{"gname":"Weizmann Institute of Science","grp_id":"15","rels":[{"rel_title":"Burden of Chronic Kidney Disease in China, 1990-2021: Findings from the 2021 Global Burden of Disease Study","rel_doi":"10.64898\/2026.06.06.26355056","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355056","rel_abs":"Introduction: To investigate the epidemiological characteristics of chronic kidney diseases (CKD) in China in 2021 and its trends between 1990 and 2021, in the context of significant population growth and lifestyle changes over the past 30 years that have likely influenced the CKD spectrum. Methods: Data on CKD prevalence, mortality, disability-adjusted life-years (DALY), and risk factors were obtained from the Global Burden of Disease Study 2021. The estimated decadal percentage changes were calculated to evaluate changes in trends in prevalence, mortality and disease burden. Results: In 2021, an estimated 118.4 (95% UI 109.4 to 127.5) million people in China were affected by CKD, contributing to 204 230 (95% UI 164 736 to 246 372) deaths and 6.13 (95% UI 5.18 to 7.21) million DALY. Although CKD due to diabetes mellitus and hypertension accounted for less than a quarter of all cases, they were responsible for over 90% of CKD-related deaths. Over the past three decades, CKD mortality and DALY rates have steadily increased, although the prevalence has stabilized in the last decade. Diabetes mellitus type 2 and hypertension have emerged as key drivers of CKD burden in China. Conclusions: The CKD burden in China shows a dual pattern of rising incidence and high mortality from diabetes and hypertension-related chronic kidney disease, alongside persistently high years lived with disability from glomerulonephritis and other causes.","rel_num_authors":5,"rel_authors":[{"author_name":"Mengwei Wang","author_inst":"Shanxi Medical University"},{"author_name":"Taoran Zhao","author_inst":"Shanxi Medical University"},{"author_name":"Heng Wang","author_inst":"The University of Sydney"},{"author_name":"Shulin Hou","author_inst":"Shanxi Medical University"},{"author_name":"Yongqiang Fu","author_inst":"Shanxi Bethune Hospital"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Polypore Mushroom Mycelia for Treatment of Active COVID-19 Infection: A Randomized Clinical Trial","rel_doi":"10.64898\/2026.06.01.26354267","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354267","rel_abs":"Use of fungal mycelia, which has antiviral properties, constitutes a novel strategy for addressing existing and newly emerging viral diseases. We evaluated safety and feasibility of fungal mycelia (Fomitopsis officinalis and Trametes versicolor, FoTv) for treatment of COVID-19 and assessed its antiviral effects and potential to reduce symptoms. In a randomized, double-blind, placebo-controlled, dual site (UCSD\/UCLA medical centers) clinical trial we examined non-hospitalized patients who contracted mild-to-moderate COVID-19 [&le;] 96 hours, and experienced symptom onset [&le;] nine days, before enrollment. FoTv was safe, well-tolerated, and feasible for COVID-19 treatment. Minor differences in biochemical markers were observed between groups (26 FoTv, 24 Placebo). FoTv significantly reduced the number and severity of symptoms, particularly sore throat\/cough, and in vitro SARS-CoV-2 (pseudovirus) cellular infection. In conclusion, FoTv was safe and reduced COVID-19 symptoms and cellular viral infection. Future studies should investigate therapeutic benefits of fungal mycelia for SARS-CoV-2 and other viruses. Clinicaltrials.gov registration:NCT04667247.","rel_num_authors":16,"rel_authors":[{"author_name":"Gordon Saxe MD\/PHD","author_inst":"University of California San Diego"},{"author_name":"Andrew Shubov MD","author_inst":"University of California Los Angeles"},{"author_name":"Christine N Smith PHD","author_inst":"University of California San Diego"},{"author_name":"Shahrokh Golshan PHD","author_inst":"University of California San Diego"},{"author_name":"Tatyana Shekhtman MS","author_inst":"University of California San Diego"},{"author_name":"Stephen Wilson PHD","author_inst":"Botnar Institute of Immune Engineering"},{"author_name":"Daniel Slater MD\/FAAFP","author_inst":"University of California San Diego"},{"author_name":"Zolton J Bair PHD","author_inst":"Fungi Perfecti, LLC"},{"author_name":"Chase Beathard PHD","author_inst":"Fungi Perfecti, LLC"},{"author_name":"Renee A Davis MA","author_inst":"University of Washington"},{"author_name":"Lauray MacElhern MBA","author_inst":"University of California San Diego"},{"author_name":"Lan K Kao DACM","author_inst":"University of California Los Angeles"},{"author_name":"Phoebe Senowitz MEd","author_inst":"University of California San Diego"},{"author_name":"Natalie Gosnell BS","author_inst":"Cornell University"},{"author_name":"David Buchholz PHD","author_inst":"University of California Los Angeles"},{"author_name":"Hector Aguilar-Carreno PHD","author_inst":"University of California Los Angeles"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Aperiodic and oscillatory activity of the human brain during induced emotional states","rel_doi":"10.64898\/2026.06.02.26354146","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354146","rel_abs":"Normal emotional experience depends on dynamic modulation of neural excitability across limbic and prefrontal circuits, yet the spectral markers that reflect these shifts in humans remain incompletely understood. In this study, we combined a validated video-based emotion induction paradigm with stereotactic electroencephalography (SEEG) in 31 patients with drug-resistant epilepsy to investigate how positive and negative affective states modulate oscillatory and aperiodic (asynchronous) neural activity. Using spectral parameterization to dissociate oscillatory power from the aperiodic 1\/f component, we found that emotional valence robustly altered the aperiodic slope in a regionally specific manner: negative valence flattened the slope in thalamus, posterior insula, and posterior cingulate cortex, whereas positive valence produced flattening in dorsolateral prefrontal cortex. Simultaneous oscillatory changes included increased high-frequency activity and decreased alpha\/beta power during negative affect, and reduced alpha power during positive affect, which were elucidated after adjusting for broadband aperiodic spectral shifts. These effects persisted after controlling for audiovisual stimulus or physiological features and were not evident in simultaneously recorded scalp EEG, underscoring their localization to intracranial sites. Together, these results provide the first direct evidence that active induction of emotional states modulates the aperiodic slope of human intracranial field potentials, reflecting valence-dependent shifts in local circuit excitability. The findings highlight the 1\/f slope as a sensitive neural marker of affective brain states and for mood dysregulation.","rel_num_authors":9,"rel_authors":[{"author_name":"Haeorum Park","author_inst":"Washington University in St. Louis"},{"author_name":"Carl Hacker","author_inst":"Emory University School of Medicine"},{"author_name":"Hohyun Cho","author_inst":"University of Alabama at Birmingham"},{"author_name":"Tao Xie","author_inst":"Washington University in St. Louis"},{"author_name":"Alexis Simmons","author_inst":"Washington University in St. Louis"},{"author_name":"Gansheng Tan","author_inst":"Washington University In St Louis"},{"author_name":"Eric C Leuthardt","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Peter Brunner","author_inst":"Washington University In St Louis: Washington University in St Louis"},{"author_name":"Jon Willie","author_inst":"University of Texas at Austin"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Mortality in people with attention-deficit\/hyperactivity disorder (ADHD): Examining how risk is embodied in a pooling of two prospective cohort studies","rel_doi":"10.64898\/2026.06.08.26355148","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355148","rel_abs":"Background. Nascent findings suggest that people with attention-deficit\/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk. Methods. We used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported. Findings. At baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive. Interpretation. In the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group. Funding. This paper received no direct funding. GDB is supported by the UK Medical Research Council (MR\/P023444\/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).","rel_num_authors":5,"rel_authors":[{"author_name":"Haibin Li","author_inst":"Capital Medical University"},{"author_name":"Tamsin Ford","author_inst":"University of Cambridge"},{"author_name":"Varun Warrier","author_inst":"University of Cambridge"},{"author_name":"Steven Bell","author_inst":"UCL"},{"author_name":"George David Batty","author_inst":"University College London"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"STDP-inspired temporal transition modeling for adaptive clinical risk prediction from electronic health records","rel_doi":"10.64898\/2026.06.04.26354919","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354919","rel_abs":"Electronic health record (EHR) prediction models often summarize longitudinal histories as static patient-level features, which may omit potentially informative event ordering. We developed a simplified spike-timing-dependent plasticity (STDP)-inspired framework that represents asynchronous EHR data as sparse, directional transition features. The approach encodes whether one clinical event precedes another within prespecified temporal windows, preserving event identity, directionality, and approximate timing while retaining feature-level interpretability. We evaluated this framework in two retrospective prediction tasks with different temporal scales: incident acute kidney injury (AKI) prediction in 17,351 MIMIC-IV ICU stays and early postoperative recurrence prediction in 713 CUMC patients with pancreatic ductal adenocarcinoma (PDAC). Models were compared with static burden features (demographics, comorbidities, raw lab measurements) and in addition with STDP transitional feature sets using patient-level cross-validation and rolling prediction horizons. In AKI, a calibrated STDP ensemble model showed higher discrimination than static burden alone at the 24-hour decision snapshot for AKI by 72 hours, with AUROC 0.838 versus 0.800, and at 48 hours for near-term AKI prediction, with AUROC 0.868 versus 0.827. In PDAC, STDP transition features modestly improved Day -30 preoperative recurrence prediction, with AUROC 0.611 versus 0.587 and AUPRC 0.323 versus 0.318 for static burden and showed similar performance at Day 0 (7 days before recorded surgery date), with AUROC 0.681 and AUPRC 0.363. Decision-curve and feature analyses suggested that selected temporal transitions were clinically interpretable across renal, inflammatory, hepatobiliary, hematologic, glycemic, and nutritional trajectories. These findings suggest that STDP-inspired transition features may provide a practical, interpretable way to incorporate temporal ordering into EHR-based risk prediction across both acute and longitudinal settings","rel_num_authors":8,"rel_authors":[{"author_name":"Liyuan Gong","author_inst":"Columbia University"},{"author_name":"Nitish Aswani","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Peter Shahinian","author_inst":"Columbia University"},{"author_name":"Jeong Yun Yang","author_inst":"Columbia University"},{"author_name":"Despina Kontos","author_inst":"Columbia University"},{"author_name":"Gulam Manji","author_inst":"Columbia University"},{"author_name":"Stella Kang","author_inst":"Columbia University"},{"author_name":"Chin Hur","author_inst":"Columbia University"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor","rel_doi":"10.64898\/2026.06.05.730515","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730515","rel_abs":"Methionine is an essential amino acid, used for protein synthesis, redox homeostasis, and methylation reactions throughout the cell. However, the compartmentalized dynamics of methionine have remained elusive, due to a lack of available tools to measure methionine with high spatial and temporal resolution. To address this limitation, we have developed a single fluorescent protein-based methionine optical reporter (Meteor) which reports subcellular changes in methionine with high dynamic range. Using Meteor, we demonstrate the subcellular uptake of methionine in multiple cell lines into several locations, including the mitochondrial matrix. Furthermore, we use Meteor to illuminate the dynamics of the methionine cycle in the cytoplasm and nucleus, finding cancer cells can rapidly increase methionine from metabolic precursors in both locations. Finally, demonstrated that Meteor can be used to visualize methionine dynamics in vivo using Caenorhabditis elegans. Thus, we have developed a new tool to measure methionine dynamics across scales with high dynamic range and spatiotemporal resolution.","rel_num_authors":8,"rel_authors":[{"author_name":"Katarina A Cohen","author_inst":"University of California, Los Angeles"},{"author_name":"Arnav Jhawar","author_inst":"University of California, Los Angeles"},{"author_name":"Gilberto Garcia","author_inst":"University of Southern California"},{"author_name":"Naiara Goni","author_inst":"University of California, Los Angeles"},{"author_name":"Megan Chen","author_inst":"University of California, Los Angeles"},{"author_name":"Athena Alcala","author_inst":"University of Southern California"},{"author_name":"Ryo Higuchi-Sanabria","author_inst":"University of Southern California"},{"author_name":"Danielle L Schmitt","author_inst":"University of California Los Angeles"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Deciphering the limitations of immortalized hepatocyte cell lines for the study of liver cis-regulatory elements","rel_doi":"10.64898\/2026.06.05.730479","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730479","rel_abs":"Immortalized cell lines are widely used in biological research despite their known differences from their tissues and cell types of origin. Such cell lines are especially popular for testing hypotheses regarding the activity of cis-regulatory elements (CREs) that regulate gene expression. Previous investigations of blood and skin cell lines revealed many differences between the transcriptional regulatory networks of the cell lines and the associated primary cells. Similar comparisons for other tissues have been limited. Here, we used ATAC-seq to profile CREs in four immortalized liver cell lines and found many CRE differences between each cell line and primary liver tissue, including differences in the transcription factors that are likely to bind the CREs and differences in the genes that they are likely to regulate. Modifying cell culture conditions based on recommendations in the literature did not improve the similarity with primary liver tissue. Our results suggest that differences between the transcriptional regulatory networks in cell lines and primary tissue should be considered when designing and interpreting cell line experiments.","rel_num_authors":12,"rel_authors":[{"author_name":"Andrew Bellesis","author_inst":"Carnegie Mellon University"},{"author_name":"Xinyi Li","author_inst":"Carnegie Mellon University"},{"author_name":"Dervla Moore-Frederick","author_inst":"Carnegie Mellon University"},{"author_name":"Deyuan Xu","author_inst":"Carnegie Mellon University"},{"author_name":"Kara Delbridge","author_inst":"Carnegie Mellon University"},{"author_name":"Junjie Ma","author_inst":"Carnegie Mellon University"},{"author_name":"Gabriella Vaccaro","author_inst":"Carnegie Mellon University"},{"author_name":"Buddhima Athukorala Aracchige Edward","author_inst":"Carnegie Mellon University"},{"author_name":"Maddie Kellogg","author_inst":"Carnegie Mellon University"},{"author_name":"Yehuda Creeger","author_inst":"Carnegie Mellon University"},{"author_name":"Alexander S Okamoto","author_inst":"Carnegie Mellon University"},{"author_name":"Irene Miriam Kaplow","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Accurate de novo design of peptides from programming biophysical landscape","rel_doi":"10.64898\/2026.06.08.731011","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.731011","rel_abs":"Peptides regulate virtually every cellular process and emerge as transformative modalities in bioengineering and therapeutics. However, the de novo design of functional peptides remains challenging, as peptide--protein interactions are governed by delicate and dynamic biophysics that are difficult to model, and experimental datasets are scarce. Here we present NeoPep, a generative deep-learning framework that encodes biophysical principles to accurately design functional peptides de novo. By integrating over 5 million peptide--protein complexes spanning experimentally determined, sequence mimics, and structure ensembles, NeoPep learns the complex biophysical landscape governing peptide function and enables its programmable control. In prospective application across 10 diverse and challenging targets, NeoPep generated potent peptide binders, agonists, and antagonists with hit rates of 12.5--66.7%, even in the absence of defined binding sites or structure information. Beyond de novo co-design, NeoPep supports standalone structure or sequence redesign, readily discriminating subtle context differences. In the structure redesign mode, it generates highly selective peptides with atomic-level conformational accuracy (C RMSD < 2.0 [A] to our solved cryo-EM structure). This structural precision circumvents the need for experimental structure determination, further accelerating iterative sequence redesign to yield a 43.3-fold improvement in potency. These findings establish a general framework for translating biophysical principles into actionable peptide functions, with broad implications for basic research, bioengineering, and medicine.","rel_num_authors":26,"rel_authors":[{"author_name":"Mingyu Li","author_inst":"Shanghai Jiao Tong University and Tsinghua University"},{"author_name":"Yini Liu","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jie Zhong","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Xinchao Shi","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jiqing Zheng","author_inst":"Tsinghua University"},{"author_name":"Kai Wang","author_inst":"Chinese Academy of Sciences"},{"author_name":"Yunxia Cui","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Chaoran Cheng","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Shijin Li","author_inst":"Tsinghua University"},{"author_name":"Xiangzhe Kong","author_inst":"Tsinghua University"},{"author_name":"Shaoning Li","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Miaojie Xv","author_inst":"Shanxi Medical University"},{"author_name":"Chunhao Zhu","author_inst":"Ningxia Medical University"},{"author_name":"Xiaobing Lan","author_inst":"Ningxia Medical University"},{"author_name":"He Yang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Kewei Chang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Zhenyu An","author_inst":"Ningxia Medical University"},{"author_name":"Shizhang Wan","author_inst":"Tsinghua University"},{"author_name":"Xiuyan Yang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Qiancheng Shen","author_inst":"Nutshell Therapeutics Co. Ltd"},{"author_name":"H. Eric Xu","author_inst":"Chinese Academy of Sciences"},{"author_name":"Zihua Wang","author_inst":"Chinese Academy of Sciences"},{"author_name":"Lei Liu","author_inst":"Tsinghua University"},{"author_name":"Youwen Zhuang","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jianzhu Ma","author_inst":"Tsinghua University"},{"author_name":"Jian Zhang","author_inst":"Shanghai Jiao Tong University, Ningxia Medical University and Shanxi Medical University"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Perturbing glycosylphosphatidylinositol (GPI)-anchor biosynthesis alters cell wall architecture and modulates fungal morphology","rel_doi":"10.64898\/2026.06.05.730525","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730525","rel_abs":"Filamentous fungi are widely used as expression hosts for industrial protein production. However, their tendency to form dense mycelial pellets limits nutrient transfer, oxygen uptake, and fermentation efficiency. While cell wall components are known to influence fungal aggregation, the molecular mechanisms linking cell wall biosynthesis to macroscopic morphology remain poorly defined. Here, we show that perturbation of glycosylphosphatidylinositol (GPI)-anchored protein biosynthesis influences fungal morphology by altering cell wall composition. Using Aspergillus oryzae as a model system, we demonstrate that disruption of the GPI ethanolamine phosphate transferase 1 (mcd4) or inhibition of glucosaminyl phosphatidylinositol acyltransferase Gwt1 using antifungal drug manogepix (MGX) induces a hyper-branching phenotype and weakens cell wall. Notably, chemical inhibition of Gwt1 by MGX caused a marked transition from pelleted to dispersed mycelial growth. Solid-state NMR (ssNMR) analysis revealed reorganisation of galactosaminogalactan (GAG) and galactomannan (GM), including complete loss of cationic galactosamine (GalN), a key determinant of hyphal adhesion. Transcriptomic profiling further revealed downregulation of genes involved in somatic cell fusion, linking altered wall composition to impaired germling aggregation. Strikingly, MGX treatment induced distinct morphological outcomes in other industrially relevant fungi, indicating species-specific cell-wall dependencies. Together, our findings establish GPI-anchored cell wall proteins as important regulators of fungal morphology and provide new strategies for rational morphology engineering in industrial fermentation.","rel_num_authors":5,"rel_authors":[{"author_name":"Hui Ting Chu","author_inst":"National University of Singapore"},{"author_name":"Isha Gautam","author_inst":"Michigan State University"},{"author_name":"Surya Pavan Yenamendra","author_inst":"Environmental Health Institute"},{"author_name":"Tuo Wang","author_inst":"Michigan State University"},{"author_name":"Prakash Arumugam","author_inst":"Singapore Institute of Food and Biotechnology Innovation (SIFBI)"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Myofibroblast- specific autophagy drives cyst growth in autosomal dominant polycystic kidney disease","rel_doi":"10.64898\/2026.06.05.730503","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730503","rel_abs":"Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst expansion, fibrosis and inflammation, leading to kidney failure. Myofibroblasts (MFs) often accumulate around cysts and promote fibrosis and cyst growth, but the cellular mechanisms enabling their pro-cystogenic activity remain unclear. Here we examined the role of autophagy within MFs, on their paracrine stimulation of cyst expansion in ADPKD. Methods: Autophagy was assessed in human ADPKD nephrectomy tissue, primary human ADPKD renal myofibroblasts (ADPKD-MFs) and male RC\/RC mouse model of ADPKD using immunostaining, LC3\/p62 analyses, and transmission electron microscopy. Autophagy in MFs was inhibited pharmacologically in ADPKD-MFs, or by conditional Atg5 deletion in PDGFR{beta}-expressing renal stromal cells in RC\/RC (RC\/RC;Atg5KO) and wild type (WT;Atg5KO) mice. Results: In human and mouse ADPKD kidneys, we detected LC3 puncta and autophagic organelles within SMA- expressing MFs. Inhibition of autophagy in ADPKD-MFs blocked their paracrine stimulation of cyst epithelial cell proliferation in vitro. RC\/RC;Atg5KO mice showed significantly reduced cystic growth, fibrosis, MF abundance, and improved kidney function. WT;Atg5KO mice showed no abnormalities in kidney structure or function. Targeted metabolomics performed on ADPKD cyst epithelial-cell conditioned media (ADPKD-ECs CM) revealed moderate increase in lactate levels compared to normal human kidney epithelial-cell conditioned media. Furthermore, lactate treatment stabilized hypoxia-inducible factor-1 (HIF1) in myofibroblasts, while pharmacological inhibition of HIF1 reduced the expression of autophagy-related genes and impaired autophagic flux. Conclusion: These findings reveal that autophagy in MFs is a previously unrecognized driver of cyst expansion and fibrosis in ADPKD. Lactate-mediated HIF1 stabilization in MFs promotes autophagy that is required for their paracrine stimulation of cyst epithelial growth. Targeting MF-specific autophagy or its upstream regulators may represent a therapeutic strategy to limit cyst growth and fibrosis in ADPKD.","rel_num_authors":10,"rel_authors":[{"author_name":"Abeda Jamadar","author_inst":"Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Viji Remadevi","author_inst":"Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Meekha M Varghese","author_inst":"Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Haichun Yang","author_inst":"3Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center"},{"author_name":"Vedant P Thakkar","author_inst":"Enabling Technologies Group, Sandford Research"},{"author_name":"Indra Chandrasekar","author_inst":"Enabling Technologies Group, Sandford Research"},{"author_name":"Wen-Xing Ding","author_inst":"University of Kansas Medical Center"},{"author_name":"Volker H Haase","author_inst":"Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center,"},{"author_name":"Darren P. Wallace","author_inst":"Jared Grantham Kidney Institute, University of Kansas Medical Center"},{"author_name":"Reena Rao","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Myofibroblast- specific autophagy drives cyst growth in autosomal dominant polycystic kidney disease","rel_doi":"10.64898\/2026.06.05.730503","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730503","rel_abs":"Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst expansion, fibrosis and inflammation, leading to kidney failure. Myofibroblasts (MFs) often accumulate around cysts and promote fibrosis and cyst growth, but the cellular mechanisms enabling their pro-cystogenic activity remain unclear. Here we examined the role of autophagy within MFs, on their paracrine stimulation of cyst expansion in ADPKD. Methods: Autophagy was assessed in human ADPKD nephrectomy tissue, primary human ADPKD renal myofibroblasts (ADPKD-MFs) and male RC\/RC mouse model of ADPKD using immunostaining, LC3\/p62 analyses, and transmission electron microscopy. Autophagy in MFs was inhibited pharmacologically in ADPKD-MFs, or by conditional Atg5 deletion in PDGFR{beta}-expressing renal stromal cells in RC\/RC (RC\/RC;Atg5KO) and wild type (WT;Atg5KO) mice. Results: In human and mouse ADPKD kidneys, we detected LC3 puncta and autophagic organelles within SMA- expressing MFs. Inhibition of autophagy in ADPKD-MFs blocked their paracrine stimulation of cyst epithelial cell proliferation in vitro. RC\/RC;Atg5KO mice showed significantly reduced cystic growth, fibrosis, MF abundance, and improved kidney function. WT;Atg5KO mice showed no abnormalities in kidney structure or function. Targeted metabolomics performed on ADPKD cyst epithelial-cell conditioned media (ADPKD-ECs CM) revealed moderate increase in lactate levels compared to normal human kidney epithelial-cell conditioned media. Furthermore, lactate treatment stabilized hypoxia-inducible factor-1 (HIF1) in myofibroblasts, while pharmacological inhibition of HIF1 reduced the expression of autophagy-related genes and impaired autophagic flux. Conclusion: These findings reveal that autophagy in MFs is a previously unrecognized driver of cyst expansion and fibrosis in ADPKD. Lactate-mediated HIF1 stabilization in MFs promotes autophagy that is required for their paracrine stimulation of cyst epithelial growth. Targeting MF-specific autophagy or its upstream regulators may represent a therapeutic strategy to limit cyst growth and fibrosis in ADPKD.","rel_num_authors":10,"rel_authors":[{"author_name":"Abeda Jamadar","author_inst":"Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Viji Remadevi","author_inst":"Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Meekha M Varghese","author_inst":"Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA"},{"author_name":"Haichun Yang","author_inst":"3Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center"},{"author_name":"Vedant P Thakkar","author_inst":"Enabling Technologies Group, Sandford Research"},{"author_name":"Indra Chandrasekar","author_inst":"Enabling Technologies Group, Sandford Research"},{"author_name":"Wen-Xing Ding","author_inst":"University of Kansas Medical Center"},{"author_name":"Volker H Haase","author_inst":"Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center,"},{"author_name":"Darren P. Wallace","author_inst":"Jared Grantham Kidney Institute, University of Kansas Medical Center"},{"author_name":"Reena Rao","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"CRISPR\/Cas9 knockout and editing of the major cysteine protease in Entamoeba histolytica","rel_doi":"10.64898\/2026.06.08.731005","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.731005","rel_abs":"Entamoeba histolytica is the cause of amoebiasis, a diarrheal infection that is a significant source of morbidity and mortality. Despite its importance to human health, the basic mechanism of disease is poorly understood. E. histolytica is dramatically understudied, even in comparison to other understudied parasites, due to challenging features of its genome and the relative paucity of genetic tools. A major limitation is the historical lack of gene knockouts or manipulation of the endogenous genome. While CRISPR\/Cas9 has led to major advances in the tractability of numerous parasites, until recently, it was not applied in E. histolytica, except for the demonstration of editing of an episomal plasmid. In this study, we further developed CRISPR\/Cas9 and demonstrated the successful targeting of the endogenous cysteine protease 5 (CP5) gene, a major virulence factor. Further, we demonstrated successful CRISPR\/Cas9-based editing of this locus, which represents the very first successful editing of the endogenous genome. In the course of these approaches, we developed the viral skip peptide approach as well as a suite of endogenous promoters to drive tunable levels of gene expression. We also performed the most extensive empirical testing of nuclear localization signals in E. histolytica that has been done. Thus, this work demonstrates effective CRISPR\/Cas9-based manipulation of the endogenous genome, together with significant advances to the overall genetic toolkit that extend beyond CRISPR\/Cas9. These great improvements in the tractability of E. histolytica thus set the stage for future studies to better define its virulence.","rel_num_authors":5,"rel_authors":[{"author_name":"Wesley Huang","author_inst":"Department of Microbiology and Molecular Genetics, University of California, Davis, USA"},{"author_name":"Rene L Suleiman","author_inst":"Department of Microbiology and Molecular Genetics, University of California, Davis, USA"},{"author_name":"Thomas J Luder","author_inst":"Department of Microbiology and Molecular Genetics, University of California, Davis, USA"},{"author_name":"Sylvia Jebiwott","author_inst":"Department of Microbiology and Molecular Genetics, University of California, Davis, USA"},{"author_name":"Katherine  S Ralston","author_inst":"Department of Microbiology and Molecular Genetics, University of