02.729033","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729033","rel_abs":"Nucleosome spacing influences higher-order chromatin fiber organization in vitro but how this relates to cellular chromosome structure remains contentious. To address this, we developed Ligation Analysis of Single-molecule Sequence Interactions (LASSI), a single-molecule epigenomic method that combines proximity ligation with near-nucleotide resolution, long-read adenine methyltransferase footprinting. LASSI measures nucleosome spacing patterns on interacting segments of chromatin genome-wide in cells, quantifying coupled chromosome organization in 1D and 3D. Applying LASSI to mouse embryonic stem cells (mESCs), we discover a genome-wide structural pattern we term 'fiber homotypy,' where chromatin fibers with similar nucleosome spacing patterns interact more frequently in 3D. This pattern persists over long intrachromosomal distances in cis and interchromosomally in trans. Fiber homotypy negatively scales with genomic distance, though differently than contact probability, implying distinct mechanisms. It is further promoted by topologically associated domains (TADs), A\/B compartments, and shared histone modification domains, suggesting instructive roles for each of these processes. Coarse-grain molecular dynamics simulations of chromatin fibers informed by LASSI reveal that the intrinsically heterogeneous spacing of nucleosomes along chromatin fibers in cells is a key regulator of homotypy. This variability tunes the free energy landscape of chromatin fiber interactions, promoting the compartmentalization of similar 1D chromatin structures via specific types of fiber-fiber interaction. Further linking compartmentalization and fiber homotypy, we demonstrate that loop extrusion antagonizes this phenomenon. Depletion of the cohesin subunit RAD21 in mESCs increases fiber homotypy genome-wide, while depletion of the cohesin unloader WAPL decreases fiber homotypy, consistent with effects seen on A\/B compartmentalization. Our results demonstrate that fiber-fiber interactions driven by shared nucleosome spacing patterns instruct higher-order chromosome organization. Moreover, we show clear structural interdependence across cellular chromatin length-scales, likely tuned by processes ranging from nucleosome positioning to loop extrusion.","rel_num_authors":5,"rel_authors":[{"author_name":"Kaite Zhang","author_inst":"UCSF \/ Gladstone Institutes"},{"author_name":"M. Julia Maristany","author_inst":"University of Cambridge"},{"author_name":"Jan Huertas","author_inst":"University of Cambridge"},{"author_name":"Rosana Collepardo-Guevara","author_inst":"University of Cambridge"},{"author_name":"Vijay Ramani","author_inst":"Gladstone Institutes"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Fluorescently-labeled split-QF hemidrivers: simplifying and enhancing methods enabling intersectional targeting of discrete cell types","rel_doi":"10.64898\/2026.06.01.729389","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729389","rel_abs":"Single cell transcriptomics data predict greater cell type diversity than previously appreciated, defined by combinatorial gene expression \"codes\". These codes can enable intersectional targeting strategies for selectively labeling and manipulating predicted cell types, thereby facilitating functional tests to resolve cell-specific roles and refine cell-type definitions. One such approach cleaves driver components of binary expression systems (e.g., Gal4\/UAS and QF\/QUAS) into two co-dependent halves, an Activation Domain (AD) and a DNA Binding Domain (DBD). The transcriptional activity of these \"split-drivers\" (aka, hemidrivers) is only reconstituted in cells that co-express them. While widely used in invertebrates, these systems have yet to be systematically deployed in vertebrates. Here, we developed a series of fluorescently labeled split-QF and QF2 hemidrivers via direct reporter fusions or the 2A viral peptide co-expression system. Fluorescent labeling serves to 1) simplify hemidriver transgenic line creation and maintenance, 2) allow AD and DBD intersects to be visualized directly, and 3) enable robust quality control assessments of on-target efficacy and off-target activity. These resources can enhance transgenic targeting specificity, enabling functional dissections of cell types revealed by single cell transcriptomics.","rel_num_authors":11,"rel_authors":[{"author_name":"Lydia G Sanders","author_inst":"Johns Hopkins University"},{"author_name":"Grant Kroeschell","author_inst":"Johns Hopkins University"},{"author_name":"Anneliese Ceisel","author_inst":"Johns Hopkins University"},{"author_name":"Caroline E Clouatre","author_inst":"Johns Hopkins University"},{"author_name":"Yiqi Gao","author_inst":"Johns Hopkins University"},{"author_name":"Gianna Graziano","author_inst":"Johns Hopkins University"},{"author_name":"Diego Alfaro Carcoba","author_inst":"Johns Hopkins University"},{"author_name":"Claire Deng","author_inst":"Johns Hopkins University"},{"author_name":"Catalina Rodriguez","author_inst":"Johns Hopkins University"},{"author_name":"James H Thierer","author_inst":"Johns Hopkins University"},{"author_name":"Jeff S Mumm","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Aggregation of misfolded proteins in the sperm head impairs preimplantation embryo development","rel_doi":"10.64898\/2026.06.01.728900","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.728900","rel_abs":"Paternal contributions to embryogenesis extend beyond DNA, yet the molecular cargo carried by sperm and its impact on development remain poorly defined. Aggresomes (AGG), cytoplasmic inclusions formed by misfolded proteins, are present in mammalian gametes, but their functional consequences are unclear. Here, we show that excessive AGG content in bovine sperm head compromises preimplantation embryo development. Using image-based flow cytometry, sperm from 32 sires were classified into low-, moderate-, and high-AGG groups. AGG levels were unrelated to sire age and did not affect in vitro capacitation or acrosome remodeling. However, embryos derived from high-AGG sires exhibited reduced blastocyst formation, delayed cleavage timing, and a higher incidence of developmental arrest at the 4-6 cell stage. Embryos from high-AGG sires also accumulated more AGG during development, showed elevated reactive oxygen species (ROS) levels, and displayed altered mitophagy dynamics. Supplementation with an ER stress inhibitor temporarily improved cleavage but did not enhance overall blastocyst formation, indicating a limited and stage-specific effect. In vivo, embryos from high-AGG sires showed lower transferable quality compared with those from low-AGG sires. These findings establish sperm head AGG content as a novel paternal determinant of embryo quality. By linking sperm-borne misfolded protein aggregates to disrupted developmental pathways in the resulting embryo, our study reveals a previously unrecognized mechanism of paternal influence on fertility and suggests new opportunities for molecular screening for male fertility.","rel_num_authors":10,"rel_authors":[{"author_name":"Everardo Anta","author_inst":"University of Wisconsin-Madison"},{"author_name":"Froylan Sosa","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jessica Drum","author_inst":"South Dakota State University"},{"author_name":"Kelsey Lockhart","author_inst":"University of Missouri"},{"author_name":"Katy McDonald","author_inst":"University of Missouri"},{"author_name":"Lindsey Fallon","author_inst":"University of Missouri"},{"author_name":"Emma Keller","author_inst":"Iowa State University"},{"author_name":"Alexandra Else-Keller","author_inst":"Iowa State University"},{"author_name":"Karl Kerns","author_inst":"Iowa State University"},{"author_name":"M.Sofia Ortega","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Predicting P-glycoprotein Substrate Status Using a Pretrained Graph Neural Network: A TDC Benchmark Study","rel_doi":"10.64898\/2026.06.01.729343","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729343","rel_abs":"P-glycoprotein (Pgp\/ABCB1) is a critical efflux transporter that significantly impacts drug bioavailability and multidrug resistance. Accurate prediction of Pgp substrate status is essential for early-stage drug discovery. In this study, we evaluate a pretrained Graph Isomorphism Network (GIN) with attribute masking on the Pgp_Broccatelli benchmark from the Therapeutics Data Commons (TDC). Our approach fine-tunes a GIN encoder pretrained on approximately 2 million molecules using a self-supervised attribute masking strategy, followed by a multilayer perceptron (MLP) classification head. On the TDC benchmark, our model achieves an AUROC of 0.937 +\/- 0.004 across five independent runs, ranking second on the leaderboard, as of May 2026. We further compare this approach against an XGBoost baseline using Morgan fingerprints (AUROC 0.912 +\/- 0.007), demonstrating the advantage of graph-based molecular representations with transfer learning for small-dataset ADMET prediction tasks.","rel_num_authors":2,"rel_authors":[{"author_name":"Jingjing Yan","author_inst":"QuantisMol LLC"},{"author_name":"Weicong Duan","author_inst":"College of Computing, Georgia Institute of Technology"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Progressive matrix stiffening of tyramine-modified silk fibroin hydrogels governs stage-specific pulmonary fibroblast activation","rel_doi":"10.64898\/2026.06.01.729382","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729382","rel_abs":"Fibrosis is a progressive and often fatal pathological process characterized by excessive extracellular matrix deposition, tissue stiffening, and irreversible organ dysfunction. Effective antifibrotic therapies remain limited by the lack of in vitro models that recapitulate the full spectrum of fibrotic disease progression. Here, we leverage tyramine-modified silk fibroin (SF-TA) hydrogels to investigate normal human lung fibroblasts (NHLF) responses to progressively stiffening environments relevant to pulmonary fibrosis. Two hydrogel formulations with distinct stiffening profiles over 14 days were prepared: a gradual-stiffening 0% SF-TA formulation reaching ~20 kPa, and a rapidly stiffening 50% SF-TA formulation reaching ~60 kPa. NHLFs were cultured on both formulations, with and without TGF{beta} (5 ng\/mL), for 