{"gname":"Brown University","grp_id":"9","rels":[{"rel_title":"Fine-Tuned Large Language Models for Detecting Social Isolation from Unstructured Clinical Notes","rel_doi":"10.64898\/2026.07.05.26357334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357334","rel_abs":"Objectives: This study aimed to leverage FLAN-T5-Large, BERT, RoBERTa, and Gemma-2-2B, with fine-tuning, to identify instances of social isolation and social support within unstructured clinical notes. Materials and Methods: Annotated clinical note spans containing social context cues were used to fine-tune each model. Performance was evaluated using Accuracy, Precision, Recall, and Macro-F1 score. A structured prompt was used to instruct the model to perform classification task and mitigate overgeneralization. Performance comparisons across the models assessed sensitivity, robustness, and false positive reduction. Results: FLAN-T5-Large achieved highest performance, with Macro-F1 of 0.92{+\/-}0.04, demonstrating balanced results across classes: social isolation (F1 = 0.91{+\/-}0.03), no social isolation (F1 = 0.94{+\/-}0.05), and social support (F1 = 0.90{+\/-}0.04). Gemma-2-2B produced comparable results, with Macro-F1 score of 0.89{+\/-}0.10. BERT and RoBERTa achieved lower Macro-F1 scores of 0.77{+\/-}0.17 and 0.80{+\/-}0.21 respectively, with variability across categories. Discussion: A major contribution of this work is precise identification of multiple concepts related to social connectedness. By integrating annotated examples of both true and false positives, including negations and contextually ambiguous terms, the model better distinguished relevant social context cues from noise. Training on both social isolation and support provided a dual framework for comparative analyses and patient stratification. Conclusion: Transformer-based NLP models, particularly FLAN-T5-Large, demonstrated potential for identifying social isolation and social support in clinical text. These findings support the use of generative AI techniques to enhance detection of social isolation from EHRs, advancing context-aware healthcare analytics.","rel_num_authors":7,"rel_authors":[{"author_name":"Lokesh K Chinthala","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Cindy Lemon","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Arash Shaban-Nejad","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Gregory Farage","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Robert L Davis","author_inst":"The University of Tennessee Health Science Center"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Charisse Madlock-Brown","author_inst":"University of Iowa"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Fine-Tuned Large Language Models for Detecting Social Isolation from Unstructured Clinical Notes","rel_doi":"10.64898\/2026.07.05.26357334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357334","rel_abs":"Objectives: This study aimed to leverage FLAN-T5-Large, BERT, RoBERTa, and Gemma-2-2B, with fine-tuning, to identify instances of social isolation and social support within unstructured clinical notes. Materials and Methods: Annotated clinical note spans containing social context cues were used to fine-tune each model. Performance was evaluated using Accuracy, Precision, Recall, and Macro-F1 score. A structured prompt was used to instruct the model to perform classification task and mitigate overgeneralization. Performance comparisons across the models assessed sensitivity, robustness, and false positive reduction. Results: FLAN-T5-Large achieved highest performance, with Macro-F1 of 0.92{+\/-}0.04, demonstrating balanced results across classes: social isolation (F1 = 0.91{+\/-}0.03), no social isolation (F1 = 0.94{+\/-}0.05), and social support (F1 = 0.90{+\/-}0.04). Gemma-2-2B produced comparable results, with Macro-F1 score of 0.89{+\/-}0.10. BERT and RoBERTa achieved lower Macro-F1 scores of 0.77{+\/-}0.17 and 0.80{+\/-}0.21 respectively, with variability across categories. Discussion: A major contribution of this work is precise identification of multiple concepts related to social connectedness. By integrating annotated examples of both true and false positives, including negations and contextually ambiguous terms, the model better distinguished relevant social context cues from noise. Training on both social isolation and support provided a dual framework for comparative analyses and patient stratification. Conclusion: Transformer-based NLP models, particularly FLAN-T5-Large, demonstrated potential for identifying social isolation and social support in clinical text. These findings support the use of generative AI techniques to enhance detection of social isolation from EHRs, advancing context-aware healthcare analytics.","rel_num_authors":7,"rel_authors":[{"author_name":"Lokesh K Chinthala","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Cindy Lemon","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Arash Shaban-Nejad","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Gregory Farage","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Robert L Davis","author_inst":"The University of Tennessee Health Science Center"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Charisse Madlock-Brown","author_inst":"University of Iowa"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"In-clinic validation of a smartphone-based finger tapping test for use in neurodegenerative and neurological populations.","rel_doi":"10.64898\/2026.06.25.26356467","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356467","rel_abs":"Background: Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods: The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson`s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results: The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. {beta}=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. {beta}=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. {beta}=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion: These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.","rel_num_authors":24,"rel_authors":[{"author_name":"Morgan O'Connor","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Mark Sanderson-Cimino","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Zi Li","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Sreya Dhanam","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Anjali Sadarangani","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Joshua Downer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Ray Fregly","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Jack Taylor","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Amy B. Wise","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Kaitlin B. Casaletto","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Leah K. Forsberg","author_inst":"Department of Neurology, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Hilary W. Heuer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Joel H. Kramer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"John Kornak","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Bruce L Miller","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Emily W Paolillo","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Riley Bove","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Gil Rabinovici","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"William W. Seeley","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Brad F. Boeve","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Howie J. Rosen","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Adam L. Boxer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Adam M. Staffaroni","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Association Between Area Deprivation and Dental Provider Density in California: A Cross-Sectional Ecological Study","rel_doi":"10.64898\/2026.07.04.26357261","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357261","rel_abs":"Abstract Background Neighborhood socioeconomic disadvantage may contribute to inequities in access to dental care by influencing the geographic distribution of providers. The Area Deprivation Index (ADI) is a validated measure of neighborhood deprivation, but its association with dental workforce availability has not been examined statewide in California. This study evaluated the relationship between neighborhood deprivation and dental provider density across California ZIP Code Tabulation Areas (ZCTAs). Methods We conducted a cross-sectional ecological study of California ZCTAs using publicly available data from the National Plan and Provider Enumeration System (April 2026), the Neighborhood Atlas 2023 ADI, and 2024 U.S. Census population estimates. Active dental providers were linked to ZCTAs and provider density was calculated per 10,000 residents. ADI was aggregated to the ZCTA level using the median ADI national percentile. Negative binomial regression was used to assess the association between ADI and dental provider density, with population included as an offset. Secondary analyses examined California-specific ADI quartiles, dental deserts, and specialist versus general dentist availability. Results The final analytic sample included 1,426 California ZCTAs representing 39,016,384 residents and 37,945 active dental providers. Greater neighborhood deprivation was significantly associated with lower dental provider density. Each one-percentile increase in ADI corresponded to a 1.8% reduction in provider density (incidence rate ratio [RR] 0.9823, 95% confidence interval [CI] 0.9799-0.9847; p < 0.001). Compared with the least deprived quartile, the most deprived quartile had 61% fewer dental providers (RR 0.39, 95% CI 0.34-0.45; p < 0.001). Overall, 15.9% of ZCTAs contained no active dental providers, increasing from 6.8% in the least deprived quartile to 31.1% in the most deprived quartile. Specialist availability demonstrated an even steeper deprivation gradient, with specialist density declining by 86% between the least and most deprived quartiles.","rel_num_authors":2,"rel_authors":[{"author_name":"Anna-Lena Asiedu","author_inst":"University of California San Francisco, School of Dentistry"},{"author_name":"Collins Gaba","author_inst":"Boston University School of Social Work"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Prevalence of cancer in patients with cardiovascular diseases and risk factors: a systematic review and meta-analysis","rel_doi":"10.64898\/2026.07.04.26357301","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357301","rel_abs":"Background No systematic review has been conducted to pool the existing evidence and quantify cancer prevalence rates in cardiovascular diseases (CVDs). We aimed to estimate pooled cancer prevalence in coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), hypertension, type 2 diabetes mellitus (DM), stroke, peripheral arterial disease (PAD), and valvular heart diseases (VHD). Methods PubMed, Web of Science, and Scopus were searched from 2010 to July 2024. The outcomes were proportions of patients with active, any, previous, blood, solid, and metastatic cancer. The prevalence rates were estimated via one-step generalized linear mixed models. Results Totally, we retrieved 676 studies with enrollment of roughly 180 million participants. The analysis for active cancer included 59 studies with a population of 4,759,695 patients. The pooled prevalence of active cancer was 4.22% (95% confidence interval (CI) 2.18-5.32), 4.43% (95% CI 2.78-6.38), 4.60% (95% CI 1.72-8.13), 4.61% (95% CI, 2.83-6.97), 4.90% (95% CI 3.84-6.37), and 5.55% (95% CI 3.97-7.01) in patients with type 2 DM, chronic HF, any stroke, CAD, VHD, and AF. For any cancer, prevalence rates ranged from 14.10% (95% CI 12.20-15.99) in AF to 7.04% (95% CI 6.05-8.03) in CAD. Conclusion Pooled prevalence rates demonstrate a measurable burden of cancer among patients with a wide range of CVDs, highlighting the need for multidisciplinary management in this population.","rel_num_authors":15,"rel_authors":[{"author_name":"Akhmetzhan