California, Davis, USA"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Conserved emergent traits enable biobank-scale prediction of community function","rel_doi":"10.64898\/2026.06.09.731074","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731074","rel_abs":"A central challenge in microbial ecology and biotechnology is predicting how species identity translates into community-level function. Using soymilk fermentation as a model, we measured three industrially relevant functions - acidification, texture, sensory grade - across 307 synthetic communities combining 33 phylogenetically diverse lactic acid bacteria strains. The functional effect of adding a strain to a community scaled linearly with the function of the receiving community. This global epistasis-like pattern summarizes each strain's contribution across communities with two emergent parameters - intercept and slope - which hold predictive power across untested combinations. We show that these parameters are phylogenetically conserved, allowing their imputation from 16S rRNA identity alone. This scales up the predictive capabilities of our method to communities composed of entirely unassayed strains. By redefining community-level function in terms of conserved species traits, our results pave the way for biobank-scale consortium engineering and genomic dissection of complex community phenotypes.","rel_num_authors":8,"rel_authors":[{"author_name":"Uros Gojkovic","author_inst":"Delft University of Technology"},{"author_name":"Zorana Miloradovic","author_inst":"Department of Animal Source Food Technology, Faculty of Agriculture, University of Belgrade, Serbia"},{"author_name":"Nikola Popovic","author_inst":"Group for Molecular Microbiology, Department of Microbiology and Plant Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade,"},{"author_name":"Goran Vukotic","author_inst":"Faculty of Biology, University of Belgrade, Serbia"},{"author_name":"Nina Medakovic","author_inst":"Group for Molecular Microbiology, Department of Microbiology and Plant Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade,"},{"author_name":"Nemanja Stanisavljevic","author_inst":"Group for Molecular Microbiology, Department of Microbiology and Plant Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade,"},{"author_name":"Nemanja Kljajevic","author_inst":"Group for Molecular Microbiology, Department of Microbiology and Plant Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade,"},{"author_name":"Djordje Bajic","author_inst":"Delft University of Technology"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Glacial meltwater drives gene-specific diversification of metal resistance genes in High Arctic soil microbiomes","rel_doi":"10.64898\/2026.06.08.730895","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730895","rel_abs":"Climate warming accelerates glacial meltwater delivery to Arctic lakes, mobilizing metals from thawing catchments and reshaping the selective landscape experienced by resident microbes. Whether these gradients leave detectable evolutionary signatures in environmental resistance genes remains unclear. We investigated four metal resistance genes (merA, arsC, cadA, and chrR) in metagenomic datasets from Lake Hazen (Nunavut, Canada), the largest High Arctic freshwater lake, sampled across a natural hydrological gradient of Control, Low-runoff, and High-runoff regimes. Using a space-for-time design, we combined population-genetic and codon-based approaches to quantify diversity and selection, including nucleotide diversity, Tajima's D, nonsynonymous\/synonymous diversity ratios, McDonald-Kreitman tests, site-level episodic selection, and Bayesian coalescent and structured-coalescent inference of gene-pool diversity and exchange. This multi-pronged approach allowed us to distinguish gene-specific evolutionary responses from broader demographic effects. We found marked heterogeneity among genes: merA showed increasing diversity and consistent evidence of adaptive evolution along the runoff gradient; cadA displayed the strongest adaptive signal under low runoff, with selective constraint patterns that varied across regimes; chrR exhibited the clearest signature of episodic positive selection, with gene-wide selection and adaptive substitutions concentrated in the high-runoff regime where chromium concentrations were greatest; while arsC remained largely consistent with neutral evolution across regimes. Together, these results show that climate-driven metal mobilization is associated with gene- and regime-specific diversification of microbial metal resistance gene pools in Arctic soil microbiomes. Differences in metal speciation (with arsenic and chromium occurring as redox-sensitive oxyanions, and mercury, cadmium and zinc as divalent cations) may contribute to the contrasting evolutionary trajectories observed across genes, although in-situ speciation was not assessed in this dataset. Our findings highlight environmental resistance genes as sensitive indicators of changing biogeochemical conditions in rapidly warming polar ecosystems.","rel_num_authors":3,"rel_authors":[{"author_name":"Franck J. Ouedraogo","author_inst":"University of Ottawa"},{"author_name":"Alexandre J Poulain","author_inst":"University of Ottawa"},{"author_name":"Stephane Aris-Brosou","author_inst":"University of Ottawa"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Glacial meltwater drives gene-specific diversification of metal resistance genes in High Arctic soil microbiomes","rel_doi":"10.64898\/2026.06.08.730895","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730895","rel_abs":"Climate warming accelerates glacial meltwater delivery to Arctic lakes, mobilizing metals from thawing catchments and reshaping the selective landscape experienced by resident microbes. Whether these gradients leave detectable evolutionary signatures in environmental resistance genes remains unclear. We investigated four metal resistance genes (merA, arsC, cadA, and chrR) in metagenomic datasets from Lake Hazen (Nunavut, Canada), the largest High Arctic freshwater lake, sampled across a natural hydrological gradient of Control, Low-runoff, and High-runoff regimes. Using a space-for-time design, we combined population-genetic and codon-based approaches to quantify diversity and selection, including nucleotide diversity, Tajima's D, nonsynonymous\/synonymous diversity ratios, McDonald-Kreitman tests, site-level episodic selection, and Bayesian coalescent and structured-coalescent inference of gene-pool diversity and exchange. This multi-pronged approach allowed us to distinguish gene-specific evolutionary responses from broader demographic effects. We found marked heterogeneity among genes: merA showed increasing diversity and consistent evidence of adaptive evolution along the runoff gradient; cadA displayed the strongest adaptive signal under low runoff, with selective constraint patterns that varied across regimes; chrR exhibited the clearest signature of episodic positive selection, with gene-wide selection and adaptive substitutions concentrated in the high-runoff regime where chromium concentrations were greatest; while arsC remained largely consistent with neutral evolution across regimes. Together, these results show that climate-driven metal mobilization is associated with gene- and regime-specific diversification of microbial metal resistance gene pools in Arctic soil microbiomes. Differences in metal speciation (with arsenic and chromium occurring as redox-sensitive oxyanions, and mercury, cadmium and zinc as divalent cations) may contribute to the contrasting evolutionary trajectories observed across genes, although in-situ speciation was not assessed in this dataset. Our findings highlight environmental resistance genes as sensitive indicators of changing biogeochemical conditions in rapidly warming polar ecosystems.","rel_num_authors":3,"rel_authors":[{"author_name":"Franck J. Ouedraogo","author_inst":"University of Ottawa"},{"author_name":"Alexandre J Poulain","author_inst":"University of Ottawa"},{"author_name":"Stephane Aris-Brosou","author_inst":"University of Ottawa"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Coordinated immune-epithelial dynamics in the nasal epithelium protect against respiratory virus infection","rel_doi":"10.64898\/2026.06.08.726938","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.726938","rel_abs":"Epithelial remodeling is a hallmark of host antiviral responses that strengthen barrier defenses against infection. Our current understanding of viral pathophysiology within the nasal epithelium, the initial site of most respiratory viral infections, remains incomplete due to limited understanding of the native tissue architecture and protective epithelial remodeling during immune events. Leveraging coronavirus disease 2019 (COVID-19) as a model, we applied spatial multi-omics on nasal cross-sectional tissues to characterize the immune-epithelial landscape during infection, identifying a coordinated increase in goblet cells and suppressive macrophages associated with elevated IL13 in the immune compartment. Our results further reveal that goblet cell and suppressive macrophage enrichment are spatially linked in proximity to IL13-expressing CD4 T cells, consistent with IL13-driven remodeling in situ. Using a primary human nasal air-liquid interface model, we demonstrate that IL13 alone is sufficient to remodel epithelial composition and morphology, subsequently restricting viral infection by reshaping the apical mucus barrier of the nasal epithelium. Our findings uncover a spatially organized, IL13-driven circuit for immune-epithelial remodeling as a protective barrier against respiratory viral infections.","rel_num_authors":22,"rel_authors":[{"author_name":"Yao Yu Yeo","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"},{"author_name":"Hsin-Yi Chen","author_inst":"Department of Microbiology, UT Southwestern Medical Center, Dallas, TX, United States"},{"author_name":"Bokai Zhu","author_inst":"Department of Pathology, Stanford University, Stanford, CA, United States"},{"author_name":"Yang Wang","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"},{"author_name":"Ivan T Lee","author_inst":"Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, United States"},{"author_name":"Tsuguhisa Nakayama","author_inst":"Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, United States"},{"author_name":"Yuchen Wang","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"},{"author_name":"Huaying Qiu","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"},{"author_name":"Kate B Juergens","author_inst":"Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA, United States"},{"author_name":"Sei Chung","author_inst":"Department of Otolaryngology-Head and Neck Surgery, UT Southwestern Medical Center, Dallas, TX, United States"},{"author_name":"Carol H Yan","author_inst":"Department of Surgery, University of California San Diego School of Medicine, La Jolla, CA, USA"},{"author_name":"Clara S Kummerer","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"},{"author_name":"Hendrik A Michel","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"},{"author_name":"Andrew Z Ma","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"},{"author_name":"Wenrui Wu","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"},{"author_name":"Jayakar V Nayak","author_inst":"Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, United States"},{"author_name":"Garry P Nolan","author_inst":"Department of Pathology, Stanford University, Stanford, CA, United States"},{"author_name":"David R McIlwain","author_inst":"Department of Microbiology and Immunology, University of Nevada Reno School of Medicine, Reno, NV, United States"},{"author_name":"Alexandar Tzankov","author_inst":"Institute of Pathology, University Hospital Basel, Basel, Switzerland"},{"author_name":"Matthias S Matter","author_inst":"Institute of Pathology, University Hospital Basel, Basel, Switzerland"},{"author_name":"Chien-Ting Wu","author_inst":"Department of Microbiology, UT Southwestern Medical Center, Dallas, TX, United States"},{"author_name":"Sizun Jiang","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Single-nucleus multiomics unveils malignant cellular states, regulatory architectures and microenvironmental reorganization across the G-CIMP epigenomic transition in IDH-mutant glioma","rel_doi":"10.64898\/2026.06.05.730437","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730437","rel_abs":"IDH-mutant gliomas stratified by glioma CpG island methylator phenotype (G-CIMP) into High (GCH) and Low (GCL) exhibit markedly divergent clinical outcomes, yet cellular and regulatory determinants of this distinction remain incompletely defined. Integrating single-nucleus RNA- and ATAC-sequencing across 18 tumor specimens from 10 patients, we resolved six malignant cellular states whose differential enrichment across G-CIMP strata delineates the GCL epigenomic transition. GCL tumors were enriched for independently prognostic Mesenchymal and Mitotic Proliferative states, driven by convergent E2F, MYC, MEF2, and NFI-family regulatory networks confirmed across chromatin, histone, and transcriptomic modalities. Pseudotime trajectory inference revealed a multifurcating developmental model from an Astrocytic-like origin, with GCL tumors gaining preferential access to proliferative and mesenchymal endpoints. A reorganized immune microenvironment and candidate therapeutic axes including CDK4\/6-E2F, MYC\/BET, KIF11, and NOTCH, potentially combinable with vorasidenib as an epigenomic backbone provide a translationally actionable framework for intercepting GCL progression in IDH-mutant glioma.","rel_num_authors":15,"rel_authors":[{"author_name":"Grayson Herrgott","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"Luciano Garofano","author_inst":"Bioinnovation and Genome Sciences Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA"},{"author_name":"Natalia Silva Morosini","author_inst":"Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA"},{"author_name":"Bogdan Done","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"Christopher L Powell","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"Ana deCarvalho","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"Laura Hasselbach","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"Andrea Transou","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"Ian Lee","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"Tobias Walbert","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"James Snyder","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"},{"author_name":"Anna Lasorella","author_inst":"Department of Public Health Sciences, Division of Biostatistics and Bioinformatics, University of Miami, Miller School of Medicine, Miami, FL, USA"},{"author_name":"Ana Valeria Castro","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA; Department of Physiology, Michigan State Univers"},{"author_name":"Antonio Iavarone","author_inst":"Department of Public Health Sciences, Division of Biostatistics and Bioinformatics, University of Miami, Miller School of Medicine, Miami, FL, USA"},{"author_name":"Houtan Noushmehr","author_inst":"Department of Neurosurgery, Omics Laboratory, Hermelin Brain Tumor Center, Henry Ford Health, Detroit, MI, USA"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Human tissue-resident CD8 T cells contribute to trophoblast homeostasis in health and during acute inflammation","rel_doi":"10.64898\/2026.06.05.730192","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730192","rel_abs":"Previous studies have highlighted that some T cell subsets in tissues can provide signals to support tissue cell homeostasis and differentiation. If and how T cell-tissue cell signaling is altered in healthy compared to inflamed tissues is poorly understood. Here, we address if communication between human T cells and tissue cells changes from steady state to an acutely inflamed state in the human placenta. We used single cell analysis strategies to examine invasive cytotrophoblasts (iCTBs) and immune cells isolated from third trimester healthy and acutely inflamed human placentas. We performed cell communication analysis to predict cell-cell communication networks, and found evidence that iCTBs provided signals to support the recruitment of T cells, as well as the formation of tissue-resident memory CD8 T cells (Trm). In exchange, Trm provide signals to support iCTB homeostasis. During acute inflammation, iCTBs and macrophages underwent profound transcriptional changes, while most T cell subsets only underwent limited transcriptional changes. This was not due to T cell exhaustion or tolerance, as T cells were functionally intact. Cell communication analysis and validation at the protein level provide evidence that T cells can maintain their homeostatic support to iCTBs during acute inflammation.","rel_num_authors":10,"rel_authors":[{"author_name":"Caitlin DeJong","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Marie Frutoso","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Nicole Potchen","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Geervani Daggupati","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Andrew Konecny","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Yin Huang","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Manu Setty","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Swati Shree","author_inst":"University of Washington"},{"author_name":"Stephen A McCartney","author_inst":"University of Washington"},{"author_name":"Martin Prlic","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Temporal transcriptomic and microbial changes in American bison during experimental SARS-CoV-2 challenge","rel_doi":"10.64898\/2026.06.08.730980","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730980","rel_abs":"SARS-CoV-2 continues to pose a threat to humans as well as domestic and wild animals. The variability in severity of clinical signs, the zoonotic potential, and the host-specific response to infection contribute to the persistence of circulation of disease. In wildlife species white-tailed deer have been shown to be more permissive to infection than bovids. However, amongst bovids, American bison have shown a greater susceptibility than cattle. In this study we investigate the transcriptomic response to experimental SARS-CoV-2 infection in bison over time. Substantial numbers of differentially expressed genes were identified between pre- and 2, 5, 7, 14, and 21 days post-infection. KEGG and GO term analysis identified associations with immune response, inflammatory response, and viral infection including COVID-19. IPA analysis of the SARS coronavirus pathway highlighted differences in signaling at days 2 versus 21 post-infection. We additionally examined changes in the nasal microbiome of bison over the course of experimental infection, which suggested an increase in opportunity for secondary infection causing pathogens such as Mannheimia. Collectively this study presents a profile of bison transcriptomic response to SARS-CoV-2 infection and continues to expand our understanding of variation in host response.","rel_num_authors":11,"rel_authors":[{"author_name":"Bruna Petry","author_inst":"Oak Ridge Institute for Science and Education, USDA-ARS National Animal Disease Center"},{"author_name":"Paola M Boggiatto","author_inst":"USDA-ARS National Animal Disease Center"},{"author_name":"Alexandra Buckley","author_inst":"USDA-ARS National Animal Disease Center"},{"author_name":"Eric D Cassmann","author_inst":"Iowa State University College of Veterinary Medicine"},{"author_name":"Kaitlyn Sarlo Davila","author_inst":"USDA-ARS National Animal Disease Center"},{"author_name":"Steven C Olsen","author_inst":"USDA-ARS National Animal Disease Center"},{"author_name":"Luis Guilherme V Fernandes","author_inst":"Oak Ridge Institute for Science and Education, USDA-ARS National Animal Disease Center"},{"author_name":"Bienvenido Tibbs-Cortes","author_inst":"USDA-ARS National Animal Disease Center"},{"author_name":"Faith M Rahic-Saggerman","author_inst":"Iowa State University, Department of Animal Science"},{"author_name":"Mitchell V Palmer","author_inst":"USDA-ARS National Animal Disease Center"},{"author_name":"Ellie J Putz","author_inst":"USDA-ARS National Animal Disease Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Single-cell transcriptomics of heterogeneous patient-derived organoids reveals novel therapeutic targets in high-grade serous ovarian cancer","rel_doi":"10.64898\/2026.06.05.730209","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730209","rel_abs":"High-grade serous ovarian carcinoma (HGSOC) is characterized by widespread peritoneal dissemination and poor long-term survival, largely driven by metastatic relapse following initial response to chemotherapy. Defining the molecular programs that enable tumor progression from the primary ovarian site to metastatic niches remains a key challenge. Here, we leverage patient-derived organoids (PDOs) coupled with single-cell RNA sequencing (scRNA-seq) to interrogate tumor evolution and identify regulators of metastatic competence in HGSOC. We profiled PDOs and matched formalin-fixed paraffin-embedded (FFPE) tumor samples from ovarian and omental disease sites across seven patients. Single-cell transcriptomic analysis revealed conserved and patient-specific cellular states and enabled reconstruction of inferred trajectories of tumor progression. Comparative trajectory analysis identified gene expression programs associated with metastatic transition from ovarian to omental tumors. Among these, the heparan sulfate proteoglycan AGRIN emerged as a consistently upregulated gene along the metastatic axis. Cell-cell communication analyses suggested that AGRIN-mediated signaling involves both epithelial tumor cells and stromal components, implicating the extracellular matrix in shaping metastatic behavior through mechanotransduction and integrin-associated pathways. Functional validation using genetic depletion of AGRIN in ovarian cancer cell lines demonstrated reduced migratory and invasive capacity, supporting a causal role for AGRIN in promoting metastatic phenotypes. Together, these findings identify AGRIN as a regulator of metastatic competence in HGSOC and highlight extracellular matrix associated signaling as a key driver of disease progression. More broadly, this study demonstrates that PDO-based single-cell transcriptomic approaches can uncover actionable regulators of metastasis and provide a scalable framework for therapeutic target discovery across cancer types.","rel_num_authors":8,"rel_authors":[{"author_name":"Bisiayo E Fashemi","author_inst":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, and Alvin J. Siteman Cancer Center. St Loui"},{"author_name":"Yukihide Ota","author_inst":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, and Alvin J. Siteman Cancer Center. St Loui"},{"author_name":"Vijayalaxmi Gupta","author_inst":"Washington University School of Medicine"},{"author_name":"Maia L Elizagaray","author_inst":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, and Alvin J. Siteman Cancer Center. St Loui"},{"author_name":"Roger Pique-Regi","author_inst":"Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA"},{"author_name":"Nardhy Gomez-Lopez","author_inst":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, and Alvin J. Siteman Cancer Center. St Loui"},{"author_name":"Mary Mullen","author_inst":"Washington University School of Medicine"},{"author_name":"Dineo Khabele","author_inst":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, and Alvin J. Siteman Cancer Center. St Loui"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Methylmalonic acid: a new target for Hadamard-edited MRS","rel_doi":"10.64898\/2026.06.05.730405","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730405","rel_abs":"Background: Methylmalonic acidemia (MMAemia) is a genetic metabolic disorder characterized by an accumulation of methylmalonic acid (MMA) and impaired energy metabolism leading to increased lactate (Lac). The signals of MMA (1.23 ppm) and Lac (1.33 ppm) overlap, making their separation using conventional MRS challenging. An MRS method to differentiate the two metabolites could enhance pathophysiological understanding and improve treatment monitoring - Hadamard-edited MRS has the potential to achieve this. Purpose: To develop a Hadamard-encoded J-difference editing approach for independent detection of MMA and Lac at 3T. Methods: A novel Hadamard-encoded editing scheme was implemented and evaluated with density-matrix simulations, phantom and in vivo experiments. The new four-step scheme uses frequency-selective editing pulses, applied at 3.2 ppm and 4.1 ppm to modulate the J-coupled methyl resonances of MMA and Lac, respectively. Hadamard combinations of the four sub-experiments yield the separate difference-edited spectra for each target metabolite. Results: Simulations and phantom experiments clearly illustrate the separated signals of MMA and Lac. In vivo validation experiments show a Lac signal (but no MMA) in a healthy infant, and both Lac and MMA (separated into their respective Hadamard-combination spectra) in a patient with MMAemia. Conclusion: Hadamard-encoded editing at 3T can separate MMA and Lac signals and shows promise for studying altered metabolism in patients with MMAemia.","rel_num_authors":12,"rel_authors":[{"author_name":"yulu Song","author_inst":"The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"author_name":"Tao Gong","author_inst":"Departments of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China"},{"author_name":"Zahra Shams","author_inst":"The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"author_name":"Xiaoya Sun","author_inst":"Departments of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China"},{"author_name":"Christopher W. Davies-Jenkins","author_inst":"The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"author_name":"Shuyuan Wang","author_inst":"Department of Mechanical Engineering, Johns Hopkins University, United States"},{"author_name":"Gizeaddis Lamesgin Simegn","author_inst":"The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"author_name":"Saipavitra Murali-Manohar","author_inst":"The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"author_name":"Abdelrahman Gad","author_inst":"The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"author_name":"Georg Oeltzschner","author_inst":"The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States"},{"author_name":"Guangbin Wang","author_inst":"Departments of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China"},{"author_name":"Richard A.E. Edden","author_inst":"The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States; F.M. Kirby Re"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"An integrated human immunoglobulin germline resource linking allele diversity to expressed repertoire structure","rel_doi":"10.64898\/2026.06.05.730236","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730236","rel_abs":"Human immunoglobulin (IG) loci are highly polymorphic, yet existing germline resources remain noisy and incomplete, limiting our ability to link inherited variation to antibody repertoires. Here, we integrate high-fidelity long-read genomic sequencing with matched adaptive immune receptor repertoire sequencing (AIRR-seq) to construct HUSA, a population-scale, evidence-resolved germline resource. Using a conservative allele inference framework, HUSA expands current references more than three-fold, identifying over 1300 alleles while preserving allele-level evidence provenance across genomic and repertoire data. By linking genotype and expressed repertoires within individuals, we show that coding-region similarity predicts the structure of adjacent recombination signal sequences and leader regions, revealing that IG alleles are organized as linked cis-regulatory units associated with differences in recombination context and allele usage. These results define key germline constraints shaping repertoire formation and establish a robust, genotype-aware foundation for the analysis of immune receptor repertoires.","rel_num_authors":15,"rel_authors":[{"author_name":"Ayelet Peres","author_inst":"Yale School of Medicine"},{"author_name":"Uddalok Jana","author_inst":"University of Louisville"},{"author_name":"Oscar Rodriguez","author_inst":"University of Louisville"},{"author_name":"Zachary M. Vanwinkle","author_inst":"University of Louisville"},{"author_name":"Eric Engelbrecht","author_inst":"University of Louisville"},{"author_name":"William S Gibson","author_inst":"University of Louisville"},{"author_name":"Kaitlyn Shields","author_inst":"University of Louisville"},{"author_name":"Brandon Croslin","author_inst":"University of Louisville"},{"author_name":"Steven Schultze","author_inst":"University of Louisville"},{"author_name":"Chandrima Bharadwaj","author_inst":"University of Louisville"},{"author_name":"Connor Murray","author_inst":"University of Louisville"},{"author_name":"William D. Lees","author_inst":"Clareo Biosciences"},{"author_name":"Melissa L. Smith","author_inst":"University of Louisville"},{"author_name":"Corey T. Watson","author_inst":"University of Louisville School of Medicine"},{"author_name":"Gur Yaari","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"The pseudoproteinase iRhom2 critically promotes acute lung inflammation","rel_doi":"10.64898\/2026.06.05.730404","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730404","rel_abs":"ADAM17 sheds cell surface molecules such as TNF-, IL-6R and L-selectin. This activity requires either iRhom1 or iRhom2 as adapter molecules. Since iRhom2 is predominantly expressed in leukocytes and upregulated in tissue cells during inflammation, it represents a potential anti-inflammatory target. We therefore investigated the effects of iRhom2 deficiency in mice using in vivo, ex vivo, and in vitro models of acute inflammation. In an in vivo model of LPS-induced lung inflammation, iRhom2 knockout mice showed reduced neutrophil recruitment into the bronchoalveolar space. Notably, the few recruited neutrophils remained L-selectin positive, whereas most neutrophils in wildtype mice were L-selectin negative, confirming that L-selectin shedding depends on the iRhom2\/ADAM17 axis. Furthermore, it suggests that impaired shedding is associated with decreased neutrophil recruitment. Additionally, ADAM17-dependent release of TNF- and IL-6R into the alveolar space was diminished in the absence of iRhom2, accompanied by reduced expression of inflammatory mediators. In isolated perfused lungs challenged with LPS, iRhom2 deficiency similarly reduced inflammatory mediator production, indicating a role for iRhom2 in resident lung tissue cells during the initiation of inflammation. To specifically assess immune cell responses, we further examined macrophages, the sole resident immune cells in the lung. In vitro, LPS-stimulated bone marrow derived macrophages lacking iRhom2 showed decreased shedding of TNF- and IL-6R and reduced induction of secondary inflammatory mediators. Thus, targeting iRhom2 effectively suppresses ADAM17-mediated inflammatory responses in the lung, while preserving basal ADAM17 activity through iRhom1, offering a more selective therapeutic strategy with fewer side effects.","rel_num_authors":9,"rel_authors":[{"author_name":"Christine Lux","author_inst":"RWTH Aachen"},{"author_name":"Selcan Kahveci-Tuerkoez","author_inst":"RWTH Aachen"},{"author_name":"Katharina Schun","author_inst":"RWTH Aachen"},{"author_name":"Aaron