14 days and assessed for viability, metabolic activity, cytokine and collagen secretion, cytoskeletal organization, and mechanotransductive gene expression. The 0% SF-TA hydrogels drove sustained fibroblast proliferation and elevated secretion of IL-6, IL-8, and MCP-1, consistent with early inflammatory fibrosis. The 50% SF-TA hydrogels induced a metabolic plateau without senescence, suppressed inflammatory cytokine secretion, and, in the presence of TGF{beta}, led to significant upregulation of ACTA2 and CTGF, alongside -SMA stress fiber incorporation, consistent with established myofibroblast persistence. Both conditions produced comparable secreted collagen output by day 14. Together, these findings establish dynamically stiffening SF-TA hydrogels as a tunable platform for investigating stage-dependent fibroblast activation and mechanobiological progression in fibrosis.","rel_num_authors":13,"rel_authors":[{"author_name":"Mariah L. Arral","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Maria Savvidou","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Adam S. Mullis","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Aria Z. Yang","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Thomas Falcucci","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Julie Leonard-Duke","author_inst":"Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA"},{"author_name":"Pamela L. Graney","author_inst":"Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA"},{"author_name":"Sabrina Madiedo-Podvrsan","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Sanjana Gopalakrishnan","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Jugal Kishore Sahoo","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Jing-Jie Huang","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"},{"author_name":"Gordana Vunjak-Novakovic","author_inst":"Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA"},{"author_name":"David L. Kaplan","author_inst":"Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Cyclin C nuclear release and mitochondrial dysfunction define molecular signatures of MED13L Syndrome","rel_doi":"10.64898\/2026.06.01.729270","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729270","rel_abs":"The Mediator Kinase Module (MKM) coordinates transcriptional programs regulating cellular metabolism, stress responses, and differentiation. Heterozygous variants of MED13L, a core MKM component, cause a neurodevelopmental disorder characterized by variable intellectual disability, developmental delay, neuromuscular dysfunction, and congenital anomalies. However, the molecular basis underlying this clinical heterogeneity is poorly defined. Previously, we identified mitochondrial dysfunction and aberrant nuclear release of another MKM component, cyclin C (CCNC), in a single MED13L syndrome patient-derived fibroblast line. Here, we expand these studies across 12 patient-derived fibroblasts harboring 11 distinct MED13L variants. We identify mitochondrial dysfunction as a consistent feature of MED13L variation, characterized by reduced mitochondrial ATP production, decreased mitochondrial DNA abundance, elevated reactive oxygen species, and impaired transcription of genes involved in mitochondrial biogenesis. In parallel, all variant lines exhibit aberrant cytoplasmic CCNC localization, consistent with its established role in mitochondrial fission. Longitudinal analyses further reveal progressive declines in mitochondrial function associated with premature cellular aging, consistent with increased metabolic deficits. Importantly, the severity of mitochondrial dysfunction shows an association with variant position within MED13L and with clinical functional measures, suggesting that mutation location may partially predict disease severity. Together, these findings establish mitochondrial dysfunction as a consistent cellular feature of MED13L heterozygosity and identify CCNC mis-localization as a candidate biomarker of MKM disruption. More broadly, this work reveals an intersection between transcriptional control and mitochondrial homeostasis in MED13L syndrome, forming the framework for biomarker-driven therapeutic development in MED13L-associated and related neurodevelopmental disorders.","rel_num_authors":9,"rel_authors":[{"author_name":"Alicia N Campbell","author_inst":"Rowan Virtua Health College of Medicine and Life Sciences"},{"author_name":"Kendall N Jung","author_inst":"Rowan Virtua Health College of Medicine and Life Sciences"},{"author_name":"Steven J Doyle","author_inst":"Cooper Hospital University Medical Center: Cooper University Health Care"},{"author_name":"Ekaterina Lebayle","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Barbara Corneo","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Joanna Feng","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Christopher L Ricupero","author_inst":"Columbia University Irving Medical Center; College of Dental Medicine"},{"author_name":"Jennifer M Bain","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Randy Strich","author_inst":"Rowan Virtua Health College of Medicine and Life Sciences"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"MicroRNA-21 restrains myD88-dependent protective inflammation worsening Staphylococcus aureus skin infection","rel_doi":"10.64898\/2026.06.01.729375","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729375","rel_abs":"Staphylococcus aureus skin infections are driven by tissue-resident and recruited immune cells. A proper immune response requires a tightly regulated balance between inflammatory responses and the prevention of tissue damage. MicroRNAs are key post-transcriptional regulators of immune responses and influence both pro- and anti-inflammatory pathways. We show that S. aureus skin infection elevates miR-21 levels in the skin, and applying a topical miR-21 antagomir improves bacterial clearance and resolution of skin infection. In MRSA-infected mice lacking miR-21 in myeloid cells (miR21{triangleup}myel), lesions are smaller, bacterial load decreases, macrophage infiltration is reduced, and collagen around the abscess increases. MiR-21 helps shape the inflammatory environment by modulating mediators such as IL-1{beta}, TNF, IL-33, and IL-10. Additionally, miR-21 deficiency increases MyD88 expression in infected skin, and blocking MyD88 actions abolishes the protective effects observed in miR21{triangleup}myel mice. Overall, the miR-21\/MyD88 pathway is a key regulator of the resolution of inflammation and antibacterial immunity during S. aureus skin infections, highlighting miR-21 inhibition as a promising therapy for antibiotic-resistant S. aureus infections.","rel_num_authors":4,"rel_authors":[{"author_name":"Ana Carolina Guerta Salina","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amondrea Blackman","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alexandra Medeiros","author_inst":"UNESP"},{"author_name":"Carlos Serezani","author_inst":"VUMC"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Profiling the CFTR Variant Selectivity and Off-Target Interactions of VX-121","rel_doi":"10.64898\/2026.06.01.729306","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729306","rel_abs":"More than 1,200 variants of the cystic fibrosis transmembrane conductance regulator gene (CFTR) are associated with cystic fibrosis (CF), an autosomal recessive pulmonary disease affecting over 100,000 people. Most people with CF bear a common CFTR variant (F508del) that can be treated with therapeutics containing correctors that suppress the misfolding of the CFTR chloride channel. However, the pharmacological responsiveness of other rare CF variants can vary tremendously. The approval of VX-121, a VX-445 analog that serves as a key component of Alyftrek, potentially provides a new therapeutic option for those with rare CF variants. Nevertheless, it remains unclear whether VX-121 offers superior rescue across the entire spectrum of rare CF variants. In this work, we use deep mutational scanning (DMS) to survey the impact of VX-121 on the plasma membrane expression of 232 rare CF variants. Our results show that VX-121 generally enhances CF variant expression more than VX-445 and is most potent towards variants with mutations in the first membrane spanning domain (MSD1). However, we identify one variant (Y1032C) with diminished proteostatic and functional selectivity for VX-121 relative to VX-445. Computational docking suggests that the native Y1032 side chain forms favorable interactions with VX-121 that are disrupted by this mutation in a manner that alters its coordination. Finally, using photo-crosslinking, we show that VX-121 avoids a key off-target interaction of VX-445. Together, our findings provide new insights into the similarities and differences between current approved CF therapeutics.","rel_num_authors":18,"rel_authors":[{"author_name":"Ashish Rajesh Jhangiani","author_inst":"Purdue University"},{"author_name":"John A Olson III","author_inst":"Vanderbilt University"},{"author_name":"Austin Tedman","author_inst":"Purdue University"},{"author_name":"Catherine Foye","author_inst":"Emory University"},{"author_name":"JaNise J Jackson","author_inst":"Emory University"},{"author_name":"Ashlyn G Winters","author_inst":"Emory University"},{"author_name":"Janiyah A White","author_inst":"Emory University"},{"author_name":"Mia Perfetti","author_inst":"Vanderbilt University"},{"author_name":"Grace M Abell","author_inst":"Vanderbilt University"},{"author_name":"Crissey D Cameron","author_inst":"Vanderbilt University"},{"author_name":"Liudmyla Arifova","author_inst":"Vanderbilt University"},{"author_name":"Brianna Corman","author_inst":"Purdue University"},{"author_name":"J. Paul Robinson","author_inst":"Purdue University"},{"author_name":"Kaitlyn Ledwitch","author_inst":"Vanderbilt University"},{"author_name":"Jens Meiler","author_inst":"Vanderbilt University"},{"author_name":"Kathryn E Oliver","author_inst":"Emory University School of Medicine"},{"author_name":"Lars Plate","author_inst":"Vanderbilt University"},{"author_name":"Jonathan P Schlebach","author_inst":"Purdue University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Cross-linked volumetric DNA microscopy for dense molecular-network phenotyping in intact tissue","rel_doi":"10.64898\/2026.06.01.729154","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729154","rel_abs":"Resolving