Galimzhanov","author_inst":"Astana Medical University"},{"author_name":"Elif Beytekin","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Leh Chuan Lim","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Abdul Basit Ali Zai","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Gemina Doolub","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Mustafa Aljarshawi","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Balamrit Singh Sokhal","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Andrija Matetic","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"},{"author_name":"Rodrigo Bagur","author_inst":"Department of Cardiology, London Health Sciences Centre Western University London Ontario Canada"},{"author_name":"Louise Sun","author_inst":"Division of Cardiothoracic Anesthesiology, Stanford University School of Medicine, Stanford, California, USA"},{"author_name":"Cheng Han Ng","author_inst":"Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore"},{"author_name":"Miguel Nobre Menezes","author_inst":"Structural and Coronary Heart Disease Unit, Cardio-Oncology Unit CHULN Hospital de Santa Maria, Cardiovascular Center of the University of Lisbon, 1649-028 Lisb"},{"author_name":"Sarah Zaman","author_inst":"Westmead Applied Research Centre, University of Sydney, Sydney, Australia."},{"author_name":"Bonnie Ky","author_inst":"Thalheimer Center for Cardio-Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Mamas Mamas","author_inst":"Keele Cardiovascular Research Group, Keele University, Keele, United Kingdom"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Recalibrating Mendelian randomization under winner's curse, sample structure and polygenicity","rel_doi":"10.64898\/2026.06.25.26356593","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356593","rel_abs":"Recently, Hu et al. (2024) conducted a benchmarking study showing that most existing Mendelian randomization (MR) methods exhibit substantial bias and inflated type-I error rates in real data. They attributed these failures to two largely neglected sources of bias: winner's curse and polygenicity-induced bias. Although a few methods have been developed to address one or both of these issues, existing approaches either do not fully account for both biases or are restricted to the univariable setting. In this paper, we propose a multivariable Rao-Blackwellization that corrects winner's curse while accounting for polygenicity and sample structure in a unified framework. Unlike univariable Rao-Blackwellization, where instrument selection yields a truncated normal statistic amenable to a Mills-ratio correction, multivariable Rao-Blackwellization conditions on a noncentral $\\chi^2$ statistic, for which no analogous correction is available. We derive closed-form conditional moments under this instrument selection model and use them to construct bias-corrected summary statistics that can be integrated into a wide range of existing MR methods. Simulations and real data analyses show that, when combined with methods such as MR-cML and MR-BEE, the proposed correction substantially improves type-I error control and yields more robust inference.","rel_num_authors":4,"rel_authors":[{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Zhaotong Lin","author_inst":"Florida State University"},{"author_name":"Haoran Xue","author_inst":"City University of Hong Kong"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Recalibrating Mendelian randomization under winner's curse, sample structure and polygenicity","rel_doi":"10.64898\/2026.06.25.26356593","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356593","rel_abs":"Recently, Hu et al. (2024) conducted a benchmarking study showing that most existing Mendelian randomization (MR) methods exhibit substantial bias and inflated type-I error rates in real data. They attributed these failures to two largely neglected sources of bias: winner's curse and polygenicity-induced bias. Although a few methods have been developed to address one or both of these issues, existing approaches either do not fully account for both biases or are restricted to the univariable setting. In this paper, we propose a multivariable Rao-Blackwellization that corrects winner's curse while accounting for polygenicity and sample structure in a unified framework. Unlike univariable Rao-Blackwellization, where instrument selection yields a truncated normal statistic amenable to a Mills-ratio correction, multivariable Rao-Blackwellization conditions on a noncentral $\\chi^2$ statistic, for which no analogous correction is available. We derive closed-form conditional moments under this instrument selection model and use them to construct bias-corrected summary statistics that can be integrated into a wide range of existing MR methods. Simulations and real data analyses show that, when combined with methods such as MR-cML and MR-BEE, the proposed correction substantially improves type-I error control and yields more robust inference.","rel_num_authors":4,"rel_authors":[{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Zhaotong Lin","author_inst":"Florida State University"},{"author_name":"Haoran Xue","author_inst":"City University of Hong Kong"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Sickle Cell Disease Demographics and Clinical Epidemiology in Gambian Urban and Rural Cohorts Retrospective Analysis","rel_doi":"10.64898\/2026.07.03.26357219","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357219","rel_abs":"Globally, approximately 75% of sickle cell disease (SCD) cases occur in sub-Saharan Africa, yet empirical data on its natural history, clinical burden, and modifiers remain scarce in the region. This retrospective study describes the demographic characteristics, complications, and routine care and examines how non-genetic factors and blood markers relate to disease severity. We analysed 8402 medical records from 840 SCD patients with confirmed HbSS genotype registered in MRCG Keneba and Fajara clinics (NKeneba=148; NFajara=692). A