{"gname":"Northeastern University","grp_id":"54","rels":[{"rel_title":"Nutrient control enables metabolic reconstruction of L. rhamnosus GG and analysis of secretions","rel_doi":"10.64898\/2026.06.02.729517","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729517","rel_abs":"Lacticaseibacillus rhamnosus GG (LGG) is an important gut commensal bacterial strain that has been extensively studied in both industrial and health settings. Despite its long history of study, a high-quality genome-scale metabolic network model (GEM) for LGG has yet to be reconstructed. Only automatically-generated draft models have been published, which have notoriously limited functional accuracy. Furthermore, comprehensive nutrient requirements have not been established for well-controlled in vitro study. Here we present the first curated GEM for LGG using a new approach for reconstruction and validation that leverages multiple automatically-generated draft models, applied study literature, and high-throughput defined media experiments. In addition, our results include a series of chemically defined media, extensive single-component nutrient dropout growth data, insights from in silico and in vitro experiments into major secretion products lactate and indole-3-carboxaldehyde, a minimal medium and in silico characterization of LGG's nutrient requirements. Our approach for developing interdisciplinary research tools for LGG metabolism comprises a new framework that could be applied to many understudied microorganisms, particularly useful in studying bacteria within the human microbiome.","rel_num_authors":5,"rel_authors":[{"author_name":"Gracelyn R Richmond","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Emanuel Cunha","author_inst":"University of Minho"},{"author_name":"Libusha Kelly","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Oscar Dias","author_inst":"University of Minho"},{"author_name":"Roger Chang","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"An Itch Receptor Drives Melanoma","rel_doi":"10.64898\/2026.06.01.729383","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729383","rel_abs":"Mas-Related GPCR X4 (MRGPRX4) is a sensory neuron-restricted receptor for cholestatic itch. Here, we identify MRGPRX4 as an unexpected melanoma driver. MRGPRX4 is upregulated in melanoma and is confined to invasive, neural-crest-like and pre-EMT states associated with dedifferentiation and therapy resistance. Ectopic MRGPRX4 expression in mouse melanocytes drives 100% penetrant, highly metastatic melanoma, demonstrating oncogenic behavior. MRGPRX4 promotes melanoma cell proliferation and invasion through basal, ligand-independent, PI3K-AKT-MAPK activation. Multi-omics links MRGPRX4 expression to a mesenchymal\/neural-crest-like program that defines a distinct invasive MRGPRX4? niche. Comparing transcptomics of MRGPRX4-driven tumors shows a broad overlap with BRAF\/NRAS-driven tumors; however, the MRGPRX4 model also enriches an ECM-rich, invasive neural crest-like melanoma state. MRGPRX4 further remodels the tumor microenvironment toward an immunosuppressive, checkpoint-high state enriched in suppressive myeloid cells. Pharmacologic MRGPRX4 inhibition suppresses basal signaling and limits melanoma growth and invasion. In sum, melanoma exploits MRGPRX4 to acquire an invasive and immunosuppressive phenotype, nominating this somatosensory GPCR as a promising therapeutic target.","rel_num_authors":13,"rel_authors":[{"author_name":"Naina Gour","author_inst":"Johns Hopkins University, School of Medicine"},{"author_name":"Aishwarya Atakkatan","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Moloud Akbarzadeh","author_inst":"Universit\u00e9 Laval"},{"author_name":"Hwan Mee Yong","author_inst":"Johns Hopkins University"},{"author_name":"Aishwarya Magesh","author_inst":"Johns Hopkins Medicine"},{"author_name":"Zhiping Wu","author_inst":"St Jude Childern's Research Hospital"},{"author_name":"Hyunkeun Joo","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Yash Chhabra","author_inst":"Fox Chase Cancer Center"},{"author_name":"Junmin Peng","author_inst":"St Jude Childern's Research Hospital"},{"author_name":"Ashani Weeraratna","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Mathieu Laplante","author_inst":"Universit\u00e9 Laval"},{"author_name":"Stephane Lajoie","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Xinzhong Dong","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"Associations Between Plasma Lipoprotein(a) Levels and Circulating Monocyte Subsets Differ across Populations","rel_doi":"10.64898\/2026.06.01.729444","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.729444","rel_abs":"Objective: Lipoprotein(a) [Lp(a)] is a causal cardiovascular disease (CVD) risk factor, with plasma concentrations generally higher in Black than White individuals. Evidence suggests that elevated Lp(a), partly through oxidized phospholipid (oxPL)-mediated signaling, promotes a pro-inflammatory monocyte phenotype that may contribute to arterial inflammation and CVD. We examined associations between Lp(a) levels, apo(a) isoform size, and circulating monocyte populations in Black and White individuals using single-cell RNA sequencing (scRNA-seq). Approach and Results: Plasma Lp(a), apo(a) isoform size, inflammatory markers, and oxPL were measured using standardized assays in stored samples from a previously characterized cohort of 128 participants. After excluding smokers and individuals with type 2 diabetes, 34 participants remained (20 Black, 14 White). Participants were stratified into normal Lp(a) (median 12.6 nmol\/L; n=15, 8 Black) and high Lp(a) (median 159 nmol\/L; n=19, 12 Black) groups. Multivariable linear regression assessed associations between plasma Lp(a), Lp(a)-bound oxPL, and monocyte subset proportions. scRNA-seq identified six classical monocyte subsets, one non-classical monocyte subset, one MHCIIhi monocyte subset, and one interferon-responsive monocyte subset. Monocyte subset distributions did not differ between normal and high Lp(a) groups. However, race modified the association between plasma Lp(a) levels and non-classical monocyte abundance (P_interaction=0.032), with an inverse association observed in White participants (P=0.028) but not Black participants (P=0.470). OxPL bound to apo(a) correlated strongly with plasma Lp(a) concentrations (R2=0.84, P=3.3x10^1) and showed a race-dependent association with non-classical monocytes (P_interaction=0.014). Race also modified the association between plasma Lp(a) levels and classical 2 monocytes (P_interaction=0.027). Conclusions: These findings suggest that associations between Lp(a), oxPL, and circulating monocyte subsets differ by race and highlight the importance of considering self-reported race in studies of Lp(a)-related immune and cardiovascular phenotypes.","rel_num_authors":12,"rel_authors":[{"author_name":"Alexander C Bashore","author_inst":"Icahn School of Medicine at Mount Sinai Cardiovascular Research Institute"},{"author_name":"Benedek Halmos","author_inst":"University Medical Center Groningen"},{"author_name":"Anastasiya Matveyenko","author_inst":"Columbia University Medical Center"},{"author_name":"Nelsa Matienzo","author_inst":"Columbia University"},{"author_name":"Anouk G. Groenen","author_inst":"University Medical Center Groningen"},{"author_name":"Lucie Y Zhu","author_inst":"Columbia University"},{"author_name":"Sergio Mosquera Restrepo","author_inst":"Pontificia Universidad Catolica Madre y Maestra Facultad de Ciencias de la Salud"},{"author_name":"Yihao Li","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Hanrui Zhang","author_inst":"Columbia University"},{"author_name":"Marit Westerterp","author_inst":"Universitair Medisch Centrum Groningen"},{"author_name":"Muredach Reilly","author_inst":"Columbia University"},{"author_name":"Gissette Reyes-Soffer","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"Quantifying Evidence for Competing Biomedical Hypotheses using Large Language Models and Bayesian Analysis","rel_doi":"10.64898\/2026.06.05.730173","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730173","rel_abs":"Science fundamentally depends on the generation and testing of hypotheses, many of them controversial. An explosion in scientific literature has made evaluating hypotheses even within a domain a problem of scale, and risks slowing an already extensive consensus-building process. While this challenge has prompted interest in automated hypothesis evaluation tools, existing methods have not yet proven effective for comparing hypotheses. Here, we introduce KM-GPT-DCH, an algorithm that combines co-occurrence methods with large language models (LLMs) to develop a transparent and reproducible literature-based algorithm to compare controversial hypotheses using a structured scoring approach with Bayesian methods to estimate confidence. When testing the algorithm on historical controversial hypotheses previously decided, KM-GPT-DCH chooses the correct hypothesis with high confidence several years before the scientific community or public do so. We further apply the algorithm to compare twenty unresolved controversial hypothesis pairs providing guidance for future research. The method can help researchers and the public to evaluate biomedical hypotheses such as \"Is it more likely that monoamine deficiency or inflammation causes depression?\" It can also be used to assess and visualize historical trends in the scientific literature. A web-based implementation of the algorithm is freely available at https:\/\/skim.morgridge.org.","rel_num_authors":12,"rel_authors":[{"author_name":"Bethany M Moore","author_inst":"Morgridge Institute for Research"},{"author_name":"Jack Freeman","author_inst":"Morgridge Institute for Research"},{"author_name":"Robert J Millikin","author_inst":"Morgridge Institute for Research"},{"author_name":"Chitrasen Mohanty","author_inst":"Morgridge Institute for Research"},{"author_name":"Kevin Shine George","author_inst":"Morgridge Institute for Research"},{"author_name":"Aviral Bal","author_inst":"Morgridge Institute for Research"},{"author_name":"Cannon Lock","author_inst":"Morgridge Institute for Research"},{"author_name":"John-Demian Sauer","author_inst":"Department of Medical Microbiology and Immunology, University of Wisconsin-Madison School of Medicine and Public Health"},{"author_name":"Megan E Spurgeon","author_inst":"Morgridge Institute for Research"},{"author_name":"Darcie L Moore","author_inst":"Department of Neuroscience, University of Wisconsin-Madison School of Medicine and Public Health"},{"author_name":"Brittany G Travers","author_inst":"Occupational Therapy Program, Department of Kinesiology, University of Wisconsin-Madison"},{"author_name":"Ron Stewart","author_inst":"Morgridge Institute for Research"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"Germline regulation of tumor evolutionary dynamics shapes multiple myeloma progression","rel_doi":"10.64898\/2026.06.05.730550","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730550","rel_abs":"Germline variation shapes cancer risk, yet its influence on the evolutionary dynamics of established tumors remains poorly understood. In multiple myeloma, subclonal diversification drives disease progression and treatment failure, but the heritable factors that modulate this process are unknown. Here, we show that germline variation is associated with tumor evolutionary features, implicating inherited regulation in subclonal expansion. Integrating germline variation with tumor evolutionary parameters identifies variants associated with evolutionary features, with signals enriched in regulatory regions, consistent with a transcriptional basis. We further identify TBKBP1 as a key locus linking germline variation to tumor evolution and clinical outcome. Germline variation at this locus is associated with TBKBP1 expression and subclonal expansion, and TBKBP1 expression correlates with adverse prognosis, consistent across independent cohorts. Functional analyses demonstrate that TBKBP1 promotes proliferation and activates MYC, mTORC1 and non-canonical NF-{kappa}B signaling pathway. Together, these findings establish germline regulatory variation as a determinant of tumor evolutionary dynamics and identify TBKBP1 as a mediator linking inherited variation to subclonal expansion and disease progression in multiple myeloma.","rel_num_authors":9,"rel_authors":[{"author_name":"Hai Chen","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Jingmin Shu","author_inst":"Arizona State University"},{"author_name":"Rekha Mudappathi","author_inst":"Arizona State University"},{"author_name":"Panwen Wang","author_inst":"Mayo Clinic"},{"author_name":"Leif Bergsagel","author_inst":"Mayo Clinic"},{"author_name":"Ping Yang","author_inst":"Mayo Clinic"},{"author_name":"Zhifu Sun","author_inst":"Mayo Clinic"},{"author_name":"Changxin Shi","author_inst":"Mayo Clinic"},{"author_name":"Li Liu","author_inst":"Arizona State University"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"Anthocyanin-associated cellular programs underlying terroir variation in Cabernet Sauvignon grape berry revealed by SEED-based deconvolution","rel_doi":"10.64898\/2026.06.05.730035","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730035","rel_abs":"Plant tissues consist of diverse cell populations that collectively contribute to development, metabolism, environmental responses, and phenotype formation. Although single-cell and single-nucleus RNA sequencing have greatly advanced the study of plant cellular heterogeneity, their application to large sample cohorts remains limited by cost, technical complexity, tissue dissociation constraints, and throughput. In contrast, bulk RNA-seq datasets have accumulated extensively across plant species, tissues, developmental stages, and environmental conditions, yet the celltype-level information embedded in these datasets remains difficult to resolve because plant-oriented deconvolution frameworks are still lacking. Existing deconvolution methods have largely been developed in mammalian systems and have not been systematically optimized for plant transcriptomic features, leaving their applicability under plant-specific constraints unclear. Here, we present SEED, an adaptive deconvolution framework optimized for plant transcriptomic data. SEED integrates candidate reference-template construction with seven deconvolution strategies and automatically identifies an optimal combination for a given dataset. In grapevine simulated benchmarking, SEED showed its clearest advantage under low-replication conditions and remained broadly competitive, rather than uniformly dominant, when larger pseudo-bulk sample sizes were evaluated. SEED further performed robustly in public Arabidopsis thaliana and Nicotiana tabacum datasets. Finally, we applied SEED to bulk RNA-seq data generated in this study from Vitis vinifera cv. Cabernet Sauvignon berries collected from Yinchuan and Yantai, identifying terroir-associated cell subtypes and coordinated celltype interaction patterns. Together, these results establish SEED as a practical framework for plant transcriptome deconvolution and provide a new tool for dissecting cellular heterogeneity associated with environmental adaptation and phenotype formation in plants.","rel_num_authors":11,"rel_authors":[{"author_name":"Xinhao Hu","author_inst":"China Agricultural University"},{"author_name":"Yu Tang","author_inst":"Chenshan Science Research Center, CAS Center for Excellence in Molecular Plant Sciences"},{"author_name":"Fulan Deng","author_inst":"Macao Polytechnic University"},{"author_name":"Zhiyu Chen","author_inst":"Fudan University"},{"author_name":"Guwei Tang","author_inst":"Jishou University"},{"author_name":"Xu Yan","author_inst":"Chenshan Science Research Center, CAS Center for Excellence in Molecular Plant Sciences"},{"author_name":"Zengqiang Xia","author_inst":"Chenshan Science Research Center, CAS Center for Excellence in Molecular Plant Sciences"},{"author_name":"Henry H.Y. Tong","author_inst":"Macao Polytechnic University"},{"author_name":"Jicheng Zhan","author_inst":"China Agricultural University"},{"author_name":"Xin Zou","author_inst":"Linyi University"},{"author_name":"Jie Hao","author_inst":"Chenshan Science Research Center, CAS Center for Excellence in Molecular Plant Sciences"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"A Web-based software toolkit for accessible and best-practice machine learning analyses in biomedical research","rel_doi":"10.64898\/2026.06.05.730487","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730487","rel_abs":"Machine learning is increasingly central to biomedical research, but using machine learning well often requires substantial computational expertise and methodological care to produce high-quality results. To make machinelearning tools more accessible to biomedical researchers while supporting best-practice approaches, we developed the Galaxy Learning and Modeling (GLEAM) software toolkit. GLEAM enables researchers to performsupervised machine learning analyses through a set of web-based, code-free software tools for tabular, image, and multimodal biomedical datasets. GLEAM standardizes data partitioning, model selection, training, evaluation,and reporting, helping researchers apply machine learning with greater rigor and consistency. GLEAM runs on the Galaxy computational workbench and uses Galaxy's core features to make all analyses accessible,reproducible, and scalable. We validated GLEAM on three biomedical tasks: predicting patient response to immunotherapy, skin lesion classification, and cancer recurrence prediction. Across these tasks, GLEAM producedhighly accurate predictive models and improved transparency, reproducibility, and rigor.","rel_num_authors":10,"rel_authors":[{"author_name":"Paulo Cilas Morais Lyra Junior","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Junhao Qiu","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Khai Van Dang","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Alyssa Pybus","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Isis Narvaez-Bandera","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Maansi A Singh","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"},{"author_name":"Qiang Gu","author_inst":"Oregon Health & Science University"},{"author_name":"Luke Sargent","author_inst":"Oregon Health and Science University"},{"author_name":"Allison L Creason","author_inst":"Oregon Health & Science University"},{"author_name":"Jeremy Goecks","author_inst":"H. Lee Moffitt Cancer Center & Research Institute"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"Hippocampal CA2 modulates trace fear conditioning through circuit-specific control of CA1","rel_doi":"10.64898\/2026.06.05.730478","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730478","rel_abs":"Forming associations between temporally separated events depends on pathways linking the CA1, the subiculum (SUB), and the entorhinal cortex. The degree to which this process requires the CA2, which shares extensive connectivity with these regions, remains unknown. Using trace fear conditioning (TFC), where mice learn to associate a tone and shock separated by a temporal gap, we showed that the dCA2 contributes to TFC. Interestingly, whereas chronic dCA2 inhibition decreased cue-associated freezing, acute dCA2[-&gt;]dCA1 projection inhibition increased freezing. Combined with differential effects on cFos expression, this suggests that global and projection-specific perturbations of the dCA2 have distinct effects on TFC and hippocampal activity states. Fiber photometry revealed that dCA2[-&gt;]dCA1 activity shifted from tone responsiveness during conditioning to expected shock activation during recall, consistent with learning-associated activity remodeling. Together, these findings identify the dCA2 as a contributor to TFC and implicate dCA2[-&gt;]dCA1 signaling in shaping fear expression across learning and recall.","rel_num_authors":9,"rel_authors":[{"author_name":"Thomas Edward Bassett","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Hui Zhang","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Zorica Petrovic","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Chihiro Nakamoto","author_inst":"Aarhus University"},{"author_name":"Ana Cicvaric","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Elizabeth Marie Wood","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Stephanie Rudolph","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Asami Tanimura","author_inst":"Aarhus University"},{"author_name":"Jelena Radulovic","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"Thalamic Nuclei Differentially Coordinate Propagation of Cortical Slow Oscillations","rel_doi":"10.64898\/2026.06.05.730542","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730542","rel_abs":"Sleep slow oscillations (SOs) vary in the spatial extent of their cortical propagation, ranging from widespread Global events to spatially restricted Frontal events. These distinctions could have functional consequences for memory consolidation. It remains unknown whether individual thalamic nuclei are differentially engaged across SO propagation types, and whether thalamic activity before SO onset predicts subsequent propagation. We analyzed simultaneous scalp EEG and thalamic stereo-EEG from 24 full-night recordings in 6 epilepsy patients, sampling 11 thalamic nuclei and enabling direct characterization of nucleus-specific thalamocortical interactions during naturally occurring sleep slow oscillations. Cortical SOs were classified by propagation type and thalamocortical coupling was characterized via peri-event histograms, phase-locking analysis, waveform morphology comparisons, and pre-onset spectral and cross-frequency coupling features. All well-sampled thalamic nuclei showed broad temporal co-occurrence with prefrontal SOs, yet occupied distinct phase positions within the cortical SO cycle. Medial pulvinar (PuM) showed the strongest phase locking across subjects, with significant preference for the ascending post-trough phase. Among the examined nuclei, Frontal SOs were associated with significant phase locking in PuM, whereas Global SOs preferentially synchronized the centromedian nucleus near the cortical down-state trough. Thalamic waveform morphology differed systematically with propagation extent, with opposing effects between pulvinar and intralaminar nuclei. Pre-onset PuM activity showed suppressed alpha, sigma, and beta power and delta-phase cross-frequency coupling before Global SOs (all p < 0.05). The human thalamus engages NREM sleep SOs through nucleus-specific, propagation-sensitive dynamics rather than as a functionally uniform structure. Pre-onset PuM activity contains predictive signatures of cortical SO propagation extent. This finding has implications for closed-loop neuromodulation targeting specific SO states, although replication in larger cohorts is needed. Keywords: Slow Oscillations; Thalamocortical Coupling; Pulvinar; Centromedian Nucleus; Cross-Frequency Coupling","rel_num_authors":5,"rel_authors":[{"author_name":"Mahmoud Alipour","author_inst":"University of Chicago"},{"author_name":"Wim van Drongelen","author_inst":"University of Chicago"},{"author_name":"Joshua Jacobs","author_inst":"University of Chicago"},{"author_name":"Joel Voss","author_inst":"University of Chicago"},{"author_name":"David Satzer","author_inst":"University of Chicago"}],"rel_date":"2026-06-07","rel_site":"biorxiv"},{"rel_title":"Structure-guided compound prioritization strategy for virtual screening identifies putative binders for the nuclear receptor LRH-1","rel_doi":"10.64898\/2026.06.04.730240","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730240","rel_abs":"Compound ranking in structure-based virtual screening notoriously yields highly ranked false positive binders due to variable poses or biases in scoring terms. We developed a compound prioritization strategy that utilizes sampled docked poses from contrasting docking approaches (targeted physics-based docking and blind docking with a generative model) against multiple models of the target protein to train a multi-layer perceptron (MLP). The model predicts binders at the orthosteric ligand-binding pocket of the nuclear receptor LRH-1 (NR5A2). Our approach circumvents the reliance on a single docked pose for scoring compounds or individual scoring metrics for compound ranking. In a separate benchmarking set, we observed that the MLP identifies known binders that are chemically dissimilar from the compounds in the training set and is sensitive to single scaffold modifications, making it a potential tool for lead optimization. We applied our strategy to a prospective virtual screening campaign, which resulted in the discovery of four putative LRH-1 binders. We found that a combination of scoring and prediction metrics enriches for the hit compounds across library sizes. In all, this implementation presents a method to leverage structural and experimental data to aid virtual screening for a challenging protein target.","rel_num_authors":5,"rel_authors":[{"author_name":"Ana C. Chang-Gonzalez","author_inst":"Vanderbilt University"},{"author_name":"Alexis N. Campbell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Eric W. Bell","author_inst":"Vanderbilt University"},{"author_name":"Raymond Blind","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jens Meiler","author_inst":"Vanderbilt University"}],"rel_date":"2026-06-07","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":"Introduction: Brain-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. Methods: T1-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). Results: Higher 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. Conclusions: Elevated 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.","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":"The Sorghum Lipid Database (SoLD): population-scale lipidomics linking environmental and genetic variation in the Sorghum Association Panel","rel_doi":"10.64898\/2026.06.05.727974","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.727974","rel_abs":"Sorghum (Sorghum bicolor ) is a climate-resilient crop whose acclimation to nutrient limitation and low temperature likely involves extensive lipidome reconfiguration. Lipids are key membrane components, carbon and energy stores, and mediators of stress signaling, yet population-scale lipidomics data for sorghum are limited. We present the Sorghum Lipid Database (SoLD), a curated lipidomics resource from the Sorghum Association Panel grown under two field regimes: (i) a nutrient-sufficient with usual planting date environment (control) and (ii) a low-input treatment with reduced nitrogen and phosphorus, earlier planting, and no application of insecticides, herbicides, or pesticides (low-input). Using high-resolution LC-MS, we quantified 244 lipid species and detected broad, largely conserved compositional shifts across field trials. However, there were four major low-input-associated lipid signatures relative to control: (i) depletion of sulfoquinovosyldiacylglycerol, (ii) triacylglycerol enrichment, (iii) phospholipid redistribution centered on phosphatidylserine, and (iv) coordinated lysophospholipid remodeling, reflected in altered lysophosphatidylcholine-to-lysophosphatidylethanolamine ratios. Analyses of lipid chemical space and lipid ontology enrichment supported these compositional changes. GWAS of lipid species, class sums, and class ratios revealed recurrent, environment-specific loci. Control-associated loci were enriched for genes involved in lipid and isoprenoid metabolism, developmental regulation, and cell-wall biosynthesis and modification. Low-input-associated loci were enriched for genes involved in nutrient-stress signaling, cell-wall remodeling, defense, developmental control, and cold-related barrier formation and proteostasis. Thus, SoLD provides a framework connecting sorghum lipid diversity with environmental and genetic variation. All information regarding the database and the experiment is freely accessible through a Shiny application: https:\/\/nirwan.shinyapps.io\/SAP-Lipidomics-Database\/. The database enables users to move from lipid-class to individual molecular species and associated candidate loci, for hypothesis generation, comparative analyses, and prioritization of targets for functional validation.","rel_num_authors":6,"rel_authors":[{"author_name":"Nirwan Tandukar","author_inst":"Department of Molecular and Structural Biochemistry, N.C. Plant Sciences Initiative, Genetics and Genomics Graduate Program, North Carolina State University, Ra"},{"author_name":"Ruthie Locklear","author_inst":"Department of Molecular and Structural Biochemistry, N.C. Plant Sciences Initiative, North Carolina State University, Raleigh, NC, USA."