cellular phenotypes in full tissue context requires methods that can retain those cells' physical neighborhoods, together with the identities of individual biomolecules, in intact three-dimensional specimens. We introduce cross-linked volumetric DNA microscopy (xVDM), in which unique molecular identifiers are seeded directly into the tissue's protein matrix and linked by uniquely labeled DNA bridges to create a dense, DNA-encoded proximity network. Cell-scale molecular communities are then reconstructed directly from this network. xVDM produces denser molecular networks and broader transcriptome recovery than when these networks are nucleated by transcripts alone. xVDM maps out genetically annotated three-dimensional networks that map onto cell states and tissue regions in intact zebrafish embryos at 12, 18, and 24~hpf. Antibody-oligonucleotide conjugates extend the same framework to protein targets in human tonsil. xVDM provides a route to three-dimensional molecular phenotyping in intact specimens using only standard bench reagents and a DNA sequencer.","rel_num_authors":5,"rel_authors":[{"author_name":"Nianchao Qian","author_inst":"University of Chicago"},{"author_name":"Reem Yasser","author_inst":"University of Chicago"},{"author_name":"Mingrui Yu","author_inst":"University of Chicago"},{"author_name":"Han Chang","author_inst":"University of Chicago"},{"author_name":"Joshua A Weinstein","author_inst":"University of Chicago"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"A growth-maintenance tradeoff determines nutrient-limited growth in phytoplankton","rel_doi":"10.64898\/2026.06.01.729340","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729340","rel_abs":"Phytoplankton encounter a range of light and nutrient conditions in nature and must adjust their internal carbon and nitrogen allocations to grow across different resource environments. Current phytoplankton carbon budget models treat respiration simply as a carbon loss. In reality, respiration is a critical cellular process that produces energy for nutrient uptake and cellular maintenance. Drawing on empirical evidence, we developed an eco-physiological model that incorporates a more realistic role of respiration. In our model, photosynthetic carbon is partitioned into: (i) the Pentose Phosphate Pathway (PPP) for assimilation and (ii) respiration for energy production that is then used in nutrient uptake. Stored nitrogen is partitioned between three pools: cellular structure, photosynthesis and nutrient uptake. Using an optimality-based approach, we identify strategies that maximize either exponential growth rate or competitive ability. We find that optimal internal allocations follow a growth-maintenance tradeoff, favoring population growth through carbon acquisition in nitrogen-replete conditions and population maintenance through nitrogen acquisition in nitrogen-limited conditions. The optimal allocations match empirically observed shifts in carbon partitioning at different dilution rates. Our model also generates an interactive growth response surface with an asymmetry, where light is the dominant limiting factor at low light intensities and co-limitation by light and nitrogen only occurs at high light levels. Furthermore, the model recovers the widely accepted Droop function for growth vs nitrogen quota and predicts a hyperbolic decline in growth vs energy quotas. Through a simple growth-maintenance tradeoff, our model provides a mechanistic foundation for predicting phytoplankton productivity in biogeochemical models.","rel_num_authors":6,"rel_authors":[{"author_name":"Ravi Ranjan","author_inst":"University of Texas at Austin, Texas, USA"},{"author_name":"Alexey Ryabov","author_inst":"University of Oldenburg"},{"author_name":"Kimberly Halsey","author_inst":"Oregon State University"},{"author_name":"Helmut Hillebrand","author_inst":"University of Oldenburg"},{"author_name":"Mridul K. Thomas","author_inst":"University of Geneva"},{"author_name":"Bernd Blasius","author_inst":"University of Oldenburg"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"A comparative analysis of promoter-proximal pausing reveals kinetic and distributional dimensions of variation","rel_doi":"10.64898\/2026.06.01.729264","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729264","rel_abs":"Promoter-proximal pausing of RNA polymerase II is a key regulatory checkpoint in metazoan transcription. Despite extensive study of this process, quantitative methods for comparing pausing dynamics across biological contexts have been lacking. Here we introduce a model-based framework for rigorous comparative analysis of both pause-escape kinetics and pause-site distributions across genes, cell types, and species. An application to available PRO-seq datasets revealed striking differences across perturbations, and comparative analyses across cell types and species highlighted distinct patterns of variation in both pause-escape kinetics and pause-site distributions, with only weak coupling between them. Integration with chromatin and sequence features showed that lower pause-escape rates are associated with stronger promoter-proximal nucleosome occupancy, whereas changes in pause-site dispersion are associated with sequence features such as GC skew. Together, these results establish a quantitative framework for comparative analysis of promoter-proximal pausing and reveal kinetic and distributional dimensions of pausing variation across biological contexts.","rel_num_authors":7,"rel_authors":[{"author_name":"Xin Zeng","author_inst":"Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA"},{"author_name":"Gilad Barshad","author_inst":"Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA"},{"author_name":"Rebecca Hassett","author_inst":"Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA"},{"author_name":"Edward J Rice","author_inst":"Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA"},{"author_name":"Charles G Danko","author_inst":"Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA"},{"author_name":"Adam Siepel","author_inst":"Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA"},{"author_name":"Yixin Zhao","author_inst":"Yazhouwan National Laboratory, Sanya, Hainan 572025, China"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Dorsal striatal circuit mechanisms contributing to astrocyte modulation of alcohol-related behaviors","rel_doi":"10.64898\/2026.06.01.729412","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729412","rel_abs":"Background: The dorsolateral striatum (DLS) is a key site for coordinating the alcohol-induced stimulant response, a behavioral marker predictive of future alcohol use disorder. Although ethanol (EtOH) affects all brain cells, little is known about the contribution of non-neuronal DLS cell types to EtOH-induced stimulation. Methods: We used ex vivo two photon calcium imaging, in vivo fiber photometry of astrocyte and neuronal GCaMP, and astrocyte-specific manipulations in mice to determine DLS astrocyte contributions to EtOH-induced stimulation and voluntary EtOH drinking behavior. Using fiber photometry of GRAB-ACh sensors and cell-type specific chemogenetics, we also assessed the role of cholinergic signaling in observed astrocyte EtOH effects. Results: As expected, intraperitoneal EtOH injections (0.5-2g\/kg) evoked a stimulant response, evidenced by increased locomotion compared to saline. In parallel, EtOH dose-dependently decreased astrocyte calcium activity but had minimal effects on direct and indirect pathway neuronal activity. Mimicking this reduction with astrocyte-specific expression of CalEX, a calcium extruding pump, facilitated EtOH stimulation compared to mice expressing a control fluorophore. Hence, EtOH-induced suppression of DLS astrocyte activity contributes to stimulation. Astrocyte calcium signaling is a well-known target of neuromodulation. Fiber photometry recordings of extracellular acetylcholine (ACh) levels via GRAB-ACh imaging showed inhibition of ACh release by acute EtOH. We virally expressed the excitatory chemogenetic actuator hM3Dq in striatal cholinergic interneurons to assess whether artificially increasing ACh release blocks EtOH-induced inhibition of astrocytic calcium activity. Despite facilitating ACh release, this manipulation did not impact astrocyte calcium activity under control (saline) or EtOH conditions. Together, this work identifies DLS astrocytes as key contributors to EtOH-induced stimulation and highlights the importance of considering astrocyte-neuron interactions in evaluating alcohol effects.","rel_num_authors":11,"rel_authors":[{"author_name":"Cherish Ardinger","author_inst":"Rutgers University"},{"author_name":"Anagha Kalelkar","author_inst":"Rutgers University"},{"author_name":"Maxwell Madden","author_inst":"Rutgers University"},{"author_name":"Ananya Gunda","author_inst":"Rutgers University"},{"author_name":"Arnav Patel","author_inst":"Rutgers University"},{"author_name":"George Xanthos","author_inst":"Rutgers University"},{"author_name":"Mariam Mahboob","author_inst":"Rutgers Health New Jersey Medical School"},{"author_name":"Ali Khawaja","author_inst":"Rutgers Health New Jersey Medical School"},{"author_name":"Nancy Collie-Beard","author_inst":"Rutgers University"},{"author_name":"Miriam Bocarsly","author_inst":"Rutgers University"},{"author_name":"Rafiq Huda","author_inst":"Rutgers University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Dorsal striatal circuit mechanisms contributing to astrocyte modulation of alcohol-related behaviors","rel_doi":"10.64898\/2026.06.01.729412","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729412","rel_abs":"Background: The dorsolateral striatum (DLS) is a key site for coordinating the alcohol-induced stimulant response, a behavioral marker predictive of future alcohol use disorder. Although ethanol (EtOH) affects all brain cells, little is known about the contribution of non-neuronal DLS cell types to EtOH-induced stimulation. Methods: We used ex vivo two photon calcium imaging, in vivo fiber photometry of astrocyte and neuronal GCaMP, and astrocyte-specific manipulations in mice to determine DLS astrocyte contributions to EtOH-induced stimulation and voluntary EtOH drinking behavior. Using fiber photometry of GRAB-ACh sensors and cell-type specific chemogenetics, we also assessed the role of cholinergic signaling in observed astrocyte EtOH