generalised linear model was employed to estimate the association of non-genetic correlates, blood biomarkers, and routine care medications with disease severity. Here, we showed 67% of patients in the Keneba cohort and 92% of those in the Fajara cohort had no documented SCD-related chronic complication. Despite no documented evidence of hydroxyurea use, rates of SCD crises (Keneba=0.57, Fajara=0.63) and infections (Keneba=0.53, Fajara=0.35), expressed per patient-year, were low in both cohorts, with 99% of patients experiencing less than or equal to 3 SCD crises per patient-year. Age at diagnosis, gender and seasonality were not significantly associated with SCD crises or other clinical outcomes\/events rates. Each additional folic acid prescription was associated with higher haemoglobin(g\/dL) (total folic acid prescriptions: Beta-Fajara=1.31, P=0.005; Beta-Keneba=1.20, P<0.001). Penicillin prophylaxis was associated with a reduced rate of infection (total Pen V prescriptions: IRR-Fajara=0.85, P=0.002; IRR-Keneba=0.93, P=0.002) and SCD crises (IRR-Fajara=0.67, P=0.001; IRR-Keneba=0.87, P=0.001). This study found low acute event rates and chronic complications prevalence in the absence of hydroxyurea use. No significant associations were observed between non-genetic correlates and clinical events, but the study highlighted the need for continued folic acid supplementation and penicillin prophylaxis due to their observed beneficial effects.","rel_num_authors":11,"rel_authors":[{"author_name":"Mustapha Dibbasey","author_inst":"Medical Research Council, the Gambia at London School of Hygiene and Tropical Medicine"},{"author_name":"Kevin Esoh","author_inst":"McKusick-Nathans Institute, and Department of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA"},{"author_name":"Bubacarr Susso","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Karen Forrest","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Bakary Sonko","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Lamin Makalo","author_inst":"Department of Paediatrics, Edward Francis Small Teaching Hospital, Banjul, The Gambia"},{"author_name":"Eniyou Oriero","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Ndong Ignatius Cheng","author_inst":"Department of Epidemiology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana"},{"author_name":"Lucas Amenga-Etego","author_inst":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, LG 54, Accra, Ghana"},{"author_name":"Carla Cerami","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"},{"author_name":"Alfred Amambua-Ngwa","author_inst":"MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Association of anti-Ro-52 positivity with cardiovascular outcomes in patients with anti-synthetase syndrome","rel_doi":"10.64898\/2026.07.04.26357290","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357290","rel_abs":"Background: Anti-synthetase syndrome (ASyS) is a subgroup of idiopathic inflammatory myopathies that is increasingly recognized as a distinct entity with features of myositis, interstitial lung disease, inflammatory arthritis, and Raynaud phenomenon. Co-reactivity with anti-Ro-52, an antibody directed against the Ro-52 E3 ubiquitin ligase, has been shown to be associated with progressive interstitial lung disease within this patient population. However, less is known regarding the association of anti-Ro-52 positivity with cardiovascular outcomes. Methods: A sub-cohort of patients with anti-synthetase antibodies at a large single institution center was retrospectively analyzed to define presence of anti-Ro-52 positivity (defined as anti-Ro-52 titer greater than or equal to 11 utilizing the line immunoblot platform, Euroline Autoimmune Inflammatory Myopathies, EuroImmun Diagnostics, Lubeck, Germany). Patients who did not meet 2017 ACR\/EULAR classification criteria for idiopathic inflammatory myopathies were excluded from the final analysis. Cardiovascular outcomes ascertained via retrospective chart review included atrial fibrillation, left bundle branch block, right bundle branch block, pulmonary hypertension (confirmed via right heart catheterization), heart failure with reduced ejection fraction (HFrEF, defined as ejection fraction less than or equal to 40 percent), acute coronary syndrome (based on clinical diagnosis and angiography if available), and myocarditis (based on clinician diagnosis and either cardiac MRI or troponin elevation). When a pre-specified cardiac outcome was identified, the date of onset was recorded. Differences in proportions were analyzed via Chi-squared and Fishers exact tests, and time-to-event analyses were performed via Cox Proportional Hazards Models, incorporating a false discovery rate correction for multiple outcomes. All analyses were performed using SAS v9.4. Results: 88 patients were included in the final analysis, of whom 69 (78.4 percent) were categorized as anti-Ro-52 positive. Patients with anti-Ro-52 positivity had a higher maximum recorded serum creatine kinase (median 1297 vs 395 units per liter, p = 0.042). No significant associations between anti-Ro-52 positivity and the pre-defined cardiovascular outcomes were found over median follow up time of 12.5 years. Conclusions: In a large, single-center cohort of patients with ASyS, anti-Ro-52 positivity was not associated with an increased burden of negative cardiovascular outcomes, including the onset of pulmonary hypertension. Future studies may seek to further elucidate the mechanisms underlying the pleiotropic effects of anti-Ro-52 antibodies on the cardiopulmonary system.","rel_num_authors":7,"rel_authors":[{"author_name":"Archit V. Potharazu","author_inst":"Johns Hopkins Medicine"},{"author_name":"Jae-Hoon Chung","author_inst":"Johns Hopkins Medicine"},{"author_name":"Lisa Yanek","author_inst":"Johns Hopkins Medicine"},{"author_name":"Will Kelly","author_inst":"Johns Hopkins Medicine"},{"author_name":"Nisha Gilotra","author_inst":"Johns Hopkins Medicine"},{"author_name":"Luigi Adamo","author_inst":"Johns Hopkins