},{"author_name":"Richard Elmer Boyles","author_inst":"Department of Plant and Environmental Sciences, Clemson University, Clemson, SC, USA"},{"author_name":"Zachary W Brenton","author_inst":"Carolina Seed Systems, Darlington, South Carolina"},{"author_name":"Katherine B Louie","author_inst":"Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94720"},{"author_name":"Ruben Rellan-Alvarez","author_inst":"Department of Molecular and Structural Biochemistry, N.C. Plant Sciences Initiative, North Carolina State University, Raleigh, NC, USA."}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Demographic history, geographic distance, and landscape features shape the genetic divergence of wild tigers in northeast India","rel_doi":"10.64898\/2026.06.02.729668","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729668","rel_abs":"Habitat fragmentation creates small, isolated populations that are vulnerable to inbreeding, genetic drift, and a high genetic load. For conservation management, it is essential to distinguish contemporary landscape resistance from historical demographic processes as drivers of these genetic patterns, especially for conservation priority regions such as northeast India, which intersects two major tigers conservation landscapes. We studied the genetic structure and landscape connectivity of tigers across four protected areas in northeast India: Kaziranga, Manas, Orang, and Nameri, using faecal samples. From 741 samples collected over two field seasons, we confirmed 654 as tigers. Using methylation-based enrichment and ddRAD-seq of 176 samples, we generated a high-quality dataset of 3091 SNPs across 44 individuals. Population structure analyses identified three genetically distinct clusters: Kaziranga-Nameri, Manas, and Orang. Isolation-by-distance and landscape resistance explained 13% and 17% of the observed genetic divergence, respectively, with human settlements influencing gene flow. Orang's pronounced divergence from Kaziranga, despite geographic proximity and corridors, suggests a post-bottleneck founder effect, as evidenced by its reduced heterozygosity (Ho = 0.21), nucleotide diversity ({pi} = 0.24), and effective population size (Ne = 1.3). These findings reveal that demographic and genetic recovery can decouple: Orang's population has recently grown, yet genome-wide evidence shows ongoing genetic erosion that monitoring has not detected. Similar patterns have been reported in other Indian tiger populations, indicating that such decoupling may be systemic. Target 4 of the Kunming-Montreal Global Biodiversity Framework requires explicit genetic diversity monitoring; this study demonstrates that non-invasive genomics can operationalise that mandate at a conservation-relevant scale.","rel_num_authors":6,"rel_authors":[{"author_name":"Vinay Sagar","author_inst":"National Centre for Biological Sciences, TIFR"},{"author_name":"Tista Ghosh","author_inst":"National Centre for Biological Sciences, TIFR"},{"author_name":"Kritagnya Vadar","author_inst":"National Centre for Biological Sciences, TIFR"},{"author_name":"Vaishnavee Kundan Mayekar","author_inst":"National Centre for Biological Sciences, TIFR"},{"author_name":"Abishek Harihar","author_inst":"Panthera 104 W 40th St 5th Floor, NY, NY 10018"},{"author_name":"Uma Ramakrishnan","author_inst":"National Centre for Biological Sciences, TIFR"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Transcriptionally Active HIV Reservoirs Enriched for Interferon-Inducible APOBEC3-Related Mutational Signatures Associate with Reduced Neuroaxonal Integrity","rel_doi":"10.64898\/2026.06.02.729658","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729658","rel_abs":"Despite sustained viral suppression with effective antiretroviral therapy (ART), neuroaxonal integrity persist in a subset of people with HIV-1 (PWH). We investigated whether interferon (IFN)-inducible APOBEC3-associated mutational signatures, reflected by premature stop codons (PSCs), and reservoir-associated drug resistance mutations (RS-DRMs) within transcriptionally active HIV-1 reservoirs influence neuroaxonal integrity in fully virally suppressed individuals. Peripheral CD4 T cells from individuals with undetectable plasma HIV-1 RNA (n = 27) were analyzed for long HIV-1 gag\/pol transcripts (>4.2 kb), and frontal white matter (FWM) neuroaxonal integrity was assessed using proton magnetic resonance spectroscopy (MRS) measurement of N-acetylaspartate (NAA). Short HIV-1 RNA transcripts, reflecting promoter-associated transcriptional activity, were detected in all participants and were associated with reduced NAA levels in FWM, consistent with a relationship between ongoing reservoir activity and impaired neuroaxonal integrity despite virological suppression. Long gag\/pol transcripts (>4.2 kb) were detected in 78% of participants and exhibited marked heterogeneity in APOBEC3-associated PSC burden. PSC-containing long transcripts were associated with higher NAA, whereas long transcripts lacking such inactivating mutations were associated with reduced NAA, suggesting that APOBEC3-associated restriction of viral translational competence may contribute to differences in the downstream neurobiological effects of transcriptionally active reservoir states. RA-DRMs were detected in 43% of participants, including triple-class resistance consistent with archived treatment exposure over more than a decade. Matching gag\/pol sequences from reactivated virions confirmed latent reservoir origin; however, RS-DRMs showed no independent association with neuroaxonal outcomes. Across systemic inflammatory markers, vascular risk factors, cerebrospinal fluid immune activation measures, and clinical neurocognitive outcomes (including HAND status), no consistent associations with NAA were observed. Overall, reduced neuroaxonal integrity in the FWM was associated with the interplay between short HIV-1 RNA transcriptional activity and APOBEC3-edited translational states of long HIV-1 RNA transcripts within peripheral reservoirs, suggesting that interferon-inducible APOBEC3-associated mutational signatures may reflect biologically distinct reservoir states that correspond to neurobiological effects during suppressive antiretroviral therapy.","rel_num_authors":12,"rel_authors":[{"author_name":"Kazuo Suzuki","author_inst":"St Vincent's Centre for Applied Medical, St Vincent's Hospital"},{"author_name":"Angelique Levert","author_inst":"St Vincent's Centre for Applied Medical Research, St Vincent's Hospital"},{"author_name":"Emma Yoo","author_inst":"St Vincent's Centre for Applied Medical Research, St Vincent's Hospital"},{"author_name":"Masakazu Matsuda","author_inst":"Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya"},{"author_name":"Takaomi Ishida","author_inst":"Denka Co. Ltd, Tokyo, Japan"},{"author_name":"Lucette A Cysique","author_inst":"UNSW Psychology, Sydney, NSW, Australia"},{"author_name":"John Zaunders","author_inst":"St Vincent's Centre for Applied Medical Research, St Vincent's Hospital"},{"author_name":"Ira W Deveson","author_inst":"Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, NSW, Australia"},{"author_name":"Kirston Barton","author_inst":"Faculty of Medicine and Health, NHMRC Clinical Trials Centre, The University of Sydney, NSW, Australia,"},{"author_name":"Hirotaka Ode","author_inst":"Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya"},{"author_name":"Yasumasa Iwatani","author_inst":"Department of Microbiology and Immunology, Hamamatsu University School of Medicine, University Graduate School of Medicine, Hamamatsu, Shizuoka, Japan."},{"author_name":"Bruce J Brew","author_inst":"St Vincent's Clinical School, Faculty of Medicine, Sydney, New South Wales,"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Transcriptionally Active HIV Reservoirs Enriched for Interferon-Inducible APOBEC3-Related Mutational Signatures Associate with Reduced Neuroaxonal Integrity","rel_doi":"10.64898\/2026.06.02.729658","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729658","rel_abs":"Despite sustained viral suppression with effective antiretroviral therapy (ART), neuroaxonal integrity persist in a subset of people with HIV-1 (PWH). We investigated whether interferon (IFN)-inducible APOBEC3-associated mutational signatures, reflected by premature stop codons (PSCs), and reservoir-associated drug resistance mutations (RS-DRMs) within transcriptionally active HIV-1 reservoirs influence neuroaxonal integrity in fully virally suppressed individuals. Peripheral CD4 T cells from individuals with undetectable plasma HIV-1 RNA (n = 27) were analyzed for long HIV-1 gag\/pol transcripts (>4.2 kb), and frontal white matter (FWM) neuroaxonal integrity was assessed using proton magnetic resonance spectroscopy (MRS) measurement of N-acetylaspartate (NAA). Short HIV-1 RNA transcripts, reflecting promoter-associated transcriptional activity, were detected in all participants and were associated with reduced NAA levels in FWM, consistent with a relationship between ongoing reservoir activity and impaired neuroaxonal integrity despite virological suppression. Long gag\/pol transcripts (>4.2 kb) were detected in 78% of participants and exhibited marked heterogeneity in APOBEC3-associated PSC burden. PSC-containing long transcripts were associated with higher NAA, whereas long transcripts lacking such inactivating mutations were associated with reduced NAA, suggesting that APOBEC3-associated restriction of viral translational competence may contribute to differences in the downstream neurobiological effects of transcriptionally active reservoir states. RA-DRMs were detected in 43% of participants, including triple-class resistance consistent with archived treatment exposure over more than a decade. Matching gag\/pol sequences from reactivated virions confirmed latent reservoir origin; however, RS-DRMs showed no independent association with neuroaxonal outcomes. Across systemic inflammatory markers, vascular risk factors, cerebrospinal fluid immune activation measures, and clinical neurocognitive outcomes (including HAND status), no consistent associations with NAA were observed. Overall, reduced neuroaxonal integrity in the FWM was associated with the interplay between short HIV-1 RNA transcriptional activity and APOBEC3-edited translational states of long HIV-1 RNA transcripts within peripheral reservoirs, suggesting that interferon-inducible APOBEC3-associated mutational signatures may reflect biologically distinct reservoir states that correspond to neurobiological effects during suppressive antiretroviral therapy.","rel_num_authors":12,"rel_authors":[{"author_name":"Kazuo Suzuki","author_inst":"St Vincent's Centre for Applied Medical, St Vincent's Hospital"},{"author_name":"Angelique Levert","author_inst":"St Vincent's Centre for Applied Medical Research, St Vincent's Hospital"},{"author_name":"Emma Yoo","author_inst":"St Vincent's Centre for Applied Medical Research, St Vincent's Hospital"},{"author_name":"Masakazu Matsuda","author_inst":"Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya"},{"author_name":"Takaomi Ishida","author_inst":"Denka Co. Ltd, Tokyo, Japan"},{"author_name":"Lucette A Cysique","author_inst":"UNSW Psychology, Sydney, NSW, Australia"},{"author_name":"John Zaunders","author_inst":"St Vincent's Centre for Applied Medical Research, St Vincent's Hospital"},{"author_name":"Ira W Deveson","author_inst":"Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, NSW, Australia"},{"author_name":"Kirston Barton","author_inst":"Faculty of Medicine and Health, NHMRC Clinical Trials Centre, The University of Sydney, NSW, Australia,"},{"author_name":"Hirotaka Ode","author_inst":"Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya"},{"author_name":"Yasumasa Iwatani","author_inst":"Department of Microbiology and Immunology, Hamamatsu University School of Medicine, University Graduate School of Medicine, Hamamatsu, Shizuoka, Japan."},{"author_name":"Bruce J Brew","author_inst":"St Vincent's Clinical School, Faculty of Medicine, Sydney, New South Wales,"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Beta-Adrenergic Stimulation and MYH7 G256E Mutant Gene Dosage Drive Hypertrophic Cardiomyopathy Phenotype Penetrance","rel_doi":"10.64898\/2026.06.02.729411","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729411","rel_abs":"Aims Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic heart disorder, characterized by significant phenotypic variability even among individuals with identical MYH7 mutations. This study aims to elucidate factors contributing to this variability and identify drivers of phenotype penetrance. We compared the baseline phenotypes of a highly penetrant MYH7 H251N mutation and the variably penetrant MYH7 G256E mutation and investigated the impact of adding beta-adrenergic stimulation and homozygosity on disease phenotype penetrance using cardiomyocytes from an isogenic line of human induced pluripotent stem cells (hiPSC-CMs). Methods and Results Isogenic hiPSCs with MYH7 H251N and MYH7 G256E mutations were generated using CRISPR\/Cas9 technology and differentiated into cardiomyocytes (CMs). Single-cell RNA sequencing (scRNAseq) and functional analysis of contractile function revealed consistent HCM phenotype presentation in H251N CMs, whereas G256E CMs exhibited a subtle and more variable phenotype. Beta-adrenergic stimulation induced a distinct metabolic stress response in G256E CMs, characterized by impaired mitochondrial ATP upregulation. Increasing mutant gene dosage from hetero- to homozygosity led to consistent increase in hypertrophic and structural gene expression changes in G256E CMs at RNA and protein levels. These changes were distinct from the changes observed with stress response. Importantly, homozygous G256E CMs exhibited a hypercontractile functional and disorganized structural phenotype. Across multiple experimental conditions, we identified consistent increase in cardiomyocyte specific transcriptomic markers such as NPPB, APOE, PDLIM3 and ANKRD1. Conclusions Our study highlights the use of a variably penetrant MYH7 mutation to investigate factors that influence HCM phenotype penetrance. Specifically, we found that mutant gene dosage and beta-adrenergic stimulation induce distinct HCM disease phenotypes, providing novel insights into mechanisms that may contribute to variable disease expression in HCM. Translational Perspective HCM is characterized by significant phenotypic variability, complicating both diagnosis and clinical management. This study explores the factors driving HCM phenotype penetrance using isogenic hiPSC-CMs with MYH7 mutations. We demonstrate that beta-adrenergic stimulation and increased mutant gene dosage significantly impact HCM disease penetrance. Beta-adrenergic stimulation triggers metabolic stress responses, while increased gene dosage leads to a hypercontractile and structurally disorganized phenotype. These findings provide insight into how specific modifiers can shape disease-associated phenotypes in HCM model systems.","rel_num_authors":22,"rel_authors":[{"author_name":"Paul Heinrich","author_inst":"Stanford University"},{"author_name":"Raina M. Jung","author_inst":"Stanford University"},{"author_name":"Jonathan S. Achter","author_inst":"University of Copenhagen"},{"author_name":"Vincent X. Nguyen","author_inst":"Stanford University"},{"author_name":"Carissa A. Lee","author_inst":"Stanford University"},{"author_name":"Carolin Sailer","author_inst":"University of Copenhagen"},{"author_name":"Henna Domian","author_inst":"Stanford University"},{"author_name":"Alison S Vander Roest","author_inst":"University of Michigan"},{"author_name":"Fabian P Suchy","author_inst":"Stanford University"},{"author_name":"James W. Jahng","author_inst":"Stanford University"},{"author_name":"Ana Kojic","author_inst":"Stanford University"},{"author_name":"Daniel Lee","author_inst":"Stanford University"},{"author_name":"Amelie Paasche","author_inst":"Stanford University"},{"author_name":"Brock Roberts","author_inst":"Allen Institute"},{"author_name":"Hiromitsu Nakauchi","author_inst":"Stanford Unviersity"},{"author_name":"Han Zhu","author_inst":"Stanford University"},{"author_name":"Joseph C. Wu","author_inst":"Stanford University"},{"author_name":"Daniel Bernstein","author_inst":"Stanford University"},{"author_name":"Alessandra Moretti","author_inst":"Technical University Munich"},{"author_name":"Alicia Lundby","author_inst":"University of Copenhagen"},{"author_name":"Soah Lee","author_inst":"Sungkyunkwan University"},{"author_name":"Sean M. Wu","author_inst":"Stanford University"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"STITCH: Spatial Transcriptomics Imputation via Flow Matching with Internal Learning","rel_doi":"10.64898\/2026.06.03.729557","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729557","rel_abs":"Spatial transcriptomics datasets frequently suffer from spatial gaps and missing regions due to sectioning artifacts, tissue damage, and the high cost of sequencing that limits tissue coverage. We present STITCH, a scalable and robust generative framework for multidimensional virtual spatial transcriptomics reconstruction. STITCH models intrinsic spatial-transcriptomic patterns directly from individual tissue samples, enabling reconstruction without requiring external reference atlases or matched histological image priors. The framework adopts a decoupled architecture that separates spatial morphology restoration from transcriptomic generation. STITCH first compresses high-dimensional transcriptomic profiles into a low-dimensional latent representation through a spatial-aware graph autoencoder. For 3D cross-slice gaps, STITCH employs optimal transport-conditioned flow matching for spatial reconstruction, whereas 2D in-slice damage is repaired through an internal learning strategy. To generate the corresponding transcriptomic profiles, STITCH further establishes a point-wise conditional flow matching model in the latent space. This module achieves linear computational complexity, enabling continuous 3D atlas reconstruction of over 11 million cells within 5 hours on a single commodity GPU. Extensive evaluations across diverse spatial transcriptomics platforms, spanning both single-cell and spot-level technologies, demonstrate that STITCH consistently preserves transcriptomic identities, spatial topologies, and anatomical continuity. Overall, STITCH provides a scalable and platform-compatible computational framework for reconstructing high-resolution continuous spatial transcriptomic atlases.","rel_num_authors":4,"rel_authors":[{"author_name":"Sui Wang","author_inst":"School of Mathematical Sciences, Peking University"},{"author_name":"Xinyu Wang","author_inst":"School of Mathematical Sciences, Peking University"},{"author_name":"Qiangwei Peng","author_inst":"School of Mathematical Sciences, Peking University"},{"author_name":"Tiejun Li","author_inst":"Peking University"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"HOPE: Interpretable Histology Analysis with Spatial Omics-Derived Signatures for Precision Oncology","rel_doi":"10.64898\/2026.06.03.729847","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729847","rel_abs":"Hematoxylin and eosin (H&E) stained images are fundamental clinical tools for disease assessment. However, even with advanced computational models, their prognostic capabilities remain limited. Spatial omics characterizes tumor microenvironments (TME) in detail yet remains clinically inaccessible due to cost and complexity. In this study, we present HOPE, a lightweight framework that learns TME signatures from paired H&E and spatial omics data during training, then applies these to H&E alone at inference. Leveraging H&E foundation models, HOPE consistently outperforms identical architectures trained without spatial omics guidance across cancer types and cohorts. It further generates interpretable annotations of TME signature on H&E regions, stratifying patients into biologically coherent groups with different prognostic outcomes. HOPE establishes a practical route to translate high-content spatial omics discoveries into scalable, clinically deployable tools.","rel_num_authors":10,"rel_authors":[{"author_name":"Tianyi Wang","author_inst":"The University of Hong Kong"},{"author_name":"Matthew Bieniosek","author_inst":"Enable Medicine; University of Pittsburgh"},{"author_name":"Tamara J. Krpicak","author_inst":"Eberhard Karls University of T\u00fcbingen; University T\u00fcbingen"},{"author_name":"Mingyuan Luan","author_inst":"University Hospital and Comprehensive Cancer Center T\u00fcbingen; University of T\u00fcbingen"},{"author_name":"Benjamin Ruf","author_inst":"Eberhard Karls University of T\u00fcbingen; University T\u00fcbingen"},{"author_name":"Christian M. Sch\u00fcrch","author_inst":"University Hospital and Comprehensive Cancer Center T\u00fcbingen; University of T\u00fcbingen"},{"author_name":"Aaron T. Mayer","author_inst":"Enable Medicine"},{"author_name":"Ruibang Luo","author_inst":"The University of Hong Kong"},{"author_name":"Alexandro E. Trevino","author_inst":"Enable Medicine"},{"author_name":"Zhenqin Wu","author_inst":"The University of Hong Kong"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance","rel_doi":"10.64898\/2026.06.04.730191","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730191","rel_abs":"Metformin is the most widely prescribed antidiabetic drug and an active candidate for repurposing in oncology. How it engages autophagy - a pathway central to both its metabolic and its anti-tumor effects - has remained unresolved, with reports of induction, suppression, and no effect. Here we show that metformin reroutes rather than induces or inhibits autophagy in human cancer cells: at therapeutic concentrations, it suppresses bulk cytosolic turnover by selectively blocking WIPI2-mediated phagophore tethering, while the ULK1 initiation complex relocates toward mitochondria and engages selective mitochondrial clearance. We trace this redirection to mitochondrial complex I inhibition, registered as a shift in the NAD\/NADH ratio before any change in the adenylate pool, and to a non-canonical reprogramming of the ULK1 complex that operates independently of mTORC1 and of the proposed PEN2-lysosomal route. AMPK is engaged in a subunit-specific manner that restrains ATG13 at initiation and enables WIPI2 displacement at maturation. The ULK1 complex is therefore the node at which metformin sets autophagic substrate selection, with direct implications for combination therapy in diabetes and cancer.","rel_num_authors":10,"rel_authors":[{"author_name":"Thuraya M Mutawi","author_inst":"University of Kansas"},{"author_name":"Shweta R Malvankar","author_inst":"University of Kansas"},{"author_name":"Andrea Graziani","author_inst":"University of Kansas"},{"author_name":"Udita Shah","author_inst":"University of Kansas"},{"author_name":"Khanh Nguyen","author_inst":"University of Kansas"},{"author_name":"David G Broadbent","author_inst":"Michigan State University"},{"author_name":"Zachary Clark","author_inst":"University of Kansas Medical Center"},{"author_name":"Michaella J. Rekowski","author_inst":"University of Kansas Medical Center"},{"author_name":"Susan M Lunte","author_inst":"University of Kansas"},{"author_name":"Carlo Barnaba","author_inst":"University of Kansas - Lawrence"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance","rel_doi":"10.64898\/2026.06.04.730191","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730191","rel_abs":"Metformin is the most widely prescribed antidiabetic drug and an active candidate for repurposing in oncology. How it engages autophagy - a pathway central to both its metabolic and its anti-tumor effects - has remained unresolved, with reports of induction, suppression, and no effect. Here we show that metformin reroutes rather than induces or inhibits autophagy in human cancer cells: at therapeutic concentrations, it suppresses bulk cytosolic turnover by selectively blocking WIPI2-mediated phagophore tethering, while the ULK1 initiation complex relocates toward mitochondria and engages selective mitochondrial clearance. We trace this redirection to mitochondrial complex I inhibition, registered as a shift in the NAD\/NADH ratio before any change in the adenylate pool, and to a non-canonical reprogramming of the ULK1 complex that operates independently of mTORC1 and of the proposed PEN2-lysosomal route. AMPK is engaged in a subunit-specific manner that restrains ATG13 at initiation and enables WIPI2 displacement at maturation. The ULK1 complex is therefore the node at which metformin sets autophagic substrate selection, with direct implications for combination therapy in diabetes and cancer.","rel_num_authors":10,"rel_authors":[{"author_name":"Thuraya M Mutawi","author_inst":"University of Kansas"},{"author_name":"Shweta R Malvankar","author_inst":"University of Kansas"},{"author_name":"Andrea Graziani","author_inst":"University of Kansas"},{"author_name":"Udita Shah","author_inst":"University of Kansas"},{"author_name":"Khanh Nguyen","author_inst":"University of Kansas"},{"author_name":"David G Broadbent","author_inst":"Michigan State University"},{"author_name":"Zachary Clark","author_inst":"University of Kansas Medical Center"},{"author_name":"Michaella J. Rekowski","author_inst":"University of Kansas Medical Center"},{"author_name":"Susan M Lunte","author_inst":"University of Kansas"},{"author_name":"Carlo Barnaba","author_inst":"University of Kansas - Lawrence"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Temporal coding expands the bandwidth of GPCR-mediated