effects. Results: As expected, intraperitoneal EtOH injections (0.5-2g\/kg) evoked a stimulant response, evidenced by increased locomotion compared to saline. In parallel, EtOH dose-dependently decreased astrocyte calcium activity but had minimal effects on direct and indirect pathway neuronal activity. Mimicking this reduction with astrocyte-specific expression of CalEX, a calcium extruding pump, facilitated EtOH stimulation compared to mice expressing a control fluorophore. Hence, EtOH-induced suppression of DLS astrocyte activity contributes to stimulation. Astrocyte calcium signaling is a well-known target of neuromodulation. Fiber photometry recordings of extracellular acetylcholine (ACh) levels via GRAB-ACh imaging showed inhibition of ACh release by acute EtOH. We virally expressed the excitatory chemogenetic actuator hM3Dq in striatal cholinergic interneurons to assess whether artificially increasing ACh release blocks EtOH-induced inhibition of astrocytic calcium activity. Despite facilitating ACh release, this manipulation did not impact astrocyte calcium activity under control (saline) or EtOH conditions. Together, this work identifies DLS astrocytes as key contributors to EtOH-induced stimulation and highlights the importance of considering astrocyte-neuron interactions in evaluating alcohol effects.","rel_num_authors":11,"rel_authors":[{"author_name":"Cherish Ardinger","author_inst":"Rutgers University"},{"author_name":"Anagha Kalelkar","author_inst":"Rutgers University"},{"author_name":"Maxwell Madden","author_inst":"Rutgers University"},{"author_name":"Ananya Gunda","author_inst":"Rutgers University"},{"author_name":"Arnav Patel","author_inst":"Rutgers University"},{"author_name":"George Xanthos","author_inst":"Rutgers University"},{"author_name":"Mariam Mahboob","author_inst":"Rutgers Health New Jersey Medical School"},{"author_name":"Ali Khawaja","author_inst":"Rutgers Health New Jersey Medical School"},{"author_name":"Nancy Collie-Beard","author_inst":"Rutgers University"},{"author_name":"Miriam Bocarsly","author_inst":"Rutgers University"},{"author_name":"Rafiq Huda","author_inst":"Rutgers University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Learning residue-level context for modeling protein-protein interactions","rel_doi":"10.64898\/2026.06.01.729118","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729118","rel_abs":"Protein language models (PLMs) enable prediction of protein properties by learning residue-level features from sequence, yet most PLM-based approaches to protein-protein interactions aggregate information across entire proteins, limiting resolution and interpretability. Here we present ReCLIP, a transformer-based framework that learns interaction-specific representations at the level of individual residues by combining intra-protein residue neighborhoods with residue-conditioned representations of interaction partners. We show that residue-centered context provides a general framework for modeling protein interactions across diverse biological settings. ReCLIP accurately predicts mutation-induced perturbations (AUROC = 0.973), generalizes to post-translational modifications that do not alter sequence (AUROC = 0.822), and enables zero-shot prediction of peptide-MHC binding across unseen alleles (AUROC up to 0.972). Analysis of learned residue neighborhoods reveals structurally and functionally coherent patterns aligned with known determinants of binding. Applied to clinically annotated genetic variants, ReCLIP identifies disease-associated interaction perturbations that link pathogenic variants to specific molecular interaction contexts. Our results establish a generalizable and interpretable framework for modeling protein interactions and provide insights into how residue-level context shapes interaction specificity and its perturbation.","rel_num_authors":8,"rel_authors":[{"author_name":"Zechuan Zhang","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Zongxin Yang","author_inst":"Harvard Medical School"},{"author_name":"Anbang Liu","author_inst":"Northwestern University"},{"author_name":"Kun-Hsing Yu","author_inst":"Harvard Medical School"},{"author_name":"Junhan Zhao","author_inst":"University of Chicago"},{"author_name":"Yi Yang","author_inst":"Zhejiang University"},{"author_name":"Benjamin Neale","author_inst":"Massachusetts General Hospital"},{"author_name":"Siwei Chen","author_inst":"University of Chicago"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"On the Distribution of Free-Energy in Metabolism","rel_doi":"10.64898\/2026.06.01.729314","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729314","rel_abs":"Chemical potential is coupled to cellular processes by the flow of metabolites through catalytic networks known collectively as metabolism. Here we describe an extensive new class of energy-coupling catalysts that act to interconnect metabolic network pathways and their potentials. Members of the class are defined by a common mechanism -- half-site reactivity. The well-established sequential subunit turnover of half-site enzymes suggests that the potentials of reactions occurring at the separate subunits are coupled to one another. Here this hypothesis is tested and validated using promiscuous half-site enzymes from two catalytically distinct enzyme families, each with broad metabolic penetrance. Fundamental catalytic parameters (Vmax and Km) and reaction endpoints are predicted and shown to change dramatically when reaction potentials are coupled -- for example, the catalytic efficiency (Vmax\/Km) and endpoint of the retinol oxidation reaction (the rate-limiting step in vitamin A synthesis) are shown to increase 900- and 3,400-fold, respectively, when the reaction is coupled to the more favorable oxidation of ethanol. For the first time it is clear that metabolism has the flexibility to react to changes in the metabolic state of the cell by redistributing chemical potential among the many metabolic pathways interconnected by half-site enzymes..","rel_num_authors":2,"rel_authors":[{"author_name":"Ian T Cook","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Thomas S Leyh","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Invasion history reconstruction and potential distribution of the ambrosia beetles Euwallacea fornicatus and E. perbrevis (Coleoptera: Scolytinae), two global emerging pests","rel_doi":"10.64898\/2026.06.01.727051","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.727051","rel_abs":"The global spread of invasive insects poses serious ecological and economic threats to forest ecosystems. Euwallacea fornicatus and E. perbrevis are cryptic ambrosia beetles native to Southeast Asia that have invaded multiple regions worldwide, damaging diverse woody hosts through gallery formation and fungal symbiont inoculation. We compiled confirmed and novel occurrence records to describe their global distributions, reconstruct invasion histories and likely origins using mitochondrial COI phylogenies, and compare their potential distributions through models based on bioclimatic variables. Euwallacea fornicatus has expanded rapidly over the past decades, establishing in North America (2003), Israel (2009), South Africa (2016), South America (2020), Australia (2021), Europe (2022) and Turkey (2024). In contrast, E. perbrevis has an earlier but slower invasion history, with establishments in Hawaii (1918), Central America (1979), Oceania (1982), and North America (2004). Phylogenetic analyses revealed at least six independent introductions for each species. Euwallacea fornicatus primarily originated from native populations in China, Taiwan and Vietnam, whereas E. perbrevis from Indonesia and Thailand, with additional introductions from unknown sources. Secondary spread from invaded regions is also likely. Distribution models indicated distinct climatic niches. Euwallacea fornicatus tolerates broader thermal ranges and drier conditions, enabling establishment from subtropical to temperate regions, whereas E. perbrevis appears restricted to tropical climates. Only 32% of predicted suitable habitat overlapped, indicating low coexistence potential. The broader climatic tolerance and faster recent spread of E. fornicatus highlights a higher invasion risk and greater management challenges. These findings provide key insights to strengthen biosecurity strategies aimed at preventing further spread.","rel_num_authors":6,"rel_authors":[{"author_name":"Maria Victoria Lantschner","author_inst":"Grupo de Ecologia de Poblaciones de Insectos, Instituto de Investigaciones Forestales y Agropecuarias Bariloche, INTA EEA Bariloche - CONICET, Bariloche, Rio Ne"},{"author_name":"Esteban Ceriani-Nakamurakare","author_inst":"INMIBO-CONICET-UBA, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Lab. de Micologia y Fitopatologia, Argentina."},{"author_name":"Andrew J Johnson","author_inst":"School of Forest, Fisheries, and Geomatics Sciences, University of Florida, and, Florida State Collection of Arthropods, FDACS-DPI, Gainesville, Florida, 32611,"},{"author_name":"Anthony I Cognato","author_inst":"Department of Entomology, Michigan State University, 288 Farm Ln, East Lansing, MI 48824, United States of America."},{"author_name":"Sarah M Smith","author_inst":"Department of Entomology, Michigan State University, 288 Farm Ln, East Lansing, MI 48824, United States of America."},{"author_name":"Demian F Gomez","author_inst":"Texas A&M Forest Service, Austin, Texas, United States of America."