Medicine"},{"author_name":"Julie Paik","author_inst":"Johns Hopkins Medicine"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Neonatal Hypothermia at and after Admission: Burden and Associations with Outside Air Temperature and Neonatal Ward Temperature in Four Sub Saharan African Countries Implementing with the NEST360 Alliance","rel_doi":"10.64898\/2026.07.04.26357151","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357151","rel_abs":"Background: Annually, 2.3 million newborns die, largely from preventable causes. Neonatal hypothermia is an important contributor to morbidity and mortality, particularly in low-resource settings. This study quantified the burden of hypothermia at and after admission in four NEST360-supported countries and examined associations between outside air temperature, ward temperature, and neonatal hypothermia. Methods: We conducted a retrospective analysis of newborn admissions (January 2021 to June 2025) across 66 neonatal units in Kenya, Malawi, Nigeria, and Tanzania. Hypothermia was defined using WHO thresholds (mild: 36.0-36.4{degrees}C, moderate: 32.0-35.9{degrees}C, severe: <32.0{degrees}C). Newborn admission and lowest after admission body temperatures were extracted from routine clinical records. Ward temperatures were captured using the Hadli Monitoring System, and environmental temperatures were obtained from Open-Meteo. Multivariate ordinal logistic regression assessed associations between air temperature, ward temperature, and hypothermia at admission and during admission. Results: Among 418,458 newborn admissions with recorded admission temperatures, 47.3% (n=220,684) were hypothermic at admission (country range: 22.8%-61.9%), while 63.5% (n=48,746) experienced hypothermia during hospital stay (country range: 18.5%-74.4%), based on 76,855 admissions (July 2024-June 2025) with temperature data. Based on admission and subsequent temperature, 28.5% had no documented hypothermia, 8.6% improved to non-hypothermic status, 29.4% developed hypothermia after admission, and 33.5% experienced hypothermia at admission and during hospital stay. Across 59 neonatal units, minimum ward temperatures >26{degrees}C were maintained on 92.6% of 365 days. At admission, ward temperatures of 30-33{degrees}C were associated with 9% lower odds of a lower thermal category versus 26-28{degrees}C (p<0.01). After admission, ward temperatures of 28-30{degrees}C reduced odds by 18% (p<0.05). Warmer outside temperatures (>24{degrees}C day, >21{degrees}C night) were protective, corresponding to 19% and 68% lower odds of a lower thermal category after admission, respectively, compared with 19-24{degrees}C and 15-21{degrees}C reference groups. Newborns had 3.6-fold higher odds of hypothermia at night than during the day. Each 1{degrees}C increase in post-admission temperature reduced odds of death by 6%. Conclusion: Neonatal hypothermia remains highly prevalent despite most units maintaining ward temperatures above WHO minimum standards (26{degrees}C). Strengthening all components of the warm chain, particularly at night and during colder seasons, is essential to reduce hypothermia and improve survival.","rel_num_authors":23,"rel_authors":[{"author_name":"Melissa Mar","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Christine A Bohne","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"John Wainaina","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Mariam Thabit Johari","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"George Okello","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Edith Gicheha","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Catherine Paul","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Rebecca Richards-Kortum","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Maria Oden","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Joy E Lawn","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Lucas Malla","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Kristina Shemwell","author_inst":"Maternal, Adolescent, Reproductive, & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"William M Macharia","author_inst":"Department of Paediatrics, Aga Khan University, Nairobi, Kenya"},{"author_name":"Hannah Mwaniki","author_inst":"Department of Paediatrics, Aga Khan University, Nairobi, Kenya"},{"author_name":"Nahya Salim Masoud","author_inst":"Department of Paediatrics and Child Health, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania"},{"author_name":"Samuel K Ngwala","author_inst":"School of Global and Public Health, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Msandeni Chiume","author_inst":"Ministry of Health, Malawi - Reproductive Health Department"},{"author_name":"Veronica Chinyere Ezeaka","author_inst":"Department of Paediatrics, College of Medicine, University of Lagos, Lagos, Nigeria"},{"author_name":"Elizabeth M Molyneux","author_inst":"Department of Paediatrics, Kamuzu University of Health Sciences, Blantyre, Malawi"},{"author_name":"Natasha R Rhoda","author_inst":"Children's Institute, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa"},{"author_name":"Vincent Otieno Ochieng","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Opeyemi Odedere","author_inst":"Rice360 Institute for Global Health Technologies, Rice University, Texas, USA"},{"author_name":"Lisa R Hirschhorn","author_inst":"Northwestern University Feinberg School of Medicine, Illinois, USA"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Organised cancer screening among women who receive medically assisted reproduction treatments","rel_doi":"10.64898\/2026.07.05.26357336","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357336","rel_abs":"There are no published data on cancer screening by women using medically assisted reproduction (MAR). Such data would aid interpretation of the cancer incidence and risk profiles for this group. Using linked population-based Australian health registries and administrative datasets, we compared organised publicly funded cervical and breast screening