neuromodulation","rel_doi":"10.64898\/2026.06.03.729927","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729927","rel_abs":"The advent of modern transcriptomic approaches has revealed a breadth of neuromodulatory G protein-coupled receptor (GPCR) co-expression far exceeding what was previously thought. This raises a fundamental question about neuromodulatory system architecture because there is a much smaller number of available G protein transducers. Does this impose an information 'bottleneck', or can a single transducer pathway distinguish the effects of different neuromodulators? We addressed this question by focusing on four GPCRs that are natively co-expressed in essentially all hippocampal pyramidal neurons and that signal through the canonical Gs-coupled cyclic AMP (cAMP) cascade. We show that each GPCR produces a similar cAMP elevation upon acute activation but the effects observed at downstream steps diverge, to the point that the GPCRs differ dramatically in their ability to drive a transcriptional response. We also show that they differ in their ability to maintain functional responsiveness, with neuropeptide receptors remaining responsive for hours but monoamine receptors rapidly losing responsiveness. We conclude that the effective chemical bandwidth of cellular neuromodulation by GPCRs is not limited by the number of available transducers, and that there exists additional temporal coding which enables individual neurons to distinguish a richer neuromodulatory input.","rel_num_authors":2,"rel_authors":[{"author_name":"Xinyi Jenny He","author_inst":"University of California, San Francisco"},{"author_name":"Mark Von Zastrow","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Nucleoporin1 maintains male germ unit organization and transport in Arabidopsis pollen tubes, likely through shaping nuclear morphology","rel_doi":"10.64898\/2026.06.04.730007","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730007","rel_abs":"The male germ unit (MGU) in Arabidopsis pollen is comprised of one vegetative nucleus (VN) and two sperm nuclei (SN). It is evolutionarily specialized to deliver immotile sperm nuclei to an ovule for fertilization. Despite some progress in research on MGU, its organization and transport remain only partially understood. Here, we identified Nucleoporin1\/136 as a new player in the structural organization and positioning of MGU in pollen tubes. We and others have previously reported the reduced fertility of nup1-1 plants; however, the mechanism remains unknown. In this work, we further examined the role of NUP1 in fertility using two mutant alleles, nup1-1 and nup1-2-\/+. The reciprocal crosses between the nup1 mutants and the Col-0 wild type indicate that the nup1 mutant pollen is defective. To study the effect of a complete NUP1 knockout on pollen, we generated a transgenic line that produces pollen with and without NUP1 expression. This work led to the surprising discovery that the NUP1 protein is inherited from the pollen mother cell to the daughter cell during microgametophyte development. Subsequent in vitro experiments showed that NUP1 is required for pollen germination and pollen tube elongation. Further microscopic studies demonstrated that NUP1 is highly expressed in VN and essential for maintaining nuclear shape and size. We also demonstrated that NUP1 is required for proper MGU organization and transport, likely through maintaining VN morphology. Notably, our finding of nuclear morphology-mediated regulation of MGU may also explain the mechanistic details underlying the defective MGU movement in previously reported mutants such as kaku4, wit, and wip, which have abnormal nuclear morphology.","rel_num_authors":13,"rel_authors":[{"author_name":"Raj K Thapa","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Gang Tian","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Binghui Shan","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Xin Xie","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Qing Lu","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Jie Shu","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Chen Chen","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Shaomin Bian","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Xuyan Li","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Sangeeta Dhaubhadel","author_inst":"Agriculture and Agri-Food Canada"},{"author_name":"Susanne E Kohalmi","author_inst":"University of Western Ontario"},{"author_name":"Steven J Rothstein","author_inst":"University of Guelph"},{"author_name":"Yuhai Cui","author_inst":"Agriculture and Agri-Food Canada"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Aerial imagery and deep learning accurately estimate maize foliar disease severity","rel_doi":"10.64898\/2026.06.03.729887","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729887","rel_abs":"Southern leaf blight (SLB) is a foliar disease of maize (Zea mays L.) caused by the necrotrophic fungal pathogen Cochliobolus heterostrophus. Genetic resistance is the most effective control method for SLB. Developing disease resistant maize lines requires field trials during which disease phenotypes must be visually assessed. Remote sensing using drones is an emerging technology that can be leveraged for high-throughput phenotyping of disease severity that is otherwise labor-intensive and subjective. This project used a deep learning approach to estimate SLB disease severity of single-row maize plots from drone imagery. Over 26,000 plot-level images produced from flights conducted across three growing seasons were labeled with in-field visual scores taken contemporaneously by expert raters. Variation in environmental conditions contributed to a labeled image dataset that reflects the complexity of agronomic field experiments. We assessed the ability of nine deep learning models from three architectural families to estimate disease severity. The best-performing model, EVA-02-B, achieved strong cross year generalization (R2 = 0.697). Error analysis found that performance was more strongly associated with seasonal disease progression and flight-score time offset than with image-level noise. UAV-based deep learning estimated SLB severity with comparable precision to expert raters. This study lays the groundwork for integrating automated phenotypes into genetic studies of disease resistance.","rel_num_authors":4,"rel_authors":[{"author_name":"Cole H Hammett","author_inst":"NCSU"},{"author_name":"Katelyn Rumley","author_inst":"NCSU"},{"author_name":"Peter Balint-Kurti","author_inst":"USDA"},{"author_name":"Joseph L. Gage","author_inst":"NCSU"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"A co-proteomic view of metabolite-specific interactions in the Botrytis cinerea-Arabidopsis pathosystem","rel_doi":"10.64898\/2026.06.05.730517","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730517","rel_abs":"To successfully infect their myriad hosts, generalist plant pathogens must tolerate a vast arsenal of plant specialized defense metabolites. To understand how host-specific metabolites influence plant-generalist pathogen interactions, we conducted a co-proteomic analysis of both Arabidopsis thaliana and Botrytis cinerea proteomes from the same samples during early infection. The Arabidopsis proteomic responses to Botrytis center around induction and suppression of defense metabolite pathways, particularly camalexin and glucosinolates. Several Botrytis proteins involved in key virulence pathways were induced within 32-48 hours, including potential defense metabolite detoxification proteins. Co-proteomic analysis using a panel of Arabidopsis genotypes with differing glucosinolate profiles revealed that disruptions to the glucosinolate pathway had broad changes on the Arabidopsis proteome, and that Botrytis induces specific proteins in response to presence\/absence of Arabidopsis defense metabolites. Among the proteins that were induced quickly on infection and linked to the presence of glucosinolates, we validated a novel isothiocyanate hydrolase in Botrytis, BcSaxA, that catabolizes isothiocyanates in vitro. Gene expression data further indicated BcSaxA is expressed only in dicot hosts containing isothiocyanates. Our study describes a highly dynamic host proteome during infection with Botrytis and elucidates metabolite-specific infection strategies for a generalist pathogen.","rel_num_authors":6,"rel_authors":[{"author_name":"Anna Jo Muhich","author_inst":"University of California Davis"},{"author_name":"Celine Caseys","author_inst":"University of California Davis"},{"author_name":"Brooke Grabbe","author_inst":"University of California Davis"},{"author_name":"Christian Montes-Serey","author_inst":"Iowa State University"},{"author_name":"Justin Walley","author_inst":"Iowa State University"},{"author_name":"Daniel J Kliebenstein","author_inst":"University of California Davis"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Population-scale Y chromosome assemblies reveal recurrent remodeling within constrained architectures","rel_doi":"10.64898\/2026.06.03.729890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729890","rel_abs":"The human Y chromosome is among the most structurally dynamic chromosomes in the human genome, yet much of its diversity remains unresolved because of extensive palindromes, ampliconic gene families, satellite-rich heterochromatin and large segmental duplications. What remained unclear was how these diverse forms of variation fit together across the full chromosome, how often similar structures recur in different lineages, and which aspects of organization remain constrained despite rapid sequence turnover. Here, we generated and analyzed 142 nearly complete human Y chromosome assemblies from 17 major haplogroups spanning approximately 180,000 years of evolution, creating a population-scale resource for studying Y chromosome biology and diversity. These assemblies show that structural change on the Y chromosome is recurrent but constrained, even in its most repetitive regions. In the fertility-associated azoospermia factor c (AZFc) region, recurrent inversions, deletions, and complex rearrangements generate a limited repertoire of structural haplotypes. Multicopy ampliconic gene families follow distinct evolutionary paths: DAZ paralogues differ in structural constraint, RBMY evolves within a modular array, and TSPY copy number varies mainly through local expansion and contraction. The centromere and Yq12 heterochromatin vary greatly in size but retain a stable higher-order organization, including a single hypomethylated centromeric core and conserved Yq12 repeat composition and orientation. Methylation across palindromic and ampliconic regions is likewise structured by repeat class, copy order and local architecture. Together, these results provide a population-scale resource for the human Y chromosome and show that its rapid structural evolution is repeatedly funneled into a limited set of architectural outcomes.","rel_num_authors":49,"rel_authors":[{"author_name":"Pille Hallast","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Arang Rhie","author_inst":"Genome Informatics Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"},{"author_name":"Mark Loftus","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"},{"author_name":"Mariateresa Mazzetto","author_inst":"Faculty of Informatics, Masaryk University, Brno, Czech Republic"},{"author_name":"Peter Ebert","author_inst":"Core Unit Bioinformatics, Medical Faculty and University Hospital Dusseldorf, Heinrich Heine University, Dusseldorf, Germany"},{"author_name":"Shenghan Gao","author_inst":"Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Gianni V. Martino","author_inst":"Clemson University, Department of Genetics & Biochemistry, Clemson, SC, USA"},{"author_name":"Peter A Audano","author_inst":"The Jackson Laboratory"},{"author_name":"Hufsah Ashraf","author_inst":"Center for Digital Medicine, Heinrich Heine University, Dusseldorf, Germany"},{"author_name":"Karol Pal","author_inst":"Department of Biology, Penn State University, University Park, PA, USA"},{"author_name":"Rebecca Siford","author_inst":"Comparative Genomics and Reproductive Health Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institut"},{"author_name":"Jana Ebler","author_inst":"Center for Digital Medicine, Heinrich Heine University, Dusseldorf, Germany"},{"author_name":"Sergey Koren","author_inst":"Genome Informatics Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"},{"author_name":"DongAhn Yoo","author_inst":"University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA, USA"},{"author_name":"Kwondo Kim","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"},{"author_name":"Yunzhe Jiang","author_inst":"Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA"},{"author_name":"Nancy F Hansen","author_inst":"NHGRI\/NIH"},{"author_name":"Prajna Hebbar","author_inst":"University of California Santa Cruz"},{"author_name":"Tomoya Kanno","author_inst":"Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, PA, USA"},{"author_name":"Oliver Purnoch","author_inst":"Faculty of Informatics, Masaryk University, Brno, Czech Republic"},{"author_name":"Caroline Montano","author_inst":"Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Jiadong Lin","author_inst":"University of Washington"},{"author_name":"Keisuke K Oshima","author_inst":"Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Luyao Ren","author_inst":"University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA, USA"},{"author_name":"Andrea Guarracino","author_inst":"Bioinnovation and Genome Sciences, Translational Genomics Research Institute (TGen), part of City of Hope, Phoenix, AZ, USA"},{"author_name":"Matthew Jensen","author_inst":"Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA"},{"author_name":"Brendan J Pinto","author_inst":"Comparative Genomics and Reproductive Health Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institut"},{"author_name":"David Porubsky","author_inst":"University of Washington, Dept. Genome Sciences"},{"author_name":"Samuel Kuziel","author_inst":"Faculty of Informatics, Masaryk University, Brno, Czech Republic"},{"author_name":"Lingbin Ni","author_inst":"University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA, USA"},{"author_name":"Jiaqi Li","author_inst":"Yale University"},{"author_name":"Parithi Balachandran","author_inst":"The Jackson Laboratory"},{"author_name":"Feyza Yilmaz","author_inst":"The Jackson Laboratory"},{"author_name":"- Human Genome Structural Variation Consortium (HGSVC)","author_inst":""},{"author_name":"- Human Pangenome Reference Consortium (HPRC)","author_inst":""},{"author_name":"Jan O Korbel","author_inst":"European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany"},{"author_name":"Benedict Paten","author_inst":"UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA, USA"},{"author_name":"Mark Gerstein","author_inst":"Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA"},{"author_name":"Kateryna D Makova","author_inst":"Department of Biology, Penn State University, University Park, PA, USA"},{"author_name":"Xinghua Shi","author_inst":"Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, PA, USA"},{"author_name":"Evan Eichler","author_inst":"University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA, USA"},{"author_name":"Christine R Beck","author_inst":"The Jackson Laboratory of Genomic Medicine and the University of Connecticut Health Center"},{"author_name":"Melissa R Wilson","author_inst":"National Institutes of Health"},{"author_name":"Miriam K Konkel","author_inst":"Clemson University, Department of Genetics & Biochemistry, Clemson, SC, USA"},{"author_name":"Tobias Marschall","author_inst":"Heinrich Heine University, The University Hospital of Dusseldorf"},{"author_name":"Monika Cechova","author_inst":"Faculty of Informatics, Masaryk University, Brno, Czech Republic"},{"author_name":"Glennis Logsdon","author_inst":"Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Adam M Phillippy","author_inst":"Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Charles Lee","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Population-scale Y chromosome assemblies reveal recurrent remodeling within constrained architectures","rel_doi":"10.64898\/2026.06.03.729890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729890","rel_abs":"The human Y chromosome is among the most structurally dynamic chromosomes in the human genome, yet much of its diversity remains unresolved because of extensive palindromes, ampliconic gene families, satellite-rich heterochromatin and large segmental duplications. What remained unclear was how these diverse forms of variation fit together across the full chromosome, how often similar structures recur in different lineages, and which aspects of organization remain constrained despite rapid sequence turnover. Here, we generated and analyzed 142 nearly complete human Y chromosome assemblies from 17 major haplogroups spanning approximately 180,000 years of evolution, creating a population-scale resource for studying Y chromosome biology and diversity. These assemblies show that structural change on the Y chromosome is recurrent but constrained, even in its most repetitive regions. In the fertility-associated azoospermia factor c (AZFc) region, recurrent inversions, deletions, and complex rearrangements generate a limited repertoire of structural haplotypes. Multicopy ampliconic gene families follow distinct evolutionary paths: DAZ paralogues differ in structural constraint, RBMY evolves within a modular array, and TSPY copy number varies mainly through local expansion and contraction. The centromere and Yq12 heterochromatin vary greatly in size but retain a stable higher-order organization, including a single hypomethylated centromeric core and conserved Yq12 repeat composition and orientation. Methylation across palindromic and ampliconic regions is likewise structured by repeat class, copy order and local architecture. Together, these results provide a population-scale resource for the human Y chromosome and show that its rapid structural evolution is repeatedly funneled into a limited set of architectural outcomes.","rel_num_authors":49,"rel_authors":[{"author_name":"Pille Hallast","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Arang Rhie","author_inst":"Genome Informatics Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"},{"author_name":"Mark Loftus","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"},{"author_name":"Mariateresa Mazzetto","author_inst":"Faculty of Informatics, Masaryk University, Brno, Czech Republic"},{"author_name":"Peter Ebert","author_inst":"Core Unit Bioinformatics, Medical Faculty and University Hospital Dusseldorf, Heinrich Heine University, Dusseldorf, Germany"},{"author_name":"Shenghan Gao","author_inst":"Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Gianni V. Martino","author_inst":"Clemson University, Department of Genetics & Biochemistry, Clemson, SC, USA"},{"author_name":"Peter A Audano","author_inst":"The Jackson Laboratory"},{"author_name":"Hufsah Ashraf","author_inst":"Center for Digital Medicine, Heinrich Heine University, Dusseldorf, Germany"},{"author_name":"Karol Pal","author_inst":"Department of Biology, Penn State University, University Park, PA, USA"},{"author_name":"Rebecca Siford","author_inst":"Comparative Genomics and Reproductive Health Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institut"},{"author_name":"Jana Ebler","author_inst":"Center for Digital Medicine, Heinrich Heine University, Dusseldorf, Germany"},{"author_name":"Sergey Koren","author_inst":"Genome Informatics Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"},{"author_name":"DongAhn Yoo","author_inst":"University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA, USA"},{"author_name":"Kwondo Kim","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"},{"author_name":"Yunzhe Jiang","author_inst":"Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA"},{"author_name":"Nancy F Hansen","author_inst":"NHGRI\/NIH"},{"author_name":"Prajna Hebbar","author_inst":"University of California Santa Cruz"},{"author_name":"Tomoya Kanno","author_inst":"Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, PA, USA"},{"author_name":"Oliver Purnoch","author_inst":"Faculty of Informatics, Masaryk University, Brno, Czech Republic"},{"author_name":"Caroline Montano","author_inst":"Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Jiadong Lin","author_inst":"University of Washington"},{"author_name":"Keisuke K Oshima","author_inst":"Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Luyao Ren","author_inst":"University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA, USA"},{"author_name":"Andrea Guarracino","author_inst":"Bioinnovation and Genome Sciences, Translational Genomics Research Institute (TGen), part of City of Hope, Phoenix, AZ, USA"},{"author_name":"Matthew Jensen","author_inst":"Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA"},{"author_name":"Brendan J Pinto","author_inst":"Comparative Genomics and Reproductive Health Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institut"},{"author_name":"David Porubsky","author_inst":"University of Washington, Dept. Genome Sciences"},{"author_name":"Samuel Kuziel","author_inst":"Faculty of Informatics, Masaryk University, Brno, Czech Republic"},{"author_name":"Lingbin Ni","author_inst":"University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA, USA"},{"author_name":"Jiaqi Li","author_inst":"Yale University"},{"author_name":"Parithi Balachandran","author_inst":"The Jackson Laboratory"},{"author_name":"Feyza Yilmaz","author_inst":"The Jackson Laboratory"},{"author_name":"- Human Genome Structural Variation Consortium (HGSVC)","author_inst":""},{"author_name":"- Human Pangenome Reference Consortium (HPRC)","author_inst":""},{"author_name":"Jan O Korbel","author_inst":"European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany"},{"author_name":"Benedict Paten","author_inst":"UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA, USA"},{"author_name":"Mark Gerstein","author_inst":"Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA"},{"author_name":"Kateryna D Makova","author_inst":"Department of Biology, Penn State University, University Park, PA, USA"},{"author_name":"Xinghua Shi","author_inst":"Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, PA, USA"},{"author_name":"Evan Eichler","author_inst":"University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA, USA"},{"author_name":"Christine R Beck","author_inst":"The Jackson Laboratory of Genomic Medicine and the University of Connecticut Health Center"},{"author_name":"Melissa R Wilson","author_inst":"National Institutes of Health"},{"author_name":"Miriam K Konkel","author_inst":"Clemson University, Department of Genetics & Biochemistry, Clemson, SC, USA"},{"author_name":"Tobias Marschall","author_inst":"Heinrich Heine University, The University Hospital of Dusseldorf"},{"author_name":"Monika Cechova","author_inst":"Faculty of Informatics, Masaryk University, Brno, Czech Republic"},{"author_name":"Glennis Logsdon","author_inst":"Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Adam M Phillippy","author_inst":"Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Charles Lee","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Climate change drives contrasting redistribution patterns in endemic and endangered Himalayan Gentiana","rel_doi":"10.64898\/2026.06.03.729779","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.729779","rel_abs":"Abstract 1. Rapid climate warming threatens mountain biodiversity, particularly species with narrow climatic niches and limited dispersal capacity. Mountain ecosystems are especially vulnerable because steep environmental gradients restrict opportunities for species redistribution. The Kashmir Himalaya, a globally important biodiversity hotspot experiencing accelerated warming, has already undergone an increase of approximately 0.8 degrees C during the 20th century and is projected to warm by 2.5-2.8 degrees C by the 2050s. Despite climatic changes, future persistence of many threatened plants remains poorly understood. 2. Here, we evaluate present and future habitat suitability for two Himalayan taxa, Gentiana cachemirica, an endemic species, and Gentiana kurroo, a critically endangered species. Specifically, we quantify how climate change and topographic variability influence species distribution and persistence under multiple emission scenarios. 3. We applied species distribution models (SDMs) to presence data of both species and forecasted habitat suitability under four Shared Socioeconomic Pathways (SSP126, SSP245, SSP370, and SSP585). We hypothesized that G. cachemirica, a narrow-niche, low-dispersal species, is expected to lose habitat due to thermal sensitivity, while G. kurroo may persist or expand under favorable scenarios because of broader tolerance and higher dispersal. We also expected microclimatic refuges to buffer populations, whereas extreme warming would accelerate habitat decline. 4. The predictions of our SDMs under current conditions indicate a highly restricted and fragmented habitat for G. cachemirica, covering 651 km2, but a broader suitable area (2,452 km2) for G. kurroo. In agreement with our hypotheses, our forecasts indicate severe habitat contraction (55-70%) for G. cachemirica across all SSPs, but scenario-dependent responses for G. kurroo, including modest expansion under low-emission scenarios and severe declines under high-emission scenarios. Centroid analyses suggest pronounced climate-driven range shifts, with G. kurroo projected to migrate up to 33 km toward the east-southeast by 2100, while G. cachemirica is projected to display limited dispersal capacity. 5. Synthesis. Our findings suggest that climatic niche breadth, dispersal limitation, and topographic buffering strongly mediate species responses to warming in mountain ecosystems. Endemic specialists are projected to experience disproportionate habitat fragmentation and range restriction, highlighting the importance of conserving climatic refugia and elevational connectivity under rapid environmental change.","rel_num_authors":6,"rel_authors":[{"author_name":"Syed Waseem Gillani","author_inst":"Department of Biology, University of Oxford, Life and Mind Building, South Parks Road, Oxford OX1 8 3EL, United Kingdom"},{"author_name":"Mushtaq Ahmad","author_inst":"Department of Plant Sciences, Quaid-i-Azam University Islamabad, 45320, Pakistan."},{"author_name":"Muhammad Manzoor","author_inst":"Department of Plant Sciences, Quaid-i-Azam University Islamabad, 45320, Pakistan."},{"author_name":"Raja Waqar Ahmed Khan","author_inst":"Plant Ecology and Environmental Science Lab, Department of Botany, University of Azad Jammu & Kashmir, Muzaffarabad. AJK 13101."