}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"One Circuit, Many Flow Fields: Mechanistic Models of Single-Trial Neural Dynamics","rel_doi":"10.64898\/2026.06.01.729208","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729208","rel_abs":"A single neural circuit can exhibit qualitatively different dynamics across trials: one circuit, many flow fields. Standard models treat this trial-to-trial variability as noise around a fixed dynamical system or as discrete switches between regimes, yet neither captures how continuous internal-state variables, such as arousal or engagement, can gradually deform the circuit's flow field. We propose that single-trial fitting can be reframed as inferring the low-dimensional control parameters that reshape a shared circuit's flow field. We realize this with a low-rank recurrent network in which trial-specific static input biases act as bifurcation parameters: constant within a trial, they deform the flow field without directly driving activity over time. In a teacher-student setting, the model recovers the underlying dynamical system and its bifurcation structure from activity alone. Applied to large-scale recordings of mouse motor cortex during a delayed movement task, the model identifies a disengagement axis that separates engaged from disengaged trials and, when perturbed in silico, causally shifts the flow field between engaged and disengaged regimes. A generative extension reproduces the distribution of single-trial activity, and the inferred latent structure partially transfers across sessions and animals, suggesting shared low-dimensional structure across motor-cortical circuits. Together, these results reframe a methodological problem of fitting single-trial activity as a scientific opportunity: reading off the control parameters of the underlying dynamics, and connecting data-driven inference of neural dynamics to mechanistic theories of how a single circuit reuses its dynamics for flexible behavior.","rel_num_authors":4,"rel_authors":[{"author_name":"Shani Kaminitz","author_inst":"Tel Aviv University"},{"author_name":"Mussi Levin","author_inst":"Tel Aviv University"},{"author_name":"Ulises Pereira-Obilinovic","author_inst":"Allen Institute"},{"author_name":"Ran Darshan","author_inst":"Tel Aviv University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling","rel_doi":"10.64898\/2026.05.30.724257","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.724257","rel_abs":"Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERB. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPAR. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.","rel_num_authors":55,"rel_authors":[{"author_name":"Iuliia Karavaeva","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Astrid Linde Basse","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Samuel A. J. Trammell","author_inst":"Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DK"},{"author_name":"Mohammed Faiz Hussain","author_inst":"Department of Biochemistry, Goodman Cancer Research Centre, McGill University Montreal, Quebec, CA"},{"author_name":"Lasse Kruse Markussen","author_inst":"Functional Genomics & Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK"},{"author_name":"Jesper F. Havelund","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK"},{"author_name":"Marie Sophie Isidor","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Hannah J. Richter","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Endocrinology, Diabe"},{"author_name":"Zafir Kaiser","author_inst":"Department of Biochemistry, Goodman Cancer Research Centre, McGill University Montreal, Quebec, CA"},{"author_name":"Yann Deleye","author_inst":"Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Divisions of Endocrinology and Cardiol"},{"author_name":"Sabina Chubanava","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Yachen Shen","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Pathology and Labo"},{"author_name":"Ditte Neess","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK"},{"author_name":"Frederike Sass","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Fabian Finger","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Lidia Argemi-Muntadas","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"David Tandio","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Tao Ma","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Elahu Gosney Sustarsic","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Hannes Embring","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Cecilie Kynding Kristensen","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Rebecca L. McIntyre","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Genesee J. Martinez","author_inst":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA"},{"author_name":"Anna Sofie Husted","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Matthew J. Emmett","author_inst":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Broa"},{"author_name":"Zachary A. Kipp","author_inst":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA"},{"author_name":"Mikkel Frost","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Mark P. Jedrychowski","author_inst":"Department of Cell Biology, Harvard Medical School, Boston, MA, USA"},{"author_name":"Michel van Weeghel","author_inst":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism; Amsterdam UMC, University of Amsterdam, Amsterdam, NL"},{"author_name":"Homa Majd","author_inst":"Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK"},{"author_name":"Ekaterina Zhuravleva","author_inst":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK"},{"author_name":"Robert W. McGarrah","author_inst":"Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA"},{"author_name":"Kaja Plucinska","author_inst":"Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA"},{"author_name":"Mohit K. Midha","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Endocrinology, Diabe"},{"author_name":"Andreas Prokesch","author_inst":"Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz,"},{"author_name":"Paul Cohen","author_inst":"Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA"},{"author_name":"James G. Granneman","author_inst":"Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA"},{"author_name":"Patrick Seale","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"},{"author_name":"Riekelt H. Houtkooper","author_inst":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism; Amsterdam UMC, University of Amsterdam, Amsterdam, NL"},{"author_name":"Jacob B. Hansen","author_inst":"Department of Biology, University of Copenhagen, Copenhagen, DK"},{"author_name":"Steven P. Gygi","author_inst":"Department of Cell Biology, Harvard Medical School, Boston, MA, USA"},{"author_name":"Thue W. Schwartz","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Matthew Paul Gillum","author_inst":"Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DK"},{"author_name":"Terry D. Hinds Jr.","author_inst":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA"},{"author_name":"Raymond Edward Soccio","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"},{"author_name":"Phillip J. White","author_inst":"Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Divisions of Endocrinology and Cardiol"},{"author_name":"Edmund R. S. Kunji","author_inst":"Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK"},{"author_name":"Thomas Moritz","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Jonas T. Treebak","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Susanne Mandrup","author_inst":"Center for Adipocyte Signaling (ADIPOSIGN), University of Southern Denmark, Odense, DK"},{"author_name":"Brice Emanuelli","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Lawrence Kazak","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK"},{"author_name":"Nils J. Faergeman","author_inst":"Department of Biochemistry, Goodman Cancer Research Centre, McGill University Montreal, Quebec, CA"},{"author_name":"Mitchell A. Lazar","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Endocrinology, Diabe"},{"author_name":"Zachary Gerhart-Hines","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling","rel_doi":"10.64898\/2026.05.30.724257","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.724257","rel_abs":"Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERB. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPAR. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.","rel_num_authors":55,"rel_authors":[{"author_name":"Iuliia Karavaeva","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Astrid Linde Basse","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Samuel A. J. Trammell","author_inst":"Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DK"},{"author_name":"Mohammed Faiz Hussain","author_inst":"Department of Biochemistry, Goodman Cancer Research Centre, McGill University Montreal, Quebec, CA"},{"author_name":"Lasse Kruse Markussen","author_inst":"Functional Genomics & Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK"},{"author_name":"Jesper F. Havelund","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK"},{"author_name":"Marie Sophie Isidor","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Hannah J. Richter","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Endocrinology, Diabe"},{"author_name":"Zafir Kaiser","author_inst":"Department of Biochemistry, Goodman Cancer Research Centre, McGill University Montreal, Quebec, CA"},{"author_name":"Yann Deleye","author_inst":"Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Divisions of Endocrinology and Cardiol"},{"author_name":"Sabina Chubanava","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Yachen Shen","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Pathology and Labo"},{"author_name":"Ditte Neess","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK"},{"author_name":"Frederike Sass","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Fabian Finger","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Lidia Argemi-Muntadas","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"David Tandio","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Tao Ma","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Elahu Gosney Sustarsic","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Hannes Embring","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Cecilie Kynding Kristensen","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Rebecca L. McIntyre","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"},{"author_name":"Genesee J. Martinez","author_inst":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA"},{"author_name":"Anna Sofie Husted","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Matthew J. Emmett","author_inst":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Broa"},{"author_name":"Zachary A. Kipp","author_inst":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA"},{"author_name":"Mikkel Frost","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Mark P. Jedrychowski","author_inst":"Department of Cell Biology, Harvard Medical School, Boston, MA, USA"},{"author_name":"Michel van Weeghel","author_inst":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism; Amsterdam UMC, University of Amsterdam, Amsterdam, NL"},{"author_name":"Homa