episodes for women who received one of three types of MAR and matched women who did not between 1991 and 2016. We modelled the proportion of women screened in the three years before and after first MAR treatment, adjusting for age, remoteness, parity, socio-economic disadvantage, cancer history, and uptake of the other screening program. After adjustment, a greater proportion of women who received MAR than women who did not had cervical screening before MAR (77.3%-84.1% vs 57.5%-62.0%, depending on treatment) and after MAR (77.0%-78.5% vs 68.1%-68.3%). Contrastingly, breast screening estimates were 7.6%-9.6% vs 9.3%-10.5% before MAR and 11.0%-15.0% vs 12.8%-14.9% after MAR.","rel_num_authors":12,"rel_authors":[{"author_name":"Adrian Raymond Walker","author_inst":"UNSW Sydney"},{"author_name":"Signe Odahl","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Christos Venetis","author_inst":"Aristotle University of Thessaloniki"},{"author_name":"Louisa Jorm","author_inst":"UNSW Sydney"},{"author_name":"Neville F Hacker","author_inst":"UNSW Sydney"},{"author_name":"Michael Chapman","author_inst":"UNSW Sydney"},{"author_name":"Antoinette C Anazodo","author_inst":"UNSW Sydney"},{"author_name":"Robert J Norman","author_inst":"Adelaide University"},{"author_name":"Catharyn Stern","author_inst":"University of Melbourne"},{"author_name":"Ursula M Sansom-Daly","author_inst":"UNSW Sydney"},{"author_name":"Georgina Mary Chambers","author_inst":"UNSW Sydney"},{"author_name":"Claire Melissa Vajdic","author_inst":"UNSW Sydney"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Bench-stepping training improves stair-walking dynamics in older women: evidence from an exploratory nonlinear kinematic analysis","rel_doi":"10.64898\/2026.07.02.26357116","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357116","rel_abs":"Introduction: Stair walking challenges balance and coordination in older people. Bench-stepping training improves stair climbing speed in healthy older women. This study assessed whether bench-stepping also improves dynamic balance and movement complexity during stair walking. Methods: Stair walking data were obtained from a previous study involving 45 healthy older women (69y+\/-4) that assessed the effects of a 12-week bench-stepping intervention with non-training controls. Centre-of-mass acceleration was measured during stair ascent and descent. Linear dynamics included time, acceleration magnitude, and harmonic ratios (HR; indicating symmetry). Movement complexity was quantified using nonlinear dynamics including sample entropy (SE), recurrence quantification analysis (RQA), and fractal dimension (FD). Results: For stair ascent, increased speed (p =0.018, R2partial =0.093,) was accompanied by proportional increases in acceleration magnitudes (p=<0.039, R2partial =0.078-0.101). SE decreased more in the intervention group (p=<0.012, R2partial =0.049-0.101), indicating more predictable dynamics. In contrast, for stair descent, no changes in speed or acceleration magnitudes were observed. However, SE (p =0.001, R2partial =0.082) and maximum RQA line length (p= 0.008, R2partial =0.057) of vertical acceleration increased significantly compared to controls, indicating lower predictability and more persistent recurring patterns. No significant changes were found for other outcomes. Exploratory factor analysis revealed distinct differences in motor behaviour between stair ascent and descent. Conclusion: Bench-stepping training induced measurable changes in stair walking dynamics. Specifically, sample entropy shows potential as a sensitive marker of altered motor complexity, particularly of vertical accelerations. Interestingly, the direction of changes in unpredictability differed between stair ascent and descent, suggesting different underlying control strategies.","rel_num_authors":8,"rel_authors":[{"author_name":"Remco Johan Baggen","author_inst":"Vrije Universiteit Amsterdam\/Neuroscience Research Australia"},{"author_name":"Kimberley Stefanie van Schooten","author_inst":"Neuroscience Research Australia\/University of New South Wales"},{"author_name":"Evelien Van Roie","author_inst":"Hasselt University"},{"author_name":"Sabine Marie Verschueren","author_inst":"KU Leuven"},{"author_name":"Christophe Delecluse","author_inst":"KU Leuven"},{"author_name":"Kim Delbaere","author_inst":"University of New South Wales\/NeuRA"},{"author_name":"Stephen R Lord","author_inst":"Neuroscience Research Australia"},{"author_name":"Jaap H. van Dieen","author_inst":"VU Amsterdam: Vrije Universiteit Amsterdam"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Designing Fidelity of CRISPR-Cas Endonucleases by Kinetic Insights","rel_doi":"10.64898\/2026.07.06.736881","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736881","rel_abs":"Finding high-fidelity CRISPR-Cas variants is critical for both the precision of in vitro DNA detection and the safety of in vivo gene-editing therapeutics. However, the large size of the Cas enzyme and the distinct selection criteria between its natural evolution and clinical practice lead to extensive experimental trials and limited success rate for de novo design, directed evolution, protein language model (PLM)-based filtering. Here, we present a PLM-assisted physics-driven approach that utilizes atomistic molecular dynamics simulations and automated path searching to efficiently obtain the complete kinetic insights, including the transition state structures, for the conformational changes of Cas before DNA cleavage. We show that these kinetic insights can pinpoint a few fidelity-diminishing protein residues during the early stage of target recognition, and have led to SpyCas9 and FnCas12a variants with ultra-high fidelity surpassing previously reported counterparts at minimal cost of a few wet-lab trials.","rel_num_authors":18,"rel_authors":[{"author_name":"Huihui Liu","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Zhenyu Zhou","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Luowei Yuan","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Bin