},{"author_name":"Amir Sohail","author_inst":"Department of Plant Sciences, Quaid-i-Azam University Islamabad, 45320, Pakistan"},{"author_name":"Roberto Salguero-Gomez","author_inst":"Department of Biology, University of Oxford, Life and Mind Building, South Parks Road, Oxford OX1 8 3EL, United Kingdom"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"ATML1-GIR1-TPL\/TPR transcriptional repression module controls glucosinolates and giant cells in Arabidopsis thaliana sepals","rel_doi":"10.64898\/2026.06.03.724713","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.724713","rel_abs":"Glucosinolates (GSLs) are sulfur- and nitrogen-containing secondary metabolites that serve as defense compounds in Arabidopsis and other members of the Brassicales. Although the enzymatic pathway that produces GSLs is well-studied, the upstream mechanisms that control their tissue-specific synthesis are poorly understood. We identified a novel repression module that transcriptionally regulates GSL levels in sepals, the modified leaves that protect reproductive tissues within the floral bud. GLABRA2 (GL2) INTERACTING REPRESSOR1 (GIR1) interacts directly with Arabidopsis thaliana MERISTEM LAYER1 (ATML1), an HD-Zip IV transcription factor known to be required for giant cell formation in the sepal epidermis. This interaction requires a predicted Zn finger of GIR1 and the C-terminal START adjacent domain (STAD) of ATML1. The gir1 loss-of-function mutants exhibit excess giant cells, in contrast to atml1 mutants which display fewer giant cells, supporting the role of GIR1 as a negative regulator of ATML1. We confirmed that GIR1 interacts with TOPLESS (TPL) and TOPLESS-RELATED (TPR) corepressors, and coimmunoprecipitation demonstrated that GIR1 acts as an adaptor protein connecting ATML1 and TPL\/TPR. RNA sequencing revealed that numerous genes involved in GSL biosynthesis, including the key transcriptional regulator MYB29, are upregulated in gir1 mutants. Consistent with the transcriptomic data, chemical analysis revealed that gir1 mutants display elevated GSL levels in sepals. Mass spectrometry imaging confirmed high GSL accumulation in gir1 sepals compared to wild type and atml1. Overall, our findings uncover a previously unrecognized link between cell expansion and GSL metabolism, suggesting strategies for engineering plants with cell-type specific GSL profiles.","rel_num_authors":12,"rel_authors":[{"author_name":"Lauren E. Apprill","author_inst":"Kansas State University"},{"author_name":"Bilal Ahmad","author_inst":"Kansas State University"},{"author_name":"Aytug Ulutas","author_inst":"Kansas State University"},{"author_name":"Amanda Agosto Ramos","author_inst":"University of California, Davis"},{"author_name":"Sumin Na","author_inst":"Iowa State University"},{"author_name":"Samira R. Laytimi","author_inst":"Kansas State University"},{"author_name":"Ayianna K. Bailey","author_inst":"Kansas State University"},{"author_name":"Adara L. Warner","author_inst":"Kansas State University"},{"author_name":"Titus R. Neumann","author_inst":"Kansas State University"},{"author_name":"Young-Jin Lee","author_inst":"Iowa State University"},{"author_name":"Daniel J. Kliebenstein","author_inst":"University of California, Davis"},{"author_name":"Kathrin Schrick","author_inst":"Kansas State University"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"ATML1-GIR1-TPL\/TPR transcriptional repression module controls glucosinolates and giant cells in Arabidopsis thaliana sepals","rel_doi":"10.64898\/2026.06.03.724713","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.03.724713","rel_abs":"Glucosinolates (GSLs) are sulfur- and nitrogen-containing secondary metabolites that serve as defense compounds in Arabidopsis and other members of the Brassicales. Although the enzymatic pathway that produces GSLs is well-studied, the upstream mechanisms that control their tissue-specific synthesis are poorly understood. We identified a novel repression module that transcriptionally regulates GSL levels in sepals, the modified leaves that protect reproductive tissues within the floral bud. GLABRA2 (GL2) INTERACTING REPRESSOR1 (GIR1) interacts directly with Arabidopsis thaliana MERISTEM LAYER1 (ATML1), an HD-Zip IV transcription factor known to be required for giant cell formation in the sepal epidermis. This interaction requires a predicted Zn finger of GIR1 and the C-terminal START adjacent domain (STAD) of ATML1. The gir1 loss-of-function mutants exhibit excess giant cells, in contrast to atml1 mutants which display fewer giant cells, supporting the role of GIR1 as a negative regulator of ATML1. We confirmed that GIR1 interacts with TOPLESS (TPL) and TOPLESS-RELATED (TPR) corepressors, and coimmunoprecipitation demonstrated that GIR1 acts as an adaptor protein connecting ATML1 and TPL\/TPR. RNA sequencing revealed that numerous genes involved in GSL biosynthesis, including the key transcriptional regulator MYB29, are upregulated in gir1 mutants. Consistent with the transcriptomic data, chemical analysis revealed that gir1 mutants display elevated GSL levels in sepals. Mass spectrometry imaging confirmed high GSL accumulation in gir1 sepals compared to wild type and atml1. Overall, our findings uncover a previously unrecognized link between cell expansion and GSL metabolism, suggesting strategies for engineering plants with cell-type specific GSL profiles.","rel_num_authors":12,"rel_authors":[{"author_name":"Lauren E. Apprill","author_inst":"Kansas State University"},{"author_name":"Bilal Ahmad","author_inst":"Kansas State University"},{"author_name":"Aytug Ulutas","author_inst":"Kansas State University"},{"author_name":"Amanda Agosto Ramos","author_inst":"University of California, Davis"},{"author_name":"Sumin Na","author_inst":"Iowa State University"},{"author_name":"Samira R. Laytimi","author_inst":"Kansas State University"},{"author_name":"Ayianna K. Bailey","author_inst":"Kansas State University"},{"author_name":"Adara L. Warner","author_inst":"Kansas State University"},{"author_name":"Titus R. Neumann","author_inst":"Kansas State University"},{"author_name":"Young-Jin Lee","author_inst":"Iowa State University"},{"author_name":"Daniel J. Kliebenstein","author_inst":"University of California, Davis"},{"author_name":"Kathrin Schrick","author_inst":"Kansas State University"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Multiple approaches for CRISPR-based targeting of DNA methylation to promoters of bacterial and viral susceptibility genes in cassava","rel_doi":"10.64898\/2026.06.04.730177","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730177","rel_abs":"Targeted epigenetic modifications of specific gene regulatory regions have the potential to confer beneficial traits for crop improvement. Two recently developed CRISPR\/Cas9-based epigenome editing tools were tested in transgenic cassava to target cytosine methylation to the promoter region of MeSWEET10a, a necessary gene for infection by the Cassava bacterial blight pathogen, Xanthomonas phaseoli pv. manihotis. The two systems leverage unique methyltransferases, and each induced distinct DNA methylation profiles at the targeted site, decreased effector-triggered MeSWEET10a expression, and attenuated water-soaking symptoms in inoculated leaves. Further, DNA methylation was simultaneously targeted, in addition to MeSWEET10a, to two susceptibility genes for Cassava brown streak virus. Relative levels of de novo DNA methylation at the three loci were inversely correlated with DNA methylation-antagonizing H3K4me3 marks. Finally, an initial assessment of DNA methylation after one generation indicated specific inheritance of CpG methylation that was unstable in the absence of the methyltransferase systems.","rel_num_authors":16,"rel_authors":[{"author_name":"Kerrigan B. Gilbert","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA"},{"author_name":"Zuh-Jyh Daniel Lin","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Bayer Crop Science, 700 W Chesterfield Pkwy W, Chesterfield, MO 63017"},{"author_name":"Kira M. Veley","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Bayer Crop Science, 700 W Chesterfield Pkwy W, Chesterfield, MO 63017"},{"author_name":"Myia K. Stanton","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Pivot Bio; 1001 N Warson Rd. St. Louis, MO 63132 USA"},{"author_name":"Marisa Yoder","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA"},{"author_name":"Joanna Norton","author_inst":"University of Hawaii Manoa, 875 Komohana Street, Hilo, Hawaii, 96720, USA"},{"author_name":"Suhua Feng","author_inst":"Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA"},{"author_name":"Yan He","author_inst":"Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA"},{"author_name":"Gabriela L. Hernandez","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA"},{"author_name":"Greg Jensen","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Oregon Health & Science University, Knight Cancer Group, Portland OR 97239 USA"},{"author_name":"Emma Wozniak","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Bayer Crop Science, 700 W Chesterfield Pkwy W, Chesterfield, MO 63017"},{"author_name":"Ke Ke","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Washington University in St Louis, 660 S. Euclid Ave., St. Louis, MO 63110-1010"},{"author_name":"Sharon A. M. Wages","author_inst":"University of Hawaii Manoa, 875 Komohana Street, Hilo, Hawaii, 96720, USA"},{"author_name":"Steven E. Jacobsen","author_inst":"Department of Molecular Cell and Developmental Biology and Howard Hughes Medical Institute, University of California. Los Angeles, Los Angeles, CA, 90095, USA"},{"author_name":"James C. Carrington","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA"},{"author_name":"Rebecca S. Bart","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Plant and Microbial Biology Department, UC Berkeley, Berkeley, CA 94720"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"rel_title":"Multiple approaches for CRISPR-based targeting of DNA methylation to promoters of bacterial and viral susceptibility genes in cassava","rel_doi":"10.64898\/2026.06.04.730177","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730177","rel_abs":"Targeted epigenetic modifications of specific gene regulatory regions have the potential to confer beneficial traits for crop improvement. Two recently developed CRISPR\/Cas9-based epigenome editing tools were tested in transgenic cassava to target cytosine methylation to the promoter region of MeSWEET10a, a necessary gene for infection by the Cassava bacterial blight pathogen, Xanthomonas phaseoli pv. manihotis. The two systems leverage unique methyltransferases, and each induced distinct DNA methylation profiles at the targeted site, decreased effector-triggered MeSWEET10a expression, and attenuated water-soaking symptoms in inoculated leaves. Further, DNA methylation was simultaneously targeted, in addition to MeSWEET10a, to two susceptibility genes for Cassava brown streak virus. Relative levels of de novo DNA methylation at the three loci were inversely correlated with DNA methylation-antagonizing H3K4me3 marks. Finally, an initial assessment of DNA methylation after one generation indicated specific inheritance of CpG methylation that was unstable in the absence of the methyltransferase systems.","rel_num_authors":16,"rel_authors":[{"author_name":"Kerrigan B. Gilbert","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA"},{"author_name":"Zuh-Jyh Daniel Lin","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Bayer Crop Science, 700 W Chesterfield Pkwy W, Chesterfield, MO 63017"},{"author_name":"Kira M. Veley","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Bayer Crop Science, 700 W Chesterfield Pkwy W, Chesterfield, MO 63017"},{"author_name":"Myia K. Stanton","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Pivot Bio; 1001 N Warson Rd. St. Louis, MO 63132 USA"},{"author_name":"Marisa Yoder","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA"},{"author_name":"Joanna Norton","author_inst":"University of Hawaii Manoa, 875 Komohana Street, Hilo, Hawaii, 96720, USA"},{"author_name":"Suhua Feng","author_inst":"Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA"},{"author_name":"Yan He","author_inst":"Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA"},{"author_name":"Gabriela L. Hernandez","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA"},{"author_name":"Greg Jensen","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Oregon Health & Science University, Knight Cancer Group, Portland OR 97239 USA"},{"author_name":"Emma Wozniak","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Bayer Crop Science, 700 W Chesterfield Pkwy W, Chesterfield, MO 63017"},{"author_name":"Ke Ke","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Washington University in St Louis, 660 S. Euclid Ave., St. Louis, MO 63110-1010"},{"author_name":"Sharon A. M. Wages","author_inst":"University of Hawaii Manoa, 875 Komohana Street, Hilo, Hawaii, 96720, USA"},{"author_name":"Steven E. Jacobsen","author_inst":"Department of Molecular Cell and Developmental Biology and Howard Hughes Medical Institute, University of California. Los Angeles, Los Angeles, CA, 90095, USA"},{"author_name":"James C. Carrington","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA"},{"author_name":"Rebecca S. Bart","author_inst":"Donald Danforth Plant Science Center, Saint Louis, MO, 63132, USA; current: Plant and Microbial Biology Department, UC Berkeley, Berkeley, CA 94720"}],"rel_date":"2026-06-06","rel_site":"biorxiv"},{"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":"Introduction: Trans 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. Methods: This 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. Results: From 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. Conclusions: TGD 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":"Introduction: Trans 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. Methods: This 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. Results: From 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. Conclusions: TGD 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":"Background Fertility 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. Study design Nationwide 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). Results: Vasectomy 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. Conclusion: Australia 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.","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":"BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimer's 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. METHODS: Capitalizing on data from 14,497 individuals with AD from the National Alzheimer's 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. RESULTS: Diabetes, 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. CONCLUSION: These 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":"BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimer's 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. METHODS: Capitalizing on data from 14,497 individuals with AD from the National Alzheimer's 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. RESULTS: Diabetes, 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. CONCLUSION: These 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":"Structural Dynamics of RNA Polymerase II During Nucleotide Addition Cycle","rel_doi":"10.64898\/2026.06.04.730248","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730248","rel_abs":"RNA polymerase II (RNAPII) drives gene expression through iterative nucleotide addition cycles (NACs) comprising translocation, substrate binding, and catalysis. The lack of pre-catalysis and post-catalysis intermediates has precluded a complete mechanistic understanding of the NAC. Here we present 43 cryo-EM structures capturing distinct stages of the S. cerevisiae RNAPII elongation complex (EC) NAC, including previously intractable transition intermediates. We establish a continuous spectrum of RNAPII EC structural dynamics during the NAC, which can be divided into two coordinated phases: a substrate-induced EC tightening phase and a post-catalysis EC relaxation phase. For the substrate-induced EC tightening phase, the substrate binding initiates allosteric conformational changes across the entire RNAPII EC, including TL folding, funnel closure, clamp closure, transcription bubble ordering, and precise alignment of the RNA 3'-end with substrate to form a catalysis-competent configuration. For the post-catalysis EC relaxation phase, we captured the long-sought, short-lived post-catalysis product state and identified a series of intermediates that reveal a reverse conformational transition that facilitates rapid translocation. Together, our findings define a comprehensive structural and dynamic framework for RNAPII NAC, yielding a molecular movie of RNAPII in action and revealing a fundamental principle by which the enzyme balances speed and fidelity through coordinated conformational dynamics.","rel_num_authors":7,"rel_authors":[{"author_name":"Gangshun Yi","author_inst":"University of Oxford"},{"author_name":"Qingrong Li","author_inst":"University of California San Diego"},{"author_name":"Hannah Holmberg","author_inst":"Louisiana State University"},{"author_name":"Shisheng Li","author_inst":"Louisiana State University"},{"author_name":"Daniel K Clare","author_inst":"Diamond Light Source"},{"author_name":"Dong Wang","author_inst":"University of California San Diego"},{"author_name":"Peijun Zhang","author_inst":"University of Oxford"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Balancing of immune activation and suppression during phage infection","rel_doi":"10.64898\/2026.06.04.730250","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730250","rel_abs":"Signaling-based anti-bacteriophage systems such as CBASS and Thoeris synthesize infection-triggered nucleotide signals that activate anti-phage effectors. However, the phage features sensed by these systems and the mechanisms phages use to evade signaling immunity remain poorly understood. Here, studying clinically relevant Pseudomonas aeruginosa phages from the Migulavirinae family, we show that closely related phages encode subtle allelic variation in side tail fiber proteins that determine sensitivity to type II Thoeris. In parallel, these same phages encode an anti-defense hotspot that contains three adjacent genes that are each sufficient to facilitate phage evasion of both CBASS and Thoeris defenses, counter-balancing the activating proteins. Comparative analysis of this anti-signaling hotspot across the broader family of related N4-like phages uncovered a new Thoeris anti-defense (Tad) protein that sponges NAD-derived molecules (e.g. gcADPR) and exhibits sequence and structural similarity to a poorly characterized nucleotide-binding region of the human ryanodine receptor. Together, these findings reveal how the balance between immune activation and antagonism shifts phage outcomes and reveals a surprising similarity between a phage molecular sponge and an important human protein.","rel_num_authors":12,"rel_authors":[{"author_name":"Iana Fedorova","author_inst":"UCSF"},{"author_name":"Yourun Yue","author_inst":"Beijing University of Chemical Technology"},{"author_name":"Zirui Gao","author_inst":"Beijing University of Chemical Technology"},{"author_name":"Michelle Grunberg","author_inst":"UCSF"},{"author_name":"Hao Wang","author_inst":"Beijing University of Chemical Technology"},{"author_name":"Junjie Li","author_inst":"Beijing University of Chemical Technology"},{"author_name":"Zhiyu Zang","author_inst":"Indiana University"},{"author_name":"Diego De Nault","author_inst":"UCSF"},{"author_name":"Xilin Yang","author_inst":"Beijing University of Chemical Technology"},{"author_name":"Joseph P. Gerdt","author_inst":"Indiana University"},{"author_name":"Yue Feng","author_inst":"Beijing University of Chemical Technology"},{"author_name":"Joseph Bondy-Denomy","author_inst":"UCSF"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Loss of the Y chromosome drives epigenetic and transcriptomic plasticity in lung adenocarcinoma","rel_doi":"10.64898\/2026.06.02.729627","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729627","rel_abs":"Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX. Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo. These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.","rel_num_authors":44,"rel_authors":[{"author_name":"Kathleen Schlueter","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Mei-Ju May Chen","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Master's Program"},{"author_name":"Gizem Altun","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Sergio Manzano-Sanchez","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Dung-Chi Wu","author_inst":"Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica"},{"author_name":"Nan Zhang","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Faculty of Biosc"},{"author_name":"Ofir Griess","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel"},{"author_name":"Luc Husemann","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Fabian Bradic","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Joseph Cornick","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Nima Esmaeelpour","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Oliver Muecke","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Riccardo Moro","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Katherine Kelly","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Sara Chocarro","author_inst":"Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Etienne Sollier","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Albert Fradera-Sola","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Claudia Scalera","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Maria Jose Alonso-De Gennaro","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Siavash Mansouri","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Madeleine Dorsch","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Patricia Munteanu","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Balazs Hegedus","author_inst":"Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, 45239, Essen, Germany"},{"author_name":"Hauke Winter","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Surgery, Thorax"},{"author_name":"Laura V. Klotz","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Surgery, Thorax"},{"author_name":"Mark Kriegsmann","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Felix J.F. Herth","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Pneumology and Critical "},{"author_name":"Thomas Muley","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Translational Research Unit, Thoraxkli"},{"author_name":"Marc A. Schneider","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Translational Research Unit, Thoraxkli"},{"author_name":"Daniel Kazdal","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Albrecht Stenzinger","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Alexander Schramm","author_inst":"West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany; Medical Faculty, University Duisburg-Essen, Essen, Germany"},{"author_name":"Felix J. Hartmann","author_inst":"West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany; Medical Faculty, University Duisburg-Essen, Essen, Germany"},{"author_name":"Pavlo Lutsik","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of On"},{"author_name":"Marcel Schilling","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Ursula Klingmueller","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Division of Systems Biology of Signal "},{"author_name":"Rajkumar Savai","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Rocio Sotillo","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Division of Molecular Thoracic Oncolog"},{"author_name":"Barbara M. Gruener","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Guy Ron","author_inst":"Racah Institute of Physics, Hebrew University, Jerusalem 9190401, Israel"},{"author_name":"Efrat Shema","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel"},{"author_name":"Michael Scherer","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Christoph Plass","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Maria Llamazares-Prada","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Loss of the Y chromosome drives epigenetic and transcriptomic plasticity in lung adenocarcinoma","rel_doi":"10.64898\/2026.06.02.729627","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729627","rel_abs":"Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX. Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo. These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.","rel_num_authors":44,"rel_authors":[{"author_name":"Kathleen Schlueter","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Mei-Ju May Chen","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Master's Program"},{"author_name":"Gizem Altun","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Sergio Manzano-Sanchez","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Dung-Chi Wu","author_inst":"Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica"},{"author_name":"Nan Zhang","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Faculty of Biosc"},{"author_name":"Ofir Griess","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel"},{"author_name":"Luc Husemann","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Fabian Bradic","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Joseph Cornick","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Nima Esmaeelpour","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Oliver Muecke","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Riccardo Moro","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Katherine Kelly","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Sara Chocarro","author_inst":"Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Etienne Sollier","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Albert Fradera-Sola","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Claudia Scalera","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Maria Jose Alonso-De Gennaro","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Siavash Mansouri","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Madeleine Dorsch","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Patricia Munteanu","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Balazs Hegedus","author_inst":"Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, 45239, Essen, Germany"},{"author_name":"Hauke Winter","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Surgery, Thorax"},{"author_name":"Laura V. Klotz","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Surgery, Thorax"},{"author_name":"Mark Kriegsmann","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Felix J.F. Herth","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Pneumology and Critical "},{"author_name":"Thomas Muley","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Translational Research Unit, Thoraxkli"},{"author_name":"Marc A. Schneider","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Translational Research Unit, Thoraxkli"},{"author_name":"Daniel Kazdal","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Albrecht Stenzinger","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Alexander Schramm","author_inst":"West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany; Medical Faculty, University Duisburg-Essen, Essen, Germany"},{"author_name":"Felix J. Hartmann","author_inst":"West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany; Medical Faculty, University Duisburg-Essen, Essen, Germany"},{"author_name":"Pavlo Lutsik","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of On"},{"author_name":"Marcel Schilling","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Ursula Klingmueller","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Division of Systems Biology of Signal "},{"author_name":"Rajkumar Savai","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Rocio Sotillo","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Division of Molecular Thoracic Oncolog"},{"author_name":"Barbara M. Gruener","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Guy Ron","author_inst":"Racah Institute of Physics, Hebrew University, Jerusalem 9190401, Israel"},{"author_name":"Efrat Shema","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel"},{"author_name":"Michael Scherer","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Christoph Plass","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Maria Llamazares-Prada","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Loss of the Y chromosome drives epigenetic and transcriptomic plasticity in lung adenocarcinoma","rel_doi":"10.64898\/2026.06.02.729627","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729627","rel_abs":"Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX. Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo. These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.","rel_num_authors":44,"rel_authors":[{"author_name":"Kathleen Schlueter","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Mei-Ju May Chen","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Master's Program"},{"author_name":"Gizem Altun","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Sergio Manzano-Sanchez","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Dung-Chi Wu","author_inst":"Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica"},{"author_name":"Nan Zhang","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Faculty of Biosc"},{"author_name":"Ofir Griess","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel"},{"author_name":"Luc Husemann","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Fabian Bradic","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Joseph Cornick","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Nima Esmaeelpour","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Oliver Muecke","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Riccardo Moro","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Katherine Kelly","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Sara Chocarro","author_inst":"Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Etienne Sollier","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Albert Fradera-Sola","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Claudia Scalera","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Maria Jose Alonso-De Gennaro","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Siavash Mansouri","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Madeleine Dorsch","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Patricia Munteanu","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Balazs Hegedus","author_inst":"Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, 45239, Essen, Germany"},{"author_name":"Hauke Winter","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Surgery, Thorax"},{"author_name":"Laura V. Klotz","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Surgery, Thorax"},{"author_name":"Mark Kriegsmann","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Felix J.F. Herth","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Department of Pneumology and Critical "},{"author_name":"Thomas Muley","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Translational Research Unit, Thoraxkli"},{"author_name":"Marc A. Schneider","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Translational Research Unit, Thoraxkli"},{"author_name":"Daniel Kazdal","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Albrecht Stenzinger","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Institute of Pathology, Heidelberg Uni"},{"author_name":"Alexander Schramm","author_inst":"West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany; Medical Faculty, University Duisburg-Essen, Essen, Germany"},{"author_name":"Felix J. Hartmann","author_inst":"West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany; Medical Faculty, University Duisburg-Essen, Essen, Germany"},{"author_name":"Pavlo Lutsik","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of On"},{"author_name":"Marcel Schilling","author_inst":"Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"author_name":"Ursula Klingmueller","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Division of Systems Biology of Signal "},{"author_name":"Rajkumar Savai","author_inst":"Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany; Max Planck Institute for Heart and Lung Research, Member of the German Center for L"},{"author_name":"Rocio Sotillo","author_inst":"Translation Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; Division of Molecular Thoracic Oncolog"},{"author_name":"Barbara M. Gruener","author_inst":"West German Cancer Center, Department of Medical Oncology, Cell Plasticity and Metastasis, University Duisburg-Essen, Essen, Germany; German Cancer Consortium ("},{"author_name":"Guy Ron","author_inst":"Racah Institute of Physics, Hebrew University, Jerusalem 9190401, Israel"},{"author_name":"Efrat Shema","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel"},{"author_name":"Michael Scherer","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany"},{"author_name":"Christoph Plass","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"},{"author_name":"Maria Llamazares-Prada","author_inst":"Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translation Lung"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Genomic Dimensionality Bounds Mixed-Model Association Power and Fine-Mapping Resolution","rel_doi":"10.64898\/2026.06.02.729628","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729628","rel_abs":"Mixed-model genome-wide association studies (GWAS) behave differently in livestock than in humans, yet a unified explanation is lacking. Analyses using the full genomic relationship matrix (full-GRM; from genome-wide SNPs) yield only a few significant peaks even with hundreds of thousands of animals, whereas leave-one-chromosome-out (LOCO), numerator-relationship-matrix, and sparse-GRM approaches report many broad associations over similar data. Here we develop a framework that traces these behaviors to the low effective genomic dimensionality, Me, of small-Ne populations. Starting from the mixed-model association statistic, we derive the per-SNP non-centrality parameter under full-GRM testing and show that its sample-size dependence is fully captured by a sigmoid sum S(N) over LD-matrix eigenmodes. S(N) grows concavely with N toward a practical ceiling Me, from which the framework predicts a full-GRM detection floor qmin {approx} 30 h2\/Me on per-SNP proportion of phenotypic variance explained at 50% power (e.g., ~0.09% for cattle at h2 = 0.3), and a fine-mapping resolution limit through both Me and 4Ned-scaled LD decay. LOCO bypasses the full-GRM ceiling but detects LD-aggregated block-level signals rather than SNP-level excess effects, explaining its inflation in livestock and agreement with full-GRM in humans. The framework is supported by analyses of real livestock chip panels, coalescent eigenvalue spectra, and phenotype simulations. The same sigmoid sum, normalized as {phi}(N) {approx} S(N)\/Me, recovers the in-sample average GBLUP reliability, unifying why genomic prediction is comparatively easy in livestock while SNP-level mapping and fine-mapping remain difficult. For livestock GWAS aimed at SNP-level interpretation (e.g., candidate-gene prioritization, fine-mapping, or molecular-QTL colocalization), the framework supports full-GRM approaches as the appropriate default.","rel_num_authors":1,"rel_authors":[{"author_name":"Jicai Jiang","author_inst":"Department of Animal Science, North Carolina State University"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Lifespan Trajectories of Resting State EEG power","rel_doi":"10.64898\/2026.06.02.729638","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729638","rel_abs":"Trajectories of resting state monopolar EEG power were analyzed using the means, variances, and correlations of data in seven frequency bands obtained from 17 electrodes of the 10-20 system from a sample of 5238 participants from the Collaborative Study on the Genetics of Alcoholism (COGA) with 11906 observations from ages 12 through 70. The values for the individual observations were calculated by standard Fourier transform based methods. In order to make the study more useful for understanding EEG in the general population only subjects who were never diagnosed with alcohol use disorder were included in the study. The trajectories of power show a clear pattern of decrease in all frequency bands and both sexes from ages 12 to 20. Subsequently there is considerable amount of variation between frequency bands and between males and females. In females, the generally lower rate of decrease after age 20 is reversed at age 35 in anterior and central regions in the alpha and beta bands, and stabilized in the theta bands. In males, the decreases continue in the theta and high alpha bands, but there are elements of the reversal in the low alpha and beta bands. Examination of the derivatives of the trajectories show that sex differences begin in the mid-twenties in alpha and beta but not until the mid-thirties in theta. In contrast to the varied power value trajectories, the trajectories of inter-frequency correlation show a pervasive increase with age of the correlation between high alpha and each of the other frequency bands except high beta. This increase is primarily anterior in the alpha-theta correlations and more regionally uniform in the alpha-beta correlations. Sex differences are very small. Trajectories of intra-frequency correlations for comparable between region pairs and within region pairs were generally high and stable across age. This is the first of a series of studies which will provide similar analyses of bipolar EEG power and bipolar EEG coherence in this sample. We know of no other study of resting state EEG power which combines the analysis of power with the analysis of both inter-frequency and intra-frequency correlation of power values.","rel_num_authors":9,"rel_authors":[{"author_name":"David B Chorlian","author_inst":"SUNY DHSU"},{"author_name":"Jacquelyn L Meyers","author_inst":"SUNY DHSU"},{"author_name":"Andrey Anokhin","author_inst":"Washington University School of Medicine"},{"author_name":"Chella B Kamarajan","author_inst":"SUNY DHSU"},{"author_name":"Ashwini Pandey","author_inst":"SUNY DHSU"},{"author_name":"Jian Zhang","author_inst":"SUNY DHSU"},{"author_name":"Sivan Kinreich","author_inst":"SUNY DHSU"},{"author_name":"Arjun Bingly","author_inst":"SUNY DHSU"},{"author_name":"Bernice Porjesz","author_inst":"SUNY DHSU"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Label-Free AI-Classification of Subcellular Organelles Based on Optical Photothermal Infrared Images","rel_doi":"10.64898\/2026.06.02.729616","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729616","rel_abs":"Cells maintain homeostasis by dynamically reorganizing their organelles to tune metabolism in response to stress. Fluorescence microscopy maps organelle locations with subcellular resolution but provides limited information on their chemical composition. Infrared (IR) imaging offers a label-free alternative for probing intrinsic molecular vibrations that report on lipids, carbohydrates, and nucleic acids. However, its broader application to subcellular biology has been limited by spatial resolution and hyperspectral data complexity. Here, we combine submicron optical photothermal IR imaging with machine learning to classify subcellular structures in fixed U-2 OS cells. Using fluorescent-labeled organelles as ground truth, we trained and evaluated random forest (RF) classifiers and U-Net convolutional neural networks to identify organelles from IR spectra. The RF model converged rapidly, requiring fewer than 75 spectra per class per cell and fewer than 25 cells, indicating that models trained on small cellular regions can be extended to classify whole-cell images. The resulting classifiers accurately identified multiple organelles, including the endoplasmic reticulum, Golgi apparatus, mitochondria, nucleus, nucleolus, and stress granules. In contrast, classification was unsuccessful for nuclear speckles, actin, and microtubules, suggesting that some structures lack sufficiently distinct IR signatures under these conditions. Classifiers trained in U-2 OS cells generalized to HEK 293 cells, consistent with conserved organelle biochemical composition across cell types. However, the classifiers failed under cellular stress, indicating sensitivity to stress-induced changes in organelle state. Together, these results establish a scalable, label-free strategy for high-resolution mapping of organelle biochemical composition and provide a foundation for subcellular biomarker discovery and disease-state diagnostics.","rel_num_authors":3,"rel_authors":[{"author_name":"Michael J Burke","author_inst":"Yale Univeristy"},{"author_name":"Victor S Batista","author_inst":"Yale University"},{"author_name":"Caitlin M Davis","author_inst":"Yale University"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Modeling the journey as well as the destination: a control theory account of rotational navigation","rel_doi":"10.64898\/2026.06.02.729319","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729319","rel_abs":"Navigation requires estimating heading and transforming these estimates into actions. Prior models explain how self-motion and landmark cues are combined into heading estimates, but less is known about how these estimates are iteratively transformed into motor commands to reach a goal. Here, we hypothesized that navigation operates as a closed-loop process in which ongoing movement is updated by sensory prediction errors. To test this hypothesis, participants performed a goal-directed rotation task in virtual reality. On select trials, visual landmarks were shifted during movement, inducing a prediction error between the heading expected from self-motion estimates and the heading observed from the shifted landmarks. In parallel, we developed a closed-loop model of turning behavior that represents heading and angular velocity as jointly estimated states over time. This model accounts not only for final position, the destination, but also for the movement dynamics that produce it, the journey. The model predicts that landmark-induced visual prediction errors should produce rapid corrective changes in movement. Participant turning behavior qualitatively paralleled these model dynamics: acceleration changed after visual feedback, with larger landmark mismatches producing larger corrective responses. Together, these findings suggest that naturalistic movement depends on continuously transforming heading estimates into motor command through closed-loop control.","rel_num_authors":9,"rel_authors":[{"author_name":"Yinqi Huang","author_inst":"Georgia Institute of Technology"},{"author_name":"Abhilasha Vishwanath","author_inst":"University of Arizona"},{"author_name":"Yu Karen Du","author_inst":"University of Western Ontario"},{"author_name":"Matthew Frederick Watson","author_inst":"University of Arizona"},{"author_name":"Osama Asiri","author_inst":"University of Arizona"},{"author_name":"Karlee Dakin","author_inst":"University of Arizona"},{"author_name":"Donette Markham","author_inst":"University of Arizona"},{"author_name":"Arne David Ekstrom","author_inst":"University of Arizona"},{"author_name":"Robert C Wilson","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Intraspecific genetic variation modulates immune responses to acute heat exposure in an aquatic ectotherm","rel_doi":"10.64898\/2026.06.02.729540","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729540","rel_abs":"Climate change-induced heatwaves threaten ectotherms, whose physiology is tightly coupled to ambient temperature. Vulnerability assessments often rely on data from one or a few populations, implicitly assuming uniform thermal sensitivity across species genetic diversity. Quantifying such variation is especially important for traits with wider ecological consequences; our focus here is on immune function, which shapes disease dynamics. We addressed this knowledge gap using ten clonal lineages of the New Zealand snail Potamopyrgus antipodarum exposed to ambient (17C) or heatwave conditions (27C) for 4 or 8 days. We measured two complementary innate immune traits: general phenoloxidase-like (PO-like) activity, which integrates the activity of multiple phenoloxidase enzymes, and laccase activity, which targets a specific PO enzyme subclass important in mollusc immunity. Heat exposure suppressed both traits, but patterns differed across clones. While PO-like activity declined uniformly, laccase activity showed substantial among-clone variation in heatwave responses at day 4, though these differences converged by day 8. Heat-induced immune suppression is thus trait-specific, depends on genetic background, and varies with exposure duration. Together, these results demonstrate that studies limited to a single genotype, population, or timepoint risk miscalculating species-level vulnerability.","rel_num_authors":4,"rel_authors":[{"author_name":"Maurine Neiman","author_inst":"University of Iowa"},{"author_name":"Katri Sepp\u00e4l\u00e4","author_inst":"University of Innsbruck"},{"author_name":"Dunja K Lamatsch","author_inst":"University of Innsbruck"},{"author_name":"Otto Sepp\u00e4l\u00e4","author_inst":"University of Innsbruck"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"NeuroCaptain v2 - Interactive Three-Dimensional fNIRS Optode and Probe Montage Design Platform Based on Blender","rel_doi":"10.64898\/2026.06.02.729322","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729322","rel_abs":"SignificanceAccurate and reproducible optode placement is crucial for obtaining high-quality fNIRS data in both individual and group-level neuroimaging studies. Conventional optode\/probe montage design tools usually transform a probe layout defined in 2D Cartesian space onto a 3D head surface using a mass-spring model. Such mechanical transformation, combined with the indirect mapping between the 2D probe definition and the 3D target space, can introduce placement variations across different head surfaces and subjects.\n\nAimWe introduce NeuroCaptain v2, an open-source Blender-based add-on designed to enable interactive, anatomically guided optode design, registration, and cortical sensitivity visualization for fNIRS head-cap and probe creation.\n\nApproachNeuroCaptain v2 enables researchers to add, move, and edit fNIRS sources and detectors directly over a 3D head surface mesh, defining anchored optode positions, as well as setting the stiffness of the springs between adjacent optodes. It then utilizes Blenders built-in physical simulation engine to relax the initial probe layout to satisfy the mechanical constraints. With the built-in mesh-based Monte Carlo (MMC) and diffusion-solver Redbird, NeuroCaptain v2 computes and renders 3D sensitivity maps to guide iterative optode adjustment. The resulting 3D optode layout is stored in the form of barycentric coordinates defined in a 10-20 landmark mesh, enabling consistent probe transfer across different head models.\n\nResultsWe demonstrate interactive 3D montage design, cross-head-atlas probe registration, and cortical sensitivity visualization across multiple head geometries. Registering a probe across seven neurodevelopmental head atlases, the proposed anatomical-coordinate approach yields a mean per-optode standard deviation of 2.29 mm, a roughly 74% reduction in cross-subject placement variability compared to 8.68 mm using a conventional 2D-to-3D registration.\n\nConclusionsNeuroCaptain v2 provides a reproducible, fully open-source workflow for fNIRS probe montage design that facilitates anatomically guided probe development and cross-subject registration directly in a three-dimensional anatomical environment.","rel_num_authors":2,"rel_authors":[{"author_name":"Ashlyn McCann","author_inst":"Northeastern University"},{"author_name":"Qianqian Fang","author_inst":"Northeastern University"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Chemically Engineered Carbon Nanotubes Map Class-Selective Metabolite Enrichment from Human Plasma","rel_doi":"10.64898\/2026.06.02.729405","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729405","rel_abs":"The spontaneous adsorption of biomolecules onto nanoparticle surfaces has been extensively characterized at the protein level, but the metabolite corona remains poorly defined while being physicochemically and biologically distinctive. Herein, we report the first class-level mapping of metabolite corona composition across 25 chemically modified carbon nanotubes in human plasma using untargeted liquid chromatography-mass spectrometry. Complementary analytical conditions detected approximately 9,000 metabolite features, of which over 5,000 yielded valid corona-versus-plasma enrichment measurements. Machine learning classifiers extended metabolite class annotations from 10-45% to the full detected set, enabling systematic analysis of class-level enrichment patterns. We find that polymer wrapping dominates corona composition, with DNA wrapping selectively enriching nonpolar lipids and PEG wrapping favoring polar metabolites. Within each polymer background, covalent quantum well defects further modulate class-level enrichment in a structure- and chemistry-dependent manner. Carboxyl aryl defects broadly enhance amphiphilic lipid recruitment, while trifluoro aryl defects suppress single-chain amphiphilic species but attenuate depletion of double-chain phospholipids. Our findings demonstrate that engineered nanotubes can serve as chemically tunable, selective scaffolds for metabolite enrichment, potentially enhancing the capability of nanotube-based platforms to recruit and detect structurally diverse, low-abundance small molecules in complex biofluids.","rel_num_authors":3,"rel_authors":[{"author_name":"In-Jun Hwang","author_inst":"Georgia Institute of Technology"},{"author_name":"Jada S. Gray","author_inst":"Georgia Institute of Technology"},{"author_name":"Mijin Kim","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Walking on the Moon: Hypogravity drives the emergence of a proprioception-dependent locomotor state","rel_doi":"10.64898\/2026.06.02.729513","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729513","rel_abs":"Animals must adapt locomotion to changing environments, but how the nervous system flexibly select gait remains unclear. Gravity is a powerful natural perturbation altering body loading and limb dynamics. Apollo astronauts often skipped on the Moon, adopting an asymmetric gait rarely used on Earth, yet the motor control basis of this behavior is unknown. Here, by studying the effect of hypogravity on locomotion in humans and mice, we identify a conserved strategy for gait adaptation. Muscle synergy analysis in humans shows that skipping in reduced gravity is generated through flexible reuse of existing motor modules rather than construction of new ones. In mice, lunar gravity elicited a skipping-like asymmetric gait and genetic elimination of muscle proprioceptors abolished it. Thus, hypogravity reveals a proprioception-dependent mechanism for flexible gait selection.","rel_num_authors":18,"rel_authors":[{"author_name":"Alessandro Santuz","author_inst":"Max Delbrueck Center for Molecular Medicine in the Helmholtz Association"},{"author_name":"Francesco Luciano","author_inst":"University of Milan"},{"author_name":"Valentina Natalucci","author_inst":"University of Milan"},{"author_name":"Adama Mbaye","author_inst":"Max Delbrueck Center for Molecular Medicine in the Helmholtz Association"},{"author_name":"Nini Ma","author_inst":"Max Delbrueck Center for Molecular Medicine in the Helmholtz Association"},{"author_name":"Dario Cazzola","author_inst":"University of Bath"},{"author_name":"Steffi Colyer","author_inst":"University of Bath"},{"author_name":"James Cowburn","author_inst":"University of Bath"},{"author_name":"Kirsten Albracht","author_inst":"Aachen University of Applied Sciences"},{"author_name":"Bjoern Braunstein","author_inst":"German Sport University"},{"author_name":"Joern Rittweger","author_inst":"Institute of Aerospace Medicine DLR"},{"author_name":"Nolan Herssens","author_inst":"European Space Agency"},{"author_name":"Tobias Weber","author_inst":"European Space Agency"},{"author_name":"David A. Green","author_inst":"European Space Agency"},{"author_name":"Joriene de Noiij","author_inst":"Columbia University"},{"author_name":"Alberto E. Minetti","author_inst":"University of Milan"},{"author_name":"Gaspare Pavei","author_inst":"University of Milan"},{"author_name":"Niccolo Zampieri","author_inst":"Max Delbrueck Center for Molecular Medicine in the Helmholtz Association"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Anti-Polyamine Therapy Restrains Kidney Cyst Growth in an Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease","rel_doi":"10.64898\/2026.06.02.729335","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729335","rel_abs":"Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic kidney disease worldwide. Tolvaptan is currently the only approved intervention to slow kidney cyst growth, but its indication is limited to rapidly progressing ADPKD and use compromises quality of life. Hence, new therapeutic options are of high clinical importance. Metabolic dysregulation is a hallmark of kidney cyst growth, including reprogramming of arginine metabolism and polyamine production. Sustained increases in polyamine synthesis drive pathological epithelial cell proliferation, tissue remodeling, and activation of M2-like macrophages, all known drivers of PKD. Difluoromethylornithine (DFMO) is an FDA approved irreversible inhibitor of ornithine decarboxylase (ODC1), the rate limiting enzyme in the arginine-polyamine pathway. Here, we treated C57Bl6\/J p.R3277C (Pkd1RC\/RC) mice for five months with DFMO-supplemented drinking water to test if DFMO treatment can slow kidney cyst growth in an orthologous model of ADPKD that mimics the disease pathophysiology seen in patients. At study end, Pkd1RC\/RC mice treated with DFMO presented with significantly reduced percent kidney weight normalized to body weight as well as kidney cystic index and cyst number compared to control. Kidney RNA-seq analyses revealed correction of many genes and pathways perturbed in PKD post DFMO treatment, as well as overall heathier kidney cellular architecture as inferred by RNAseq-base cell type deconvolution. Our data highlight significant potential to repurpose DFMO for the treatment of