Babendreyer","author_inst":"RWTH Aachen University"},{"author_name":"Christian Martin","author_inst":"RWTH Aachen"},{"author_name":"Petr Kasparek","author_inst":"University of California"},{"author_name":"Radislav Sedlacek","author_inst":"Insitute of Molecular Genetics"},{"author_name":"Stefan Duesterhoeft","author_inst":"HMU Duesseldorf\/Krefeld"},{"author_name":"Andreas Ludwig","author_inst":"RWTH Aachen University"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"HSSM: A Widely Applicable Toolbox for Hierarchical Bayesian Neuro-cognitive Modeling","rel_doi":"10.64898\/2026.06.05.730398","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730398","rel_abs":"Computational models are central to cognitive neuroscience, but their rigorous application to experimental datasets is often constrained to a narrow set of canonical models that afford tractable analytical computations. We introduce the HSSM (Hierarchical Sequential Sampling Model) ecosystem, a Python toolbox that democratizes access to a broad, extensible array of neuro-cognitive process models through hierarchical Bayesian inference. Naturally leveraging simulation-based inference via likelihood surrogates, HSSM enables fast parameter estimation for models lacking closed-form likelihoods. Built atop PyMC and Bambi, HSSM provides a user-friendly formula syntax for specifying hierarchical mixed-effects regressions on model parameters, incorporating trial-by-trial neural or physiological covariates. The ecosystem allows fast model simulation and training data generation, as well as the neural network training utilities to deploy surrogate likelihood networks via HuggingFace. Contributions are designed to benefit not only the single researcher working on a problem, but organically, the entire research community. Together, the tools in the HSSM ecosystem bridge the interests of computational theorists as well as experimentalists, accelerating the cycle from model development to rigorous empirical testing.","rel_num_authors":6,"rel_authors":[{"author_name":"Alexander Fengler","author_inst":"Brown University"},{"author_name":"Yang Xu","author_inst":"Brown University"},{"author_name":"Krishn Bera","author_inst":"Brown University"},{"author_name":"Carlos Paniagua","author_inst":"Brown University"},{"author_name":"Aisulu Omar","author_inst":"Brown University"},{"author_name":"Michael J Frank","author_inst":"Brown University"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Spatially-resolved integration of microglia morphological diversity and gene expression using Visium with protein co-detection","rel_doi":"10.64898\/2026.06.05.730425","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730425","rel_abs":"Microglia exhibit a dynamic range of morphologies that actively shift in response to local environmental cues. There has been a concerted effort as a field to move away from dualistic characterization of all microglia as 'resting' or 'activated', which is often described in terms of their morphological differences alone, towards more integrated definitions of microglial 'states' based on multiple data types. Recent advances in spatially-resolved transcriptomics offer new ways to understand microglial gene expression in situ. Here, we related microglia morphology to gene expression within a published, spatially-resolved proteogenomics (Visium-SPG) dataset of the human dorsolateral prefrontal cortex as proof of principle to combine the contributions of microglia morphology to regional transcriptomics differences in the brain. The published dataset uniquely combined spatial transcriptomics with immunofluorescent staining for four major brain cell types, including microglia, which enabled us to link microglial morphologies to gene expression in a spatially-resolved manner. Using a computational toolset, MicrogliaMorphology and MicrogliaMorphologyR, we classified individual microglia into morphological subtypes, assigned microglia to spots, and integrated these data with transcriptomic profiles for each Visium-SPG spot. We applied non-negative matrix factorization to account for contributions from multiple cell types, morphological features, and regional context in downstream differential expression modeling. Our approach offers a methodological framework for investigating the relationship between microglial morphology and gene expression in larger cohorts and within disease contexts where changes in microglia morphology are anticipated.","rel_num_authors":5,"rel_authors":[{"author_name":"Jennifer Kim","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Stephanie C Hicks","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Kristen Maynard","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Paul Pavlidis","author_inst":"University of British Columbia"},{"author_name":"Annie  Vogel Ciernia","author_inst":"The University of British Columbia"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Memory stabilizes complex ecological systems but delays full restoration","rel_doi":"10.64898\/2026.06.05.730340","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730340","rel_abs":"Memory effects---defined as the capacity of system states to exert long-lasting influence on subsequent dynamics---are widely recognized as central features of complex living systems. In ecological systems, however, their consequences for stability and recovery dynamics remain poorly understood. To fill this gap, we develop a general theoretical framework that incorporates memory into the dynamics of species-rich ecological systems with complex interaction structures. Our analyses reveal that memory effects expand the stability domain, enabling systems that would otherwise be unstable to persist following perturbations, particularly in cases where instability involves oscillatory behavior. At the same time, memory can accelerate short-term recovery, allowing systems to return more rapidly toward equilibrium in the early stages after perturbation. These apparent benefits, however, come at a cost: memory effects markedly slow long-term recovery, thereby delaying full restoration, as memory retains the influence of past perturbations and hinders a full return to equilibrium. We further support these results by integrating empirical data into the framework. Together, these results reveal fundamental trade-offs mediated by memory---enhanced stability and faster short-term recovery at the expense of delayed full restoration---highlighting the dual role of memory in shaping resilience in complex ecological systems and, more broadly, complex living systems.","rel_num_authors":3,"rel_authors":[{"author_name":"Yuguang Yang","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Serguei Saavedra","author_inst":"MIT"},{"author_name":"Aming Li","author_inst":"Peking University"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Cytotoxic T cells targeting lytic KSHV gene products infiltrate Kaposi sarcoma tumors","rel_doi":"10.64898\/2026.06.05.730414","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730414","rel_abs":"Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and KSHV-associated multicentric Castleman's disease (MCD), malignancies that predominantly arise in the context of T-cell deficiency. Unlike responses to other human herpesviruses such as EBV and CMV, KSHV-specific T-cell responses detected in blood have been described as heterogeneous and low-intensity. Hypothesizing that KSHV-specific T cells are recruited to KS tumors, we analyzed the T-cell receptor (TCR) repertoire of biopsies from 144 Ugandan adults with KS (106 people living with HIV [PLWH], 38 HIV-seronegative) and identified >4,000 {beta} TCRs with predicted specificity for KSHV- or HIV-encoded peptides presented by specific MHC alleles. We tested 14 putative KSHV- or HIV-specific TCRs for recognition of cells presenting cognate peptides in the predicted MHC context. Three novel HIV-specific TCRs, found only in tumors from PLWH, exhibited high-avidity, MHC-restricted recognition of HIV Vpr and Nef peptides previously identified as CD8+ T-cell targets. Four KSHV-specific TCRs, detected in tumors from both PLWH and HIV-seronegative individuals, recognized peptides encoded by the lytic KSHV genes ORF6, ORF57, and ORF59. The ORF6- and ORF57-specific TCRs were observed in multiple individuals and constitute the first examples of public T-cell responses to KSHV. We then confirmed that these four KSHV-specific TCRs recognized KSHV-infected cells undergoing lytic reactivation. Identification of TCRs specific for KSHV lytic gene products will enable the development of T-cell-based therapies for KS and other KSHV-associated diseases.","rel_num_authors":20,"rel_authors":[{"author_name":"Shashidhar Ravishankar","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Andrea  M.H Towlerton","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Iyabode  L Tiamiyu","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Chris  P Miller","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Peter Mooka","author_inst":"Hutchinson Centre Research Institute - Uganda"},{"author_name":"Janet Nankoma","author_inst":"Hutchinson Centre Research Institute - Uganda"},{"author_name":"James Kafeero","author_inst":"Uganda Cancer Institute"},{"author_name":"Dennis Mubiru","author_inst":"Uganda Cancer Institute"},{"author_name":"Semei Sekitene","author_inst":"Uganda Cancer Institute"},{"author_name":"Lauri  D Aicher","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"David  G Coffey","author_inst":"University of Miami Hospitals and Clinics: Sylvester Comprehensive Cancer Center"},{"author_name":"Lazarus Okoche","author_inst":"Uganda Cancer Institute"},{"author_name":"Prisca Atwinirembabazi","author_inst":"Uganda Cancer Institute"},{"author_name":"Joseph Okonye","author_inst":"Uganda Cancer Institute"},{"author_name":"Kelvin  R Mubiru","author_inst":"Uganda Cancer Institute"},{"author_name":"Jessica White","author_inst":"University of Washington"},{"author_name":"Lichen Jing","author_inst":"University of Washington"},{"author_name":"David  M Koelle","author_inst":"University of Washington"},{"author_name":"Warren  T Phipps","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Edus  H Warren","author_inst":"Fred Hutch Cancer Center: Fred Hutchinson Cancer Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Motor automaticity in natural keyboard typing","rel_doi":"10.64898\/2026.06.04.730281","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730281","rel_abs":"Certain features of everyday motor skills become automatic while others remain controlled. Here we use a novel keyboard typing task to investigate whether motor automaticity depends on the frequency of naturally learned motor sequences. Participants type five-letter strings that vary in their word and bigram (two-letter sequence) frequency in natural language, allowing us to examine the influence of prior exposure without laboratory training. Novel pseudo word strings are tested as well. We find greater sequence frequency in natural language is associated with faster inter-keypress intervals and lower temporal variability within the sequence. In contrast, latencies to initiate a sequence are slower for novel pseudo-word strings but are otherwise insensitive to natural word frequency. We also find individual differences in inter-keypress speed and variability are robust across frequency levels but are unrelated to conventional measures of typing skill. Our method establishes keyboard typing as a scalable, ethologically valid framework for probing features of a naturally acquired human motor skill. This research will help extend laboratory-based studies of motor sequence learning and sets the stage for future investigations of linguo-motor processes. Moreover, our findings demonstrate which features within naturally acquired motor sequences become automatic and that typing proficiency is not determined solely by automaticity.","rel_num_authors":5,"rel_authors":[{"author_name":"Rubi Ruopp","author_inst":"University of Oregon"},{"author_name":"Emily A Williams","author_inst":"Univeristy of Leeds"},{"author_name":"Mary Gach","author_inst":"University of Oregon"},{"author_name":"Melissa Baese-Berk","author_inst":"Univeresity of Chicago"},{"author_name":"Ian Greenhouse","author_inst":"University of Oregon"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Sex-related structural alterations across common epilepsies: a worldwide ENIGMA study","rel_doi":"10.64898\/2026.06.06.730611","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730611","rel_abs":"Epilepsy is characterized by widespread structural brain alterations extending beyond the epileptic zone, involving both cortical and subcortical regions. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy have been seldomly reported in neuroimaging studies, partly due to limited sample sizes and single-center designs. Here, we systematically investigated sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multi-center cohort of 1,253 epilepsy patients and 1,077 healthy controls. We studied cortical thickness and subcortical volume in two types of epilepsy: temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Both male and female patients with TLE showed widespread cortical and subcortical thinning compared with controls. In GGE, when compared separately to controls, male patients showed only subtle structural alterations, whereas female patients exhibited more widespread structural alterations. Sex-stratified analyses revealed some variation in the extent and distribution of cortical thickness and subcortical volume alterations between male and female patients in both epilepsy cohorts. Yet, we did not find significant sex-by-diagnosis interaction effects in TLE and GGE. Similarly, no significant interaction effects were observed between sex and age of onset or disease duration in either patient group. Overall, although we observed some differences in regional cortical thickness and subcortical volume between male and female patients with epilepsy, we did not find significant sex-by-diagnosis interactions. Our findings indicate that sex differences in behavioral and clinical outcomes of epilepsy may involve biological or functional processes that require further investigation.","rel_num_authors":69,"rel_authors":[{"author_name":"Huantao Wen","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Cen"},{"author_name":"Bin Wan","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Department of Psychiatry, University Hospitals of Gen\u00e8ve, Thonex, Switzerland"},{"author_name":"Taha Gholipour","author_inst":"Department of Neurosciences, 9300 Campus Point Drive, #7740, La Jolla, 92037, CA, USA."},{"author_name":"Ke Xie","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Judy Chen","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Bianca Serio","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Cen"},{"author_name":"Meike Dorothee Hettwer","author_inst":"Penn Lifespan Informatics & Neuroimaging Center, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, "},{"author_name":"Marina Koutsodontis Machado Alvim","author_inst":"Department of Neurology, University of Campinas-UNICAMP, Rua Tessalia Vieira de Camargo 126, Campinas, 13083-887, SP, Brazil"},{"author_name":"Donatello Arienzo","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA"},{"author_name":"Rafael Batista Jo\u00e3o","author_inst":"Department of Neurology, University of Campinas-UNICAMP, Rua Tessalia Vieira de Camargo 126, Campinas, 13083-887, SP, Brazil; Brazilian Institute of Neuroscienc"},{"author_name":"Tobias Bauer","author_inst":"Department of Neuroradiology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany; Department of Epileptology, University Hospital Bonn, Venusber"},{"author_name":"Andrea Bernasconi","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Neda Bernasconi","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Paolo Bonanni","author_inst":"Scientific Institute IRCCS E.Medea, Epilepsy and Clinical Neurophysiology Unit, Conegliano, Italy"},{"author_name":"Maria Eugenia Caligiuri","author_inst":"Neuroscience Research Center, Department of Medical and Surgical Sciences, University ''Magna Gr\u00e6cia'' of Catanzaro, Catanzaro, Italy"},{"author_name":"Fernando Cendes","author_inst":"Brazilian Institute of Neuroscience and Neurotechnology, Rua Vital Brasil 251, Campinas, 13083888, SP, Brazil."},{"author_name":"Rapha\u00ebl Christin","author_inst":"Department of Neurology, 505 Parnassus Avenue, San Francisco, 94143, CA, USA"},{"author_name":"Luis Concha","author_inst":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Quer\u00e9taro, Mexico"},{"author_name":"Arielle Dascal","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Edward Davoodi Boyd","author_inst":"Department of Neurology, Henry Ford Health, 2799 W Grand Blvd, Detriot, 48202, MI, USA."},{"author_name":"Orrin Devinsky","author_inst":"Epilepsy Center, Neurology Department, NYU Grossman School of Medicine , 223 E 34 Street , New York, 10016, NY, USA; Department of Neurology, Langone School of "},{"author_name":"Niels Kiran Neele Focke","author_inst":"University Medical Center G\u00f6ttingen, Clinic for Neurology, G\u00f6ttingen, Germany."},{"author_name":"Francesco Fortunato","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy, Viale Europa, Catanzaro, 88100, Italy."},{"author_name":"Marian Galovic","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, Zurich, 8091, Switzerland."},{"author_name":"Antonio Gambardella","author_inst":"Department of Medical and Surgical Sciences, Institute of Neurology, Magna Graecia University, Viale Europa, Catanzaro, 88100, Calabria, Italy."},{"author_name":"Renzo Guerrini","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, viale Pieraccini 24, Florence, 50139, Italy; 31 University of Florence, Piazza San "},{"author_name":"Sean N Hatton","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA."},{"author_name":"Mirana Iliza","author_inst":"Department of Psychology, Bishop's University, Sherbrooke, QC, Canada."},{"author_name":"Sara Inati","author_inst":"Neurophysiology of Epilepsy Unit, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Rm 7-5680, Bethesda,"},{"author_name":"Victoria Ives-Deliperi","author_inst":"Department of Psychiatry, Neuroscience Institute, University of Cape Town, Anzio Road, Cape Town, 7800, Western Cape, South Africa."},{"author_name":"Robert-Paul Juster","author_inst":"Department of Psychiatry and Addiction, University of Montreal, Montreal, H3T1J4, QC, Canada."},{"author_name":"Jonathan Kleen","author_inst":"Department of Neurology, 505 Parnassus Avenue, San Francisco, 94143, CA, USA."},{"author_name":"Mohamad Z Koubeissi","author_inst":"Department of Neurology and Rehabilitation Medicine. George Washington University ,Washington, USA."},{"author_name":"Angelo Labate","author_inst":"Neurology Clinic, Department of Neuroscience, Biomedicine and Advanced Diagnostic, University of Palermo, Palermo, Italy, Via del vespro 129, Palermo, 90127, PA"},{"author_name":"Sara Larivi\u00e8re","author_inst":"Department of Medical imaging and radiation sciences, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC, Canada."},{"author_name":"Meng Law","author_inst":"Department of Neuroscience, School of Translational Medicine, The Alfred Hospital, Monash University, 99 Commercial Road, Melbourne, 3004, Victoria, Australia."},{"author_name":"Matteo Lenge","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, viale Pieraccini 24, Florence, 50139, Italy."},{"author_name":"Stefano Meletti","author_inst":"Biomedical Metabolic and Neural Sciences, OCB Hospital, Via giardini 1355, Modena, 41126, Italy; Neurophysiology Unit and epilepsy Centre, OCB Hospital, Modena,"},{"author_name":"Patrick B. Moloney","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom."},{"author_name":"Marlo Naish","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Alexander Ngo","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Terence J. O'Brien","author_inst":"Department of Neuroscience, School of Translational Medicine, The Alfred Hospital, Monash University, 99 Commercial Road, Melbourne, 3004, Victoria, Australia"},{"author_name":"Raluca Pana","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Sofia Panzeri","author_inst":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, via Gaslini 5, Genoa, 16147, Italy."},{"author_name":"Heath Pardoe","author_inst":"New York University Grossman School of Medicine, 223 E 34th St, New York, 10016, NY, USA; Florey Institute of Neuroscience and Mental Health, 245 Burgundy St, H"},{"author_name":"Erik H.U. Rauf","author_inst":"University Medical Center G\u00f6ttingen, Clinic for Neurology, G\u00f6ttingen, Germany."},{"author_name":"Antonella Riva","author_inst":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Via Gerolamo Gaslini 5, Genoa, 16147, Geno"},{"author_name":"Ra\u00fal Rodr\u00edguez-Cruces","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Jessica Royer","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Theodor R\u00fcber","author_inst":"Department of Neuroradiology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany; Department of Epileptology, University Hospital Bonn, Venusber"},{"author_name":"Ella Sahlas","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Lucas Sc\u00e1rdua-Silva","author_inst":"Neuroimaging Laboratory, University of Campinas (UNICAMP), Brazil, Campinas, S\u00e2o Paulo, Brazil."},{"author_name":"Kai Michael Schubert","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, Zurich, 8091, Switzerland."},{"author_name":"Leigh N. Sepeta","author_inst":"Department of Neuropsychology, Children's National Hospital, 111 Michigan Avenue NW Washington, 20010, USA."},{"author_name":"Mariasavina Severino","author_inst":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, via Gaslini 5, Genoa, 16147, Italy."},{"author_name":"Benjamin Sinclair","author_inst":"School of Translational Medicine, Monash University, 99 Commercial Road, Melbourne, 3004, VIC, Australia."},{"author_name":"Hamid Soltanian-Zadeh","author_inst":"Departments of Research Administration and Radiology, Henry Ford Health, 1 Ford Place, Detriot, 48202, MI, USA; School of Electrical and Computer Eng., North Ka"},{"author_name":"Travis Stoub","author_inst":"Neurological Sciences Rush University Medical Center, Chicago, IL, USA."},{"author_name":"Pasquale Striano","author_inst":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Via Gerolamo Gaslini 5, Genoa, 16147, Geno"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 4676 Admiralt"},{"author_name":"Nina V. Valientes","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Anna Elisabetta Vaudano","author_inst":"Department of Biomedical, Metabolic and Neuronal sciences, University of Modena and Reggio-Emilia, Modena, Italy."},{"author_name":"Lucy Vivash","author_inst":"Department of Neuroscience, School of Translational Medicine, The Alfred Hospital, Monash University, 99 Commercial Road, Melbourne, 3004, Victoria, Australia; "},{"author_name":"Clarissa L. Yasuda","author_inst":"Brazilian Institute of Neuroscience and Neurotechnology, Rua Vital Brasil 251, Campinas, 13083888, SP, Brazil; Neurology Department, University of Campinas (UNI"},{"author_name":"Paul M. Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 4676 Admiralt"},{"author_name":"Sanjay Sisodiya","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom; Chalfont Centre for Epilepsy, Chesham "},{"author_name":"Carrie McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA; Department of Psychiatr"},{"author_name":"Boris Bernhardt","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Sofie L. Valk","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Cen"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Sex-related structural alterations across common epilepsies: a worldwide ENIGMA study","rel_doi":"10.64898\/2026.06.06.730611","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730611","rel_abs":"Epilepsy is characterized by widespread structural brain alterations extending beyond the epileptic zone, involving both cortical and subcortical regions. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy have been seldomly reported in neuroimaging studies, partly due to limited sample sizes and single-center designs. Here, we systematically investigated sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multi-center cohort of 1,253 epilepsy patients and 1,077 healthy controls. We studied cortical thickness and subcortical volume in two types of epilepsy: temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Both male and female patients with TLE showed widespread cortical and subcortical thinning compared with controls. In GGE, when compared separately to controls, male patients showed only subtle structural alterations, whereas female patients exhibited more widespread structural alterations. Sex-stratified analyses revealed some variation in the extent and distribution of cortical thickness and subcortical volume alterations between male and female patients in both epilepsy cohorts. Yet, we did not find significant sex-by-diagnosis interaction effects in TLE and GGE. Similarly, no significant interaction effects were observed between sex and age of onset or disease duration in either patient group. Overall, although we observed some differences in regional cortical thickness and subcortical volume between male and female patients with epilepsy, we did not find significant sex-by-diagnosis interactions. Our findings indicate that sex differences in behavioral and clinical outcomes of epilepsy may involve biological or functional processes that require further investigation.","rel_num_authors":69,"rel_authors":[{"author_name":"Huantao Wen","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Cen"},{"author_name":"Bin Wan","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Department of Psychiatry, University Hospitals of Gen\u00e8ve, Thonex, Switzerland"},{"author_name":"Taha Gholipour","author_inst":"Department of Neurosciences, 9300 Campus Point Drive, #7740, La Jolla, 92037, CA, USA."},{"author_name":"Ke Xie","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Judy Chen","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Bianca Serio","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Cen"},{"author_name":"Meike Dorothee Hettwer","author_inst":"Penn Lifespan Informatics & Neuroimaging Center, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, "},{"author_name":"Marina Koutsodontis Machado Alvim","author_inst":"Department of Neurology, University of Campinas-UNICAMP, Rua Tessalia Vieira de Camargo 126, Campinas, 13083-887, SP, Brazil"},{"author_name":"Donatello Arienzo","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA"},{"author_name":"Rafael Batista Jo\u00e3o","author_inst":"Department of Neurology, University of Campinas-UNICAMP, Rua Tessalia Vieira de Camargo 126, Campinas, 13083-887, SP, Brazil; Brazilian Institute of Neuroscienc"},{"author_name":"Tobias Bauer","author_inst":"Department of Neuroradiology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany; Department of Epileptology, University Hospital Bonn, Venusber"},{"author_name":"Andrea Bernasconi","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Neda Bernasconi","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Paolo Bonanni","author_inst":"Scientific Institute IRCCS E.Medea, Epilepsy and Clinical Neurophysiology Unit, Conegliano, Italy"},{"author_name":"Maria Eugenia Caligiuri","author_inst":"Neuroscience Research Center, Department of Medical and Surgical Sciences, University ''Magna Gr\u00e6cia'' of Catanzaro, Catanzaro, Italy"},{"author_name":"Fernando Cendes","author_inst":"Brazilian Institute of Neuroscience and Neurotechnology, Rua Vital Brasil 251, Campinas, 13083888, SP, Brazil."},{"author_name":"Rapha\u00ebl Christin","author_inst":"Department of Neurology, 505 Parnassus Avenue, San Francisco, 94143, CA, USA"},{"author_name":"Luis Concha","author_inst":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Quer\u00e9taro, Mexico"},{"author_name":"Arielle Dascal","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Edward Davoodi Boyd","author_inst":"Department of Neurology, Henry Ford Health, 2799 W Grand Blvd, Detriot, 48202, MI, USA."},{"author_name":"Orrin Devinsky","author_inst":"Epilepsy Center, Neurology Department, NYU Grossman School of Medicine , 223 E 34 Street , New York, 10016, NY, USA; Department of Neurology, Langone School of "},{"author_name":"Niels Kiran Neele Focke","author_inst":"University Medical Center G\u00f6ttingen, Clinic for Neurology, G\u00f6ttingen, Germany."},{"author_name":"Francesco Fortunato","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy, Viale Europa, Catanzaro, 88100, Italy."},{"author_name":"Marian Galovic","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, Zurich, 8091, Switzerland."},{"author_name":"Antonio Gambardella","author_inst":"Department of Medical and Surgical Sciences, Institute of Neurology, Magna Graecia University, Viale Europa, Catanzaro, 88100, Calabria, Italy."},{"author_name":"Renzo Guerrini","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, viale Pieraccini 24, Florence, 50139, Italy; 31 University of Florence, Piazza San "},{"author_name":"Sean N Hatton","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA."},{"author_name":"Mirana Iliza","author_inst":"Department of Psychology, Bishop's University, Sherbrooke, QC, Canada."},{"author_name":"Sara Inati","author_inst":"Neurophysiology of Epilepsy Unit, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Rm 7-5680, Bethesda,"},{"author_name":"Victoria Ives-Deliperi","author_inst":"Department of Psychiatry, Neuroscience Institute, University of Cape Town, Anzio Road, Cape Town, 7800, Western Cape, South Africa."},{"author_name":"Robert-Paul Juster","author_inst":"Department of Psychiatry and Addiction, University of Montreal, Montreal, H3T1J4, QC, Canada."},{"author_name":"Jonathan Kleen","author_inst":"Department of Neurology, 505 Parnassus Avenue, San Francisco, 94143, CA, USA."},{"author_name":"Mohamad Z Koubeissi","author_inst":"Department of Neurology and Rehabilitation Medicine. George Washington University ,Washington, USA."},{"author_name":"Angelo Labate","author_inst":"Neurology Clinic, Department of Neuroscience, Biomedicine and Advanced Diagnostic, University of Palermo, Palermo, Italy, Via del vespro 129, Palermo, 90127, PA"},{"author_name":"Sara Larivi\u00e8re","author_inst":"Department of Medical imaging and radiation sciences, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC, Canada."},{"author_name":"Meng Law","author_inst":"Department of Neuroscience, School of Translational Medicine, The Alfred Hospital, Monash University, 99 Commercial Road, Melbourne, 3004, Victoria, Australia."},{"author_name":"Matteo Lenge","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, viale Pieraccini 24, Florence, 50139, Italy."},{"author_name":"Stefano Meletti","author_inst":"Biomedical Metabolic and Neural Sciences, OCB Hospital, Via giardini 1355, Modena, 41126, Italy; Neurophysiology Unit and epilepsy Centre, OCB Hospital, Modena,"},{"author_name":"Patrick B. Moloney","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom."},{"author_name":"Marlo Naish","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Alexander Ngo","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Terence J. O'Brien","author_inst":"Department of Neuroscience, School of Translational Medicine, The Alfred Hospital, Monash University, 99 Commercial Road, Melbourne, 3004, Victoria, Australia"},{"author_name":"Raluca Pana","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Sofia Panzeri","author_inst":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, via Gaslini 5, Genoa, 16147, Italy."