Pang","author_inst":"Fudan University"},{"author_name":"Kun Xi","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Xinyu Li","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Wenzhuo Ma","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Rujuan Ti","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Jinchu Liu","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Nuo Chen","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Yang Xu","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Jianyu Yang","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Yiping Yu","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Yuchen Yang","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Ruobing Ren","author_inst":"Fudan University"},{"author_name":"Arieh Warshel","author_inst":"University of Southern California"},{"author_name":"Yong Lei","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Lizhe Zhu","author_inst":"The Chinese University of Hong Kong, Shenzhen"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Assessment of homing gene drive efficiency using multiplexed sgRNAs targeting doublesex in the global crop pest Drosophila suzukii","rel_doi":"10.64898\/2026.07.03.736304","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736304","rel_abs":"Drosophila suzukii (Matsumura, 1931, Diptera: Drosophilidae) is a globally invasive pest of soft-skinned fruits that is currently controlled largely through the use of broad-spectrum insecticides. Increasing resistance to pesticides and regulatory pressures have motivated the development of genetic control strategies. We previously developed a CRISPR\/Cas9-based homing gene drive targeting the coding sequence of the female-specific exon of the sex-determination gene doublesex, achieving highly efficient inheritance (94-99%) in both male and female germlines. A major limitation of homing gene drives is the formation of resistant alleles that evade cleavage yet retain gene function. Multiplexing guide RNAs (gRNAs) could reduce the formation of such functional resistance alleles. Here, we generated and tested homing constructs expressing one, two, or three gRNAs targeting different regions of the female-specific exon of doublesex, including a splice-junction target site. A single gRNA targeting the splice junction supported high inheritance in males but showed reduced efficiency in females. Combining this gRNA with a coding sequence-targeting guide further reduced drive efficiency, particularly in the female germline. Constructs expressing two gRNAs performed similarly whether guides were linked by transfer RNA (tRNA) sequences or expressed from independent promoters. Constructs expressing three gRNAs using tRNA processing showed consistently low drive inheritance in both sexes, likely a consequence of reduced cleavage efficiency due to inefficient gRNA production. Inheritance was significantly higher in male than female germlines for several constructs, indicating that germline context strongly influences drive performance. Our findings highlight that the approach used for multi-gRNA expression, target site choice and sex-specific germline environments can impact gene drive efficiency, and emphasize the need to optimize construct design within the biological context of the target species.","rel_num_authors":4,"rel_authors":[{"author_name":"Amarish  K. Yadav","author_inst":"North Carolina State University at Raleigh: North Carolina State University"},{"author_name":"Weizhe Chen","author_inst":"Peking University"},{"author_name":"Jackson Champer","author_inst":"Peking University"},{"author_name":"Maxwell  J. Scott","author_inst":"North Carolina State University"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Assessment of homing gene drive efficiency using multiplexed sgRNAs targeting doublesex in the global crop pest Drosophila suzukii","rel_doi":"10.64898\/2026.07.03.736304","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736304","rel_abs":"Drosophila suzukii (Matsumura, 1931, Diptera: Drosophilidae) is a globally invasive pest of soft-skinned fruits that is currently controlled largely through the use of broad-spectrum insecticides. Increasing resistance to pesticides and regulatory pressures have motivated the development of genetic control strategies. We previously developed a CRISPR\/Cas9-based homing gene drive targeting the coding sequence of the female-specific exon of the sex-determination gene doublesex, achieving highly efficient inheritance (94-99%) in both male and female germlines. A major limitation of homing gene drives is the formation of resistant alleles that evade cleavage yet retain gene function. Multiplexing guide RNAs (gRNAs) could reduce the formation of such functional resistance alleles. Here, we generated and tested homing constructs expressing one, two, or three gRNAs targeting different regions of the female-specific exon of doublesex, including a splice-junction target site. A single gRNA targeting the splice junction supported high inheritance in males but showed reduced efficiency in females. Combining this gRNA with a coding sequence-targeting guide further reduced drive efficiency, particularly in the female germline. Constructs expressing two gRNAs performed similarly whether guides were linked by transfer RNA (tRNA) sequences or expressed from independent promoters. Constructs expressing three gRNAs using tRNA processing showed consistently low drive inheritance in both sexes, likely a consequence of reduced cleavage efficiency due to inefficient gRNA production. Inheritance was significantly higher in male than female germlines for several constructs, indicating that germline context strongly influences drive performance. Our findings highlight that the approach used for multi-gRNA expression, target site choice and sex-specific germline environments can impact gene drive efficiency, and emphasize the need to optimize construct design within the biological context of the target species.","rel_num_authors":4,"rel_authors":[{"author_name":"Amarish  