patients with ADPKD and investigate the role of polyamines in modulating epithelial as well as myeloid cell fate in the setting of PKD.","rel_num_authors":6,"rel_authors":[{"author_name":"Katharina Hopp","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Marie-Louise T Monaghan","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Sizhao Lu","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Timothy A Fields","author_inst":"University of Kansas Medical Center"},{"author_name":"Michael P Vitek","author_inst":"Duke University Medical Center"},{"author_name":"Katherine I Swenson-Fields","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"From recognition to neglect: Molecular and physiological responses to heterospecific pollen decay with evolutionary distance","rel_doi":"10.64898\/2026.06.02.729600","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729600","rel_abs":"Post-mating, pre-zygotic (PMPZ) reproductive barriers are often attributed to precise molecular recognition between male and female gametes, yet little is known about how these interactions change as species diverge. In flowering plants, pollen tube growth depends on coordinated signaling between pollen and pistil, raising the question of whether PMPZ barriers arise through active incompatibility mechanisms or gradual loss of pollen-pistil coordination. Here, we combined transcriptomic profiling and pollen tube growth assays across a phylogenetically structured set of crosses in a diverse alpine plant community. We show that the magnitude of the pistillar transcriptomic response to pollination declined quantitatively with evolutionary distance rather than shifting in a binary compatible\/incompatible manner. Pollination-associated functional gene ontology categories were strongest in conspecific and intrageneric crosses and weakened with divergence. Heterospecific pollen tubes also grew more slowly than conspecific tubes, with growth rates declining overall with genetic distance. However, the slowest growth occurred in intrageneric crosses, suggesting that close relatives may represent a distinct evolutionary zone where reduced maternal support coincides with additional hindrance mechanisms. Together, these results support a graded, divergence-dependent model of pollen-pistil incongruence driven primarily by attenuation of coordinated growth rather than strict heterospecific rejection.","rel_num_authors":5,"rel_authors":[{"author_name":"Rachel O. Cohen","author_inst":"Columbia University"},{"author_name":"Alessandra Masi","author_inst":"Columbia University"},{"author_name":"Sarah M. Chin","author_inst":"Columbia University"},{"author_name":"Joseph O. Williams","author_inst":"University of Tennessee"},{"author_name":"Deren A.R. Eaton","author_inst":"Columbia University"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Vesicular pseudopodia define the fusion site on large secretory vesicles of the Drosophila salivary glands","rel_doi":"10.64898\/2026.06.02.729163","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729163","rel_abs":"Large secretory vesicles (LSVs) pose a scaling problem for regulated exocytosis. Their micron-scale dimensions greatly increase the vesicular membrane surface area, making productive engagement between the vesicular and target membrane fusion machinery unlikely. Here, we show that vesicular pseudopodia define the fusion sites of LSVs in Drosophila larval salivary glands. Focused ion beam scanning electron microscopy revealed that most LSVs project polarized pseudopodia that interconnect neighboring vesicles and orient toward the apical membrane. Exposed pseudopodia were frequently observed at the apical surface and associated with narrow fusion pores, indicating that fusion occurs at these structures. Three-dimensional correlative light and electron microscopy showed that the I-BAR protein Missing in Metastasis (MIM) selectively localizes to exposed pseudopodia. Proteomic analysis based on a MIM pull-down assay identified exocyst components, including Sec15, which localizes to pseudopodia and persists at fusion sites throughout secretion. Finally, the tetraspanin Tsp42Ee marked complementary apical fusion domains and was required for efficient exocytosis. Our findings support a model in which prepatterned vesicular and apical membrane domains coordinate efficient exocytosis.\n\nSummaryRegulated exocytosis of large secretory vesicles is facilitated by vesicular pseudopodia and an apical fusion domain that spatially organizes membrane tethering and fusion during secretion.","rel_num_authors":11,"rel_authors":[{"author_name":"Nadav Scher","author_inst":"Weizmann Institute of Science"},{"author_name":"Tom Biton","author_inst":"Weizmann Institute of Science"},{"author_name":"Vishnu Mohan","author_inst":"Weizmann Institute of Science"},{"author_name":"Neta Varsano","author_inst":"Weizmann Institute of Science"},{"author_name":"Noa Aharoni","author_inst":"Weizmann Institute of Science"},{"author_name":"Shari Carmon","author_inst":"Weizmann Institute of Science"},{"author_name":"Kamalesh Kumari","author_inst":"Weizmann Institute of Science"},{"author_name":"Eyal D Schejter","author_inst":"Weizmann Institute of Science"},{"author_name":"Tamar Geiger","author_inst":"Weizmann Institute of Science"},{"author_name":"Yael Elbaz-Alon","author_inst":"Weizmann Institute of Science"},{"author_name":"Ori Avinoam","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"inGSEA: An Improved Method for Gene Set Enrichment Analysis Using a Weighted Integral Statistic","rel_doi":"10.64898\/2026.06.02.729106","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.02.729106","rel_abs":"Gene Set Enrichment Analysis (GSEA) is one of the most popular methods for transcriptomic analysis, yet its statistical power is limited when the biological pathways exhibit heterogeneous or non-concordant expression patterns. We propose an improved GSEA method, integral-based GSEA (inGSEA). inGSEA introduces a novel enrichment score based on the Anderson-Darling weighted integral statistic. The new enrichment score enhances detection power for complex signals, particularly sparse and bidirectional ones, while the Cauchy combination of integral and classic maximum statistics provides robustness across diverse expression patterns. Extensive numerical studies demonstrate that inGSEA achieves superior power and well-calibrated false discoveries. Application to real-world datasets reveals biologically relevant pathways missed by the standard GSEA. inGSEA reduces the computational burden of permutation testing by employing a generalized gamma distribution to approximate the null distribution. inGSEA is accessible as a user-friendly web-based software tool (https:\/\/amss-stat.github.io\/inGSEA).","rel_num_authors":2,"rel_authors":[{"author_name":"Qinyuan Zhang","author_inst":"University of Chinese Academy of Sciences"},{"author_name":"Qizhai Li","author_inst":"Chinese Academy of Sciences"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"RISOP, a Reference-Assisted Approach for Enhanced Identification of Oxidized Phospholipids","rel_doi":"10.64898\/2026.06.01.728773","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.01.728773","rel_abs":"Oxidized phospholipids (OxPLs) play critical roles in inflammation, ferroptosis, and other oxidative stress-associated processes, yet their systematic characterization in biological systems remains a major analytical challenge owing to their low abundance and vast structural diversity. Here we report RISOP (Reference-Assisted Identification of Sample-specific Oxidized Phospholipids), an untargeted LC-MS\/MS workflow that leverages chemically enriched OxPL reference pools to substantially improve OxPL annotation. Reference pools encompassing diverse oxidative modifications and a wide abundance range were experimentally generated using Fenton reaction and H2O2 treatment, providing broad coverage of OxPLs. Reference-assisted integrative analysis yielded a more than twofold increase in identified OxPL species in biological samples under elevated oxidative stress, as demonstrated in ML210-treated cells, a model of ferroptotic stress. We further show that the widely used BODIPY C11 lipid peroxidation probe captures cellular oxidative burden in only a subset of OxPLs identified by RISOP, highlighting the importance of untargeted, comprehensive OxPL profiling. Overall, RISOP provides a versatile platform readily applicable to other classes of oxidized complex lipids for comprehensive characterization in physiological and pathological contexts.","rel_num_authors":4,"rel_authors":[{"author_name":"Zixing Chen","author_inst":"Yale University"},{"author_name":"Andrew Erickson","author_inst":"Yale University"},{"author_name":"Natalie Ito","author_inst":"Yale University"},{"author_name":"Xiaoai Zhao","author_inst":"Yale University"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Asymmetric neural dynamics of visuospatial attention in autism spectrum disorder","rel_doi":"10.64898\/2026.06.04.730213","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730213","rel_abs":"Background: Selective attention enables the prioritization of behaviorally relevant information in complex sensory environments. Despite substantial evidence for altered attention in autism spectrum disorder (ASD), the neurophysiological mechanisms underlying these differences remain poorly understood. Methods: Here, we integrate high-density electroencephalography (EEG), pupillometry, and behavioral measures collected during a cued covert visuospatial selective attention task to characterize mechanisms of spatial attention in children and adolescents with ASD (n = 18; 13.4 {+\/-} 3.0 YO), and how they differ from age- and IQ- matched individuals with typical-development (TD) (n = 21; 14.7 {+\/-} 3.8 YO). Results: Both groups demonstrated high target detection accuracy and comparable response times, with no significant between-group differences in behavioral performance. Furthermore, neurophysiological measures demonstrated that during leftward attention, both TD and ASD participants exhibited canonical attentional processes, including lateralized anticipatory parieto-occipital alpha modulation and enhanced P1 sensory responses to attended stimuli. Additionally, across both groups, trial-level analyses revealed that decreased anticipatory alpha power and increased P1 amplitude contralateral to the attended hemifield were associated with faster reaction times. In contrast, there were notable group differences in the neural dynamics supporting rightward spatial attention. TD participants showed early sensory gain (P1 modulation) without alpha-band modulation, whereas ASD participants exhibited modulation of posterior alpha power without effective sensory gain. Interestingly, for rightward attention, only P1 amplitude predicted reaction time, and this was the case for both groups. Resting-state alpha dynamics did not differ between groups, indicating that the attended hemifield differences reflect task-dependent differences in attentional control rather than baseline oscillatory differences. Limitations: Limitations include modest sample size and restriction to autistic individuals with relatively low support needs, which may limit the generalizability of these findings to the broader autism spectrum. Conclusions: The similarity of leftward attention mechanisms across groups, which includes intact recruitment of anticipatory alpha modulation, argues against a global disruption of basic visuo-spatial attentional function in autistic individuals with low support needs. However, group differences emerged specifically during rightward attention, where ASD participants showed a more uniform pattern of oscillatory modulation, warranting further investigation. Collectively, these findings provide novel insight into the neural architecture of visuospatial attention in ASD, revealing how preparatory oscillatory activity shapes early sensory responses and behavior during selective attention. Keywords: autism spectrum disorder, EEG, visuospatial attention, pseudoneglect","rel_num_authors":5,"rel_authors":[{"author_name":"Megan Darrell","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Theo Vanneau","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Chloe Brittenham","author_inst":"Albert Einstein College of Medicine"},{"author_name":"John J. Foxe","author_inst":"University of Rochester School of Medicine"},{"author_name":"Sophie J. Molholm","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"rel_title":"Inherited input and local transformations shape the spatiotemporal organization of pathway specific striatal signals for motivated behavior","rel_doi":"10.64898\/2026.06.04.730000","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.04.730000","rel_abs":"Adaptive behavior requires neural circuits to link sensory events with their location, predictive value, and temporal relationship to outcomes. Although striatal circuits are implicated in this process, it remains unclear how motivationally relevant signals are organized across striatal regions and direct- and indirect-pathway spiny projection neurons, and which components reflect afferent input versus local transformations. Using striatum-wide calcium recordings during visual conditioning in mice, we found that learned cue value, reward proximity, cue location, and lick-related behavior were encoded in distinct regions and time windows. These signals included both pathway-convergent representations and pathway-opponent dynamics. Striatum-wide measurements of glutamatergic input targeted to each SPN subtype revealed that rapid cue-location and lick-related signals were present in afferent input to both pathways, consistent with inherited representations. In contrast, pathway-opponent pDMS value signals and dSPN-selective pVLS ramping were absent from corresponding glutamatergic input dynamics, indicating local striatal transformations. These findings reveal region-specific input-output transformations that organize striatal signals for distinct components of motivated behavior.","rel_num_authors":6,"rel_authors":[{"author_name":"Zicheng Zhang","author_inst":"Boston University"},{"author_name":"Yizhuo Ding","author_inst":"Penn State University"},{"author_name":"Mai-Anh Vu","author_inst":"Boston University"},{"author_name":"Lydia Mroz","author_inst":"Northeastern University"},{"author_name":"Yuxin Tong","author_inst":"Dartmouth College"},{"author_name":"Mark Howe","author_inst":"Boston University"}],"rel_date":"2026-06-05","rel_site":"biorxiv"},{"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@1a9c24borg.highwire.dtl.DTLVardef@130646org.highwire.dtl.DTLVardef@1010ce3org.highwire.dtl.DTLVardef@1f53ee3org.highwire.dtl.DTLVardef@1f3bd93_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"},{"rel_title":"Lifetime adversity exposure, mood symptoms, and immune mitochondrial bioenergetics","rel_doi":"10.64898\/2026.06.02.26354718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354718","rel_abs":"Despite their prevalence, the pathophysiology of depression and anxiety remains poorly understood. Although adversity is a known risk factor, the mechanisms and biological contexts through which it contributes to mood disorder symptoms remain unclear. Immune and mitochondrial adaptations have both been implicated in mood disorders, suggesting the biological embedding of adversity may involve both systems. However, inconsistencies in the literature remain, partly due to reliance on mixed peripheral blood mononuclear cell (PBMC) populations despite substantial variability in mitochondrial biology across immune cell subtypes. We therefore investigated associations between adversity, mood disorder symptoms, immune cell proportions, and immune cell-specific mitochondrial bioenergetics (enzyme activities and respirometry) in participants from the Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study (n=105, age 18-60, 68% female, 35% with mitochondrial disease). Depressive and anxiety symptoms were positively associated with the monocyte-to-lymphocyte ratio, suggesting a shift toward greater innate relative to adaptive immunity. Associations between mood disorder symptoms and immune cell count were stronger in those exposed to greater early life adversity. Mood disorder symptoms were negatively associated with lymphocyte maximal mitochondrial respiratory capacity (MRC). As expected, the associations between mood disorder symptoms and lymphocyte mitochondrial bioenergetics (enzyme-based MRC and respiratory measurements) were stronger and more consistent among individuals exposed to higher lifetime adversity compared to those with lower lifetime adversity. Overall, these results suggest a complex interplay between adversity, immune cell mitochondrial bioenergetics, and mood disorder symptoms, highlighting immune mitochondrial biology as a potential allostatic pathway linking adversity to psychiatric disorders.","rel_num_authors":11,"rel_authors":[{"author_name":"Cynthia C Liu","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Catherine Kelly","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Anna S Monzel","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Mandakh Bekhbat","author_inst":"Emory University"},{"author_name":"Natalia Bobba-Alves","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Veronica Ramirez","author_inst":"University of California, Irvine"},{"author_name":"George M Slavich","author_inst":"University of California, Irvine"},{"author_name":"Robert-Paul Juster","author_inst":"University of Montreal"},{"author_name":"Steve W Cole","author_inst":"University of California, Los Angeles"},{"author_name":"Martin Picard","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Caroline Trumpff","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"MealRes-Gate: Forecasting Glucose Dynamics from CGM and Sparse Meal Logs Using Residual-Gated Multimodal Transformer","rel_doi":"10.64898\/2026.06.01.26354646","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354646","rel_abs":"Continuous glucose monitoring (CGM) enables personalized metabolic health support, but forecasting glucose in free-living settings remains challenging because future trajectories depend on both endogenous dynamics and sparsely recorded meals. We developed MealRes-Gate, a multimodal transformer that incorporates meal information as a gated residual refinement to a strong CGM-based backbone. In 1,752 non-diabetic and pre-diabetic adults from the Framingham Heart Study, MealRes-Gate consistently outperformed recurrent, Transformer-based, and GluFormer baselines across 30-, 60-, 90-, and 120-minute horizons. Gains were largest in postprandial, high glucose, and low glucose windows, and extended to clinically relevant postprandial summaries that included peak glucose, time-to-peak, and glucose area under the curve. Ablation analysis showed that engineered CGM features provided the dominant predictive backbone, while explicit meal features contributed smaller but meaningful gains when integrated through the proposed residual-gating mechanism. These results demonstrate that sparse dietary information can improve glucose forecasting without destabilizing prediction, provided it is incorporated through a selective, residual gating mechanism.","rel_num_authors":11,"rel_authors":[{"author_name":"Jung Lee","author_inst":"Boston University"},{"author_name":"Suheng Yao","author_inst":"Boston University"},{"author_name":"Lin Tang","author_inst":"Boston University"},{"author_name":"Xiaowei Yu","author_inst":"Missouri University of Science and Technology"},{"author_name":"Michael Cheney","author_inst":"Boston University"},{"author_name":"Honghuan Lin","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Xuezhou Zhang","author_inst":"Boston University"},{"author_name":"Debarghya Mukherjee","author_inst":"Boston University"},{"author_name":"Maura Walker","author_inst":"Boston University"},{"author_name":"Nicole Spartano","author_inst":"Boston University"},{"author_name":"Huimin Cheng","author_inst":"Boston University"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Oxygen extraction fraction brain charts for human lifespan and application for brain disorders","rel_doi":"10.64898\/2026.06.02.26354684","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354684","rel_abs":"Cerebral oxygen extraction fraction (OEF) reflects the balance between cerebral oxygen delivery and metabolic demand, but its normative evolution across the human lifespan remains unknown. Here we used rapid, non-contrast TRUST MRI to establish a multisite normative model of global cerebral OEF in 2,025 healthy individuals aged 0-93 years from 17 imaging sites. OEF increased from the neonatal period to middle adulthood, followed by a slower rise and plateau in later life, with the fastest change occurring during early development and no significant sex differences. Individual OEF deviation scores were associated with vascular risk burden in healthy adults. Applying the model to 885 patients revealed disease-related OEF alterations, including positive deviations in pediatric obstructive sleep apnea, autoimmune disorders, brain tumors, mild cognitive impairment and dementia. OEF deviation further tracked tumor grade and Ki-67 proliferation. These findings establish lifespan OEF charting as a scalable framework for individualized physiological neuroimaging.","rel_num_authors":51,"rel_authors":[{"author_name":"Zixuan Lin","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Xiang Fan","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Tianyu Gao","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"},{"author_name":"Shuyue Wang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Yiwen Hong","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Yifan Yan","author_inst":"Department of Psychiatry, School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jianpeng Liu","author_inst":"Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yuchuan Fu","author_inst":"The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China"},{"author_name":"Tao Hua","author_inst":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yue Cai","author_inst":"Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China"},{"author_name":"Gaigai Lu","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Ying Qi","author_inst":"Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China"},{"author_name":"Bing Yu","author_inst":"Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China"},{"author_name":"Zhizheng Zhuo","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"},{"author_name":"Jiani Wu","author_inst":"Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Dayong Ge","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Qingyu Xu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Yizhe Hu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Chuhan Xiong","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Weijia Liu","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Runyu Tang","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Qiuping Ding","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Qiongbin Zhu","author_inst":"Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Lisan Zhang","author_inst":"Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Zhicai Chen","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Hongfu Li","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Wei Luo","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Zhidong Cen","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jianzhong Sun","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Minming Zhang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jiawei Liang","author_inst":"Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China"},{"author_name":"Hongxi Zhang","author_inst":"Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China"},{"author_name":"Zhihan Yan","author_inst":"The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China"},{"author_name":"Yixin Emu","author_inst":"MR Scientific Collaboration, United Imaging Healthcare, Shanghai, China"},{"author_name":"Xijing Zhang","author_inst":"MR Scientific Collaboration, United Imaging Healthcare, Shanghai, China"},{"author_name":"Keyan Yu","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Guanxun Cheng","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Yadong Liu","author_inst":"Department of Radiology, Guiqian International General Hospital, Guiyang, China"},{"author_name":"Libo Zhang","author_inst":"Department of Radiology, Third Hospital of Heilongjiang, Beian, China"},{"author_name":"Sven Haller","author_inst":"Centre d'Imagerie Medicale de Cornavin (CIMC), 1201 Geneva, Switzerland"},{"author_name":"James Cole","author_inst":"Department of Computer Science, University College London, London, UK"},{"author_name":"Yuxin Li","author_inst":"Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Chao Wang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Peiyu Huang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Fang Xie","author_inst":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Hanzhang Lu","author_inst":"Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Dan Wu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Tengfei Guo","author_inst":"Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China"},{"author_name":"Xin Xu","author_inst":"Department of Psychiatry, School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Dengrong Jiang","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Yaou Liu","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Oxygen extraction fraction brain charts for human lifespan and application for brain disorders","rel_doi":"10.64898\/2026.06.02.26354684","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354684","rel_abs":"Cerebral oxygen extraction fraction (OEF) reflects the balance between cerebral oxygen delivery and metabolic demand, but its normative evolution across the human lifespan remains unknown. Here we used rapid, non-contrast TRUST MRI to establish a multisite normative model of global cerebral OEF in 2,025 healthy individuals aged 0-93 years from 17 imaging sites. OEF increased from the neonatal period to middle adulthood, followed by a slower rise and plateau in later life, with the fastest change occurring during early development and no significant sex differences. Individual OEF deviation scores were associated with vascular risk burden in healthy adults. Applying the model to 885 patients revealed disease-related OEF alterations, including positive deviations in pediatric obstructive sleep apnea, autoimmune disorders, brain tumors, mild cognitive impairment and dementia. OEF deviation further tracked tumor grade and Ki-67 proliferation. These findings establish lifespan OEF charting as a scalable framework for individualized physiological neuroimaging.","rel_num_authors":51,"rel_authors":[{"author_name":"Zixuan Lin","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Xiang Fan","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Tianyu Gao","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"},{"author_name":"Shuyue Wang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Yiwen