},{"author_name":"Heath Pardoe","author_inst":"New York University Grossman School of Medicine, 223 E 34th St, New York, 10016, NY, USA; Florey Institute of Neuroscience and Mental Health, 245 Burgundy St, H"},{"author_name":"Erik H.U. Rauf","author_inst":"University Medical Center G\u00f6ttingen, Clinic for Neurology, G\u00f6ttingen, Germany."},{"author_name":"Antonella Riva","author_inst":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Via Gerolamo Gaslini 5, Genoa, 16147, Geno"},{"author_name":"Ra\u00fal Rodr\u00edguez-Cruces","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Jessica Royer","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Theodor R\u00fcber","author_inst":"Department of Neuroradiology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany; Department of Epileptology, University Hospital Bonn, Venusber"},{"author_name":"Ella Sahlas","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Lucas Sc\u00e1rdua-Silva","author_inst":"Neuroimaging Laboratory, University of Campinas (UNICAMP), Brazil, Campinas, S\u00e2o Paulo, Brazil."},{"author_name":"Kai Michael Schubert","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Frauenklinikstrasse 26, Zurich, 8091, Switzerland."},{"author_name":"Leigh N. Sepeta","author_inst":"Department of Neuropsychology, Children's National Hospital, 111 Michigan Avenue NW Washington, 20010, USA."},{"author_name":"Mariasavina Severino","author_inst":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, via Gaslini 5, Genoa, 16147, Italy."},{"author_name":"Benjamin Sinclair","author_inst":"School of Translational Medicine, Monash University, 99 Commercial Road, Melbourne, 3004, VIC, Australia."},{"author_name":"Hamid Soltanian-Zadeh","author_inst":"Departments of Research Administration and Radiology, Henry Ford Health, 1 Ford Place, Detriot, 48202, MI, USA; School of Electrical and Computer Eng., North Ka"},{"author_name":"Travis Stoub","author_inst":"Neurological Sciences Rush University Medical Center, Chicago, IL, USA."},{"author_name":"Pasquale Striano","author_inst":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Via Gerolamo Gaslini 5, Genoa, 16147, Geno"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 4676 Admiralt"},{"author_name":"Nina V. Valientes","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Anna Elisabetta Vaudano","author_inst":"Department of Biomedical, Metabolic and Neuronal sciences, University of Modena and Reggio-Emilia, Modena, Italy."},{"author_name":"Lucy Vivash","author_inst":"Department of Neuroscience, School of Translational Medicine, The Alfred Hospital, Monash University, 99 Commercial Road, Melbourne, 3004, Victoria, Australia; "},{"author_name":"Clarissa L. Yasuda","author_inst":"Brazilian Institute of Neuroscience and Neurotechnology, Rua Vital Brasil 251, Campinas, 13083888, SP, Brazil; Neurology Department, University of Campinas (UNI"},{"author_name":"Paul M. Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 4676 Admiralt"},{"author_name":"Sanjay Sisodiya","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom; Chalfont Centre for Epilepsy, Chesham "},{"author_name":"Carrie McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA; Department of Psychiatr"},{"author_name":"Boris Bernhardt","author_inst":"Centre for Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University,"},{"author_name":"Sofie L. Valk","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Cen"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Menstrual cycle selectively elevates anticipatory effort cost without altering reward sensitivity in human motivation","rel_doi":"10.64898\/2026.06.05.730335","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730335","rel_abs":"Motivation fluctuates across the menstrual cycle, yet the computational mechanisms underlying these changes remain unclear. We tested whether hormonally defined cycle phases selectively alter distinct components of effort-based motivation in naturally cycling women (n=51), who completed an effort-reward decision-making task and an effort psychophysics task in both the late-follicular and mid-luteal phases, alongside electrocardiography and ecological momentary assessment. Hierarchical Bayesian modelling revealed that the anticipated cost of physical effort (effort sensitivity) was selectively elevated in the mid-luteal phase, with no corresponding change in reward sensitivity. The luteal increase in effort sensitivity was attenuated in women who entered that phase after days of higher affective valence and arousal, indicating that positive affective state buffers cyclical motivational vulnerability. Complementing these findings, phase-related individual differences in effort the mapping between objective and perceived effort (effort differentiation) were not different by phase, but were moderated by heart rate variability and momentary affective states, revealing stable person-level variation in how the cycle shapes effortful experience. Together, these results identify effort sensitivity as a specific computational mechanism of cyclical motivational change, with implications for understanding the elevated burden of cycle-related psychiatric conditions across the female reproductive lifespan.","rel_num_authors":3,"rel_authors":[{"author_name":"Nitsan Schwarz","author_inst":"Tel Aviv University"},{"author_name":"Daniel Harlev","author_inst":"Tel Aviv University"},{"author_name":"Noham Wolpe","author_inst":"Tel Aviv University"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Adipose tissue as a site of immune activation and dysfunction in individuals with obesity and asthma","rel_doi":"10.64898\/2026.06.08.730463","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730463","rel_abs":"Obesity increases local inflammatory responses in adipose tissue. Individuals with obesity have increased asthma incidence and severity and reduced responses to asthma therapeutics through unknown mechanisms. To identify mechanisms by which increased fat mass augments asthma pathogenesis, single cell RNA sequencing of the immune-rich stromovascular fraction of subcutaneous adipose tissue was conducted from well-characterized adults with obesity-associated asthma matched to adults without asthma. Individuals with asthma had increased abundance of perivascular macrophages and lymphoid-associated macrophages (LAMs) and reduced abundance of classical monocytes and CD4+ and CD8+ naive T cells. Pseudo-bulk differential expression (DE) identified upregulation of cellular metabolism, specifically oxidative phosphorylation, and decreased immune homeostatic pathways in asthma across immune cell subsets. Cell type specific DE analysis of effector cell subtypes identified significant induction of metallothionein gene expression in asthma, a signature of immune cell dysfunction characterized by both an activation and exhaustion phenotype. Gene co-expression analysis identified gene modules associated with asthma diagnosis, lung function, and biomarkers of type 2 inflammation were enriched in effector cells. These data identify adipose tissue dysfunction occurs in obesity-associated asthma and support adipose tissue as therapeutic target to address the enhanced asthma risk among those with obesity.","rel_num_authors":15,"rel_authors":[{"author_name":"Dawn C Newcomb","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alessandra Tomasello","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jean-Pierre Cartailler","author_inst":"Vanderbilt University"},{"author_name":"Bilgunay Ilkin Safa","author_inst":"Vanderbilt University Medical Center"},{"author_name":"LaToya Hannah","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Shristi Shrestha","author_inst":"Vanderbilt University"},{"author_name":"Shahar Hartman","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Melissa H Bloodworth","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kevin Niswender","author_inst":"Vanderbilt University Medical Center"},{"author_name":"John R Koethe","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Samuel Bailin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"James Matthew Luther","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Nancy J Brown","author_inst":"Yale University"},{"author_name":"Mona Mashayekhi","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Katherine N Cahill","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Adipose tissue as a site of immune activation and dysfunction in individuals with obesity and asthma","rel_doi":"10.64898\/2026.06.08.730463","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730463","rel_abs":"Obesity increases local inflammatory responses in adipose tissue. Individuals with obesity have increased asthma incidence and severity and reduced responses to asthma therapeutics through unknown mechanisms. To identify mechanisms by which increased fat mass augments asthma pathogenesis, single cell RNA sequencing of the immune-rich stromovascular fraction of subcutaneous adipose tissue was conducted from well-characterized adults with obesity-associated asthma matched to adults without asthma. Individuals with asthma had increased abundance of perivascular macrophages and lymphoid-associated macrophages (LAMs) and reduced abundance of classical monocytes and CD4+ and CD8+ naive T cells. Pseudo-bulk differential expression (DE) identified upregulation of cellular metabolism, specifically oxidative phosphorylation, and decreased immune homeostatic pathways in asthma across immune cell subsets. Cell type specific DE analysis of effector cell subtypes identified significant induction of metallothionein gene expression in asthma, a signature of immune cell dysfunction characterized by both an activation and exhaustion phenotype. Gene co-expression analysis identified gene modules associated with asthma diagnosis, lung function, and biomarkers of type 2 inflammation were enriched in effector cells. These data identify adipose tissue dysfunction occurs in obesity-associated asthma and support adipose tissue as therapeutic target to address the enhanced asthma risk among those with obesity.","rel_num_authors":15,"rel_authors":[{"author_name":"Dawn C Newcomb","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alessandra Tomasello","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jean-Pierre Cartailler","author_inst":"Vanderbilt University"},{"author_name":"Bilgunay Ilkin Safa","author_inst":"Vanderbilt University Medical Center"},{"author_name":"LaToya Hannah","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Shristi Shrestha","author_inst":"Vanderbilt University"},{"author_name":"Shahar Hartman","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Melissa H Bloodworth","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kevin Niswender","author_inst":"Vanderbilt University Medical Center"},{"author_name":"John R Koethe","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Samuel Bailin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"James Matthew Luther","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Nancy J Brown","author_inst":"Yale University"},{"author_name":"Mona Mashayekhi","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Katherine N Cahill","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Foveal vision in fast-flying birds hunting on the wing","rel_doi":"10.64898\/2026.06.05.730304","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730304","rel_abs":"Processing rapid motion while maintaining high spatial acuity is a fundamental evolutionary challenge for the vertebrate visual system. Here, we investigated the structural adaptations enabling aerial insectivores - swifts (Apus apus) and swallows (Hirundo rustica, Delichon urbicum) - to track and capture prey at high speeds. We show that these phylogenetically distinct species share highly specialized temporal foveae that provide sharp frontal vision. Strikingly, this avian specialization converges on primate foveal architecture, featuring cones with long axons and a unique cluster of large, orthotopic ganglion cells (soma area bigger than 200 square micrometer) surrounding a deep foveal pit. By tracking their large axons, we mapped their neural representation within the optic nerve and tectum. Despite the low abundance of these foveal cells, their substantial tectal magnification reflects high processing demands. This cluster of putative motion-sensitive ganglion cells suggests that foveal neural circuitry links high-acuity vision to rapid temporal processing in these birds.","rel_num_authors":8,"rel_authors":[{"author_name":"Tania Rodrigues","author_inst":"University of Geneva, Switzerland"},{"author_name":"Michel Marc Matter","author_inst":"University of Applied Sciences and Arts Western Switzerland"},{"author_name":"Alain Chiodini","author_inst":"THALES LAS OME, France"},{"author_name":"Bernard Genton","author_inst":"Nos Oiseaux, Switzerland"},{"author_name":"Emilie Brethaut","author_inst":"La Vaux-Lierre, Switzerland"},{"author_name":"Florence Chiodini","author_inst":"University Hospitals of Geneva, Switzerland"},{"author_name":"Lidia Matter-Sadzinski","author_inst":"Foundation Gene & Vision.ch, Switzerland"},{"author_name":"Jean-Marc Matter","author_inst":"University of Geneva, Switzerland"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Auditory Working Memory and Sound Segregation Ability Predict Speech-in-Noise in Adult Cochlear Implant Users","rel_doi":"10.64898\/2026.06.05.730315","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730315","rel_abs":"Abstract Objectives: Outcomes following cochlear implantation vary substantially across adult recipients, and the cognitive and perceptual factors contributing to this variability are not fully understood. This poses a challenge for developing strategies to improve cochlear implant outcomes, as such approaches require a clearer understanding of the mechanisms underlying individual listening difficulties. In this study, we investigated auditory cognitive measures in cochlear implant (CI) users to further elucidate the origins of this variability. Design: Thirty-seven adult cochlear implant users completed measures of auditory cognition, comprising auditory working memory (AWM) and sound segregation ability, measured using an auditory figure-ground task (AFG), as well as measures of peripheral temporal and spectral processing, comprising the temporal modulation detection threshold (TMDT) and spectral ripple discrimination threshold (SRDT). Speech perception outcomes were assessed using word-in-noise (WIN) and sentence-in-noise (SIN) tasks. Separate multiple linear regression models evaluated the unique contribution of the auditory cognition measures to WIN and SIN performance, after accounting for the peripheral measures. Results: Both regression models explained a substantial proportion of variance in speech-in-noise outcomes (WIN: adjusted Rsquare = 0.55; SIN: adjusted Rsquare =0.57, both p < 0.001). For WIN performance, AFG and AWM were significant predictors. A similar pattern was found for SIN performance, where lower AWM ability and poorer AFG segregation were linked to poorer sentence listening in noise. No significant effects of spectral ripple discrimination or temporal modulation detection were observed in either model, even though both were significantly correlated with WIN performance. Conclusions: These findings indicate that auditory working memory and sound segregation ability are robust predictors of speech-in-noise outcomes in adult cochlear implant users, across both word- and sentence-level measures. Together, the results may help explain why speech-in-noise outcomes remain highly variable among CI users, even when basic sensory encoding abilities are taken into account. Incorporating measures of auditory working memory and fundamental sound segregation may therefore improve outcome prediction and help in developing more individualised rehabilitation strategies.","rel_num_authors":8,"rel_authors":[{"author_name":"Hasan Colak","author_inst":"Newcastle University"},{"author_name":"Xiaoxuan Guo","author_inst":"Newcastle University"},{"author_name":"Ester Benzaquen","author_inst":"Instituto de Neurociencias de Alicante"},{"author_name":"Madhusagar Gurusiddappa","author_inst":"James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom"},{"author_name":"Anirvan Banerjee","author_inst":"James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom"},{"author_name":"Inyong Choi","author_inst":"Department of Communication Sciences and Disorders, University of Iowa, Iowa City, IA, USA"},{"author_name":"William Sedley","author_inst":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University"},{"author_name":"Timothy D. Griffiths","author_inst":"Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Untargeted cord blood metabolomics reveals altered lipid metabolism in neonates with gastroschisis","rel_doi":"10.64898\/2026.06.04.730243","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730243","rel_abs":"Gastroschisis is a congenital abdominal wall defect in which fetal intestines herniate into the amniotic cavity. Despite 97% surgical repair success rate, 40% of affected infants require hospital readmission due to gastrointestinal complications, where underlying mechanisms remain poorly characterized. We hypopthesized that the cord blood metabolome of neonates with gastroschisis differs systematically from controls and may reveal pathway-level alterations relevant to neonatal physiology. Cord blood plasma collected at delivery (23 samples each group) was analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Unsupervised principal component analysis and hierarchical clustering demonstrated significant separation between groups (PERMANOVA pseudo-F = 4.632, R-square = 0.095, p = 0.001). 53 metabolites met criteria for differential abundance, 75% were lipids. Key alterations included reduced free fatty acids, increased fatty acid amides and ceramides, disrupted steroid and bile acid metabolism, and decreased biliverdin and bilirubin isomers. Our findings provide insight into gastroschisis pathophysiology and identify potential biomarkers for future investigation.","rel_num_authors":7,"rel_authors":[{"author_name":"Hsuan-Yuan Wang","author_inst":"Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, CA"},{"author_name":"Bryan T. Oshiro","author_inst":"Department of Gynecology and Obstetrics, Loma Linda University School of Medicine, Loma Linda, CA"},{"author_name":"Neela Rahseparian","author_inst":"Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, CA"},{"author_name":"Lauren Crabtree","author_inst":"Department of Gynecology and Obstetrics, Loma Linda University School of Medicine, Loma Linda, CA"},{"author_name":"Joshua F. Robinson","author_inst":"Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, CA"},{"author_name":"Stephanie Gaw","author_inst":"University of California, San Francisco"},{"author_name":"Ciprian Gheorghe","author_inst":"Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Loma Linda University School of Medicine, Loma Linda, CA"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Quantitative determination of longitudinal CNS cholesterol loss during myelin damage and repair","rel_doi":"10.64898\/2026.06.04.729895","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.729895","rel_abs":"Cholesterol in the central nervous system (CNS) is largely unesterified (>99%) and is predominantly present in the myelin sheath (~70% of total CNS cholesterol). Damage to the myelin sheath can result in the conversion of cholesterol to cholesterol esters, which occurs in many neurological diseases, including multiple sclerosis. In this study, we measured longitudinal CNS free cholesterol and cholesterol ester levels in a genetic mouse model during postnatal myelination, demyelination, and remyelination using gas chromatography-mass spectrometry with single ion monitoring technique (GC-MS-SIM) and liquid chromatography mass spectrometry (LC-MS). Cholesterol levels in healthy mouse brains increased up to 38 weeks. In contrast, cholesterol in the healthy spinal cord increased during postnatal timepoints, but then remained steady out to 38 weeks. Interestingly, cholesterol esters in the spinal cord were highest at P1 and drastically reduced by P42, while the brain had similar levels during all postnatal time points. During demyelination, both brain and spinal cord cholesterol levels were significantly reduced as compared to healthy mice and failed to return to normal cholesterol levels even during remyelination. Absolute quantification of cholesterol esters during peak demyelination revealed that cholesterol esters comprise 19% of the total cholesterol pool in the brain and 65% in the spinal cord. The lack of recovery in CNS cholesterol levels after demyelination suggests that healthy de novo cholesterol synthesis pathways are disrupted in this model. Absolute quantification of CNS cholesterol is critical for revealing mechanisms of cholesterol regulation during disease and identifying targets for restoring cholesterol to promote myelin repair.","rel_num_authors":10,"rel_authors":[{"author_name":"Disni Dedunupitiya","author_inst":"University of Kansas"},{"author_name":"Eden P. Go","author_inst":"University of Kansas"},{"author_name":"Travis Witte","author_inst":"University of Kansas"},{"author_name":"Ashlynn Elliott","author_inst":"University of Kansas"},{"author_name":"Nishama De Silva Mohotti","author_inst":"University of Kansas"},{"author_name":"Jenna M. Williams","author_inst":"University of Kansas"},{"author_name":"Hiroko Kobayashi","author_inst":"University of Kansas"},{"author_name":"Rashmi Binjawadagi","author_inst":"University of Kansas"},{"author_name":"Heather Desaire","author_inst":"University of Kansas"},{"author_name":"Meredith D. Hartley","author_inst":"University of Kansas"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Spatiotemporal unfolding of prefrontal neural response divergence in adolescent depression during naturalistic experience","rel_doi":"10.64898\/2026.06.04.730065","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730065","rel_abs":"Depression alters how emotional experience is interpreted and regulated, yet how depression-related neural divergence unfolds during ongoing experience remains poorly understood, leaving unresolved whether such divergence reflects stable trait-like abnormalities or state-dependent responses that emerge only at particular moments. This question is especially consequential in adolescence, when depression often emerges amid heightened social sensitivity and continuing maturation of prefrontal regulatory systems. Here, we used naturalistic film watching fMRI data of 36 adolescents with depression and 36 matched controls to map where, how, and when neural responses diverge between diagnostic groups. Neural polarization analysis localized group-level divergence to two prefrontal hubs, the dmPFC-rACC and left dlPFC, where individual similarity to the depression-group response pattern was associated with depressive symptom severity across the cohort. These local divergence sites were not spatially isolated. Seed-based inter-subject functional connectivity showed that they were embedded within distributed stimulus-locked coupling patterns spanning prefrontal control, salience, and subcortical reward circuits. Time-resolved phase synchrony further revealed that this divergence was not continuous, but arose at specific narrative moments, with the dmPFC-rACC diverging during socio-emotional events and the left dlPFC during cognitively demanding ones. Together, these findings move beyond static localization to reveal depression-related neural divergence as a spatially organized, network-embedded, and temporally gated response pattern shaped by the unfolding content of naturalistic experience.","rel_num_authors":9,"rel_authors":[{"author_name":"Qianhui Liu","author_inst":"University of Chinese Academy of Sciences"},{"author_name":"Weiyang Shi","author_inst":"Institute of Automation, Chinese Academy of Science"},{"author_name":"Haiyan Wang","author_inst":"Institute of Automation, Chinese Academy of Science"},{"author_name":"Wenlu Li","author_inst":"Institute of Automation, Chinese Academy of Sciences"},{"author_name":"Nianyi Liu","author_inst":"Institute of Automation, Chinese Academy of Science"},{"author_name":"Siyao Dong","author_inst":"Institute of Automation, Chinese Academy of Science"},{"author_name":"Congying Chu","author_inst":"Institute of Automation, Chinese Academy of Science"},{"author_name":"Lingzhong Fan","author_inst":"Institute of Automation, Chinese Academy of Science"},{"author_name":"Tianzi Jiang","author_inst":"Institute of Automation, Chinese Academy of Sciences"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Acute stress induces circuit-specific alterations in mesolimbic and nigrostriatal inhibitory transmission and potentiates operant learning","rel_doi":"10.64898\/2026.06.04.729088","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.729088","rel_abs":"Acute stress can facilitate learning about stimuli that predict rewarding outcomes, yet whether stress similarly potentiates acquisition of reward-directed actions remains less well understood. Reward learning broadly depends on dopamine signaling within mesolimbic and nigrostriatal pathways. Dopamine transmission in the mesolimbic system is traditionally associated with cue-reward learning, whereas nigrostriatal dopamine signaling has been implicated in movement vigor and the acquisition of instrumental actions. Stress can alter dopamine transmission within these circuits and thereby influence reward learning. Previous work demonstrated that acute stress downregulates the potassium-chloride cotransporter KCC2 in ventral tegmental area GABA neurons. These stress-induced adaptations in inhibitory transmission enhance mesolimbic dopamine signaling and potentiate associative learning. Here, we show that prior exposure to acute restraint stress facilitates acquisition of operant sucrose self-administration in male and female rats. Enhanced learning was associated with increased temporal coincidence of GABA release events onto dopamine neurons and increased excitability of GABAergic inputs, alterations previously linked to enhanced dopamine signaling. These stress-induced adaptations exhibited marked circuit specificity within mesolimbic and nigrostriatal systems, selectively affecting inhibitory transmission onto dopamine neurons projecting to the nucleus accumbens lateral shell and dorsomedial striatum. Importantly, pharmacological enhancement of KCC2 function with CLP290 normalized inhibitory transmission within these pathways and attenuated stress-induced potentiation of operant learning. Together, these findings identify circuit-specific alterations in midbrain inhibitory signaling induced by acute stress that contribute to enhanced reward learning.","rel_num_authors":5,"rel_authors":[{"author_name":"Helena de Carvalho Schuch","author_inst":"Georgetown University"},{"author_name":"Joyce Woo","author_inst":"Georgetown University"},{"author_name":"Hannah Kugler","author_inst":"Georgetown University"},{"author_name":"Kelly Jiang","author_inst":"University of Pennsylvania"},{"author_name":"Alexey Ostroumov","author_inst":"Georgetown University Medical Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Delta and Theta Activity Provide Shared and Unique Sensitivity to Alcohol and Cocaine Use Disorder","rel_doi":"10.64898\/2026.06.04.723639","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.723639","rel_abs":"The P300 amplitude reduction, or P3AR, is a decrease in the magnitude of the P300 event-related potential (ERP) waveform, typically measured via EEG during oddball tasks, and widely observed in those diagnosed with Alcohol use Disorder (AUD). Though widely acknowledged as a biological correlate of AUD, most of the extant literature on the P3AR features conventional time-domain measurement approaches, and further, the work has predominantly focused on alcohol use specifically. In order to precisely capture the nature of this association as well as assess generalizability to other substances, the current study utilized advanced time-frequency analyses to compare P3 activity in individuals with AUD, cocaine use disorder, and comorbid alcohol and cocaine use. Time-frequency analyses indexed separable theta and delta activity underlying the conventional time-domain P3. Findings revealed that in the conventional time-domain, we observed P3AR shared across alcohol and cocaine use. These findings replicate literature suggesting P3AR associated with substance use. Within time-frequency analyses, we found broad delta reductions across substances, aligning with literature suggesting that delta is mostly comprised of the P3 ERP. For theta-band activity, we found reductions in amplitude specific to alcohol users only, with no significant diminutions present for cocaine users. As most previous literature focused on alcohol use, unique theta modulations relative to cocaine users provides theoretical clarity in terms of the association of P3AR to substance use more broadly. The findings of the current study highlight the utility of time-frequency measurement approaches in parsing overlapping activity and indexing separable processes with relevance to substance use otherwise unaccounted for in the time domain.","rel_num_authors":5,"rel_authors":[{"author_name":"Devin R Butler","author_inst":"University of Iowa"},{"author_name":"Edward Bernat","author_inst":"University of Maryland, College Park"},{"author_name":"Nadia Mattanah","author_inst":"University of Maryland, College Park"},{"author_name":"Sophia Nahabedian","author_inst":"University of Maryland, College Park"},{"author_name":"Vaughn Steele","author_inst":"Yale University"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Delta and Theta Activity Provide Shared and Unique Sensitivity to Alcohol and Cocaine Use Disorder","rel_doi":"10.64898\/2026.06.04.723639","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.723639","rel_abs":"The P300 amplitude reduction, or P3AR, is a decrease in the magnitude of the P300 event-related potential (ERP) waveform, typically measured via EEG during oddball tasks, and widely observed in those diagnosed with Alcohol use Disorder (AUD). Though widely acknowledged as a biological correlate of AUD, most of the extant literature on the P3AR features conventional time-domain measurement approaches, and further, the work has predominantly focused on alcohol use specifically. In order to precisely capture the nature of this association as well as assess generalizability to other substances, the current study utilized advanced time-frequency analyses to compare P3 activity in individuals with AUD, cocaine use disorder, and comorbid alcohol and cocaine use. Time-frequency analyses indexed separable theta and delta activity underlying the conventional time-domain P3. Findings revealed that in the conventional time-domain, we observed P3AR shared across alcohol and cocaine use. These findings replicate literature suggesting P3AR associated with substance use. Within time-frequency analyses, we found broad delta reductions across substances, aligning with literature suggesting that delta is mostly comprised of the P3 ERP. For theta-band activity, we found reductions in amplitude specific to alcohol users only, with no