Majd","author_inst":"Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK"},{"author_name":"Ekaterina Zhuravleva","author_inst":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK"},{"author_name":"Robert W. McGarrah","author_inst":"Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA"},{"author_name":"Kaja Plucinska","author_inst":"Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA"},{"author_name":"Mohit K. Midha","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Endocrinology, Diabe"},{"author_name":"Andreas Prokesch","author_inst":"Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz,"},{"author_name":"Paul Cohen","author_inst":"Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA"},{"author_name":"James G. Granneman","author_inst":"Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA"},{"author_name":"Patrick Seale","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"},{"author_name":"Riekelt H. Houtkooper","author_inst":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism; Amsterdam UMC, University of Amsterdam, Amsterdam, NL"},{"author_name":"Jacob B. Hansen","author_inst":"Department of Biology, University of Copenhagen, Copenhagen, DK"},{"author_name":"Steven P. Gygi","author_inst":"Department of Cell Biology, Harvard Medical School, Boston, MA, USA"},{"author_name":"Thue W. Schwartz","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Matthew Paul Gillum","author_inst":"Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DK"},{"author_name":"Terry D. Hinds Jr.","author_inst":"Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA"},{"author_name":"Raymond Edward Soccio","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"},{"author_name":"Phillip J. White","author_inst":"Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Divisions of Endocrinology and Cardiol"},{"author_name":"Edmund R. S. Kunji","author_inst":"Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK"},{"author_name":"Thomas Moritz","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Jonas T. Treebak","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Susanne Mandrup","author_inst":"Center for Adipocyte Signaling (ADIPOSIGN), University of Southern Denmark, Odense, DK"},{"author_name":"Brice Emanuelli","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK"},{"author_name":"Lawrence Kazak","author_inst":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK"},{"author_name":"Nils J. Faergeman","author_inst":"Department of Biochemistry, Goodman Cancer Research Centre, McGill University Montreal, Quebec, CA"},{"author_name":"Mitchell A. Lazar","author_inst":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Endocrinology, Diabe"},{"author_name":"Zachary Gerhart-Hines","author_inst":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK; Center for Adipocyte Signaling (ADIPOSIGN), University of"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Validation of optogenetic approach to investigate fatigable weakness using a zebrafish model of congenital myasthenic syndrome","rel_doi":"10.64898\/2026.05.30.728923","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728923","rel_abs":"Congenital myasthenic syndromes (CMS) are rare inherited diseases of the neuromuscular junction (NMJ). There are 40 identified CMS genes, but many patients go without genetic diagnosis, which suggests new genes have yet to be discovered and characterised. Here, we describe an optogenetic approach to study fatigable muscle weakness and NMJ function in larval zebrafish to facilitate screening approaches for uncovering novel CMS genes. Using blue-light illumination of spinal motoneurons that express channelrhodopsin-2 (ChR2) to induce muscle contraction, we measure motor defects at the behavioural, synaptic, and genetic level through a novel behavioural assay, standard whole-cell electrophysiology of individual muscle fibers and a customized NMJ gene panel. We employ this approach in synaptotagmin-2 (syt2) morphant zebrafish, an identified CMS gene model, to validate its usefulness. Our customized optogenetic behavioural assay successfully demonstrates reduced, fatigable, locomotor response during repeated activation of spinal motoneurons. Whole-cell electrophysiology recordings of optogenetically-elicited endplate currents in muscle fibers reveal similarities to altered properties of NMJ function in syt2 morphants reported in other studies using the standard paired motoneuron-muscle electrophysiology technique. Finally, we develop a genetic panel of CMS and NMJ-related genes to characterize the expression landscape of syt2 morphants to elucidate potential pathomechanisms and novel therapeutic targets. We propose that this three-tiered approach successfully links behaviour, synaptic motor function, and genetic expression and can be used as a tool in the screening of novel genes associated with CMS.","rel_num_authors":6,"rel_authors":[{"author_name":"Jarred  Michael Gary Lau","author_inst":"CHEO Research Institute: Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Stephanie  F Gaudreau","author_inst":"University of Ottawa Faculty of Science"},{"author_name":"Hanns  KM Lochm\u00fcller","author_inst":"CHEO Research Institute: Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Tuan  V Bui","author_inst":"University of Ottawa Faculty of Science"},{"author_name":"Katerina  K Palacek","author_inst":"CHEO Research Institute: Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Sally Spendiff","author_inst":"CHEO Research Institute: Children's Hospital of Eastern Ontario Research Institute"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Validation of optogenetic approach to investigate fatigable weakness using a zebrafish model of congenital myasthenic syndrome","rel_doi":"10.64898\/2026.05.30.728923","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.30.728923","rel_abs":"Congenital myasthenic syndromes (CMS) are rare inherited diseases of the neuromuscular junction (NMJ). There are 40 identified CMS genes, but many patients go without genetic diagnosis, which suggests new genes have yet to be discovered and characterised. Here, we describe an optogenetic approach to study fatigable muscle weakness and NMJ function in larval zebrafish to facilitate screening approaches for uncovering novel CMS genes. Using blue-light illumination of spinal motoneurons that express channelrhodopsin-2 (ChR2) to induce muscle contraction, we measure motor defects at the behavioural, synaptic, and genetic level through a novel behavioural assay, standard whole-cell electrophysiology of individual muscle fibers and a customized NMJ gene panel. We employ this approach in synaptotagmin-2 (syt2) morphant zebrafish, an identified CMS gene model, to validate its usefulness. Our customized optogenetic behavioural assay successfully demonstrates reduced, fatigable, locomotor response during repeated activation of spinal motoneurons. Whole-cell electrophysiology recordings of optogenetically-elicited endplate currents in muscle fibers reveal similarities to altered properties of NMJ function in syt2 morphants reported in other studies using the standard paired motoneuron-muscle electrophysiology technique. Finally, we develop a genetic panel of CMS and NMJ-related genes to characterize the expression landscape of syt2 morphants to elucidate potential pathomechanisms and novel therapeutic targets. We propose that this three-tiered approach successfully links behaviour, synaptic motor function, and genetic expression and can be used as a tool in the screening of novel genes associated with CMS.","rel_num_authors":6,"rel_authors":[{"author_name":"Jarred  Michael Gary Lau","author_inst":"CHEO Research Institute: Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Stephanie  F Gaudreau","author_inst":"University of Ottawa Faculty of Science"},{"author_name":"Hanns  KM Lochm\u00fcller","author_inst":"CHEO Research Institute: Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Tuan  V Bui","author_inst":"University of Ottawa Faculty of Science"},{"author_name":"Katerina  K Palacek","author_inst":"CHEO Research Institute: Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Sally Spendiff","author_inst":"CHEO Research Institute: Children's Hospital of Eastern Ontario Research Institute"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"\u03b1-Synuclein and \u03b3-Tubulin Cooperatively Regulate Activity-Evoked Presynaptic Microtubule Nucleation to Gate Dopamine Release","rel_doi":"10.64898\/2026.05.29.728874","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.29.728874","rel_abs":"alpha-Synuclein has long been implicated in the regulation of synaptic activity, but the molecular basis that underlies this function has been elusive. Here, we identify a microtubule (MT)-dependent mechanism through which alpha-synuclein regulates synaptic dopamine release. Using live imaging of cultured dopaminergic neurons, we visualize dynamic MTs at individual presynaptic boutons and show that neuronal activity triggers local gamma-tubulin-dependent MT nucleation. We find that this nucleation is essential for interbouton synaptic vesicle (SV) transport and for sustained dopamine release during high activity. We further discover that alpha-synuclein acts as a positive regulator of presynaptic MT nucleation by binding directly to gamma-tubulin and the alpha\/beta-tubulin heterodimer. Activity-evoked phosphorylation of alpha-synuclein at serine 129, a modification that accumulates in synucleinopathies and a molecular switch for alpha-synuclein binding to synaptic proteins, occurs in the region of alpha\/beta- tubulin binding and is both necessary and sufficient for MT initiation. Our findings reveal a previously unrecognized, activity-dependent role for alpha-synuclein in the nucleation of axonal MTs that enables on-demand SV interbouton redistribution and dopamine release. This mechanism provides a novel molecular link between alpha-synuclein phosphorylation and MT-dependent modulation of dopamine release, offering insight into how its dysregulation may contribute to dopaminergic synaptic dysfunction, a central feature of synucleinopathies.","rel_num_authors":9,"rel_authors":[{"author_name":"Alessandro Comincini","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Se Joon Choi","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Eugene Mosharov","author_inst":"Columbia University"},{"author_name":"Edoardo