Hong","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Yifan Yan","author_inst":"Department of Psychiatry, School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jianpeng Liu","author_inst":"Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yuchuan Fu","author_inst":"The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China"},{"author_name":"Tao Hua","author_inst":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yue Cai","author_inst":"Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China"},{"author_name":"Gaigai Lu","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Ying Qi","author_inst":"Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China"},{"author_name":"Bing Yu","author_inst":"Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China"},{"author_name":"Zhizheng Zhuo","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"},{"author_name":"Jiani Wu","author_inst":"Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Dayong Ge","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Qingyu Xu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Yizhe Hu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Chuhan Xiong","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Weijia Liu","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Runyu Tang","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Qiuping Ding","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Qiongbin Zhu","author_inst":"Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Lisan Zhang","author_inst":"Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Zhicai Chen","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Hongfu Li","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Wei Luo","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Zhidong Cen","author_inst":"Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jianzhong Sun","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Minming Zhang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Jiawei Liang","author_inst":"Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China"},{"author_name":"Hongxi Zhang","author_inst":"Department of Radiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China"},{"author_name":"Zhihan Yan","author_inst":"The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China"},{"author_name":"Yixin Emu","author_inst":"MR Scientific Collaboration, United Imaging Healthcare, Shanghai, China"},{"author_name":"Xijing Zhang","author_inst":"MR Scientific Collaboration, United Imaging Healthcare, Shanghai, China"},{"author_name":"Keyan Yu","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Guanxun Cheng","author_inst":"Department of Medical Imaging, Peking University Shenzhen Hospital, Shenzhen, China"},{"author_name":"Yadong Liu","author_inst":"Department of Radiology, Guiqian International General Hospital, Guiyang, China"},{"author_name":"Libo Zhang","author_inst":"Department of Radiology, Third Hospital of Heilongjiang, Beian, China"},{"author_name":"Sven Haller","author_inst":"Centre d'Imagerie Medicale de Cornavin (CIMC), 1201 Geneva, Switzerland"},{"author_name":"James Cole","author_inst":"Department of Computer Science, University College London, London, UK"},{"author_name":"Yuxin Li","author_inst":"Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Chao Wang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Peiyu Huang","author_inst":"Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Fang Xie","author_inst":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Hanzhang Lu","author_inst":"Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Dan Wu","author_inst":"Zhejiang Key Laboratory of Intelligent Sensing Technology and Advanced Medical Instrument and Key Laboratory for Biomedical Engineering of Ministry of Education"},{"author_name":"Tengfei Guo","author_inst":"Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China"},{"author_name":"Xin Xu","author_inst":"Department of Psychiatry, School of Public Health, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"},{"author_name":"Dengrong Jiang","author_inst":"National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong"},{"author_name":"Yaou Liu","author_inst":"Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Epigenetic Clock CpGs form Tumor methylation Programs that Predict Survival Across Cancers","rel_doi":"10.64898\/2026.06.01.26354667","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354667","rel_abs":"Epigenetic clocks have been widely evaluated as cancer biomarkers, but findings have been inconsistent across tumor types and clinical endpoints. This inconsistency may reflect a fundamental misspecification: standard clock analyses treat clock CpGs as scalar aging readouts, assuming that tumors shift along the same methylation-aging axis as normal tissue. We tested this assumption across nine TCGA (The Cancer Genome Atlas) cancer types using Horvath clock CpGs. Tumors did not show a consistent mean shift in Horvath age acceleration relative to normal tissue. Instead, they showed an order-of-magnitude increase in age-acceleration variance. Scalar clock summaries also failed as survival biomarkers, producing zero nominal associations after adjustment for age, sex, and stage.\n\nWe therefore analyzed Horvath clock CpGs as a coordinated methylation system. PCA-derived tumor methylation programs captured 34.9%-50.8% of clock-CpG variance across cancers, and this structure persisted after adjustment for tumor purity, proliferative history, and global methylation instability. This indicates that tumor-associated clock-CpG variation is not random methylation disorder, but is organized along major axes of covariation. In fully adjusted Cox models, tumor methylation programs produced 15 nominal survival associations, four of which remained significant after FDR correction. Survival-associated programs were linked to transcriptional pathway activity, including UPR, EMT, IFN-{gamma} response, and stemness, in directions consistent with their survival effects. These programs also persisted after controlling for tumor-normal differentially methylated regions, indicating that they were not explained by average cancer-associated methylation shifts. External validation in GSE72308 showed that two of three TCGA-nominated BRCA survival associations reproduced in the same protective direction.\n\nThe dominance of tumor methylation programs over scalar clock summaries shows that the cancer-relevant signal in epigenetic clock CpGs is not methylation age, but coordinated tumor-state structure. In tumors, Horvaths clock CpGs are reorganized into methylation programs that capture survival-relevant and transcriptionally linked cancer biology.","rel_num_authors":5,"rel_authors":[{"author_name":"Pranava Gande","author_inst":"UC San Diego"},{"author_name":"Alfred Kao","author_inst":"UC San Diego"},{"author_name":"Omar Mokhashi","author_inst":"UC San Diego"},{"author_name":"Wei Tse Li","author_inst":"UCSF School of Medicine"},{"author_name":"Weg Ongkeko","author_inst":"VA San Diego Healthcare System"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Epigenetic Clock CpGs form Tumor methylation Programs that Predict Survival Across Cancers","rel_doi":"10.64898\/2026.06.01.26354667","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354667","rel_abs":"Epigenetic clocks have been widely evaluated as cancer biomarkers, but findings have been inconsistent across tumor types and clinical endpoints. This inconsistency may reflect a fundamental misspecification: standard clock analyses treat clock CpGs as scalar aging readouts, assuming that tumors shift along the same methylation-aging axis as normal tissue. We tested this assumption across nine TCGA (The Cancer Genome Atlas) cancer types using Horvath clock CpGs. Tumors did not show a consistent mean shift in Horvath age acceleration relative to normal tissue. Instead, they showed an order-of-magnitude increase in age-acceleration variance. Scalar clock summaries also failed as survival biomarkers, producing zero nominal associations after adjustment for age, sex, and stage.\n\nWe therefore analyzed Horvath clock CpGs as a coordinated methylation system. PCA-derived tumor methylation programs captured 34.9%-50.8% of clock-CpG variance across cancers, and this structure persisted after adjustment for tumor purity, proliferative history, and global methylation instability. This indicates that tumor-associated clock-CpG variation is not random methylation disorder, but is organized along major axes of covariation. In fully adjusted Cox models, tumor methylation programs produced 15 nominal survival associations, four of which remained significant after FDR correction. Survival-associated programs were linked to transcriptional pathway activity, including UPR, EMT, IFN-{gamma} response, and stemness, in directions consistent with their survival effects. These programs also persisted after controlling for tumor-normal differentially methylated regions, indicating that they were not explained by average cancer-associated methylation shifts. External validation in GSE72308 showed that two of three TCGA-nominated BRCA survival associations reproduced in the same protective direction.\n\nThe dominance of tumor methylation programs over scalar clock summaries shows that the cancer-relevant signal in epigenetic clock CpGs is not methylation age, but coordinated tumor-state structure. In tumors, Horvaths clock CpGs are reorganized into methylation programs that capture survival-relevant and transcriptionally linked cancer biology.","rel_num_authors":5,"rel_authors":[{"author_name":"Pranava Gande","author_inst":"UC San Diego"},{"author_name":"Alfred Kao","author_inst":"UC San Diego"},{"author_name":"Omar Mokhashi","author_inst":"UC San Diego"},{"author_name":"Wei Tse Li","author_inst":"UCSF School of Medicine"},{"author_name":"Weg Ongkeko","author_inst":"VA San Diego Healthcare System"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Longitudinal Receptive-Expressive Language Profiles in Young Autistic Children","rel_doi":"10.64898\/2026.06.02.26354680","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354680","rel_abs":"Background & AimsLanguage development in autism is heterogeneous and strongly predicts later functioning. The balance between receptive and expressive abilities and their developmental trajectories, however, remains poorly understood. While some autistic children exhibit a relative expressive advantage (ExpAdv), others show receptive advantage (RecAdv) or a balanced profile. Prior studies report inconsistent findings and are often limited by cross-sectional designs and small samples. The present study aimed to (1) describe longitudinal trajectories of receptive and expressive language in autistic and typically developing (TD) children; (2) classify children into ExpAdv, Balanced, and RecAdv profiles across early childhood; and (3) examine the stability and transitions of these profiles over time, including associated clinical features.\n\nMethodsWe analyzed 1,174 longitudinal time points from 318 autistic children and 294 time points from 108 TD children (1.2-5.8 years) from the Geneva Autism Cohort. Receptive and expressive language were assessed with the Mullen Scales of Early Learning. Receptive-expressive balance was quantified as the ratio of receptive to expressive age equivalent scores, classifying children into ExpAdv, Balanced, and RecAdv profiles using adapted cut-offs. Mixed-effects models examined developmental trajectories, and Sankey diagrams visualized profile transitions. Autism features and adaptive behavior were compared across profiles.\n\nResultsAutistic children displayed lower expressive and receptive language than TD peers, with receptive abilities exceeding expressive skills in both groups. Overall, 30-35% of autistic children were classified as ExpAdv at 18-36 months, declining to [~]12% by 48-54 months, while Balanced and RecAdv profiles became more prevalent with age. ExpAdv was associated with slower verbal and non-verbal developmental gains. Stability was highest for Balanced and RecAdv profiles (50-60%), whereas ExpAdv often transitioned to Balanced. Autistic children with stable ExpAdv profiles were more often female, less likely to receive early intervention, and showed weaker adaptive communication.\n\nConclusionsReceptive-expressive language profiles in autistic children are dynamic. ExpAdv profile is more frequent in younger autistic children, less stable, and linked to slower verbal and non-verbal development and higher autism severity.\n\nImplicationsExpAdv may represent an early marker of autism associated with slower expressive and receptive language growth. Longitudinal monitoring of receptive and expressive skills is essential, as transitions toward Balanced or RecAdv profiles are associated with improved developmental outcomes. Early intervention before age three may facilitate transitions toward Balanced or RecAdv profiles, supporting more favorable language development and long-term outcomes.","rel_num_authors":5,"rel_authors":[{"author_name":"Kenza Latreche","author_inst":"University of Geneva"},{"author_name":"Michel Godel","author_inst":"University of Geneva"},{"author_name":"Fiona Journal","author_inst":"University of Geneva"},{"author_name":"Nada Kojovic","author_inst":"University of Geneva"},{"author_name":"Marie Schaer","author_inst":"University of Geneva"}],"rel_date":"2026-06-03","rel_site":"medrxiv"},{"rel_title":"Multi-pathogen serosurveillance reveals correlated routine vaccination performance, waning tetanus immunity, and diphtheria boosting among children in Zambia","rel_doi":"10.64898\/2026.06.01.26354612","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354612","rel_abs":"BackgroundVaccination coverage estimates and case-based surveillance have limitations in evaluating immunization programs. Serosurveillance offers a complementary approach by directly measuring population immunity. We assessed whether serologic analyses across multiple antigens (i.e., measles, diphtheria, tetanus) could provide additional insights into vaccination program performance.\n\nMethodsWe conducted a matched case-control study among children aged 2- to 10-years-old (n=1286) in Zambia using specimens from the 2016 ZAMPHIA survey. Using previously generated data on measles serostatus, measles seronegative children (i.e., \"cases\") were matched to measles seropositive children (i.e., \"controls\") on sex, age, HIV infection status, and province. Samples were tested for tetanus and diphtheria antitoxin IgG antibodies using commercial enzyme immunoassays. We estimated the odds of tetanus and diphtheria seropositivity by measles serostatus using conditional logistic regression and examined age-specific antibody dynamics.\n\nResultsMeasles seronegative children had 1.7-fold increased odds (95% credible interval [CrI]: 1.3-2.1) of being tetanus seronegative compared to measles seropositive children. Diphtheria serostatus had no significant association with measles serostatus (odds ratio: 1.3; 95% CrI: 0.9-1.7). Tetanus seroprevalence declined monotonically with age. However, diphtheria seroprevalence initially declined through 5 years of age, then increased again beginning at 6 years of age despite the lack of vaccine booster doses given after the primary series in infancy, potentially from asymptomatic or subclinical infections.\n\nConclusionsSerologic analyses revealed measles serostatus was positively associated with tetanus serostatus (where seropositivity arises only via vaccination and not infection), suggesting children who are measles seronegative are more likely to have missed DTP vaccination. We additionally found that measles serostatus was not associated with diphtheria serostatus, suggesting that antibody responses to diphtheria continue to boost beyond infancy when DTP vaccination is given. Our findings support consideration of DTP booster doses in Zambia to address waning tetanus immunity and further investigation of potential diphtheria carriage and transmission.","rel_num_authors":14,"rel_authors":[{"author_name":"Alyssa N Sbarra","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Simon Mutembo","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Andrea  C N Carcelen","author_inst":"Johns Hopkins University International Vaccine Access Center"},{"author_name":"Christine Prosperi","author_inst":"Johns Hopkins University International Vaccine Access Center"},{"author_name":"William  J. Moss","author_inst":"Johns Hopkins University International Vaccine Access Center"},{"author_name":"Shaun A Truelove","author_inst":"Johns Hopksin Bloomberg School of Public Health"},{"author_name":"Amy K Winter","author_inst":"University of Georgia"},{"author_name":"Innocent C Bwalya","author_inst":"National Health Research and Training Institute"},{"author_name":"Evans Betha","author_inst":"National Health Research and Training Institute"},{"author_name":"Lombe Kampamba","author_inst":"National Health Research and Training Institute"},{"author_name":"Elizabeth Kabeta","author_inst":"National Health Research and Training Institute"},{"author_name":"Gershom Chongwe","author_inst":"National Health Research and Training Institute"},{"author_name":"Amy Wesolowski","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Saki Takahashi","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Baseline Gut Microbiome-Metabolome Signatures Are Associated with Drinking Severity and Reduction Following Dutasteride Treatment in Alcohol Use Disorder","rel_doi":"10.64898\/2026.05.26.26354041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354041","rel_abs":"The gut microbiome has been implicated in alcohol use disorder (AUD), but its relationship to drinking intensity and treatment response remains poorly understood. We conducted a longitudinal multi-omics analysis of stool samples collected at baseline and endpoint (after 12 weeks) from 122 participants enrolled in a double-blind, placebo-controlled trial of dutasteride for AUD. Gut microbiome composition was characterized using 16S rRNA gene sequencing, and fecal metabolites were measured by LC-MS-based metabolomics. At baseline, drinking intensity was associated with increasingly lower microbial richness. Genera in the class Clostridia emerged as key microbial hubs associated with drinking intensity in an age- and sex-dependent manner. Drinking intensity promoted co-enrichment of [Ruminococcus] gnavus group and [Clostridium] inocuum group with amino acid catabolites, as well as the co-depletion of diverse Clostridia taxa and lipid metabolites. Dutasteride treatment and drinking reduction had minimal impact on gut microbiome composition. Random forest models integrating baseline clinical, microbiome, and metabolome data improved the classification of clinically meaningful drinking reduction compared to models using clinical data alone. These findings show that a coupled baseline gut microbiome-metabolome signature is associated with drinking intensity and future treatment response in AUD, highlighting the potential for multi-omics integration to inform precision treatment approaches.","rel_num_authors":10,"rel_authors":[{"author_name":"Liv R. Dedon","author_inst":"Department of Medicine, UConn School of Medicine"},{"author_name":"Darren J. Lee","author_inst":"Department of Medicine, UConn School of Medicine"},{"author_name":"Qingqi Lin","author_inst":"Department of Computer Science and Engineering, University of Connecticut"},{"author_name":"Hanshu Yuan","author_inst":"Department of Medicine, UConn School of Medicine"},{"author_name":"Jinhua Chi","author_inst":"Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University"},{"author_name":"Lingjun Li","author_inst":"Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University"},{"author_name":"Haiwei Gu","author_inst":"Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University"},{"author_name":"Howard Tennen","author_inst":"Department of Public Health Sciences, UConn School of Medicine"},{"author_name":"Jonathan M. Covault","author_inst":"Department of Psychiatry, UConn School of Medicine"},{"author_name":"Yanjiao Zhou","author_inst":"Department of Medicine, UConn School of Medicine"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"One size fits all: A systematic review of the sample types used for the diagnostics of respiratory viruses in children","rel_doi":"10.64898\/2026.06.02.26354258","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354258","rel_abs":"Nasopharyngeal (NP) swabs remain the dominant gold standard for respiratory infection diagnostics. While there has been increased use of alternative sample types since the COVID-19 pandemic, guidance on their use for detecting respiratory viruses is not yet definitive, especially for children. In this systematic review and meta-analysis, we aimed to compare the diagnostic accuracy and tolerability of multiple respiratory specimen types for detecting respiratory viruses in pediatric populations.\n\nSearches were conducted on July 17, 2025 in MEDLINE, Embase, Web of Science, and Scopus, with screening and data extraction performed in Covidence. English-language primary research articles published since 2000 comparing respiratory virus detection rates in children, using nucleic acid amplification tests between paired respiratory specimens, were included. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies criteria. We calculated pooled sensitivities and specificities of index specimens: nasopharyngeal aspirates (NPA), mid-turbinate swabs (MT), anterior nasal swabs (ANS), oropharyngeal swabs (OP), and bronchoalveolar lavage fluid (BAL), as compared to the reference, NP swabs, using random-effects modeling, firstly without discrimination by virus. Index specimens were then grouped by sample collection site as nasal, oral, and lower respiratory tract (LRT) specimens for virus-specific analyses. Overall performance and statistical validity were evaluated by hierarchical summary receiver operating characteristic (HSROC) analysis. Data regarding sampling tolerability was also assessed.\n\nWe screened 2,448 studies and identified 36 publications (total N participants = 10,687) that reported diagnostic test accuracy using paired index-reference data in children. Of these, 18 (total N participants = 4,310) used NP specimens as the reference and were included in the diagnostic test accuracy analysis. Virus-agnostic pooled sensitivity estimates indicated that MT (0.92%) performed most similarly to NP, though sensitivities of ANS (0.79%) and OP (0.70%) were also moderately high for detection of any respiratory virus. BAL sensitivity was the lowest (0.37%). All sample types demonstrated high specificity (0.98%-0.99%). Group estimates and HSROC statistics found that nasal specimens, when grouped, had the highest sensitivity and accuracy for all examined viruses, including for influenza (92%) and RSV (90%). By comparison, oral and LRT specimens performed less well, with more variability, though both showed moderately high sensitivities for RSV (78%, 76%, respectively) and influenza (82%, 80%, respectively), and LRT samples showed high sensitivity for HMPV (82%). Analysis of sample tolerability found that NP swabs consistently ranked as the least comfortable and least preferred, while nasal swabs and saliva both performed well. Datasets for LRT and oral specimens were sparser than for nasal, and this contributed to greater variability, underscoring the need for further diagnostic accuracy studies on alternatives to NP sampling.\n\nThese data support the viability of nasal and oral alternatives to NP swabs and affirm their application in pediatric care, particularly in outpatient settings. Such alternatives could greatly improve sampling tolerability and increase global access, including in resource-limited settings, to accurate diagnostic methods for respiratory infections.","rel_num_authors":9,"rel_authors":[{"author_name":"Orchid M Allicock","author_inst":"Yale School of Medicine"},{"author_name":"Arushi Dogra","author_inst":"Yale School of Medicine"},{"author_name":"Jacqueline H Cho","author_inst":"Yale School of Medicine"},{"author_name":"Keyner Rojas","author_inst":"Yale School of Medicine"},{"author_name":"Hannah O Hasson","author_inst":"Ben-Gurion University of the Negev"},{"author_name":"Britney Omene","author_inst":"Yale School of Medicine"},{"author_name":"Melissa C Funaro","author_inst":"Harvey Cushing\/John Hay Whitney Medical Library, Yale University"},{"author_name":"Claire S Laxton","author_inst":"Yale School of Medicine"},{"author_name":"Inci S Yildirim","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"A Three-Item Functional Screen for Multimodal Prognostic Triage in Mild Cognitive Impairment: Benchmarking Against Entorhinal Tau PET and Plasma p-tau217","rel_doi":"10.64898\/2026.06.01.26354584","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354584","rel_abs":"ImportanceBroadening access to biomarker-informed risk stratification in mild cognitive impairment (MCI) has become even more critical to early assessment in Alzheimer disease given recent developments in regulatory approvals of disease-modifying therapies and advancements of blood-based biomarkers. This requires accessible approaches that can be deployed at scale to better differentiate the disease biology from the clinical progression risk prediction. While entorhinal tau positron emission tomography (PET) can refine near-term prognostic assessment, the cost and logistic burden of imaging limit broad clinical use.\n\nObjectiveEvaluate whether a brief informant-reported screen derived from the Functional Activities Questionnaire (FAQ) could better stratify scalable biologically anchored prognostic information for 3-year progression from MCI to Alzheimer disease dementia. The primary study was designed around FAQ-derived screens performance relative to entorhinal tau PET standardized uptake value ratio (SUVR), plasma phosphorylated tau 217 (p-tau217) and Mini-Mental State Examination (MMSE) score. Secondary analyses evaluated the stable FAQ-derived screen selected for clinical risk separation, tau and amyloid PET biological context, additional plasma biomarkers, resource-use scenarios and sensitivity analyses around subgroups, calibration, decision-curve, survival, timing, early-progressor exclusions and endpoint-ascertainment IPW.\n\nDesign, Setting, and ParticipantsThis retrospective secondary progression risk prediction study analyzed 350 Alzheimers Disease Neuroimaging Initiative (ADNI) participants with a baseline clinical diagnosis of MCI at the tau PET anchor visit. All studies were conducted in cohorts with 3-year progression status known. The first primary benchmarking included 157 participants (including 32 progressors) for FAQ with entorhinal tau PET SUVR comparisons and 153 participants (including 31 progressors) for FAQ, entorhinal tau PET SUVR and MMSE comparisons. The second primary benchmarking was derived from a smaller UPENN plasma p-tau217 subset of 66 participants (including 13 progressors).