significant diminutions present for cocaine users. As most previous literature focused on alcohol use, unique theta modulations relative to cocaine users provides theoretical clarity in terms of the association of P3AR to substance use more broadly. The findings of the current study highlight the utility of time-frequency measurement approaches in parsing overlapping activity and indexing separable processes with relevance to substance use otherwise unaccounted for in the time domain.","rel_num_authors":5,"rel_authors":[{"author_name":"Devin R Butler","author_inst":"University of Iowa"},{"author_name":"Edward Bernat","author_inst":"University of Maryland, College Park"},{"author_name":"Nadia Mattanah","author_inst":"University of Maryland, College Park"},{"author_name":"Sophia Nahabedian","author_inst":"University of Maryland, College Park"},{"author_name":"Vaughn Steele","author_inst":"Yale University"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Recreating the Native Airway Microenvironment Using Tissue-Specific Extracellular Matrix Bioinks for Proximal Airway Engineering","rel_doi":"10.64898\/2026.06.04.730194","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730194","rel_abs":"Ex vivo airway engineering approaches such as 3D bioprinting are an attractive option for replacing diseased or damaged tissue and have the potential to replicate the ultrastructural complexities of human airways with high fidelity. However, the ability to bioprint hollow, patient-specific proximal airway scaffolds using translationally relevant bioinks remains incompletely realized and may advance future treatments for individuals suffering from end stage disease or congenital airway defects. This work demonstrates the development and utility of biocompatible, polymer-blended human airway-derived decellularized extracellular matrix (AW-dECM) bioinks for the generation of structurally and mechanically relevant proximal airway constructs. Herein, we identify an optimal bioink composition of 30 mg\/mL AW-dECM + commercially available alginate, nanofibrillar cellulose conjugated to the integrin-binding sequence Arg-Gly-Asp or RGD (Cellink-RGD) that results in 1) the successful printability of simple and complex hollow, airway structures with similar mechanical properties to native airways and 2) excellent primary airway epithelial cell viability, adhesion and differentiation. Rheological assessments of airway bioinks reveal similar viscoelastic and stiffness properties to native airway tissue (~8-10 kPa). In vitro studies of isolated human airway epithelial cells cultured on bioinks for 28 days at air-liquid interface demonstrate the excellent biocompatibility of AW-dECM Cellink-RGD bioinks as evidenced by their differentiation to mucociliary and secretory phenotypes. Finally, subcutaneous implantation of bioinks in vivo over 30 days in immunocompetent rats confirms their biodegradative stability and overall biocompatibility as evidenced by lack of infection and necrosis. Overall, this work lays the foundation for the development of improved, physiological airway models and tissue engineered constructs. Most importantly, it also informs optimal biomaterial design of physiological airway-specific bioinks with tunable mechanical properties to promote airway stem cell growth and differentiation.","rel_num_authors":5,"rel_authors":[{"author_name":"Heather Wanczyk","author_inst":"University of Connecticut Health Center"},{"author_name":"Nina Kosciuszek","author_inst":"University of Connecticut Health Center"},{"author_name":"Joanne Walker","author_inst":"University of Connecticut Health Center"},{"author_name":"Daniel J Weiss","author_inst":"University of Vermont"},{"author_name":"Christine Finck","author_inst":"Connecticut Children's Medical Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"A global regulatory atlas of Streptomyces reveals conserved and diversified transcriptional networks across actinomycetes","rel_doi":"10.64898\/2026.06.06.730586","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730586","rel_abs":"Transcriptional regulatory networks determine how bacteria integrate environmental signals with growth, metabolism and stress adaptation. Actinomycetes encode exceptionally large repertoires of transcription factors (TFs) coordinating morphological development, environmental adaptation and specialized metabolism, yet their regulatory networks remain poorly defined. Here, we apply DNA affinity purification sequencing (DAP-seq) to 789 predicted TFs of Streptomyces coelicolor, generating genome-wide binding maps for 393 regulators and expanding the experimentally supported regulome from ~8% to ~50%. Integration with ChIP-seq reveals pleiotropic regulators and hierarchical network architecture linking primary metabolism, development and biosynthetic gene clusters (BGCs). Multiplexed DAP-seq (multiDAP) across 16 additional actinomycetes uncovered deeply conserved regulatory circuits alongside widespread divergence in TF-target interactions. Together, these data establish a regulatory atlas for Streptomyces and related actinomycetes, enabling researchers to explore control of genes, pathways, BGCs and conserved network modules. This provides a foundation for predictive analysis and engineering of complex bacterial phenotypes in biotechnology and medicine.","rel_num_authors":15,"rel_authors":[{"author_name":"Hannah E. Augustijn","author_inst":"Leiden Univertity, Leiden, The Netherlands"},{"author_name":"Hiroshi Otani","author_inst":"Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Augustin Rigolet","author_inst":"Institute of Biology, Leiden University, Leiden, The Netherlands"},{"author_name":"Rachel Stuij","author_inst":"Institute of Biology, Leiden University, Leiden, The Netherlands"},{"author_name":"Leo Baumgart","author_inst":"3.\tUS Department of Energy Joint Genome Institute"},{"author_name":"Vina M. Pham","author_inst":"Institute of Biology, Leiden University, Leiden, The Netherlands"},{"author_name":"Le Zhang","author_inst":"Leiden University, Institute Biology Leiden"},{"author_name":"Yu Zhang","author_inst":"DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Chao Du","author_inst":"Institute of Biology, Leiden University, Leiden, The Netherlands"},{"author_name":"Simona Cernat","author_inst":"Institute of Biology, Leiden University, The Netherlands"},{"author_name":"Sebastien Rigali","author_inst":"InBioS, Center for Protein Engineering, Liege University, Liege, Belgium"},{"author_name":"Ronan O'Malley","author_inst":"DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Marnix H Medema","author_inst":"Wageningen University and Research"},{"author_name":"Nigel Mouncey","author_inst":"DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, US"},{"author_name":"Gilles P. van Wezel","author_inst":"Institue of Biology, Leiden University, Leiden, The Netherlands"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Finding the Goldilocks zone: Modulating glycoprotein cleavage and fusogenicity optimizes the efficacy of a candidate Crimean-Congo hemorrhagic fever virus vaccine","rel_doi":"10.64898\/2026.06.07.730762","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730762","rel_abs":"Crimean-Congo hemorrhagic fever virus (CCHFV) is the etiologic agent of a lethal hemorrhagic disease spread by ticks throughout Europe, the Middle East, Africa and Asia. The lack of approved medical countermeasures and fundamental understanding of molecular mechanisms of viral assembly and egress have thus far curtailed disease prevention. Here, we identify and characterize key residues within the viral glycoprotein through forward and reverse genetics for vesicular stomatitis virus (VSV)-based vaccine candidates that are highly protective in animal models. These residues are broadly applicable across divergent CCHFV strains and lead to greater protection in vivo against heterologous challenge. We further characterize the essential role of proteolytic processing in the maintenance of a stable fusogenic state required for effective VSV-based CCHFV vaccines. This study establishes a toolkit for better understanding orthonairovirus glycoprotein processing and vaccine development.","rel_num_authors":18,"rel_authors":[{"author_name":"Jacob Berrigan","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Stephanie Monticelli","author_inst":"USAMRIID"},{"author_name":"Pieter Spealman","author_inst":"Merrimack College"},{"author_name":"Courtney Cohen","author_inst":"United States Army Medical Research Institute for Infectious Diseases"},{"author_name":"Thomas G. Batchelor","author_inst":"University of California at Santa Cruz Department of Microbiology and Environmental Toxicology"},{"author_name":"Albert Wang","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Elizabeth McFadden","author_inst":"The University of Texas at Austin"},{"author_name":"Russell Bakken","author_inst":"United States Army Medical Research Institute for Infectious Diseases"},{"author_name":"Megan M Slough","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Ariel S. Wirchnianski","author_inst":"Boehringer Ingelheim Pharma GmbH & Co KG"},{"author_name":"Eva Mittler","author_inst":"Albert Einstein College of  Medicine"},{"author_name":"Robert W Cross","author_inst":"Tulane University"},{"author_name":"Thomas Geisbert","author_inst":"The University of Texas Medical Branch at Galveston Department of Microbiology and Immunology"},{"author_name":"Jesse Erasmus","author_inst":"HDT Bio"},{"author_name":"David W. Hawman","author_inst":"NIH, NIAID, DIR"},{"author_name":"Jason S. McLellan","author_inst":"The University of Texas at Austin"},{"author_name":"Andrew S Herbert","author_inst":"US Army Medical Research Institute of Infectious Diseases"},{"author_name":"Kartik Chandran","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Posture and support geometry, rather than body size, dictate lateral dynamic stability in walking mammalian quadrupeds","rel_doi":"10.64898\/2026.06.04.730117","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730117","rel_abs":"Body size and limb posture vary widely across mammals and are expected to shape locomotor stability, yet direct comparative evidence remains limited. Here, we tested whether smaller, crouched mammals exhibit greater lateral dynamic stability than larger, more upright species by comparing treadmill walking in mice and cats at dynamically similar speeds. Using kinematic analyses and size normalized measures of stability, we show that mice are substantially more laterally stable than cats. This increased stability is associated with relatively wider step widths and more crouched limb posture, indicating that support geometry and posture play dominant roles in stabilizing locomotion. Despite these differences, both species regulate lateral balance on a step-by-step basis, as revealed by relationships between center of mass motion and subsequent adjustments of the border of support. Our findings demonstrate that locomotor stability does not scale simply with body size but depends critically on posture dependent strategies that differ across species. These results identify lateral stability as a key factor of locomotor adaptation and suggest that crouched postures in small mammals may reduce reliance on active neural control while enhancing robustness in complex environments.","rel_num_authors":7,"rel_authors":[{"author_name":"Turgay Akay","author_inst":"Dalhousie University"},{"author_name":"Alexander N Klishko","author_inst":"Georgia Institute of Technology"},{"author_name":"Claire E Hanson","author_inst":"Georgia Institute of Technology"},{"author_name":"Seyed Mohammadali Rahmati","author_inst":"Georgia Institute of Technology"},{"author_name":"Kenzie G MacKinnon","author_inst":"Dalhousie University"},{"author_name":"Hangue Park","author_inst":"Sungkyunkwan University"},{"author_name":"Boris I Prilutsky","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"TaxoFormer: Hierarchical Transformer for Predicting the Full Taxonomic Lineage of Protein Sequences","rel_doi":"10.64898\/2026.06.06.730618","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730618","rel_abs":"Predicting labels in massive, hierarchically structured output spaces is a core challenge in machine learning. In this work, we use the problem of predicting the full taxonomic lineage of a protein from its sequence as a case study for this challenge. We introduce TaxoFormer, an architecture whose primary contribution is a structured tokenization scheme that losslessly represents the entire NCBI phylogenetic tree, a graph with over 1.3 million nodes using a compact vocabulary of just 15,000 tokens. By coupling a pre-trained ESM-2 model with an autoregressive decoder and training with a standard cross-entropy objective, we test the hypothesis that a simple generative objective is sufficient to learn complex, latent structure when the output space is explicitly modeled. We show that this approach is highly effective: on a dataset of 188 million proteins, the model not only achieves accurate lineage prediction but also implicitly learns a continuous, phylogenetically-structured latent space. This work provides a scalable, alignment-free method for taxonomic annotation and demonstrates that explicitly modeling the structure of a complex output space is a powerful mechanism for learning meaningful representations.","rel_num_authors":3,"rel_authors":[{"author_name":"Mohammad Parsa","author_inst":"University of California, Berkeley"},{"author_name":"Kooshiar Azimian","author_inst":"310.ai"},{"author_name":"Kathy Y Wei","author_inst":"University of Washington"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"PanKbase Integrated Single-Cell Map: A Comprehensive Atlas of Human Pancreatic Islets","rel_doi":"10.64898\/2026.06.02.729719","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729719","rel_abs":"Abstract Aims\/hypothesis Single-cell RNA sequencing (scRNA-seq) of pancreatic islet tissue is a powerful tool for investigating Type 1 Diabetes (T1D). However, individual datasets are limited in size and fragmented across donors, laboratories, and experimental conditions, highlighting the need for a unified single-cell atlas. This study aimed to construct a comprehensive, integrated scRNA-seq map of human isolated pancreatic islets by collating data from diverse sources. Methods Publicly available scRNA-seq datasets derived from isolated pancreatic islets, generated and\/or provided by the Human Pancreas Analysis Program (HPAP), Prodo Labs, and the Integrated Islet Distribution Program (IIDP), were collected. Systematic quality controls were implemented to select high-quality samples, reads and cells. Data integration was conducted, accounting for important variables such as age, sex, body mass index (BMI), origin study, treatments, islet data\/distribution resources, and sequencing chemistry. Results We generated a comprehensive single-cell atlas of human pancreatic islets comprising 191 high-quality assays from 140 donors (59 female, 81 male) across five phenotypic groups: controls without diabetes (69 donors), autoantibody-positive donors without diabetes (12), pre-diabetic donors (11), donors with type 1 diabetes (12), and donors with type 2 diabetes (36). The atlas also includes experimentally perturbed samples, including those exposed to SARS-CoV-2 infection and pro-inflammatory cytokines. In total, the atlas contains 448,935 cells, capturing major endocrine islet populations, such as alpha cells (43.3%) and beta cells (26.8%), as well as non-endocrine populations such as endothelial cells (0.75%) and immune cells (0.6%). Conclusions\/interpretation By uniformly harmonizing and integrating data from multiple sources, we have developed a comprehensive single-cell atlas of isolated human pancreatic islets, which is publicly available at www.pankbase.org. The atlas provides a platform for hypothesis-driven investigation of diabetes pathophysiology and, given rigorous quality control at the read, barcode, and sample levels alongside careful metadata curation, is well suited for downstream machine-learning applications.","rel_num_authors":35,"rel_authors":[{"author_name":"Ha T.H. Vu","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Han Sun","author_inst":"Department of Pediatrics, Stanford School of Medicine, Stanford University, CA, USA"},{"author_name":"Parul Kudtarkar","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Seth A. Sharp","author_inst":"Department of Pediatrics, Stanford School of Medicine, Stanford University, CA, USA"},{"author_name":"Liza Brusman","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Yiqun Wang","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Yuanhao Huang","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Runbo Mao","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Fan Feng","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Sierra Corban","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Amanda K. Huber","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Alex Shilin","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Ying Sun","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Sara Narayanaswamy","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Dongkeun Jang","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Julie Jurgens","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Cassie C. Robertson","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Shristi Shrestha","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Thomas Bate","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Trang Nguyen","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Patrick Smadbeck","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Lu Zhang","author_inst":"Department of Pediatrics, Stanford School of Medicine, Stanford University, CA, USA"},{"author_name":"Mackenzie Brandes","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"- The PanKbase Consortium","author_inst":""},{"author_name":"Jason Flannick","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Noel Burtt","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Shuibing Chen","author_inst":"Center for Genomic Health, Weill Cornell Medicine, New York, NY, USA"},{"author_name":"Jie Liu","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Jean-Philippe Cartailler","author_inst":"Center for Stem Cell Biology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Benjamin F. Voight","author_inst":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Michael L. Stitzel","author_inst":"Department of Genetics and Genome Sciences, University of Connecticut, Farmington, CT, USA"},{"author_name":"Marcela Brissova","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Anna L. Gloyn","author_inst":"Department of Pediatrics, Stanford School of Medicine, Stanford University, CA, USA"},{"author_name":"Kyle J. Gaulton","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Stephen C.J. Parker","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"PanKbase Integrated Single-Cell Map: A Comprehensive Atlas of Human Pancreatic Islets","rel_doi":"10.64898\/2026.06.02.729719","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729719","rel_abs":"Abstract Aims\/hypothesis Single-cell RNA sequencing (scRNA-seq) of pancreatic islet tissue is a powerful tool for investigating Type 1 Diabetes (T1D). However, individual datasets are limited in size and fragmented across donors, laboratories, and experimental conditions, highlighting the need for a unified single-cell atlas. This study aimed to construct a comprehensive, integrated scRNA-seq map of human isolated pancreatic islets by collating data from diverse sources. Methods Publicly available scRNA-seq datasets derived from isolated pancreatic islets, generated and\/or provided by the Human Pancreas Analysis Program (HPAP), Prodo Labs, and the Integrated Islet Distribution Program (IIDP), were collected. Systematic quality controls were implemented to select high-quality samples, reads and cells. Data integration was conducted, accounting for important variables such as age, sex, body mass index (BMI), origin study, treatments, islet data\/distribution resources, and sequencing chemistry. Results We generated a comprehensive single-cell atlas of human pancreatic islets comprising 191 high-quality assays from 140 donors (59 female, 81 male) across five phenotypic groups: controls without diabetes (69 donors), autoantibody-positive donors without diabetes (12), pre-diabetic donors (11), donors with type 1 diabetes (12), and donors with type 2 diabetes (36). The atlas also includes experimentally perturbed samples, including those exposed to SARS-CoV-2 infection and pro-inflammatory cytokines. In total, the atlas contains 448,935 cells, capturing major endocrine islet populations, such as alpha cells (43.3%) and beta cells (26.8%), as well as non-endocrine populations such as endothelial cells (0.75%) and immune cells (0.6%). Conclusions\/interpretation By uniformly harmonizing and integrating data from multiple sources, we have developed a comprehensive single-cell atlas of isolated human pancreatic islets, which is publicly available at www.pankbase.org. The atlas provides a platform for hypothesis-driven investigation of diabetes pathophysiology and, given rigorous quality control at the read, barcode, and sample levels alongside careful metadata curation, is well suited for downstream machine-learning applications.","rel_num_authors":35,"rel_authors":[{"author_name":"Ha T.H. Vu","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Han Sun","author_inst":"Department of Pediatrics, Stanford School of Medicine, Stanford University, CA, USA"},{"author_name":"Parul Kudtarkar","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Seth A. Sharp","author_inst":"Department of Pediatrics, Stanford School of Medicine, Stanford University, CA, USA"},{"author_name":"Liza Brusman","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Yiqun Wang","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Yuanhao Huang","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Runbo Mao","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Fan Feng","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Sierra Corban","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Amanda K. Huber","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Alex Shilin","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Ying Sun","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Sara Narayanaswamy","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Dongkeun Jang","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Julie Jurgens","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Cassie C. Robertson","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Shristi Shrestha","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Thomas Bate","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Trang Nguyen","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Patrick Smadbeck","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Lu Zhang","author_inst":"Department of Pediatrics, Stanford School of Medicine, Stanford University, CA, USA"},{"author_name":"Mackenzie Brandes","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"- The PanKbase Consortium","author_inst":""},{"author_name":"Jason Flannick","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Noel Burtt","author_inst":"Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Shuibing Chen","author_inst":"Center for Genomic Health, Weill Cornell Medicine, New York, NY, USA"},{"author_name":"Jie Liu","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Jean-Philippe Cartailler","author_inst":"Center for Stem Cell Biology, Vanderbilt University, Nashville, Tennessee, USA"},{"author_name":"Benjamin F. Voight","author_inst":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Michael L. Stitzel","author_inst":"Department of Genetics and Genome Sciences, University of Connecticut, Farmington, CT, USA"},{"author_name":"Marcela Brissova","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Anna L. Gloyn","author_inst":"Department of Pediatrics, Stanford School of Medicine, Stanford University, CA, USA"},{"author_name":"Kyle J. Gaulton","author_inst":"Department of Pediatrics, University of California, San Diego, La Jolla, CA USA"},{"author_name":"Stephen C.J. Parker","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Leptin Drives Osteoarthritis Pain Through Sensory Neuron Reprogramming Independent of Cartilage Signaling","rel_doi":"10.64898\/2026.05.22.727205","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.22.727205","rel_abs":"Objective: Pain in osteoarthritis (OA) is often discordant with structural joint damage, particularly in obesity-associated OA, where adipose-derived signals may drive nociception independently of cartilage pathology. Leptin has been demonstrated to be necessary, but not sufficient, to drive obesity-associated OA. Here, we tested the hypothesis that leptin mediates OA-associated pain through sensory neuron reprogramming rather than chondrocyte-intrinsic signaling, suggesting a fat-sensory nerve axis. Design: Male and female constitutive leptin-deficient (Ob\/Ob), heterozygous (Ob\/+), and wild-type (WT) mice, as well as chondrocyte-specific leptin receptor knockout mice (Aggrecan-CreERT2;LepRfl\/fl), were challenged with destabilization of the medial meniscus (DMM) surgery to induce OA. Pain-related behaviors, joint pathology, serum cytokines, and lumbar dorsal root ganglia (DRG) transcriptomes were assessed. Human DRG cultures treated with leptin underwent transcriptomic profiling. Secondary analyses of human infrapatellar fat pad and synovium single-cell datasets evaluated leptin and leptin receptor expression patterns. Results: Chondrocyte-specific deletion of the leptin receptor did not mitigate OA pathology or pain. Global leptin-deficient (Ob\/Ob) mice exhibited worse structural joint outcomes than WT and Ob\/+ animals following DMM yet were robustly protected from OA-associated hyperalgesia - directly dissociating pain from structural pathology and demonstrating that leptin is involved in nociceptive sensitization. Serum cytokine profiles were sex-dependent and did not align with pain outcomes, separating systemic inflammation from nociceptive differences. Transcriptomic analysis of DRGs revealed that leptin drives enrichment of lipid metabolism, eicosanoid, and inflammatory programs, whereas leptin deficiency shifts sensory neurons toward a cytoskeletal remodeling state that does not sustain pain signaling. In human DRG cultures, leptin treatment produced a transcriptomic shift to enrich for neuronal excitability while vehicle treated cells were enriched for inflammatory signaling. Human infrapatellar fat pad and synovium transcriptomic data demonstrated adipocyte-enriched leptin expression and broad distribution of the leptin receptor across stromal, vascular, immune, and adipocyte populations. Conclusions: Leptin contributes to OA pain through neuro-immune crosstalk between adipose tissue and sensory neurons rather than through direct cartilage signaling. These findings identify leptin-associated neuronal programs linked to nociceptor sensitization and support targeting leptin-modulated neuro-immune pathways as a strategy to alleviate OA pain independently of structural disease progression.","rel_num_authors":13,"rel_authors":[{"author_name":"Hope Welhaven","author_inst":"University of California San Francisco"},{"author_name":"Elise K Truchan","author_inst":"University of California San Francisco"},{"author_name":"Kristin L Lenz","author_inst":"Washington University in St. Louis"},{"author_name":"Bethany A Andoko","author_inst":"University of California San Francisco"},{"author_name":"Michael Mazzucco","author_inst":"The Rockefeller University"},{"author_name":"Reyna E Villa","author_inst":"University of California San Francisco"},{"author_name":"Arin K Oestreich","author_inst":"Washington University in St. Louis"},{"author_name":"Bo Zhang","author_inst":"Washington University in St. Louis"},{"author_name":"Dana E Orange","author_inst":"The Rockefeller University"},{"author_name":"Joseph B Lesnak","author_inst":"University of Texas at Dallas"},{"author_name":"Theodore J Price","author_inst":"University of Texas at Dallas"},{"author_name":"Farshid Guilak","author_inst":"Washington University and Shriners Hospitals for Children"},{"author_name":"Kelsey H. Collins","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Leptin Drives Osteoarthritis Pain Through Sensory Neuron Reprogramming Independent of Cartilage Signaling","rel_doi":"10.64898\/2026.05.22.727205","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.22.727205","rel_abs":"Objective: Pain in osteoarthritis (OA) is often discordant with structural joint damage, particularly in obesity-associated OA, where adipose-derived signals may drive nociception independently of cartilage pathology. Leptin has been demonstrated to be necessary, but not sufficient, to drive obesity-associated OA. Here, we tested the hypothesis that leptin mediates OA-associated pain through sensory neuron reprogramming rather than chondrocyte-intrinsic signaling, suggesting a fat-sensory nerve axis. Design: Male and female constitutive leptin-deficient (Ob\/Ob), heterozygous (Ob\/+), and wild-type (WT) mice, as well as chondrocyte-specific leptin receptor knockout mice (Aggrecan-CreERT2;LepRfl\/fl), were challenged with destabilization of the medial meniscus (DMM) surgery to induce OA. Pain-related behaviors, joint pathology, serum cytokines, and lumbar dorsal root ganglia (DRG) transcriptomes were assessed. Human DRG cultures treated with leptin underwent transcriptomic profiling. Secondary analyses of human infrapatellar fat pad and synovium single-cell datasets evaluated leptin and leptin receptor expression patterns. Results: Chondrocyte-specific deletion of the leptin receptor did not mitigate OA pathology or pain. Global leptin-deficient (Ob\/Ob) mice exhibited worse structural joint outcomes than WT and Ob\/+ animals following DMM yet were robustly protected from OA-associated hyperalgesia - directly dissociating pain from structural pathology and demonstrating that leptin is involved in nociceptive sensitization. Serum cytokine profiles were sex-dependent and did not align with pain outcomes, separating systemic inflammation from nociceptive differences. Transcriptomic analysis of DRGs revealed that leptin drives enrichment of lipid metabolism, eicosanoid, and inflammatory programs, whereas leptin deficiency shifts sensory neurons toward a cytoskeletal remodeling state that does not sustain pain signaling. In human DRG cultures, leptin treatment produced a transcriptomic shift to enrich for neuronal excitability while vehicle treated cells were enriched for inflammatory signaling. Human infrapatellar fat pad and synovium transcriptomic data demonstrated adipocyte-enriched leptin expression and broad distribution of the leptin receptor across stromal, vascular, immune, and adipocyte populations. Conclusions: Leptin contributes to OA pain through neuro-immune crosstalk between adipose tissue and sensory neurons rather than through direct cartilage signaling. These findings identify leptin-associated neuronal programs linked to nociceptor sensitization and support targeting leptin-modulated neuro-immune pathways as a strategy to alleviate OA pain independently of structural disease progression.","rel_num_authors":13,"rel_authors":[{"author_name":"Hope Welhaven","author_inst":"University of California San Francisco"},{"author_name":"Elise