Milanetti","author_inst":"IIT, Rome, Italy"},{"author_name":"Ellen Kanter","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Giancarlo Ruocco","author_inst":"IIT, Sapienza University, Rome, Italy"},{"author_name":"Graziella Cappelletti","author_inst":"Universita degli Studi di Milano"},{"author_name":"David Louis Sulzer","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Francesca Bartolini","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Tet Trim-Away: A conditional rapid protein degradation system for Tetrahymena thermophila","rel_doi":"10.64898\/2026.05.29.728803","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.29.728803","rel_abs":"Tetrahymena thermophila is a ciliated protist that has played pivotal roles in biological discovery. Functional studies of Tetrahymena proteins have largely relied on gene knockouts. Because protein depletion upon knockout typically spans multiple cell cycles, compensatory mechanisms can confound phenotypic interpretation. To instead enable rapid and acute protein depletion, we modified and adapted the Trim-Away system for use in Tetrahymena (Tet Trim-Away). Trim-Away is based on the E3 ubiquitin ligase, TRIM21, that binds to antibody-bound proteins and targets them for proteasome mediated degradation. Here, Trim-Away was modified with a fusion of the N-terminal RBCC (RING, B-box, coiled-coil) domains of TRIM21 with an -mCherry (mCh) nanobody sequence that recognizes endogenously tagged mCh proteins of interest (NbmCh). Expression of the RBCC:NbmCh degron, which is controlled by an inducible promotor, promotes rapid target protein depletion within 30 minutes and can be sustained for weeks. Tet Trim-Away is reversible, functions against targets in multiple cellular compartments, and produces loss-of-function phenotypes in Tetrahymena cells.","rel_num_authors":5,"rel_authors":[{"author_name":"Gayatri L Dholakia","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Alexander J Stemm-Wolf","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Aaisha Anzar","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Aaron Turkewitz","author_inst":"University of Chicago"},{"author_name":"Chad G Pearson","author_inst":"Univ of Colorado - School of Medicine"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"The emergent mental operation of the learning brain","rel_doi":"10.64898\/2026.06.03.729881","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729881","rel_abs":"How does the learning brain give rise to emergent mental operations that enable skill internalization and generalization? Using five-year longitudinal tracking of children acquiring abacus-based mental calculation, we reveal how sustained practice progressively reconfigures whole-brain states. Learning induces nonlinear transitions from stable baseline configurations through a transient exploratory phase toward restabilized associative brain networks. This hierarchical remodeling cascades from perceptual systems to action and default networks, mediated by adaptive neural variability and selective connectivity reweighting, with the salience-parietal memory network acting as a dynamic relay. These brain-state transitions accompany an ordered cognitive transfer cascade, emerging within arithmetic and extending to visuospatial and executive functions. Our findings are reproducible and provide a systems-level account of how ecological learning sculpts large-scale networks to enable complex skill acquisition.","rel_num_authors":13,"rel_authors":[{"author_name":"Tianyong Xu","author_inst":"School of Physics, Zhejiang University; Hangzhou, 310058, China"},{"author_name":"Peng Tao","author_inst":"Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of S"},{"author_name":"Jiali Mu","author_inst":"School of Physics, Zhejiang University; Hangzhou, 310058, China"},{"author_name":"Xiao Han","author_inst":"School of Physics, Zhejiang University; Hangzhou, 310058, China"},{"author_name":"Fan Liu","author_inst":"School of Physics, Zhejiang University; Hangzhou, 310058, China"},{"author_name":"Peng Gao","author_inst":"State Key Laboratory of Cognitive Neuroscience and Learning, Faculty of Psychology, Beijing Normal University; Beijing, 100875, China"},{"author_name":"Tian Xia","author_inst":"Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of S"},{"author_name":"Zhu-Qing Gong","author_inst":"State Key Laboratory of Cognitive Neuroscience and Learning, Faculty of Psychology, Beijing Normal University; Beijing, 100875, China"},{"author_name":"Hongjian He","author_inst":"School of Physics, Zhejiang University; Hangzhou, 310058, China"},{"author_name":"Ting Xu","author_inst":"Kunming Institute of Zoology, Chinese Academy of Sciences; Kunming, 650201, China"},{"author_name":"Luonan Chen","author_inst":"School of Mathematical Sciences and School of AI, Shanghai Jiao Tong University; Shanghai, 200240, China"},{"author_name":"Feiyan Chen","author_inst":"School of Physics, Zhejiang University; Hangzhou, 310058, China"},{"author_name":"Xi-Nian Zuo","author_inst":"State Key Laboratory of Cognitive Neuroscience and Learning, Faculty of Psychology, Beijing Normal University; Beijing, 100875, China"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Neural decoding of speech using deep neural ensembles","rel_doi":"10.64898\/2026.06.02.729705","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729705","rel_abs":"Speech brain-computer interfaces (BCIs) can restore rapid communication to people with paralysis, but decoding errors still limit performance. In recent brain-to-text decoding competitions, deep ensemble methods, which combine predictions from multiple independently trained decoders, have delivered striking accuracy improvements and account for the largest gains over baseline approaches. However, these methods have not previously been tested in real-time, require substantial computational resources, and their performance under various clinically relevant constraints remains poorly understood. Here, we present the first closed-loop test of deep ensembles in a participant with bilateral intracortical microelectrode arrays, demonstrating a reduction in word error rate from 33.7% to 26.0% on a large-vocabulary task. Using additional data from three participants, we then assess how these gains depend on baseline error rate, training dataset size, and ensemble size, including the resource-accuracy tradeoffs most relevant for real-world deployment. Finally, we introduce a computationally efficient pseudoensembling approach based on test-time augmentation that improves decoding accuracy while requiring only a single base decoder, greatly reducing the computational burden of ensembling. Together, these results show that the benefits of deep ensembling can be realized in real time and under practical resource constraints, bringing speech BCIs closer to broader clinical adoption.","rel_num_authors":24,"rel_authors":[{"author_name":"Seonghyun Yoon","author_inst":"Stanford University"},{"author_name":"Donald T Avansino","author_inst":"Stanford University"},{"author_name":"Sasidhar Madugula","author_inst":"Stanford University"},{"author_name":"Alisa Danielle Levin","author_inst":"Stanford University"},{"author_name":"Chaofei Fan","author_inst":"Stanford University"},{"author_name":"Benyamin Abramovich Krasa","author_inst":"Stanford University"},{"author_name":"Akansha Singh","author_inst":"Stanford University"},{"author_name":"Christina Vo","author_inst":"Stanford University"},{"author_name":"Nick V Hahn","author_inst":"Stanford University"},{"author_name":"Nicholas S Card","author_inst":"University of California, Davis"},{"author_name":"Zachery Fogg","author_inst":"University of California, Davis"},{"author_name":"Maitreyee Wairagkar","author_inst":"University of California, Davis"},{"author_name":"Samuel R Nason-Tomaszewski","author_inst":"Emory University and Georgia Institute of Technology"},{"author_name":"Brandon G Jacques","author_inst":"Emory University and Georgia Institute of Technology"},{"author_name":"Payton H Bechefsky","author_inst":"Emory University and Georgia Institute of Technology"},{"author_name":"Carrina Iacobacci","author_inst":"University of California, Davis"},{"author_name":"Darrel R Deo","author_inst":"Stanford University"},{"author_name":"Leigh R Hochberg","author_inst":"Brown University"},{"author_name":"David M Brandman","author_inst":"University of California, Davis"},{"author_name":"Sergey D Stavisky","author_inst":"University of California, Davis"},{"author_name":"Nicholas Au Yong","author_inst":"Emory University"},{"author_name":"Chethan Pandarinath","author_inst":"Emory University"},{"author_name":"Jaimie M Henderson","author_inst":"Stanford University"},{"author_name":"Francis R Willett","author_inst":"Stanford University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Neural decoding of speech using deep neural ensembles","rel_doi":"10.64898\/2026.06.02.729705","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729705","rel_abs":"Speech brain-computer interfaces (BCIs) can restore rapid communication to people with paralysis, but decoding errors still limit performance. In recent brain-to-text decoding competitions, deep ensemble methods, which combine predictions from multiple independently trained decoders, have delivered striking accuracy improvements and account for the largest gains over baseline approaches. However, these methods have not previously been tested in real-time, require substantial computational resources, and their performance under various clinically relevant constraints remains poorly understood. Here, we present the first closed-loop test of deep ensembles in a participant with bilateral intracortical microelectrode arrays, demonstrating a reduction in word error rate from 33.7% to 26.0% on a large-vocabulary task. Using additional data from three participants, we then assess how these gains depend on baseline error rate, training dataset size, and ensemble size, including the resource-accuracy tradeoffs most relevant for real-world deployment. Finally, we introduce a computationally efficient pseudoensembling approach based on test-time augmentation that improves decoding accuracy while requiring only a single base decoder, greatly reducing the computational burden of ensembling. Together, these results show that the benefits of deep ensembling can be realized in real time and under practical resource constraints, bringing