\n\nExposuresThe FAQ-derived candidate screens were evaluated by leakage-controlled repeated nested cross-validation. The stable 3-item FAQ-derived screen selected was defined as any informant-reported difficulty in at least one of the three activities comprising finances\/checkbook, shopping and games\/hobbies (\"Locked FAQ Trio\"). The Locked FAQ Trio was compared against both biological and cognitive comparators: entorhinal tau PET SUVR, plasma p-tau217 and MMSE score. Amyloid PET status and Centiloid burden as well as plasma biomarkers paired per same-file plasma such as A{beta}42\/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and a directionally adjusted 4- marker plasma composite were used for biology or exploratory context and not for defining the clinical endpoint.\n\nMain Outcomes and MeasuresThe primary binary endpoint was progression from baseline MCI at the tau PET anchor visit to Alzheimer disease dementia within 3 years. Model performance used the cross-validated area under the receiver operating characteristic curve (AUC), the difference in AUC ({Delta}AUC) was bootstrap 95% confidence intervals (CI) at the participant level with P values adjusted using the Benjamini-Hochberg (BH) procedure. Other measures included Brier scores, calibration summaries, survival discrimination and operating characteristics such as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and screen-positivity prevalence, while decision-curve analyses and resource-use scenarios remained exploratory.\n\nResultsA leakage-controlled nested cross-validation selection repeatedly identified a 3-item screen defined as any difficulty in at least one of the three following activities comprising finances\/checkbook, shopping and games\/hobbies (Locked FAQ Trio). In an independent 3-year progression benchmark analysis of base-covariate models, the Locked FAQ Trio showed higher numerical, directional but not statistically significant, discrimination than entorhinal tau PET among 157 participants including 32 progressors (AUC, 0.787 vs 0.780; {Delta}AUC, +0.007; 95% CI, -0.099 to 0.113; BH-adjusted P = 0.926) and was statistically significantly higher than MMSE score (AUC, 0.796 vs 0.637; {Delta}AUC, +0.159; 95% CI, 0.045 to 0.276; BH-adjusted P = 0.029). The Locked FAQ Trio was positive in 37.6% of participants and captured 27 of 32 progressors, showing sensitivity of 84.4%, specificity of 74.4%, PPV of 45.8%, and NPV of 94.9%. Progression within 3 years occurred in 45.8% of screen-positive participants versus 5.1% of screen-negative participants and the corresponding adjusted hazard ratio over full follow-up was 7.46. The screen was also associated with higher entorhinal tau burden and remained consistent across survival, timing-sensitive, amyloid and missingness analyses. A different 3-item FAQ-derived companion screen (\"Companion FAQ Trio\") was evaluated for sensitivity, it was defined as any impairment in at least one of the three activities comprising forms\/papers, shopping and remembering appointments\/medications\/holidays. The Companion FAQ Trio was positive in 54.1% participants and captured 96.9% of progressors, with 36.5% of screen-positive progressing to dementia versus 1.4% of screen-negative.\n\nIn a second primary benchmark analysis of a smaller matched plasma subset of 66 participants including 13 progressors, plasma p-tau217 showed the highest discrimination (AUC, 0.890) across all single predictors in a base-covariates model, compared with the Locked FAQ Trio (AUC, 0.749) and entorhinal tau PET SUVR (AUC, 0.798). A stratification study of the Locked FAQ Trio combined with p-tau217 showed separation of observed risk, differentiating lower and higher risk of progression per strata. Notably, none (0 of 31) of the participants in the lower risk cohort progressed and 64.3% (9 of 14) of participants in the higher risk cohort progressed. Nevertheless, 37.5% (3 of 8) of participants in the Locked FAQ Trio-negative\/p-tau 217-high cohort progressed. This emphasizes that patients should not be excluded from further biomarker testing when clinical concern remains.\n\nConclusionA brief 3-item stable FAQ-derived screen was identified as a compelling front-end additional layer to prognostic triage in MCI patients. This Locked FAQ Trio screen demonstrated a higher numerical discrimination than entorhinal tau PET SUVR in 3-year base-covariates prediction risk models. Plasma p-tau217 remained the strongest scalable predictor of progression to dementia in a smaller plasma subset. These findings reinforce that adding a brief functional screen to the staged prognosis assessment triage pathway can help prioritize and contextualize biomarker escalation, offering a scalable, deployable, and low burden solution to expand screening to a broader patient population.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSCan a low-burden brief informant-reported functional questionnaire support staged prognostic triage, before biomarker escalation, for near-term progression risk from mild cognitive impairment to Alzheimer disease dementia?\n\nFindingsIn this progression risk prediction study of 350 individuals with mild cognitive impairment, a 3-item Functional Activities Questionnaire (FAQ) was identified as a stable early signal for progression risk using a leakage-controlled repeated nested cross-validation. The screen was defined as any impairment in at least one of the three activities comprising finances\/checkbook, shopping and games\/hobbies (\"Locked FAQ Trio\"). In an independent prognosis prediction study, the Locked FAQ Trio was numerically, but not statistically significantly, higher than entorhinal tau positron emission tomography (PET) standardized uptake value ratio (SUVR) and statistically significantly higher than Mini-Mental State Examination (MMSE) score. In a smaller plasma subset of 66 participants, plasma phosphorylated tau 217 (p-tau217) showed the highest discrimination and the Locked FAQ Trio combined with p-tau217 differentiated lower and higher risk of progression.\n\nMeaningAn informant-reported brief 3-item functional questionnaire can help to inform and prioritize biomarker testing. A selected Locked FAQ Trio showed a higher numerical discrimination than specialized entorhinal tau PET biomarker and contextualized plasma p-tau217 biomarker. The suggested staged framework starts with Locked FAQ Trio screen triage, then plasma p-tau217 refinement before selective confirmation disease pathology with cerebrospinal fluid biomarkers or amyloid PET and\/or tau PET for staging or prognostic prediction.","rel_num_authors":2,"rel_authors":[{"author_name":"Juliette Lafille","author_inst":"No Patient Left Behind Inc"},{"author_name":"Frank Provenzano","author_inst":"Columbia University"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Quantifying donor-recipient mismatches using recipient-derived sources of donor DNA","rel_doi":"10.64898\/2026.06.01.26354606","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354606","rel_abs":"Non-HLA donor-recipient (D-R) genetic mismatches contribute to kidney allograft injury and long-term graft loss, but their clinical use is limited by the unavailability of donor DNA after transplantation. We tested whether non-invasively obtained, recipient-derived samples could be used to infer donor genotype and D-R mismatches. Genomic DNA (g-DNA) of 11 unselected kidney transplant recipients and donors underwent whole-exome sequencing (100x). Additional customized probes were added for intronic coverage (300x) of 55 targeted non-HLA genes of reported clinical relevance. Variants identified from sequencing results were compared with plasma cell-free DNA (cfDNA), urine cell-pellet DNA (U-DNA) obtained from the same recipients. Genome-wide-, exonic-, or non-synonymous exonic- mismatches in transmembrane or secreted proteins, and mismatches within target genes were benchmarked using donor g-DNA to generate mismatch scores for each D-R pair. Within each of these genomic scales of mismatch, U-DNA identified D-R mismatches significantly better than the corresponding cfDNA (P<0.001 for each comparison). U-DNA also identified gene-level mismatches in the LIMS1 gene, and correctly inferred established donor-origin risk alleles, including SHROOM3 and APOL1. Our findings demonstrate proof-of-concept that U-DNA in tandem with recipient genome, can non-invasively infer relevant non-HLA loci\/mismatches circumventing the need for the donors genomic DNA.","rel_num_authors":17,"rel_authors":[{"author_name":"Nallakkandi Rajeevan","author_inst":"Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Gabriel Caldato Barsotti","author_inst":"Yale University School of Medicine"},{"author_name":"Ashwani Kumar","author_inst":"Yale School of Medicine"},{"author_name":"Zeguo Sun","author_inst":"Yale School of Medicine"},{"author_name":"Anand Reghuvaran","author_inst":"Yale School of Medicine"},{"author_name":"Irina Tikhonova","author_inst":"Yale School of Medicine"},{"author_name":"E M Tanvir","author_inst":"Yale School of Medicine"},{"author_name":"Niketa Sareen","author_inst":"Yale School of Medicine"},{"author_name":"Ashley Swan","author_inst":"Yale School of Medicine"},{"author_name":"Richard Formica","author_inst":"Yale School of Medicine"},{"author_name":"Caleigh Mandel-Brehm","author_inst":"Yale School of Medicine"},{"author_name":"Arundati Rao","author_inst":"Yale School of Medicine"},{"author_name":"Whitney Besse","author_inst":"Yale School of Medicine"},{"author_name":"Maureen Miller","author_inst":"Yale School of Medicine"},{"author_name":"Laurine Bow","author_inst":"Yale School of Medicine"},{"author_name":"Bony De Kumar","author_inst":"Versiti Blood Research institute"},{"author_name":"Madhav C Menon","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"A Pilot Study of the EMPOWER Music-based Intervention to Reduce Pulmonary Air Trapping in COPD","rel_doi":"10.64898\/2026.05.26.26350616","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26350616","rel_abs":"RationaleAir trapping in functional areas of the lung is common in chronic obstructive pulmonary disease (COPD). We developed a novel music-based intervention, Engagement of Music for Pulmonary Obstruction With Expiratory Restoration (EMPOWER) aimed at reducing air trapping and functional small airways disease (fSAD) in patients with COPD.\n\nObjectivesWe conducted a pilot study to assess if air trapping and fSAD in COPD patients are reduced by our targeted EMPOWER music-based singing intervention.\n\nMethodsParticipants completed four weeks of singing and vocalizing with a board-certified music therapist. Pre- and post-intervention assessments of standard pulmonary function tests (PFTs), and quantitative computed tomography (qCT) lung imaging documented changes in air trapping. Pre- and post-intervention change in psychological and patient-reported outcomes of hope, emotional wellbeing, agency and COPD symptom burden were also obtained.\n\nMain ResultsAll five adult participants with COPD who enrolled completed the study and reported strong interest in continuing with a similar program. Additionally, we observed trends toward improvement in qCT-measured fSAD, six-minute walk distance, and patient-reported symptoms on the COPD Assessment Test.\n\nConclusionResults of this preliminary study showed improvements in both patient-reported and imaging respiratory outcomes, suggesting that targeted singing components in music-based interventions such as the EMPOWER intervention may support physiological lung function changes in COPD patients.","rel_num_authors":9,"rel_authors":[{"author_name":"Jasmine Taylor","author_inst":"The University of Kansas Medical Center"},{"author_name":"Jiwoong Choi","author_inst":"University of Kansas Health System"},{"author_name":"Asma Abdolijomoor","author_inst":"University of Kansas Health System"},{"author_name":"Melissa C. Brunkan","author_inst":"University of Oregon"},{"author_name":"Amy L. Wilson","author_inst":"University of Kansas"},{"author_name":"Mario Castro","author_inst":"University of Kansas Health System"},{"author_name":"Nancy Stewart","author_inst":"University of Kansas Health System"},{"author_name":"Deanna Hanson-Abromeit","author_inst":"University of Kansas"},{"author_name":"Rebecca J Lepping","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Climate change is already reshaping schistosomiasis transmission across Africa","rel_doi":"10.64898\/2026.06.01.26354594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354594","rel_abs":"Climate change is shifting infectious disease burdens1-6, but attributing transmission changes remains difficult where interventions and socioeconomic development interact with temperature-dependent signals7-11. Mechanistic models can isolate temperature-dependent signals from non-climatic influences5,12-16 but are often not tested against independent data. Here, we present a validation-first framework using a temperature-dependent R transmission model17 to detect and attribute temperature-mediated climate impacts on schistosomiasis transmission across Africa. First, semi-natural mesocosm experiments confirmed the models biological constraints, with high temperatures suppressing the host-parasite system above [~]33{degrees}C. Next, we established epidemiological relevance in the Lake Victoria Basin using 141,829 longitudinal infection records. Interannual temperature anomalies predicted infection risk, with anthropogenic warming accounting for 17.1% of observed infections relative to a natural-forcing-only counterfactual. Finally, across Africa, the mechanistic R predictor explained prevalence better than correlative climate metrics, even after accounting for intervention and socioeconomic covariates. Applying the validated framework to ensemble climate model simulations and a natural-forcing-only counterfactual (1984-2014) showed that anthropogenic warming increased transmission potential in cooler regions while suppressing it in hotter regions across Africa, a contrast projected to intensify under higher-emissions scenarios by mid-century. Climate impacts are not solely future threats, but present-day forces already reshaping transmission and disease burden.","rel_num_authors":12,"rel_authors":[{"author_name":"Meghan Forstchen","author_inst":"University of Notre Dame"},{"author_name":"Ibrahim Aslan","author_inst":"Stanford University"},{"author_name":"Caroline Bice","author_inst":"University of Notre Dame"},{"author_name":"Heather Buelow","author_inst":"University of Notre Dame"},{"author_name":"Andrew J. Chamberlin","author_inst":"Stanford University"},{"author_name":"Giulio A. De Leo","author_inst":"Stanford University"},{"author_name":"Kristie L. Ebi","author_inst":"University of Washington"},{"author_name":"Nicholas A. Galle","author_inst":"University of Notre Dame"},{"author_name":"Patrick Heffernan","author_inst":"University of Notre Dame"},{"author_name":"Karena H. Nguyen","author_inst":"Georgia Institute of Technology"},{"author_name":"Matthew Sisk","author_inst":"University of Notre Dame"},{"author_name":"Jason R. Rohr","author_inst":"University of Notre Dame"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Trajectories of depressive symptoms across pregnancy and the extended postpartum period and future cardiovascular health.","rel_doi":"10.64898\/2026.05.26.26353833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353833","rel_abs":"BackgroundIndividuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH.\n\nMethodsThis secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications.\n\nResultsA total of 3,934 participants (mean (M) {+\/-} standard deviation (SD) age=27.6{+\/-}5.6 years) met inclusion criteria with a mean follow-up interval of 3.2{+\/-}0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: {beta}=0.06, p<0.01; decreasing severity: {beta}=0.05, p=0.02; increasing severity: {beta}=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24).\n\nDiscussionThe longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.\n\nClinical PerspectiveWhat is New? O_LIWe examined the longitudinal relationship between differing trajectories of depressive symptoms during pregnancy and throughout the extended postpartum period and future cardiovascular health.\nC_LIO_LIWe found that individuals with stably elevated, decreasing severity and increasing severity depressive symptoms from pregnancy to 2-7 years post-delivery exhibited lower cardiovascular health 2-7 years post-delivery relative to individuals with stably low depressive symptoms.\nC_LI\n\nWhat are the Clinical Implications? O_LIThe longitudinal course depressive symptoms from pregnancy through the extended postpartum period varies across individuals, and individuals with consistently elevated, elevated with decreasing severity, and low with increasing severity symptoms exhibit poorer cardiovascular health compared to those with consistently low severity symptoms. This suggests that any elevation of depressive symptoms, regardless of whether they exceed clinical thresholds indicative of a depressive episode, may relate to cardiovascular risk.\nC_LIO_LIRoutine assessment of depressive symptoms across pregnancy and in the years following delivery may facilitate early detection of individuals who may be at risk of CVD in the future.\nC_LI","rel_num_authors":15,"rel_authors":[{"author_name":"Shannon D Donofry","author_inst":"Rand Corporation"},{"author_name":"Megan Marie McLaughlin","author_inst":"UCSF"},{"author_name":"Emily S Miller","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Neil J. Wimmer","author_inst":"Christiana Care"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Lauren H Theilen","author_inst":"University of Utah Health; Intermountain Healthcare"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Caroline E. Rouse","author_inst":"Indiana University"},{"author_name":"Jessica Page","author_inst":"Intermountain Health"},{"author_name":"Kelly Zafman","author_inst":"Penn Medicine"},{"author_name":"Alexandra Berra","author_inst":"MetroHealth Medical Center Department of Obstetrics and Gynecology"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Trajectories of depressive symptoms across pregnancy and the extended postpartum period and future cardiovascular health.","rel_doi":"10.64898\/2026.05.26.26353833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353833","rel_abs":"BackgroundIndividuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH.\n\nMethodsThis secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications.\n\nResultsA total of 3,934 participants (mean (M) {+\/-} standard deviation (SD) age=27.6{+\/-}5.6 years) met inclusion criteria with a mean follow-up interval of 3.2{+\/-}0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: {beta}=0.06, p<0.01; decreasing severity: {beta}=0.05, p=0.02; increasing severity: {beta}=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24).\n\nDiscussionThe longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.\n\nClinical PerspectiveWhat is New? O_LIWe examined the longitudinal relationship between differing trajectories of depressive symptoms during pregnancy and throughout the extended postpartum period and future cardiovascular health.\nC_LIO_LIWe found that individuals with stably elevated, decreasing severity and increasing severity depressive symptoms from pregnancy to 2-7 years post-delivery exhibited lower cardiovascular health 2-7 years post-delivery relative to individuals with stably low depressive symptoms.\nC_LI\n\nWhat are the Clinical Implications? O_LIThe longitudinal course depressive symptoms from pregnancy through the extended postpartum period varies across individuals, and individuals with consistently elevated, elevated with decreasing severity, and low with increasing severity symptoms exhibit poorer cardiovascular health compared to those with consistently low severity symptoms. This suggests that any elevation of depressive symptoms, regardless of whether they exceed clinical thresholds indicative of a depressive episode, may relate to cardiovascular risk.\nC_LIO_LIRoutine assessment of depressive symptoms across pregnancy and in the years following delivery may facilitate early detection of individuals who may be at risk of CVD in the future.\nC_LI","rel_num_authors":15,"rel_authors":[{"author_name":"Shannon D Donofry","author_inst":"Rand Corporation"},{"author_name":"Megan Marie McLaughlin","author_inst":"UCSF"},{"author_name":"Emily S Miller","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Neil J. Wimmer","author_inst":"Christiana Care"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Lauren H Theilen","author_inst":"University of Utah Health; Intermountain Healthcare"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Caroline E. Rouse","author_inst":"Indiana University"},{"author_name":"Jessica Page","author_inst":"Intermountain Health"},{"author_name":"Kelly Zafman","author_inst":"Penn Medicine"},{"author_name":"Alexandra Berra","author_inst":"MetroHealth Medical Center Department of Obstetrics and Gynecology"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"Trajectories of depressive symptoms across pregnancy and the extended postpartum period and future cardiovascular health.","rel_doi":"10.64898\/2026.05.26.26353833","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353833","rel_abs":"BackgroundIndividuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH.\n\nMethodsThis secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications.\n\nResultsA total of 3,934 participants (mean (M) {+\/-} standard deviation (SD) age=27.6{+\/-}5.6 years) met inclusion criteria with a mean follow-up interval of 3.2{+\/-}0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: {beta}=0.06, p<0.01; decreasing severity: {beta}=0.05, p=0.02; increasing severity: {beta}=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24).\n\nDiscussionThe longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.\n\nClinical PerspectiveWhat is New? O_LIWe examined the longitudinal relationship between differing trajectories of depressive symptoms during pregnancy and throughout the extended postpartum period and future cardiovascular health.\nC_LIO_LIWe found that individuals with stably elevated, decreasing severity and increasing severity depressive symptoms from pregnancy to 2-7 years post-delivery exhibited lower cardiovascular health 2-7 years post-delivery relative to individuals with stably low depressive symptoms.\nC_LI\n\nWhat are the Clinical Implications? O_LIThe longitudinal course depressive symptoms from pregnancy through the extended postpartum period varies across individuals, and individuals with consistently elevated, elevated with decreasing severity, and low with increasing severity symptoms exhibit poorer cardiovascular health compared to those with consistently low severity symptoms. This suggests that any elevation of depressive symptoms, regardless of whether they exceed clinical thresholds indicative of a depressive episode, may relate to cardiovascular risk.\nC_LIO_LIRoutine assessment of depressive symptoms across pregnancy and in the years following delivery may facilitate early detection of individuals who may be at risk of CVD in the future.\nC_LI","rel_num_authors":15,"rel_authors":[{"author_name":"Shannon D Donofry","author_inst":"Rand Corporation"},{"author_name":"Megan Marie McLaughlin","author_inst":"UCSF"},{"author_name":"Emily S Miller","author_inst":"Brown University Warren Alpert Medical School"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Neil J. Wimmer","author_inst":"Christiana Care"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Lauren H Theilen","author_inst":"University of Utah Health; Intermountain Healthcare"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Caroline E. Rouse","author_inst":"Indiana University"},{"author_name":"Jessica Page","author_inst":"Intermountain Health"},{"author_name":"Kelly Zafman","author_inst":"Penn Medicine"},{"author_name":"Alexandra Berra","author_inst":"MetroHealth Medical Center Department of Obstetrics and Gynecology"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-02","rel_site":"medrxiv"},{"rel_title":"High prevalence of soil-transmitted helminth co-infections in persons with tuberculosis in South India","rel_doi":"10.64898\/2026.05.26.26353735","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353735","rel_abs":"Soil-transmitted helminths (STH) are a plausible but under-characterized comorbidity in tuberculosis. In this prospective South Indian cohort, multiplex stool PCR detected STH in 43% of 137 adults with pulmonary tuberculosis and 34% of 230 household contacts. Food insecurity independently predicted co-infection. Current adult deworming gaps warrant evaluation.","rel_num_authors":23,"rel_authors":[{"author_name":"Prakash Babu Narasimhan","author_inst":"Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Komal Jain","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Nonika Rajkumari","author_inst":"Department of Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Madolyn Rose Dauphinais","author_inst":"University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"},{"author_name":"Jasemina R Priyanga","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Sana Shaikh","author_inst":"Section of Infectious Diseases, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA"},{"author_name":"Jainish Uresh Patel","author_inst":"Section of Infectious Diseases, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA"},{"author_name":"Senbagavalli Prakash Babu","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Chelsie Cintron","author_inst":"Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, USA"},{"author_name":"Meagan Karoly","author_inst":"Department of Medicine, Section of Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA"},{"author_name":"Madeline Elizabeth Carwile","author_inst":"Department of Medicine, Section of Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA"},{"author_name":"Anne Fan Liu","author_inst":"Department of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA"},{"author_name":"Kimberly Maloomian","author_inst":"HMX, Harvard Medical School, Boston, Massachusetts, USA"},{"author_name":"Lindsey M Locks","author_inst":"Department of Health Sciences, Boston University College of Health and Rehabilitation Sciences: Sargent College, Boston, Massachusetts, USA"},{"author_name":"Saurabh Mehta","author_inst":"Cornell Joan Klein Jacobs Center for Precision Nutrition and Health, Cornell University, Ithaca, New York, USA"},{"author_name":"Sonali Sarkar","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Urvashi B Singh","author_inst":"Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India"},{"author_name":"Jerrold J Ellner","author_inst":"Center for Emerging Pathogens, Department of Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA"},{"author_name":"Padmini Salgame","author_inst":"Center for Emerging Pathogens, Department of Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA"},{"author_name":"Scott Kirkland Heysell","author_inst":"Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA"},{"author_name":"Natasha S Hochberg","author_inst":"5)\tSection of Infectious Diseases, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA"},{"author_name":"Subitha Lakshminarayanan","author_inst":"Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Pranay Sinha","author_inst":"Boston Medical Center"}],"rel_date":"2026-06-02","rel_site":"medrxiv"}]}