K Truchan","author_inst":"University of California San Francisco"},{"author_name":"Kristin L Lenz","author_inst":"Washington University in St. Louis"},{"author_name":"Bethany A Andoko","author_inst":"University of California San Francisco"},{"author_name":"Michael Mazzucco","author_inst":"The Rockefeller University"},{"author_name":"Reyna E Villa","author_inst":"University of California San Francisco"},{"author_name":"Arin K Oestreich","author_inst":"Washington University in St. Louis"},{"author_name":"Bo Zhang","author_inst":"Washington University in St. Louis"},{"author_name":"Dana E Orange","author_inst":"The Rockefeller University"},{"author_name":"Joseph B Lesnak","author_inst":"University of Texas at Dallas"},{"author_name":"Theodore J Price","author_inst":"University of Texas at Dallas"},{"author_name":"Farshid Guilak","author_inst":"Washington University and Shriners Hospitals for Children"},{"author_name":"Kelsey H. Collins","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Leptin Drives Osteoarthritis Pain Through Sensory Neuron Reprogramming Independent of Cartilage Signaling","rel_doi":"10.64898\/2026.05.22.727205","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.22.727205","rel_abs":"Objective: Pain in osteoarthritis (OA) is often discordant with structural joint damage, particularly in obesity-associated OA, where adipose-derived signals may drive nociception independently of cartilage pathology. Leptin has been demonstrated to be necessary, but not sufficient, to drive obesity-associated OA. Here, we tested the hypothesis that leptin mediates OA-associated pain through sensory neuron reprogramming rather than chondrocyte-intrinsic signaling, suggesting a fat-sensory nerve axis. Design: Male and female constitutive leptin-deficient (Ob\/Ob), heterozygous (Ob\/+), and wild-type (WT) mice, as well as chondrocyte-specific leptin receptor knockout mice (Aggrecan-CreERT2;LepRfl\/fl), were challenged with destabilization of the medial meniscus (DMM) surgery to induce OA. Pain-related behaviors, joint pathology, serum cytokines, and lumbar dorsal root ganglia (DRG) transcriptomes were assessed. Human DRG cultures treated with leptin underwent transcriptomic profiling. Secondary analyses of human infrapatellar fat pad and synovium single-cell datasets evaluated leptin and leptin receptor expression patterns. Results: Chondrocyte-specific deletion of the leptin receptor did not mitigate OA pathology or pain. Global leptin-deficient (Ob\/Ob) mice exhibited worse structural joint outcomes than WT and Ob\/+ animals following DMM yet were robustly protected from OA-associated hyperalgesia - directly dissociating pain from structural pathology and demonstrating that leptin is involved in nociceptive sensitization. Serum cytokine profiles were sex-dependent and did not align with pain outcomes, separating systemic inflammation from nociceptive differences. Transcriptomic analysis of DRGs revealed that leptin drives enrichment of lipid metabolism, eicosanoid, and inflammatory programs, whereas leptin deficiency shifts sensory neurons toward a cytoskeletal remodeling state that does not sustain pain signaling. In human DRG cultures, leptin treatment produced a transcriptomic shift to enrich for neuronal excitability while vehicle treated cells were enriched for inflammatory signaling. Human infrapatellar fat pad and synovium transcriptomic data demonstrated adipocyte-enriched leptin expression and broad distribution of the leptin receptor across stromal, vascular, immune, and adipocyte populations. Conclusions: Leptin contributes to OA pain through neuro-immune crosstalk between adipose tissue and sensory neurons rather than through direct cartilage signaling. These findings identify leptin-associated neuronal programs linked to nociceptor sensitization and support targeting leptin-modulated neuro-immune pathways as a strategy to alleviate OA pain independently of structural disease progression.","rel_num_authors":13,"rel_authors":[{"author_name":"Hope Welhaven","author_inst":"University of California San Francisco"},{"author_name":"Elise K Truchan","author_inst":"University of California San Francisco"},{"author_name":"Kristin L Lenz","author_inst":"Washington University in St. Louis"},{"author_name":"Bethany A Andoko","author_inst":"University of California San Francisco"},{"author_name":"Michael Mazzucco","author_inst":"The Rockefeller University"},{"author_name":"Reyna E Villa","author_inst":"University of California San Francisco"},{"author_name":"Arin K Oestreich","author_inst":"Washington University in St. Louis"},{"author_name":"Bo Zhang","author_inst":"Washington University in St. Louis"},{"author_name":"Dana E Orange","author_inst":"The Rockefeller University"},{"author_name":"Joseph B Lesnak","author_inst":"University of Texas at Dallas"},{"author_name":"Theodore J Price","author_inst":"University of Texas at Dallas"},{"author_name":"Farshid Guilak","author_inst":"Washington University and Shriners Hospitals for Children"},{"author_name":"Kelsey H. Collins","author_inst":"University of California San Francisco"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Connectivity Logic of Dendritic Spines in Cortex: Increased Inputs and Ensemble Formation","rel_doi":"10.64898\/2026.06.07.730704","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730704","rel_abs":"Dendritic spines, small protrusions covering the dendrites of most neurons, are fundamental elements of synaptic connectivity, yet their network-level organization remains poorly understood. Here we leverage the large-scale MICrONS volumetric electron microscopy dataset of mouse primary visual cortex to explore the connectivity logic of dendritic spines across multiple spatial scales. Our analysis provides structural support for the ``connectivity and diversity'' hypothesis, showing that, for both excitatory and inhibitory neurons, dendritic spine density correlates with the number and the diversity of presynaptic partners. We further show that the preference for excitatory axons to form synapses on spines increases with distance from the soma. In addition, we find that spines serve as postsynaptic targets for high-output neurons (``out hubs''). We finally uncover an input\/output correlation, in which neurons that share their input also preferentially target spines through their axonal output. These correlations persist across network sizes, consistent with a scale-invariant structural organization of cortical connectivity. We hypothesize that dendritic spines provide a structural substrate for network-level cooperation, by enabling distributed cortical activity to propagate through parallel synchronous chains, potentially amplified by nonlinear voltage responses at the spine and cellular level. These findings suggest that dendritic spines are key structural mechanisms for neuronal ensembles, attractor dynamics, and pattern completion.","rel_num_authors":5,"rel_authors":[{"author_name":"Dean Geckt","author_inst":"The Hebrew University of Jerusalem"},{"author_name":"Netanel Ofer","author_inst":"Ariel University"},{"author_name":"Michael W. Reimann","author_inst":"Open Brain Institute"},{"author_name":"Rafael Yuste","author_inst":"Columbia University"},{"author_name":"Idan Segev","author_inst":"The Hebrew University of Jerusalem"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Two melanic pigment patterns are associated with a sex chromosome-linked oncogene in the mountain swordtail Xiphophorus nezahualcoyotl","rel_doi":"10.64898\/2026.06.08.730778","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730778","rel_abs":"Sex-linked traits are widespread, but their genetic architecture has been challenging to characterize, due in part to the repetitive and structurally complex nature of sex chromosomes. In swordtails and platyfish of the genus Xiphophorus, diverse melanic pigmentation patterns are thought to be controlled by a region on the sex chromosomes classically referred to as the \"macromelanophore determining locus\". Despite nearly a century of study, the identity of the causal gene remains controversial, partially due to previous inability to fully sequence the sex chromosomes. Here, we characterize and investigate two melanin-based pigmentation phenotypes in the species X. nezahualcoyotl: \"spotted side\" and \"marmoratus\". We generate a gapless near-telomere-to-telomere X. nezahualcoyotl assembly and perform GWAS to identify regions associated with pigmentation pattern variation and sex-determination. We find both patterns map near the sex-determining region and to a narrow interval near the oncogene xmrk. By generating additional long-read assemblies of sex chromosomes derived from individuals with distinct phenotypes, we find haplotypes containing xmrk can be both X- and Y-linked, and vary dramatically in gene content, structure, and accumulation of repetitive elements including a newly described composite satellite. This variability may impact the region's stability and affect recombination between haplotypes associated with each pattern. Our results shed light on a longstanding debate surrounding the genetic architecture of sex-linked phenotypes. More generally, we showcase how long-read sequencing can reveal phenotypic variation linked to complex and dynamic genomic regions, which may contribute to the evolution of diverse sex-linked traits.","rel_num_authors":12,"rel_authors":[{"author_name":"Lyle A Given","author_inst":"Department of Biology, Stanford University, Stanford, CA, USA"},{"author_name":"Landen Gozashti","author_inst":"Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA"},{"author_name":"John J Baczenas","author_inst":"Howard Hughes Medical Institute, Stanford, CA, USA"},{"author_name":"Rhea Sood","author_inst":"Department of Biology, Stanford University, Stanford, CA, USA"},{"author_name":"Nadia B Haghani","author_inst":"Department of Biology, Stanford University, Stanford, CA, USA"},{"author_name":"Kelsie E Hunnicutt","author_inst":"Department of Biology, Stanford University, Stanford, CA, USA"},{"author_name":"Theresa R Gunn","author_inst":"Department of Biology, Stanford University, Stanford, CA, USA"},{"author_name":"Gabriel A Preising","author_inst":"Department of Biology, Stanford University, Stanford, CA, USA"},{"author_name":"Peter H Sudmant","author_inst":"Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA"},{"author_name":"Daniel L Powell","author_inst":"Department of Biology, Louisiana State University, Baton Rouge, LA, USA"},{"author_name":"Tristram O. Dodge","author_inst":"Stanford University"},{"author_name":"Molly Schumer","author_inst":"Department of Biology, Stanford University, Stanford, CA, USA"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Choriodecidual Ureaplasma parvum infection induces fetal lung inflammation prior to intra-amniotic infection in a nonhuman primate model","rel_doi":"10.64898\/2026.06.06.730594","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730594","rel_abs":"Preterm birth before 28 weeks remains a leading cause of neonatal mortality and long-term morbidity. Intrauterine infection-driven chorioamnionitis is strongly associated with preterm labor, fetal inflammatory response syndrome, and neonatal lung disease. Ureaplasma species are among the most common organisms isolated in chorioamnionitis and are frequently detected in the placenta, amniotic fluid, and respiratory tract of preterm infants. Clinical and experimental data implicate Ureaplasma exposure in early lung inflammation, impaired alveolar development, and bronchopulmonary dysplasia (BPD), yet the pathogenic events preceding microbial invasion of the amniotic cavity or fetal tissues remain poorly defined. To characterize early intrauterine and fetal lung inflammatory responses to localized choriodecidual U. parvum infection, we used a chronically catheterized pregnant rhesus macaque (Macaca mulatta) model. Time-mated animals underwent surgical placement of maternal, amniotic, and choriodecidual catheters and were inoculated with low-passage U. parvum serovar 1 or vehicle control at approximately 117 days gestational age. Placenta, fetal membranes, fetal plasma, and fetal lungs were assessed by qRT-PCR, multiplex cytokine assays, immunoblotting, immunohistochemistry, and trichrome staining to evaluate inflammatory signaling, inflammasome activation, prostaglandin pathways, immune cell infiltration, fibrosis, and lung maturation markers. Choriodecidual infection was confirmed in all inoculated animals. Amniotic fluid remained culture- and PCR-negative, and fetal lungs were largely free of detectable bacterial DNA. Despite the absence of intra-amniotic infection, fetal lung cytokine profiling revealed broad pro-inflammatory activation, with elevated GM-CSF, IL-1{beta}, IL-6, IL-8, MIP-1\/{beta}, MCP-1, VEGF and reduced IL-10 contrasting with a modest systemic response limited to elevated plasma IL-18. Fetal lungs showed increased immune cell infiltration, upregulation of NLRP3, PYCARD, and CASP1, and activation of SAPK\/JNK and NF-{kappa}B signaling. Histopathology demonstrated increased alveolar macrophages and intra-alveolar neutrophils with minimal fibrosis. Surfactant gene expression was altered (increased SFTPA, decreased SFTPB), and elevated -SMA indicated early myofibroblast activation. Localized choriodecidual U. parvum infection induces fetal lung inflammation prior to detectable intra-amniotic infection, demonstrating that direct infection of the amniotic fluid or fetal lung is not required for the initiation of fetal pulmonary inflammation. These findings suggest that subclinical ascending infection may initiate fetal lung injury and increase susceptibility to postnatal respiratory morbidity associated with preterm birth.","rel_num_authors":5,"rel_authors":[{"author_name":"Sudeshna Tripathy","author_inst":"Oregon Health & Science University"},{"author_name":"Nathan Crilley","author_inst":"Oregon Health & Science University"},{"author_name":"Terry  K Morgan","author_inst":"Oregon Health & Science University"},{"author_name":"Robert  L Schelonka","author_inst":"Oregon Health & Science University"},{"author_name":"Meredith  A. Kelleher","author_inst":"Oregon Health & Science University Oregon National Primate Research Center"}],"rel_date":"2026-06-09","rel_site":"biorxiv"},{"rel_title":"Neonatal Brain Network Integration Trajectories Predict Neurodevelopment in Congenital Heart","rel_doi":"10.64898\/2026.06.06.26355074","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355074","rel_abs":"Impact statementO_LIIn infants with critical congenital heart disease, perioperative growth in whole-brain network integration was associated with cognitive, language, and motor outcomes in early childhood.\nC_LIO_LIWhite matter injury was associated with slower growth in network integration, whereas cardiac physiology subtype was not associated with network development.\nC_LIO_LIThis study extends prior work by showing that a longitudinal measure of neonatal whole-brain network development, rather than a single imaging timepoint, predicts neurodevelopment across multiple domains.\nC_LIO_LIThese findings identify early network development as a potential biomarker of neurodevelopmental risk and resilience, and support future risk-stratification and intervention studies in this population.\nC_LI\n\nBackgroundInfants with critical congenital heart disease (CHD) are at high risk for abnormal brain development and later neurodevelopmental impairment. We hypothesized that the trajectory of perioperative whole-brain network development would predict neurodevelopmental outcomes in early childhood.\n\nMethodsThis prospective longitudinal cohort of neonates with critical CHD (n = 97) underwent preoperative and\/or postoperative brain MRI with diffusion imaging. Whole-brain network measures were derived from structural connectomes. Neurodevelopment was assessed between 1 and 4 years using the Bayley Scales of Infant and Toddler Development.\n\nResultsWhite matter injury was associated with slower perioperative growth in global efficiency (p = 0.013), a measure of network integration, whereas cardiac physiology was not associated with network development. Infants with greater perioperative increases in global efficiency had higher cognitive (p = 0.001), language (p < 0.001), and motor (p = 0.008) scores. For each 1-standard deviation increase in the trajectory of global efficiency, cognitive scores increased by 8.2 points (95% CI, 3.64-12.78), independent of brain injury and socioeconomic factors.\n\nConclusionIn infants with critical CHD, longitudinal whole-brain network development was associated with neurodevelopment across multiple domains. Early network development may represent a candidate biomarker of neurodevelopmental risk and resilience in this population.","rel_num_authors":7,"rel_authors":[{"author_name":"Lauren Harasymiw","author_inst":"University of California, San Francisco"},{"author_name":"Amy Kuang","author_inst":"University of California, San Francisco"},{"author_name":"Duan Xu","author_inst":"University of California, San Francisco"},{"author_name":"Aaron Scheffler","author_inst":"University of California, San Francisco"},{"author_name":"Elizabeth George","author_inst":"University of California, San Francisco"},{"author_name":"Shabnam Peyvandi","author_inst":"University of California, San Francisco"},{"author_name":"Patrick McQuillen","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Associations between initial treatments for acute low back pain and opioid use disorder and overdose risk in Medicaid patients","rel_doi":"10.64898\/2026.06.05.26355003","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26355003","rel_abs":"Introduction: Acute low back pain is a leading cause of disability worldwide. Clinical guidelines recommend non-pharmacological therapies as first-line treatment and advise caution with opioid prescribing. However pharmacological therapies, including opioids and gabapentinoids, remain commonly used. The comparative risks of subsequent opioid use disorder (OUD) and overdose diagnosis associated with initial treatment modality in large, real-world populations is not well characterized. We estimated the incidence of new-onset OUD and overdose diagnosis among opioid-naive, Medicaid-insured adults with newly diagnosed acute low back pain and estimated the association between initial treatment modalities and subsequent OUD and overdose diagnosis risk. Methods: We conducted a retrospective cohort study using Medicaid T-MSIS Analytic files from 25 states (2016-2019). We identified opioid-naive adults with a new diagnosis of acute low back pain who initiated pharmacologic or non-pharmacologic treatment within 1 month of diagnosis. The primary outcome was incident OUD and overdose diagnosis (based on diagnosis codes in claims) during follow-up. Associations between initial treatment modality and OUD and overdose diagnosis risk were estimated using a non-parametric, doubly robust estimator to adjust for measured confounding. Results: The cohort included 525,002 opioid-naive adults initiating treatment for low back pain. The cumulative incidence of OUD and overdose diagnosis was 1.5% and 2.4% at 7 and 13 months, respectively. Compared to non-use, use of gabapentinoids during the first month of treatment was associated with the highest relative risk (increasing risk) by 130.1%, 95% confidence interval (CI): 117.8%, 142.3%), the second-highest relative risk was estimated for higher-dose opioids, defined as > 50 daily Morphine Milligram Equivalents (MME) (118.1%, 95% CI: 99.2%, 137.0%). Lower-dose, short-duration opioids ([&le;] 50 MME, [&le;] 7 days) were also associated with elevated risk, though substantially smaller in magnitude (20.8%, 95% CI: 13.8%, 27.9%). In contrast, non-pharmacologic, non-interventional therapies were associated with reduced OUD and overdose diagnosis risk, with physical therapy demonstrating the largest relative reduction of 34.0% (95% CI: -40.9%, -27.1%). Discussion: In opioid-naive Medicaid patients with acute low back pain, initial non-pharmacologic treatment was associated with reduced OUD and overdose diagnosis risk. Gabapentinoids and opioids were each associated with increased risk; for opioids, the degree of risk increased with higher doses and durations. These results support guideline recommendations favoring non-pharmacologic treatment as first-line therapy and indicate the importance of cautious prescribing when pharmacologic treatment is considered.","rel_num_authors":5,"rel_authors":[{"author_name":"Lisa V Doan","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Anton M Hung","author_inst":"Columbia University"},{"author_name":"Mark Olfson","author_inst":"Columbia University"},{"author_name":"Nicholas T Williams","author_inst":"University of California at Berkeley"},{"author_name":"Kara E Rudolph","author_inst":"Columbia University"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry analysis of POLG variants in Parkinson's disease","rel_doi":"10.64898\/2026.06.07.26354811","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354811","rel_abs":"Introduction: Variants in the polymerase gamma (POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinson's disease (PD); yet, results remain inconclusive. Objectives: To investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries. Methods: We leveraged multi-ancestry genetic data from the Global Parkinson's Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses. Results: Five PD cases carried potentially biallelic rare pathogenic\/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic\/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD. Conclusions: POLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG-related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.","rel_num_authors":14,"rel_authors":[{"author_name":"Yi Wen Tay","author_inst":"University of Malaya, Malaysia"},{"author_name":"Inas Elsayed","author_inst":"University of Gezira, Wad Medani, Sudan"},{"author_name":"Dennis Yeow","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Mikayla James","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Pin-Jui Kung","author_inst":"National Taiwan University Hospital, Taipei, Taiwan"},{"author_name":"Laurel Screven","author_inst":"GP2, Bethesda, USA"},{"author_name":"Allison A. Dilliott","author_inst":"Parkinsons Foundation, NewYork, NY 10018, USA"},{"author_name":"Roy N. Alcalay","author_inst":"Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"Zih-Hua Fang","author_inst":"DataTecnica LLC, Washington, DC 20037, USA"},{"author_name":"Ai Huey Tan","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"- Global Parkinson's Genetics Program (GP2)","author_inst":"-"},{"author_name":"Carolyn M Sue","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Lara M Lange","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Maria Teresa Perinan","author_inst":"Queen Mary University of London, London, United Kingdom"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry analysis of POLG variants in Parkinson's disease","rel_doi":"10.64898\/2026.06.07.26354811","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354811","rel_abs":"Introduction: Variants in the polymerase gamma (POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinson's disease (PD); yet, results remain inconclusive. Objectives: To investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries. Methods: We leveraged multi-ancestry genetic data from the Global Parkinson's Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses. Results: Five PD cases carried potentially biallelic rare pathogenic\/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic\/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD. Conclusions: POLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG-related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.","rel_num_authors":14,"rel_authors":[{"author_name":"Yi Wen Tay","author_inst":"University of Malaya, Malaysia"},{"author_name":"Inas Elsayed","author_inst":"University of Gezira, Wad Medani, Sudan"},{"author_name":"Dennis Yeow","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Mikayla James","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Pin-Jui Kung","author_inst":"National Taiwan University Hospital, Taipei, Taiwan"},{"author_name":"Laurel Screven","author_inst":"GP2, Bethesda, USA"},{"author_name":"Allison A. Dilliott","author_inst":"Parkinsons Foundation, NewYork, NY 10018, USA"},{"author_name":"Roy N. Alcalay","author_inst":"Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"Zih-Hua Fang","author_inst":"DataTecnica LLC, Washington, DC 20037, USA"},{"author_name":"Ai Huey Tan","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"- Global Parkinson's Genetics Program (GP2)","author_inst":"-"},{"author_name":"Carolyn M Sue","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Lara M Lange","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Maria Teresa Perinan","author_inst":"Queen Mary University of London, London, United Kingdom"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Stochastic Morphodynamics of the Human Aorta Across the Lifespan","rel_doi":"10.64898\/2026.06.05.26355015","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26355015","rel_abs":"Biological systems evolve as continuous dynamical processes, but at organ-scale and across human lifespans they are rarely observed longitudinally--population data typically exist instead as sparse, cross-sectional snapshots. Inferring lifespan dynamics from such data requires methods distinct from those used at cellular and tissue scales where dense observations are accessible. We address this problem in the thoracic aorta, where surgical decisions currently rest on static, age- and sex-agnostic diameter thresholds that reduce three-dimensional morphology to a single scalar. Treating normal aortic morphology as a stochastic dynamical system, we pose a continuous-time drift-diffusion process in a two-coordinate state space of normalized surface area (A) and normalized fluctuation in integrated Gaussian curvature ({delta} K), and fit closed-form solutions of the Fokker-Planck equation by maximum likelihood to a sex-balanced, age-uniform cohort spanning infancy to age 99. Inter-individual variability is treated as a fitted diffusion parameter rather than as residual scatter, which is distinct from prior normative studies that report variability as scatter around a regression line. The framework identifies two growth regimes for aortic size (childhood expansion followed by persistent adult growth, with adult males growing approximately 70% faster than adult females) and a single dynamical regime for aortic shape, with heteroscedastic variability accumulating at a rate comparable to the mean drift over the lifespan. Applied to independent cohorts of acute and chronic thoracic aortic dissections, the multivariate model identifies over 95% as statistical outliers via Mahalanobis distance, consistently outperforming either coordinate alone. The same probabilistic envelope that describes normal aging thus defines a baseline against which disease can be detected, supporting a shift toward dynamic, age- and sex-aware assessment of thoracic aortic pathology.","rel_num_authors":6,"rel_authors":[{"author_name":"Kelly C. Twohig","author_inst":"University of Chicago"},{"author_name":"Michael Mansour","author_inst":"University of Chicago"},{"author_name":"Joseph A. Pugar","author_inst":"University of Chicago"},{"author_name":"Karen Yuan","author_inst":"Northwestern University"},{"author_name":"Luka Pocivavsek","author_inst":"University of Chicago"},{"author_name":"Andrei A. Klishin","author_inst":"University of Hawai'i at Manoa"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Parental educational attainment polygenic scores contribute to phenotypic heterogeneity in offspring with autism","rel_doi":"10.64898\/2026.06.03.26354779","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354779","rel_abs":"Educational attainment-related polygenic scores have been implicated in autism spectrum disorder (ASD), but how parental polygenic scores shape offspring phenotypes remains unclear. Using genotyping and exome-sequencing data from 142,357 individuals (55,252 ASD cases) in a large ASD cohort, we dissected the direct and indirect genetic effects of educational attainment-related polygenic scores on ASD phenotypes. Trio-model analyses showed that parental polygenic scores for educational attainment (PGSEA ) were associated with milder core ASD symptoms, including social deficits and repetitive behaviors, predominantly through indirect genetic effects, whereas their associations with comorbidities were driven predominantly by direct genetic effects. PGSEA was also significantly negatively associated with rare variant burden and prenatal factors, although these factors contributed largely independently to most phenotypes. Adjustment for full-scale intelligence quotient (FSIQ) and socioeconomic status (SES) partially attenuated the indirect effects of PGSEA on offspring phenotypes. Finally, higher parental PGSEA was associated with later age at diagnosis in offspring, partly through its protective effects on ASD phenotypes. These findings indicate that indirect genetic effects of parentalPGSEA contribute substantially to phenotypic variation in ASD and highlight family-mediated pathways as an important component of ASD heterogeneity.","rel_num_authors":7,"rel_authors":[{"author_name":"Shilin Gao","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Yang Sui","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA."},{"author_name":"Panhui Tian","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Xiaoli Rao","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Chenghao Yan","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Yue Xu","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Tianyun Wang","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Integrated cardiometabolic and nutritional risk profiling identifies pregnancy loss as a marker of systemic metabolic vulnerability","rel_doi":"10.64898\/2026.06.04.26354910","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354910","rel_abs":"BackgroundPregnancy loss has important implications for womens health. Although maternal age is a well-established risk factor, the contribution of routinely measured cardiometabolic and behavioral markers at population-scale remains incompletely characterized.\n\nObjectiveTo examine associations between cardiometabolic, nutritional, and behavioral risk markers and pregnancy loss among U.S. women of reproductive age.\n\nMethodsWe conducted a cross-sectional analysis of 4,842 U.S. women aged 20-44 years with [&ge;]1 pregnancy using the National Health and Nutrition Examination Survey data (2013-2023). Pregnancy loss was defined as [&ge;]1 prior miscarriages. Exposures included body mass index, smoking exposure (cotinine), lipid biomarkers, vitamin D and folate, and a composite cardiometabolic-nutritional risk score. Survey-weighted logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals, with bootstrap resampling for predictor robustness.\n\nResultsThe weighted prevalence of pregnancy loss was 23%. Higher odds of pregnancy loss were associated with increasing age (aOR per year=1.02; 95% CI: 1.00-1.04), Non-Hispanic Black race (aOR=1.32; 95% CI: 1.00-1.74), overweight (aOR=1.56; 95% CI: 1.16-2.11), obesity (aOR=2.06; 95% CI: 1.39-3.05), and smoking (aOR=1.58; 95% CI: 1.19-2.10).