speech BCIs closer to broader clinical adoption.","rel_num_authors":24,"rel_authors":[{"author_name":"Seonghyun Yoon","author_inst":"Stanford University"},{"author_name":"Donald T Avansino","author_inst":"Stanford University"},{"author_name":"Sasidhar Madugula","author_inst":"Stanford University"},{"author_name":"Alisa Danielle Levin","author_inst":"Stanford University"},{"author_name":"Chaofei Fan","author_inst":"Stanford University"},{"author_name":"Benyamin Abramovich Krasa","author_inst":"Stanford University"},{"author_name":"Akansha Singh","author_inst":"Stanford University"},{"author_name":"Christina Vo","author_inst":"Stanford University"},{"author_name":"Nick V Hahn","author_inst":"Stanford University"},{"author_name":"Nicholas S Card","author_inst":"University of California, Davis"},{"author_name":"Zachery Fogg","author_inst":"University of California, Davis"},{"author_name":"Maitreyee Wairagkar","author_inst":"University of California, Davis"},{"author_name":"Samuel R Nason-Tomaszewski","author_inst":"Emory University and Georgia Institute of Technology"},{"author_name":"Brandon G Jacques","author_inst":"Emory University and Georgia Institute of Technology"},{"author_name":"Payton H Bechefsky","author_inst":"Emory University and Georgia Institute of Technology"},{"author_name":"Carrina Iacobacci","author_inst":"University of California, Davis"},{"author_name":"Darrel R Deo","author_inst":"Stanford University"},{"author_name":"Leigh R Hochberg","author_inst":"Brown University"},{"author_name":"David M Brandman","author_inst":"University of California, Davis"},{"author_name":"Sergey D Stavisky","author_inst":"University of California, Davis"},{"author_name":"Nicholas Au Yong","author_inst":"Emory University"},{"author_name":"Chethan Pandarinath","author_inst":"Emory University"},{"author_name":"Jaimie M Henderson","author_inst":"Stanford University"},{"author_name":"Francis R Willett","author_inst":"Stanford University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Emergence of social recognition in auditory and integrative circuits during pair bonding","rel_doi":"10.64898\/2026.06.01.729418","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729418","rel_abs":"Social relationships profoundly shape the perception of communication signals. In animals that form long-term social bonds, sensory cues such as vocalizations, scent, or physical appearance, and rewarding mating experiences can become associated with a bonded mate. While this natural process has hallmarks of some forms of associative learning, little is known about where or how these experiences shape neural circuits over the course of pair bonding. We used whole-brain BOLD fMRI in female songbirds to explore experience-dependent changes in neural activity in response to male songs. Pair bonding experiences drove changes in activation in response to the partner's song within secondary auditory areas as well as two regulatory hubs that receive sensory input and connect to circuits that generate behavioral responses. In contrast, mere exposure to the vocal interactions of a neighboring pair did not result in changes in response to the neighbor's song within the same areas, suggesting that pair bonding uniquely impacts auditory responses to familiar songs in select sensory and integrative circuits. Moreover, within the areas that showed increased activation for the partner's song over the course of pair bonding, we observed diminished activation in response to the partner's song after blocking D1 dopamine receptors, indicating a potential role for dopamine in the expression or maintenance of preference for the partner's song. Eavesdropping females had changes in neural activation in response to the familiar song in a different suite of brain regions that were not affected by dopamine manipulation. Our data identify a potential circuit in which concurrent activation of sensory, reward, and regulatory hubs integrates multisensory information from social interactions and leads to the emergence of acoustic preferences and formation of long-lasting social bonds.","rel_num_authors":7,"rel_authors":[{"author_name":"Erin M Wall","author_inst":"McGill University"},{"author_name":"Nicholas Vidas-Guscic","author_inst":"Bio-Imaging Lab, University of Antwerp"},{"author_name":"Jasmien Orije","author_inst":"Bio-Imaging Lab, University of Antwerp"},{"author_name":"Elisabeth Jonckers","author_inst":"Bio-Imaging Lab, University of Antwerp"},{"author_name":"Marleen Verhoye","author_inst":"Bio-Imaging Lab, University of Antwerp"},{"author_name":"Annemie Van der Linden","author_inst":"Bio-Imaging Lab, University of Antwerp"},{"author_name":"Sarah Cushing Woolley","author_inst":"McGill University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"rel_title":"Distinct associations between multimodal brain measures and psychopathology domains predict adolescent functioning","rel_doi":"10.64898\/2026.06.03.729937","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729937","rel_abs":"Adolescent psychopathology is partly rooted in measurable disruptions across key neural networks, yet the field still lacks an integrated, multimodal understanding of these brain-behavior links. Here, we examined how structural, microstructural, and functional measures across corticostriatal, corticolimbic, and executive control networks relate to psychopathology domains and explored how these associations predicted future psychosocial functioning. We used data from the Adolescent Brain Cognitive DevelopmentSM Study (n=5,408) and ran a regularized canonical correlation analysis to identify distinct modes of covariation between multiple brain measures and psychopathology domains when youth were 13-14 years old. The resulting canonical brain and psychopathology scores were used to predict school-related impairment one year later. First, higher diffusivity and decreased activation during a reward task across all three networks as well as lower corticostriatal surface area were related to higher broad psychopathology. Second, lower corticolimbic diffusivity, executive control volume and surface area, and cortical thickness across all three networks as well as higher corticostriatal and corticolimbic volumes were related to higher anxiety but lower externalizing. For the first mode, higher psychopathology scores predicted more school-related impairment one year later. For the second mode, higher brain and higher psychopathology scores predicted less school-related impairment one year later. Identifying how specific neural measures align with psychopathology domains, as well as how both forecast real-world functioning, advances the conceptualization of adolescent mental health. This approach clarifies which levels of analysis provide distinct versus shared information about youth functioning and highlights potential mechanisms that may inform future targets for change.","rel_num_authors":6,"rel_authors":[{"author_name":"Jivesh Ramduny","author_inst":"Yale University"},{"author_name":"Aidan G Mulvey","author_inst":"Yale University"},{"author_name":"Robert Kohler","author_inst":"Yale University"},{"author_name":"Steven Riley","author_inst":"Yale University"},{"author_name":"Sarah W Yip","author_inst":"Yale University"},{"author_name":"Arielle Baskin-Sommers","author_inst":"Yale University"}],"rel_date":"2026-06-04","rel_site":"biorxiv"},{"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":"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"},{"author_name":"Assaf Vardi","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":"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.\n\nSearches 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.\n\nWe 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.\n\nThese 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":"ImportanceBroadening 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.\n\nObjectiveEvaluate 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.\n\nDesign, Setting, and ParticipantsThis retrospective secondary progression risk prediction study analyzed 350 Alzheimers 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).\n\nExposuresThe 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.\n\nMain Outcomes and MeasuresThe 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.\n\nResultsA 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.\n\nIn 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.\n\nConclusionA 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.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSCan a low-burden brief informant-reported functional questionnaire support staged prognostic triage, before biomarker escalation, for near-term progression risk from mild cognitive impairment to Alzheimer disease dementia?\n\nFindingsIn this progression risk prediction study of 350 individuals with mild cognitive impairment, a 3-item Functional Activities Questionnaire (FAQ) was identified as a stable early signal for progression risk using a leakage-controlled repeated nested cross-validation. The screen was defined as any impairment in at least one of the three activities comprising finances\/checkbook, shopping and games\/hobbies (\"Locked FAQ Trio\"). In an independent prognosis prediction study, the Locked FAQ Trio was numerically, but not statistically significantly, higher than entorhinal tau positron emission tomography (PET) standardized uptake value ratio (SUVR) and statistically significantly higher than Mini-Mental State Examination (MMSE) score. In a smaller plasma subset of 66 participants, plasma phosphorylated tau 217 (p-tau217) showed the highest discrimination and the Locked FAQ Trio combined with p-tau217 differentiated lower and higher risk of progression.\n\nMeaningAn informant-reported brief 3-item functional questionnaire can help to inform and prioritize biomarker testing. A selected Locked FAQ Trio showed a higher numerical discrimination than specialized entorhinal tau PET biomarker and contextualized plasma p-tau217 biomarker. The suggested staged framework starts with Locked FAQ Trio screen triage, then plasma p-tau217 refinement before selective confirmation disease pathology with cerebrospinal fluid biomarkers or amyloid PET and\/or tau PET for staging or prognostic prediction.","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 models 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"}]}