\n\nAdverse lipid profiles, particularly elevated triglycerides (aOR=1.83; 95% CI: 1.16-2.90) and high low-density lipoprotein (aOR=2.97; 95% CI: 1.45-6.61), were independently associated with pregnancy loss. Vitamin D\/folate were not stable predictors. Higher composite cardiometabolic-nutritional risk scores were observed among women with pregnancy loss (P=0.026).\n\nConclusionPregnancy loss clustered with adverse cardiometabolic and behavioral risk markers in a nationally representative population. These findings highlight pregnancy loss as a marker of broader metabolic vulnerability supporting the need for longitudinal studies and cardiometabolic profiling to inform preconception care and risk stratification.","rel_num_authors":3,"rel_authors":[{"author_name":"Tanya Agarwal","author_inst":"Rutgers University: Rutgers The State University of New Jersey"},{"author_name":"Janaki  Ramya Namburu","author_inst":"Rutgers University: Rutgers The State University of New Jersey"},{"author_name":"Priyadarshini Kachroo","author_inst":"Rutgers The State University of New Jersey"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"A mechanistic model for genetic regulation of postmenopausal bone loss","rel_doi":"10.64898\/2026.06.04.26354968","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354968","rel_abs":"Bone remodeling is a tightly regulated physiological process that maintains bone health through coordinated action of bone-resorbing osteoclasts and bone-forming osteoblasts. Disruption of this balance, such as the one induced by estrogen decline after menopause, results in bone loss and osteoporosis. Genetic factors play an important role in determining bone mineral density (BMD) loss over time. However, translating genetic associations into individualized risk prediction remains challenging due to small effect size of individuals variants and non-linear interactions within the bone remodeling unit. Here, we present a bone cell population dynamics model that includes major regulatory pathways, such as the RANK\/RANKL\/OPG axis, Wnt signaling, and hormonal regulation by estrogen, parathyroid hormone, and TGF-{beta}. We calibrate the model on clinical data from healthy postmenopausal women, and women with reduced BMD undergoing anti-osteoporotic therapy. The calibrated model captures healthy BMD decline in postmenopausal women and therapeutic response to anti-osteoporotic medications. We mechanistically incorporate the effect of 22 variants across 8 genes involved in bone remodeling and simulate BMD trajectories in 1,000 virtual subjects differing by ancestry and genetic makeup. The median predicted 5-year BMD loss was 3.57% (95% prediction interval: 1.31-5.24), consistent with the values reported in the literature. The virtual individuals with African ancestry were predicted to experience the highest average 5-year BMD loss. The strongest genetic risk factors for bone loss were predicted to be CYP19A1 rs727479 and OPG rs3102735, while LRP5 rs11228240 emerged as a protective factor that could partially counteract the detrimental effects of other variants. Several epistatic effects were observed in the genetic interaction analysis. Mechanistically, our model suggested that estrogen exerts its effect on bone remodeling primarily by modulating osteoclast apoptosis. Overall, this framework demonstrates a proof-of-concept for integration of genetic risk factors into mechanistic models of disease and can be extended to other conditions with polygenic inheritance.","rel_num_authors":4,"rel_authors":[{"author_name":"Ilia Rattsev","author_inst":"Johns Hopkins University"},{"author_name":"Feilim Mac Gabhann","author_inst":"Johns Hopkins University"},{"author_name":"Daniel Hertz","author_inst":"University of Michigan"},{"author_name":"Casey Overby Taylor","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Characterizing artificial intelligence (AI) psychosis in a large academic medical setting: evidence of the new clinical phenomenon and the vulnerability of those in early phases of psychosis","rel_doi":"10.64898\/2026.06.04.26354939","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354939","rel_abs":"Background: Concerns about \"AI psychosis\" have swirled in the media since ChatGPT's release, but few systematic analyses exist. We therefore conducted an electronic health record (EHR) analysis to identify the frequency, clinical characteristics, and quality of AI interactions in patients experiencing psychosis treated in a medical center. Methods: AI keywords (e.g., ChatGPT, AI) were used to search Vanderbilt University Medical Center's EHR from 12\/1\/2022-4\/1\/2026. Records were discarded if they were not AI-related or if the primary diagnosis did not include psychosis. Three raters read notes to determine if a patient was experiencing AI psychosis and classified the interactions using 4 a-priori categories (Catalyst, Amplifier, Co-Author, Object) formulated to explain how AI-related negative outcomes emerge. Findings: 73 patients met our criteria. 28 patients were rated as experiencing AI psychosis, 17 had neutral interactions, and 28 expressed delusional content related to AI without documented evidence of conversational AI use. ChatGPT was the matching keyword for 53.6% patients experiencing AI psychosis. The majority of AI psychosis cases were documented after ChatGPT's \"4o\" model was released in May 2024. Notably, the AI Psychosis group had significantly more patients experiencing a first psychotic episode (60.7%) compared to the other two groups. Amplifier was the most common (64.3%) qualitative rating in the AI Psychosis group. Interpretation: \"AI psychosis\" is an infrequent but real phenomenon observed in clinical practice. Most affected patients were experiencing their first psychotic episode and presented with AI psychosis following the release of the more sycophantic GPT-4o. Among the affected patients, AI most often exacerbated an existing condition by reinforcing distorted ideas.","rel_num_authors":7,"rel_authors":[{"author_name":"Zachary Bergson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sarah G Vassall","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Adam Wright","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Allison B McCoy","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Katherine M Schafer","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Margaret C Achee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Julia M Sheffield","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Clonal Hematopoiesis of Indeterminate Potential Refines Cardiovascular Risk Stratification in Cardiovascular-Kidney-Metabolic Syndrome Stages 0-3","rel_doi":"10.64898\/2026.06.04.26354963","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354963","rel_abs":"BackgroundChronic low-grade inflammation drives cardiovascular-kidney-metabolic (CKM) syndrome. Clonal hematopoiesis of indeterminate potential (CHIP), an age-related driver of systemic inflammation, is linked to several cardiometabolic disorders. However, whether CHIP modifies CKM progression and contributes to heterogeneity in cardiovascular disease (CVD) risk within the CKM framework remains uninvestigated.\n\nMethodsThis cohort study included 307,025 UK Biobank participants at CKM stages 0-3 free of baseline CVD. CHIP status was identified via whole-exome sequencing (WES). The association between CHIP and baseline CKM severity was examined, along with the independent and joint effects of CHIP and CKM stages on incident CVD risk. The joint effects of CHIP and polygenic risk scores (PRS) were further assessed, and the incremental predictive value of incorporating CHIP into the AHA PREVENT equations was evaluated.\n\nResultsCHIP carriers were more likely to present with advanced CKM stages [OR 1.14 (1.09-1.20), P < 0.001] and exhibited higher incident CVD risk during follow-up [HR 1.13 (1.08-1.18), P < 0.001]. Significant joint effects between CHIP and CKM stages were observed, with the highest risk among CHIP carriers at CKM stage 3 [HR 1.63 (1.50-1.78), P < 0.001]. Large or multiple CHIP mutations conferred greater hazards, with distinct gene-specific effects observed. Moreover, CHIP and high genetic risk also jointly amplified CVD susceptibility. Most importantly, incorporating CHIP into AHA PREVENT significantly improved risk discrimination.\n\nConclusionsCHIP is a significant risk factor associated with more advanced CKM stages and amplifies incident CVD risk. Integrating CHIP into existing prevention strategies may refine CVD risk stratification.\n\nGraphic Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC=\"FIGDIR\/small\/26354963v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (54K):\norg.highwire.dtl.DTLVardef@1049576org.highwire.dtl.DTLVardef@1f0a29borg.highwire.dtl.DTLVardef@143a680org.highwire.dtl.DTLVardef@68472e_HPS_FORMAT_FIGEXP  M_FIG C_FIG Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIThis study provides large-scale evidence that clonal hematopoiesis of indeterminate potential (CHIP) is associated with more advanced cardiovascular-kidney-metabolic (CKM) stages and jointly amplifies future cardiovascular disease (CVD) risk within the CKM staging framework.\nC_LIO_LISomatic CHIP and germline polygenic susceptibility were jointly associated with CKM severity and CVD risk, with the greatest risk observed among individuals with both high polygenic risk and CHIP.\nC_LI\n\nWhat Are the Clinical Implications?O_LICHIP significantly refines CVD risk stratification across AHA PREVENT risk categories and provides incremental predictive value. Incorporating CHIP into CKM-based prevention strategies may help identify individuals with excess residual cardiovascular risk before the development of clinical CVD.\nC_LI","rel_num_authors":7,"rel_authors":[{"author_name":"Jian Lu","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Shuaigang Sun","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Zekai Deng","author_inst":"Xuanwu Hospital Capital Medical University"},{"author_name":"Shunwei Wang","author_inst":"Capital Medical University"},{"author_name":"Chenping Wei","author_inst":"Capital Medical University"},{"author_name":"Shimin Jiang","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Wenge Li","author_inst":"China-Japan Friendship Hospital"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"A Decade of the Center for Disease Control and Prevention's FluSight Influenza Forecasting","rel_doi":"10.64898\/2026.06.05.26354941","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354941","rel_abs":"Since the U.S. 2013\/14 influenza season, the CDC's FluSight Challenge has provided a platform for evaluating influenza forecasting models and fostering collaboration across institutions. The Challenge aims to improve the science and enhance the utility of infectious disease forecasts for public health decision making. We analyzed ten years of submitted forecasts (2014\/15-2019\/20 (influenza-like illness seasons) and 2021\/22-2024\/25 (hospital admissions seasons)) across a range of model types, including statistical, mechanistic, machine learning, and hybrid models. Influenza-like illness (ILI) forecasts were evaluated using the exponentiated logarithmic score (skill metric) while hospital admissions forecasts were evaluated using the log transformed relative Weighted Interval Score. Corresponding potential performance differences were assessed using Wilcoxon rank-sum tests, and associations with team participation history were evaluated using Spearman's rank correlation. Model performance varied by season, and no single model type consistently outperformed others. In ILI seasons, statistical models generally performed better than mechanistic and machine learning models, though consistent differences were not observed in more recent hospital admissions seasons. Ensemble forecasts showed better overall performance across seasons, and the CDC's FluSight ensemble ranked among the top-performing forecasts every year. We also found a positive correlation between forecast accuracy and the number of years a team participated in the Challenge, with statistically significant associations in four seasons. These findings highlight the benefits of ensemble approaches and sustained engagement in improving forecasting performance, while also underscoring the continued value of forecast evaluation before and following the COVID-19 pandemic. Insights from the FluSight Challenge can guide future infectious disease forecasting efforts and support more effective public health preparedness.","rel_num_authors":6,"rel_authors":[{"author_name":"Annabella G Hines","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sarabeth M. Mathis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Michael A. Johansson","author_inst":"Northeastern University"},{"author_name":"Matthew Biggerstaff","author_inst":"Centers for Disease Control & Prevention"},{"author_name":"Carrie Reed","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Rebecca Borchering","author_inst":"Centers for Disease Control and Prevention"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Albuminuria Changes as a surrogate endpoint in Apolipoprotein L1 Mediated Kidney Disease in Vanderbilt BioVU and the Million Veteran Program","rel_doi":"10.64898\/2026.06.04.26354945","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354945","rel_abs":"ImportanceRecently, proteinuria has been accepted as a surrogate end point for clinical trials in focal segmental glomerulosclerosis (FSGS) ang IgA nephropathy. However, proteinuria has not been evaluated in Apolipoprotein L1 (APOL1)-mediated kidney disease (AMKD).\n\nMethodsReal world data (RWD) analysis of 128 patients of African ancestry with APOL1 high risk genotypes, without diabetes, enrolled in the Million Veteran Program (MVP; n=109) or the biorepository at Vanderbilt University (BioVU; n=19), who had urine albumin-creatinine ratio (UACR) >= 420 mg\/g (PCR[~]0.9 g\/g) with a concurrent GFR value. The main predictor was change in the log-UACR at 12 months. The primary outcome was annual GFR slope over 24 months. Secondary outcomes included a kidney composite of a sustained 30% GFR decline, end stage kidney disease (ESKD) or death and ESKD as a single outcome. Linear regression and Cox proportional hazards models were used to assess the effect of changes in UACR and the outcomes.\n\nResultsIn the pooled analysis the mean age was 56.8 (SD 15.5) y, 116 were male (90.6%) and three patients had diagnosis of FSGS at baseline. Mean baseline eGFR was 46.8 (SD 16.1) mL\/min\/1.73m2, mean baseline UACR was 1240.8 (1107.7) mg\/g, mean eGFR slope was - 4.67[-6.00, -3.33] mL\/min\/1.73m2\/year and the geometric mean percentage changes in the UACR at 12 months were -57.5% [-65.0%, -48.4%]. For every 1 unit of log (UACR) increment at 12 months, the annual eGFR slope decreased by -1.80 [-2.56, -1.03] mL\/min\/1.73m2 in the pooled analysis. For every 1 unit of log (UACR) increment at 12 months, the Cox regression showed a 61% increase in the risk of a kidney composite (p=0.002) and a 98% increase in the risk of ESKD (p<0.001). It was estimated that a 50% reduction of UACR at 12 months was associated with a 28% reduction in the kidney composite endpoint (adjusted hazard ratio [aHR]=0.72; 95% confidence interval [CI]:0.59-0.88; p=0.002), and a 38% reduction in the risk of ESKD (aHR=0.62; 95% CI:0.49-0.80; p<0.001).\n\nConclusions and relevanceChanges in UACR at 12 months significantly modify the rate of decline of GFR over 24 months and clinically meaningful endpoints, supporting the use of UACR changes as surrogate endpoint in AMKD.","rel_num_authors":13,"rel_authors":[{"author_name":"Fatih Mamak","author_inst":"Vanderbilt Health"},{"author_name":"Zhihong Yu","author_inst":"Vanderbilt University"},{"author_name":"Jefferson L Triozzi","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Robert Corty","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Lee Wheless","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Guanchao Wang","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Ayush Giri","author_inst":"Vanderbilt University"},{"author_name":"Hua Chang Chen","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Otis Wilson Wilson","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare and Harvard Medical School"},{"author_name":"Ran Tao","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Adriana M Hung","author_inst":"Nashville VA (TVHS) and Vanderbilt University"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Using colorectal cancer screening evidence to stratify for personal risk among those with a family history of colorectal cancer: a 42-year cohort study","rel_doi":"10.64898\/2026.06.04.26354891","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354891","rel_abs":"Objective To determine if it is possible to assess individual patient risk of the development of colorectal cancer (CRC) in people in high-risk groups due to their family history. Design\/Method Retrospective observational study of prospectively collected data from consecutive patients referred for a colonoscopy. 2,478 consecutive patients were referred to a single colorectal surgical practice in Sydney, Australia between 1977 and 2018 for a colonoscopy because of a family history of CRC. Of these, 1,963 have been followed for more than 10 years and are the subject of this paper. Histopathological findings categorised as normal (N), non-advanced adenoma (NAA) or advanced neoplasia (AN) with AN proven to be the precursor to CRC. Intervention Colonoscopic screening on the basis of contemporary practice to 2006 and subsequently according to Australian National Health and Medical Research Council guidelines. Results Participants with normal or low-risk findings in the first decade remain at lower risk of CRC for 30 years from the commencement of screening. Conclusion It is possible to stratify individual patients in a high relative risk cohort into those with high or low personal risk of CRC based on colonoscopic findings in the first 10 years of surveillance. Those with no AN in the first ten years have a lower 30-year risk of developing AN than the general community. This offers the possibility of structuring surveillance programs around individual risk rather than group risk, lessening the need for multiple surveillance colonoscopies in the majority of such patients and improving the cost effectiveness of CRC screening at the population level.","rel_num_authors":8,"rel_authors":[{"author_name":"Denis  W King","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Pamela  E King","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Megan  W Blanchard","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Nickson  W Ning","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Sebastian  K King","author_inst":"The Royal Children's Hospital Melbourne"},{"author_name":"Michael  C Grimm","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Tam Ha","author_inst":"University of Wollongong"},{"author_name":"Kathy Eagar","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"A-to-I mRNA editing recodes CqsA and affects T6SS-mediated killing in Vibrio","rel_doi":"10.64898\/2026.06.08.730849","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730849","rel_abs":"Adenosine-to-inosine (A-to-I) RNA editing alters genetic information post-transcriptionally, yet its ecological and evolutionary significance in bacteria remains largely unexplored. Here, we show that endogenous RNA editing has functional consequences in bacteria. Using Vibrio alginolyticus as a model, we identified 38 editing events - the highest number reported for any bacterium to date. Editing frequencies varied across growth phases and occurred within a shorter conserved sequence motif than observed in other bacteria, suggesting species-specific determinants. The mRNA of the quorum-sensing (QS) autoinducer synthase cqsA was the most extensively edited, with 70-90% of transcripts modified. Phylogenetic and experimental analyses revealed that cqsA editing is evolutionarily conserved across diverse Vibrio species, including human pathogens. Protein mass spectrometry showed that editing replaces a tyrosine with a cysteine residue at position 193 of endogenously expressed CqsA without altering its expression or the canonical downstream QS signaling pathway. However, we found that endogenous editing of cqsA alters the expression of a subset of genes and is required for efficient type VI secretion system (T6SS)-mediated interbacterial killing. Together, these findings suggest that CqsA has additional roles beyond its canonical QS function and that RNA editing can modulate bacterial physiology.","rel_num_authors":9,"rel_authors":[{"author_name":"Rinat Cohen-Pavon","author_inst":"Ben-Gurion University of the Negev"},{"author_name":"Chaya Mushka Fridman","author_inst":"Tel Aviv University"},{"author_name":"Danielle Arad","author_inst":"Ben-Gurion University of the Negev"},{"author_name":"Sahar Melamed","author_inst":"The Hebrew University of Jerusalem"},{"author_name":"Irina Rostovsky","author_inst":"Ben-Gurion University of the Negev"},{"author_name":"Neta Sal-Man","author_inst":"Ben-Gurion University of the Negev"},{"author_name":"Liam Aspit","author_inst":"Ben-Gurion University of the Negev"},{"author_name":"Dor Salomon","author_inst":"Tel Aviv University"},{"author_name":"Dan Bar Yaacov","author_inst":"Ben-Gurion University of the Negev"}],"rel_date":"2026-06-08","rel_site":"biorxiv"},{"rel_title":"Elevated HbA1c is associated with advanced brain age in severe obesity","rel_doi":"10.64898\/2026.06.04.26354935","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354935","rel_abs":"IntroductionBrain-predicted age, estimated from structural MRI data, is a machine learning biomarker of biological brain aging. Greater brain age gap (BAG) indicates advanced brain aging and is associated with cognitive decline and mortality. Cardiometabolic risk factors, including elevated blood glucose, body mass index (BMI), blood pressure, and cholesterol, increase risk of cognitive impairment and dementia in aging. Their relationship with BAG in severe obesity remains poorly characterized despite increased prevalence of cardiometabolic risk factors among this population.\n\nMethodsT1-weighted MRI data from 97 adults (BMI 35-73) were used to calculate BAG using ENIGMA and Pyment brain age models. Associations between BAG and HbA1c, BMI, hypertension, and hyperlipidemia were examined using multiple linear regression and MM-estimation robust regression, adjusting for age, sex, and race. Post hoc analyses stratified models by clinical HbA1c cutoffs (normoglycemic, prediabetic, diabetic).\n\nResultsHigher HbA1c was associated with greater BAGENIGMA (B = 1.58, p = .014) and BAGPyment (B = 0.93, p = .013) in linear regression models. In robust models, HbA1c remained significantly associated with BAGENIGMA (B = 1.70, p = .002) but not BAGPyment (B = 0.71, p = .13). BMI, hypertension, and hyperlipidemia were not associated with BAG in either linear or robust models. HbA1c was associated with greater BAGENIGMA (B = 2.15, p = .01) and BAGPyment (B =1.21, p = .04) in those at or above prediabetic levels and with BAGENIGMA (B = 2.49, p = .047) in those with diabetes.\n\nConclusionsElevated HbA1c is associated with accelerated brain aging in individuals with severe obesity. BAG was not associated with BMI, hypertension, and hyperlipidemia, which may reflect the restricted BMI range inherent to the sample with severe obesity.\n\nHIGHLIGHTSO_LIElevated HbA1c was associated with advanced brain aging in individuals with severe obesity.\nC_LIO_LIHbA1c-BAG associations were seen primarily in the context of clinically elevated levels (i.e. prediabetes and diabetes).\nC_LIO_LIThe study did not provide evidence to support that BMI, hypertension, and hyperlipidemia are associated with BAG in individuals with severe obesity\nC_LIO_LIENIGMA and Pyment models showed limited agreement in BAG estimates in a sample of individuals with severe obesity.\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Joshua Juhasz","author_inst":"University of Florida"},{"author_name":"Brittany DeFeis","author_inst":"University of Florida"},{"author_name":"Mark K Britton","author_inst":"Yale University"},{"author_name":"Hannah Hoogerwoerd","author_inst":"University of Florida"},{"author_name":"Kate Worwag","author_inst":"University of Florida"},{"author_name":"Keyanni J Johnson","author_inst":"University of Florida"},{"author_name":"Angel Uribe","author_inst":"San Diego State University"},{"author_name":"John B Williamson","author_inst":"University of Florida"},{"author_name":"Eric C Porges","author_inst":"University of Florida"},{"author_name":"Ronald A Cohen","author_inst":"University of Florida"}],"rel_date":"2026-06-06","rel_site":"medrxiv"},{"rel_title":"Serological thresholds of risk reduction for infant group B streptococcus disease","rel_doi":"10.64898\/2026.05.29.26353453","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.29.26353453","rel_abs":"Vaccines to prevent infant group B streptococcus (GBS) disease are advancing, with licensure likely based on safety and immunologic endpoints rather than clinical efficacy data. This approach requires robust, generalisable serological thresholds of risk reduction (SToRRs). We combined data from six case-control studies in Europe and Africa to define SToRRs for early-onset (EOD) and late-onset (LOD) GBS disease. Across diverse epidemiological and healthcare settings, anti-capsular polysaccharide IgG concentrations were consistently higher in infants who remained disease free than in those who developed disease. Higher antibody concentrations were required to reduce the risk of EOD than LOD, and higher concentrations were required for serotype Ia than for serotype III. This study provides a quantitative framework to support correlates-based evaluation and potential licensure of maternal GBS vaccines.","rel_num_authors":26,"rel_authors":[{"author_name":"Liberty Cantrell","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK & NIHR Oxford Biomedical Research Centre"},{"author_name":"Kostas Karampatsas","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Nick Andrews","author_inst":"UK Health Security Agency, London, UK"},{"author_name":"Simon Beach","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Emily Bentley","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Alberto Berardi","author_inst":"Neonatal Intensive Care Unit, Azienda Ospedaliero-Universitaria Policlinico, Policlinico,Modena, Italy"},{"author_name":"Merijn W Bijlsma","author_inst":"Department of Paediatrics, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands."},{"author_name":"Cemal Cagil Kocana","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Olwenn Daniel","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Neil French","author_inst":"University of Liverpool, Liverpool, UK; Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi"},{"author_name":"Tom Hall","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Alane Izu","author_inst":"South African Medical Research Council Wits Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersran"},{"author_name":"Asma Khalil","author_inst":"City St George's, University of London, London, UK"},{"author_name":"Gaurav Kwatra","author_inst":"South African Medical Research Council Wits Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersran"},{"author_name":"Mary Kyohere","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK; Makerere University-Johns Hopkins Universi"},{"author_name":"Shabir A Madhi","author_inst":"University of the Witwatersrand"},{"author_name":"Robert Mboizi","author_inst":"Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda"},{"author_name":"Francesca Miselli","author_inst":"Neonatal Intensive Care Unit, Azienda Ospedaliero-Universitaria Policlinico, Policlinico,Modena, Italy"},{"author_name":"Maryke Nielsen","author_inst":"London School of Hygiene and Tropical Medicine, London, UK"},{"author_name":"Natasha Thorn","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Diederik van de Beek","author_inst":"Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands"},{"author_name":"Kate Walker","author_inst":"Centre for Perinatal Research (CePR), University of Nottingham, Nottingham, UK"},{"author_name":"Paul T Heath","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Kirsty Le Doare","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK; Makerere University-Johns Hopkins Universi"},{"author_name":"Merryn Voysey","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK & NIHR Oxford Biomedical Research Centre"},{"author_name":"- PREPARE WP3 Study Group","author_inst":""}],"rel_date":"2026-06-06","rel_site":"medrxiv"},{"rel_title":"Functionally Focused Evaluation: A Novel Comparative Protocol for Wearable Electroencephalography Headsets","rel_doi":"10.64898\/2026.06.03.26354802","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354802","rel_abs":"With the emergence of electroencephalography (EEG) as a tool in the cognitive domain, new demands are being placed on the technology to keep up with functional applications - especially in the context of at-home neural monitoring. New use cases have fostered development of wearable EEG (wEEG) devices: portable, low-cost headsets used for EEG monitoring. This evolution of technology and application has not been accompanied by development in technology evaluation, often relying on function-agnostic markers to assess devices for efficacy in this new space. With current methods limited in scope, this study designed, tested and evaluated a novel functionally-focused comparative protocol for wEEG devices. Eight participants undertook a protocol for the evaluation of four established wEEG devices, assessing cognitive resolution and general usability. Compared to a well-established traditional analysis method (eyes open\/eyes closed protocol), the novel design proposed here enabled the same analysis of headset resolution, while also providing additional context into user preferences and opening downstream possibilities for specific cognitive insights. Future research could enable the development of this protocol into a standardised method to ensure the performance of wEEG technology can satisfy emerging clinical needs.","rel_num_authors":5,"rel_authors":[{"author_name":"Anand Bhuyan","author_inst":"University of Sydney"},{"author_name":"Michael Wong","author_inst":"The University of Sydney"},{"author_name":"Alistair McEwan","author_inst":"The University of Sydney"},{"author_name":"Cameron Higgins","author_inst":"The University of Oxford"},{"author_name":"Navin Cooray","author_inst":"CSIRO"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"rel_title":"Education\/training for health workers\/students on inclusive and gender-affirmative care for trans and gender-diverse people: a systematic review","rel_doi":"10.64898\/2026.06.04.26354880","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354880","rel_abs":"IntroductionTrans and gender-diverse (TGD) individuals often face stigma and discrimination in healthcare, hindering access to gender-affirming care. Training healthcare workers on TGD health aims to foster inclusive and affirming care practices. This review aimed to evaluate the effectiveness of TGD health training programs for healthcare workers.\n\nMethodsThis systematic review followed the PRISMA guidelines and was registered with PROSPERO (CRD42023443288). We searched 13 databases for studies up to March 2024, with no language\/geographic restrictions. Ten reviewers screened studies in pairs, resolving discrepancies via discussion or third-reviewer input. We included randomized\/non-randomized comparative and before-after studies for quantitative analysis (mean difference [MD] or standardized mean difference [SMD] with 95% CIs), and qualitative\/mixed-methods studies for thematic synthesis. Evidence certainty was assessed using GRADE (quantitative) and GRADE-CERQual (qualitative). Outcomes included knowledge, attitudes, skills, discrimination, competence, comfort, TGD quality of life, and stakeholder preferences.\n\nResultsFrom 20,188 records, 85 studies were included. Training appears to have improved healthcare workers knowledge (SMD=1.08, 95% CI 0.78-1.39), attitudes (SMD=0.22, 95% CI 0.05-0.39), skills (SMD=0.96, 95% CI 0.56-1.37), competence (SMD=0.55, 95% CI 0.29-0.81), and comfort (SMD=0.69, 95% CI 0.17-1.21). Qualitative analysis of 130 findings identified 18 categories and four key themes on intervention design and impact.\n\nConclusionsTGD training programs may enhance health workers knowledge, attitudes, skills, competence, and comfort. Well-structured, interactive, and inclusive programs showed promise, but evidence certainty was low with limited follow-up. Further high-quality research is needed to confirm these findings.","rel_num_authors":13,"rel_authors":[{"author_name":"Jun Xia","author_inst":"Nottingham Ningbo GRADE Centre, School of Economics, University of Nottingham Ningbo, China"},{"author_name":"Zheng Zhu","author_inst":"Fudan University"},{"author_name":"Guowen Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Quan Shen","author_inst":"The Third Xiangya Hospital of Central South University, Changsha, China"},{"author_name":"Esther Su","author_inst":"The University of Sydney, Australia"},{"author_name":"Jan Schoones","author_inst":"Leiden University Medical Center, Leiden, The Netherlands"},{"author_name":"Jon Arcelus","author_inst":"School of Medicine, University of Nottingham, UK"},{"author_name":"Tiantian Hu","author_inst":"Fudan University School of Nursing, Fudan University, Shanghai, China"},{"author_name":"Mengqi Xu","author_inst":"The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Xiaoxin Zhang","author_inst":"School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing,China"},{"author_name":"Zhan Zhao","author_inst":"Tianjin Suyuan Evience based Technology Co.,Ltd., Tianjin, China"},{"author_name":"Zheng Ye","author_inst":"Systematic Review Solution (SRS) Ltd, UK"},{"author_name":"Xiaomei Yao","author_inst":"Department of Health Research Methods, Evidence and Impact; Department of Oncology, McMaster University, Canada"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"rel_title":"Education\/training for health workers\/students on inclusive and gender-affirmative care for trans and gender-diverse people: a systematic review","rel_doi":"10.64898\/2026.06.04.26354880","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354880","rel_abs":"IntroductionTrans and gender-diverse (TGD) individuals often face stigma and discrimination in healthcare, hindering access to gender-affirming care. Training healthcare workers on TGD health aims to foster inclusive and affirming care practices. This review aimed to evaluate the effectiveness of TGD health training programs for healthcare workers.\n\nMethodsThis systematic review followed the PRISMA guidelines and was registered with PROSPERO (CRD42023443288). We searched 13 databases for studies up to March 2024, with no language\/geographic restrictions. Ten reviewers screened studies in pairs, resolving discrepancies via discussion or third-reviewer input. We included randomized\/non-randomized comparative and before-after studies for quantitative analysis (mean difference [MD] or standardized mean difference [SMD] with 95% CIs), and qualitative\/mixed-methods studies for thematic synthesis. Evidence certainty was assessed using GRADE (quantitative) and GRADE-CERQual (qualitative). Outcomes included knowledge, attitudes, skills, discrimination, competence, comfort, TGD quality of life, and stakeholder preferences.\n\nResultsFrom 20,188 records, 85 studies were included. Training appears to have improved healthcare workers knowledge (SMD=1.08, 95% CI 0.78-1.39), attitudes (SMD=0.22, 95% CI 0.05-0.39), skills (SMD=0.96, 95% CI 0.56-1.37), competence (SMD=0.55, 95% CI 0.29-0.81), and comfort (SMD=0.69, 95% CI 0.17-1.21). Qualitative analysis of 130 findings identified 18 categories and four key themes on intervention design and impact.\n\nConclusionsTGD training programs may enhance health workers knowledge, attitudes, skills, competence, and comfort. Well-structured, interactive, and inclusive programs showed promise, but evidence certainty was low with limited follow-up. Further high-quality research is needed to confirm these findings.","rel_num_authors":13,"rel_authors":[{"author_name":"Jun Xia","author_inst":"Nottingham Ningbo GRADE Centre, School of Economics, University of Nottingham Ningbo, China"},{"author_name":"Zheng Zhu","author_inst":"Fudan University"},{"author_name":"Guowen Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Quan Shen","author_inst":"The Third Xiangya Hospital of Central South University, Changsha, China"},{"author_name":"Esther Su","author_inst":"The University of Sydney, Australia"},{"author_name":"Jan Schoones","author_inst":"Leiden University Medical Center, Leiden, The Netherlands"},{"author_name":"Jon Arcelus","author_inst":"School of Medicine, University of Nottingham, UK"},{"author_name":"Tiantian Hu","author_inst":"Fudan University School of Nursing, Fudan University, Shanghai, China"},{"author_name":"Mengqi Xu","author_inst":"The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Xiaoxin Zhang","author_inst":"School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing,China"},{"author_name":"Zhan Zhao","author_inst":"Tianjin Suyuan Evience based Technology Co.,Ltd., Tianjin, China"},{"author_name":"Zheng Ye","author_inst":"Systematic Review Solution (SRS) Ltd, UK"},{"author_name":"Xiaomei Yao","author_inst":"Department of Health Research Methods, Evidence and Impact; Department of Oncology, McMaster University, Canada"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"rel_title":"Acute rejection timing in the first post-transplant year is not associated with incident cardiac allograft vasculopathy","rel_doi":"10.64898\/2026.05.28.26354171","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.28.26354171","rel_abs":"Heart transplantation (HT) is the durable therapy for end-stage heart failure (HF). Despite advances in immunosuppression, cardiac allograft vasculopathy (CAV) remains a leading cause of late graft failure and mortality in the modern era. Prior studies have established donor age and immunological phenomena, such as acute cellular rejection (ACR), antibody-mediated rejection (AMR), and development of donor-specific antibodies (DSAs) as risk factors for CAV1-5. However, it remains unclear whether acute rejection (AR) that occurs early post-HT, when individuals experience the highest degree of immunosuppression, reflects higher baseline immune activity and confers a higher risk of future CAV compared to later AR, when immunosuppression is minimized. We therefore examined whether AR occurring during pre-specified early and intermediate intervals compared to those who did not experience AR in the first post-HT year was associated with future CAV among recipients without CAV at 1 year.","rel_num_authors":10,"rel_authors":[{"author_name":"Blake Butler","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Shi Huang","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Aniket S. Rali","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Hasan K. Siddiqi","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jonathan N. Menachem","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Nelson Chow","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Eric Farber-Eger","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Quinn S. Wells","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kelly H. Schlendorf","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kaushik Amancherla","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"rel_title":"Snip Happens: A Retrospective Study of Vasectomy and Birth rates in Australia","rel_doi":"10.64898\/2026.06.03.26354864","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354864","rel_abs":"BackgroundFertility rates in Australia have been declining over recent decades, reaching a record low total fertility rate of 1.48 births per woman in 2024. Concurrently, vasectomy remains widely accessible and increasingly normalised as a permanent contraceptive option. Despite extensive commentary on falling birth rates, no contemporary Australian study has examined vasectomy rates relative to birth rates over time. We aimed to compare population level vasectomy and birth rates across Australian jurisdictions and age groups.\n\nStudy designNationwide retrospective time-series study. Retrospective population-based study using Medicare Benefits Schedule item 37623 to identify vasectomy procedures performed between July 2015 and December 2024. Rates were calculated per 100,000 male population using quarterly Australian Bureau of Statistics (ABS) population estimates and summarised as rolling 12-month averages. Birth rates were derived using matched ABS data for women across equivalent age strata (18-24, 25-34, 35-44 years).\n\nResultsVasectomy rates increased nationally from 32 per 100,000 in 2016 to 55 per 100,000 in 2023 before declining modestly in 2024. Birth rates declined from 5,200 to 3,800 per 100,000 over the same period. Trends were consistent across states and age groups, with the greatest vasectomy uptake in men aged 35-44 years.\n\nConclusionAustralia is undergoing a demographic shift characterised by rising vasectomy uptake and declining fertility. While vasectomy rates remain lower than birth rates, their convergence signals changing reproductive intentions and contraceptive behaviours. Ongoing monitoring of permanent and long-acting contraception is essential to understand evolving population dynamics and inform reproductive health policy.\n\nShort summary for non-expertsThis nationwide study demonstrates that rising vasectomy uptake in Australia coincides with declining birth rates, particularly among men aged 35-44 years. Monitoring permanent contraceptive use alongside fertility trends may help clinicians and policymakers better understand changing reproductive intentions and inform future reproductive health planning.\n\nShort summary for non-expertsAustralias birth rate has fallen to record lows, raising growing concerns about how changing reproductive choices may shape future society and healthcare needs. In this study, we found that vasectomy rates increased steadily across Australia between 2016 and 2024 while birth rates declined, particularly among adults aged 35-44 years. These findings suggest Australian men are increasingly choosing permanent contraception and highlight the need for ongoing monitoring of reproductive health trends to inform future policy and service planning.","rel_num_authors":8,"rel_authors":[{"author_name":"Jack Janetzki","author_inst":"adelaide university"},{"author_name":"Natansh Modi","author_inst":"Adelaide University"},{"author_name":"Bianca Varney","author_inst":"University of New South Wales"},{"author_name":"Nicole Pratt","author_inst":"Adelaide University"},{"author_name":"Michael Ward","author_inst":"Adelaide University"},{"author_name":"Michael Wiese","author_inst":"Adelaide University"},{"author_name":"Renly Lim","author_inst":"Adelaide University"},{"author_name":"Lisa Kalisch Ellett","author_inst":"Adelaide University"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"rel_title":"Exploring the role of binge eating in the association between ADHD and BMI: A twin study","rel_doi":"10.64898\/2026.05.28.26354354","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.28.26354354","rel_abs":"ObjectiveADHD has been associated with obesity indicators, including BMI, across the lifespan. A possible mechanism linking ADHD and BMI is binge eating. Previous research has found associations between ADHD, binge eating and BMI. However, the role of genetic and environmental influences on these associations remains unclear.\n\nMethodWe utilized data from the Twins Early Development Study (TEDS), comprising 3,675 monozygotic and 7,063 dizygotic twin pairs. ADHD symptoms in childhood and adolescence were assessed using parent-reported questionnaires. Adult ADHD symptoms were measured using both self-report and parent-report questionnaires. Phenotypic mediation models examined whether binge eating mediated the association between ADHD and BMI, without controlling for genetic confounding. Subsequently, the etiological architecture underlying the associations among the three traits across childhood, adolescence, and adulthood were investigated by incorporating genetic and environmental influences into the models.\n\nResultsBinge eating significantly mediated the association between ADHD symptoms and BMI in both adolescence and adulthood. However, these mediation effects were no longer present once genetic and environmental influences were incorporated into the models. The best-fitting model in childhood, adolescence and adulthood was Cholesky decomposition models, where covariance between traits was explained by shared aetiology.\n\nConclusionsThis twin study reveals shared liability across ADHD, binge eating, and BMI. The mediating role of binge eating in the relationship between ADHD symptoms and BMI was largely confounded by shared genetic influences. Intervention strategies could focus more on common underlying behavioural and self-regulatory mechanisms across these traits, as well as placing more emphasis on symptom patterns within families.","rel_num_authors":6,"rel_authors":[{"author_name":"YUAN YOU","author_inst":"King's College London"},{"author_name":"Tom McAdams","author_inst":"King's College London"},{"author_name":"Olakunle Oginni","author_inst":"Cardiff University"},{"author_name":"Chaoyu Liu","author_inst":"Yale University"},{"author_name":"Moritz Herle","author_inst":"King's College London"},{"author_name":"Helena Zavos","author_inst":"King's College London"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"rel_title":"Impact of Modifiable Risk Factors and APOE on Neuropsychiatric Symptoms in Alzheimers Disease","rel_doi":"10.64898\/2026.06.04.26353599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26353599","rel_abs":"BACKGROUNDNeuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimers disease (AD). Existing pharmacologic treatments are often ineffective and associated with serious adverse events. Identifying modifiable risk factors (MRFs) is critical for prevention and treatment.\n\nMETHODSCapitalizing on data from 14,497 individuals with AD from the National Alzheimers Coordinating Center (NACC) database, we examined longitudinal associations between modifiable risk factors, APOE genotype and NPI-Q-assessed NPS using Cox proportional hazards models adjusted for demographics.\n\nRESULTSDiabetes, alcohol consumption, smoking, and TBI were associated with an increased risk of specific NPS in AD. APOE{varepsilon}4 carrier status was linked to multiple NPS, showing a dose-response relationship. Education, LDL-C, and corrective lenses were protective; hypertension showed no associations.\n\nCONCLUSIONThese findings strongly suggest that individual MRFs are associated with specific NPS in line with a complex etiology underlying these symptoms. Early detection and management of vascular, lifestyle and sensory factors could reduce NPS.","rel_num_authors":14,"rel_authors":[{"author_name":"Hasib Mia","author_inst":"Columbia University"},{"author_name":"Pamela Del Rosario","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Ajneesh Kumar","author_inst":"Columbia University"},{"author_name":"Nicholas Ross Ray","author_inst":"Columbia University"},{"author_name":"Jiji Thulaseedhara Kurup","author_inst":"Columbia University"},{"author_name":"Masood Manoochehri","author_inst":"Brown University"},{"author_name":"Colin Stein","author_inst":"Brown University"},{"author_name":"Alyssa N De Vito","author_inst":"Brown University"},{"author_name":"Brenna Cholerton","author_inst":"Stanford University School of Medicine"},{"author_name":"Robert Sweet","author_inst":"University of Pittsburgh"},{"author_name":"Michael  L Cuccaro","author_inst":"University of Miami Miller School of Medicine: University of Miami School of Medicine"},{"author_name":"Gary W. Beecham","author_inst":"Department of Biostatistics and Data Science, Wake Forest University, Winston-Salem, NC"},{"author_name":"Edward D. Huey","author_inst":"Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI"},{"author_name":"Christiane Reitz","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"rel_title":"Impact of Modifiable Risk Factors and APOE on Neuropsychiatric Symptoms in Alzheimers Disease","rel_doi":"10.64898\/2026.06.04.26353599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26353599","rel_abs":"BACKGROUNDNeuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimers disease (AD). Existing pharmacologic treatments are often ineffective and associated with serious adverse events. Identifying modifiable risk factors (MRFs) is critical for prevention and treatment.\n\nMETHODSCapitalizing on data from 14,497 individuals with AD from the National Alzheimers Coordinating Center (NACC) database, we examined longitudinal associations between modifiable risk factors, APOE genotype and NPI-Q-assessed NPS using Cox proportional hazards models adjusted for demographics.\n\nRESULTSDiabetes, alcohol consumption, smoking, and TBI were associated with an increased risk of specific NPS in AD. APOE{varepsilon}4 carrier status was linked to multiple NPS, showing a dose-response relationship. Education, LDL-C, and corrective lenses were protective; hypertension showed no associations.\n\nCONCLUSIONThese findings strongly suggest that individual MRFs are associated with specific NPS in line with a complex etiology underlying these symptoms. Early detection and management of vascular, lifestyle and sensory factors could reduce NPS.","rel_num_authors":14,"rel_authors":[{"author_name":"Hasib Mia","author_inst":"Columbia University"},{"author_name":"Pamela Del Rosario","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Ajneesh Kumar","author_inst":"Columbia University"},{"author_name":"Nicholas Ross Ray","author_inst":"Columbia University"},{"author_name":"Jiji Thulaseedhara Kurup","author_inst":"Columbia University"},{"author_name":"Masood Manoochehri","author_inst":"Brown University"},{"author_name":"Colin Stein","author_inst":"Brown University"},{"author_name":"Alyssa N De Vito","author_inst":"Brown University"},{"author_name":"Brenna Cholerton","author_inst":"Stanford University School of Medicine"},{"author_name":"Robert Sweet","author_inst":"University of Pittsburgh"},{"author_name":"Michael  L Cuccaro","author_inst":"University of Miami Miller School of Medicine: University of Miami School of Medicine"},{"author_name":"Gary W. Beecham","author_inst":"Department of Biostatistics and Data Science, Wake Forest University, Winston-Salem, NC"},{"author_name":"Edward D. Huey","author_inst":"Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI"},{"author_name":"Christiane Reitz","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"}],"rel_date":"2026-06-05","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":"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":"BackgroundKaposi 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.\n\nMethodsPRIME-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.\n\nDiscussionPRIME-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.\n\nTrial registrationClinicalTrials.gov NCT06898203, registered 27 March 2025. Pan African Clinical Trials Registry PACTR202603523439856.\n\nStructured summary\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@1e7f00eorg.highwire.dtl.DTLVardef@413157org.highwire.dtl.DTLVardef@e781forg.highwire.dtl.DTLVardef@1f06863org.highwire.dtl.DTLVardef@554af0_HPS_FORMAT_FIGEXP  M_TBL C_TBL Protocol version {2}Version 1.2, 2 May 2026.","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.\n\nAuthor SummaryHuman metapneumovirus (HMPV) circulates each year in the United States and contributes to respiratory illness, particularly among young children and older adults. Although HMPV epidemics show clear seasonal patterns, the mechanisms underlying these patterns are not well understood. In this study, we combined surveillance data from multiple regions in the United States with mathematical modeling to investigate the drivers of HMPV transmission. We evaluated whether environmental factors or interactions with respiratory syncytial virus (RSV) better explained differences in epidemic timing and intensity. Our findings indicate that interactions between HMPV and RSV play an important role in shaping HMPV epidemics. In particular, RSV circulation appeared to suppress HMPV transmission, helping explain the alternating epidemic patterns observed in some regions. Our model also suggested that expanded RSV prevention programs are unlikely to substantially increase HMPV burden. This work provides new insights into respiratory virus interactions and highlights the importance of considering pathogen interactions when predicting seasonal outbreaks and evaluating intervention strategies.","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":"ObjectivesStudy 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, TMs 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.\n\nMaterials and MethodsTherefore, 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.\n\nResultsFor 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.\n\nDiscussion and ConclusionTM 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":"PurposeTo 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.\n\nMethodsThrough-plane 2D PC-MRI of the ascending aorta was acquired using multiple velocity encodings (150, 200, 300 cm\/s) and flip angles (0{degrees}, 5{degrees}, 15{degrees}, 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).\n\nResultsVelocity 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.\n\nConclusionVelocity 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-ethnic cohort of 444 placentas from the Hawaii 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":"STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary 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.\n\nOBJECTIVESTo determine the association between IC and statin use in CAD based on APO ({varepsilon}) genotype, sex, and lipid levels.\n\nDESIGN, SETTING, AND PARTICIPANTSWe 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.\n\nMEASURESWe assessed the association between IC and statin use using logistic regression analysis, while adjusting for clinical factors, sociodemographics, and APO ({varepsilon}) genotypes before and after propensity score matching. We further performed stratified analysis by sex, and APO ({varepsilon}) 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.\n\nRESULTSThe 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 ({varepsilon}) 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 {varepsilon}3\/{varepsilon}3 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 ([&le;] 10mg\/dl: OR:1.61;1.22-2.15, p=8e-4).\n\nCONCLUSIONIn the AllofUS cohort, IC was significantly associated with statin use in CAD participants. We observed the strongest association in the APO {varepsilon}3{varepsilon}3 group, among females, and with a greater increase in HDL levels in statin users.\n\nKey MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment or all-cause dementia, share genetic, sociodemographic, and clinical risk factors but the association of IC with statin use in CAD remains unclear.\n\nWhat this study addsWe observed an association between IC and statin use in CAD participants after adjusting for sociodemographics, clinical factors, and APO ({varepsilon}) genotypes. The association persisted after propensity score matching for sociodemographics, clinical factors, and APO ({varepsilon}) genotypes. Further, when CAD participants were stratified across APO ({varepsilon}) groups and by sex, we observed strongest magnitude of association between IC and statin use in the APO {varepsilon}3{varepsilon}3 compared to other APO ({varepsilon}) genotypes, and in females compared to males. Among CAD participants with documented baseline and latest lipids (total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL)), IC was associated with statin use regardless of baseline lipid levels or latest lipid levels. While we did not observe any change in association between IC and statin use, based on the magnitude of decrease in TC and LDL levels, we observed a higher magnitude of association between IC and statin use, with a greater increase in HDL levels.\n\nHow this study might affect research, practice or policyOur observations highlight the association of IC and statin use in CAD and the role of APO ({varepsilon}) genotype evaluation, and serial lipid level assessments for evaluating for statin associated IC in CAD.","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":"STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary 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.\n\nOBJECTIVESTo determine the association between IC and statin use in CAD based on APO ({varepsilon}) genotype, sex, and lipid levels.\n\nDESIGN, SETTING, AND PARTICIPANTSWe 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.\n\nMEASURESWe assessed the association between IC and statin use using logistic regression analysis, while adjusting for clinical factors, sociodemographics, and APO ({varepsilon}) genotypes before and after propensity score matching. We further performed stratified analysis by sex, and APO ({varepsilon}) 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.\n\nRESULTSThe 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 ({varepsilon}) 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 {varepsilon}3\/{varepsilon}3 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 ([&le;] 10mg\/dl: OR:1.61;1.22-2.15, p=8e-4).\n\nCONCLUSIONIn the AllofUS cohort, IC was significantly associated with statin use in CAD participants. We observed the strongest association in the APO {varepsilon}3{varepsilon}3 group, among females, and with a greater increase in HDL levels in statin users.\n\nKey MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment or all-cause dementia, share genetic, sociodemographic, and clinical risk factors but the association of IC with statin use in CAD remains unclear.\n\nWhat this study addsWe observed an association between IC and statin use in CAD participants after adjusting for sociodemographics, clinical factors, and APO ({varepsilon}) genotypes. The association persisted after propensity score matching for sociodemographics, clinical factors, and APO ({varepsilon}) genotypes. Further, when CAD participants were stratified across APO ({varepsilon}) groups and by sex, we observed strongest magnitude of association between IC and statin use in the APO {varepsilon}3{varepsilon}3 compared to other APO ({varepsilon}) genotypes, and in females compared to males. Among CAD participants with documented baseline and latest lipids (total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL)), IC was associated with statin use regardless of baseline lipid levels or latest lipid levels. While we did not observe any change in association between IC and statin use, based on the magnitude of decrease in TC and LDL levels, we observed a higher magnitude of association between IC and statin use, with a greater increase in HDL levels.\n\nHow this study might affect research, practice or policyOur observations highlight the association of IC and statin use in CAD and the role of APO ({varepsilon}) genotype evaluation, and serial lipid level assessments for evaluating for statin associated IC in CAD.","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":"BackgroundPre-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 ashealth 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.\n\nMethods and analysisA 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.\n\nResultsRecruitment and enrollment of participants began in January 2026 and is currently ongoing.\n\nDiscussionThis 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 inferiority than 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 being more cost-effective. With the ongoing advancement of AI technologies, PrEP-bot hold substantial promise for widespread implementation in PrEP adherence, potentially revolutionizing HIV prevention for MSM in China through this innovative intervention modality.\n\nTrial registrationChiCTR2500111280 (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":"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":"BackgroundAutism 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.\n\nMethodsWe 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.\n\nResultsSix 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.\n\nConclusionsAutism 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":"BackgroundProstate 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.\n\nMethodsWe 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.\n\nResultsAmong 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.\n\nConclusionsNeighborhood deprivation and insurance-related access explained part, but not all, of the excess odds of metastatic diagnosis among Black men.\n\nImpactIntegrating 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.\n\nImportanceThe spread of antibiotic resistance poses a serious and escalating threat to human health worldwide. While antibiotic use is widely recognized as a key driver, non-antibiotic pharmaceuticals released into the environment through wastewater have received far less attention. Antidepressants are among the most frequently detected drugs in treated wastewater effluents, yet their potential to promote antibiotic resistance transfer in bacteria remains poorly understood. This study demonstrates that desvenlafaxine, one of the most abundant antidepressants found in municipal wastewater, increases the uptake of antibiotic resistance genes in environmental bacteria and identifies the bacterial cell-surface changes that enable this.","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":"BackgroundStudies show 53-74% 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.\n\nMethodsThe 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 analyzed using mixed-effects logistic models over one year.\n\nResultsOf 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.\n\nConclusionLower 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.","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":"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 womens comfort with AI and its association with PrEP awareness. 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. 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. 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":"ObjectiveAlzheimers disease (AD) is a leading cause of death and disability, and treatment options for Alzheimers 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).\n\nMethodsWe 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.\n\nFindingsThe 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%).\n\nImplicationsThis 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"}]}