K. Yadav","author_inst":"North Carolina State University at Raleigh: North Carolina State University"},{"author_name":"Weizhe Chen","author_inst":"Peking University"},{"author_name":"Jackson Champer","author_inst":"Peking University"},{"author_name":"Maxwell  J. Scott","author_inst":"North Carolina State University"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"IFN and IFN mimetics prevent IFN-I-mediated TB susceptibility by regulating iron metabolism and lipid peroxidation","rel_doi":"10.64898\/2026.07.01.735930","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735930","rel_abs":"Type I interferons (IFN-I) and IFN{gamma} exert divergent effects during tuberculosis, but the mechanisms that determine whether macrophage activation promotes host defense or inflammatory pathology remain incompletely understood. Here, we dissect the interplay between IFN-I and IFN{gamma} in macrophage activation using genetically susceptible B6.Sst1S macrophages. We show that, during tumor necrosis factor (TNF) stimulation, susceptible macrophages enter a persistent pathological activation state (pPAS) characterized by sustained lipid peroxidation and super-induction of IFN-I responses. This pathological state is maintained by autocrine IFN-I signaling. In contrast, IFN{gamma} priming prevents pPAS development by enhancing macrophage resilience to oxidative stress, in part through regulation of iron metabolism and induction of ferritin expression. Computational cell state transition assessment and regulation (cSTAR) analysis identified pathways and small molecules predicted to promote the transition of susceptible macrophages toward an IFN{gamma}-induced, Mtb-resistant state. Consistent with these predictions, the CDK4\/6 inhibitor trilaciclib reduced lipid peroxidation by regulating iron metabolism, whereas retinoic acid signaling enhanced GPX4 expression and lipid biosynthesis programs. Combined CDK4\/6 inhibition and retinoic acid receptor activation efficiently prevented the pathological activation state. Together, these findings delineate a mechanism of IFN-I\/IFN{gamma} crosstalk during macrophage activation and identify pharmacologic strategies to prevent IFN-I-dominant, lipid peroxidation-driven macrophage pathology.","rel_num_authors":11,"rel_authors":[{"author_name":"Prasanna Babu Araveti","author_inst":"The National Emerging Infectious Diseases Laboratories, Boston University, Boston, United States"},{"author_name":"Shivraj M. Yabaji","author_inst":"The National Emerging Infectious Diseases Laboratories, Boston University, Boston, United States"},{"author_name":"Muhammad Zainul Arifin","author_inst":"Systems Biology Ireland, School of Medicine, University College Dublin, Dublin, Ireland"},{"author_name":"Suruchi Lata","author_inst":"The National Emerging Infectious Diseases Laboratories, Boston University, Boston, United States"},{"author_name":"Yuriy O. Alekseyev","author_inst":"The Department of Pathology and Laboratory Medicine, Boston University Chobanian Avedisian School of Medicine, Boston, United States"},{"author_name":"Alexander A. Gimelbrant","author_inst":"Altius Institute for Biomedical Sciences, Seattle, United States"},{"author_name":"William R. Bishai","author_inst":"Center for TB Research, Johns Hopkins School of Medicine, Baltimore, United States"},{"author_name":"Vadim Zhernovkov","author_inst":"Systems Biology Ireland, School of Medicine, University College Dublin, Dublin, Ireland"},{"author_name":"Oleksii S. Rukhlenko","author_inst":"Systems Biology Ireland, School of Medicine, University College Dublin, Dublin, Ireland"},{"author_name":"Boris N. Kholodenko","author_inst":"Systems Biology Ireland, University College Dublin, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland; Departm"},{"author_name":"Igor Kramnik","author_inst":"The National Emerging Infectious Diseases Laboratories, Boston University, Boston, USA; Pulmonary Center, Department of Medicine, BU School of Medicine, USA; De"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Opposing GIPR brainstem circuits differentially control feeding behaviour","rel_doi":"10.64898\/2026.07.01.735388","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735388","rel_abs":"Central glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling is required for the efficacy of GIP-based obesity therapeutics, yet how distinct subpopulations of GIPR neurons shape appetite remains undefined. Here we show that GIPR neurons in adjacent brainstem nuclei, the area postrema (AP) and nucleus tractus solitarius (NTS), exert opposing control over ingestion. We find GIPRAP neurons dampen post-ingestive satiation, permitting hyperphagia, whereas GIPRNTS neurons are anorectic. In line with this model, we show Gipr expression in AP, but not NTS, neurons is necessary for appetite suppression following GIPR antagonism. Additionally, we reveal that GIPR neurons in the AP and NTS occupy distinct gut-brain circuits, and are differentially sensitive to obesity-driven circuit remodelling. These data offer a framework for understanding how current GIPR agonist and antagonist strategies elicit weight loss.","rel_num_authors":15,"rel_authors":[{"author_name":"Natalie S Figueredo Burgos","author_inst":"Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom"},{"author_name":"Alejandro Lopez-Cruz","author_inst":"Howard Hughes Medical Institute, University of California, San Francisco, USA"},{"author_name":"Cecilia Skoug","author_inst":"Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom"},{"author_name":"Anna G Roberts","author_inst":"Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom"},{"author_name":"Kathryn Xie","author_inst":"Howard Hughes Medical Institute, University of California, San Francisco, USA"},{"author_name":"Iona Davies","author_inst":"Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK"},{"author_name":"Norio Harada","author_inst":"Department of Endocrinology and Metabolism, School of Medical Sciences, University of Fukui, Fukui, Japan"},{"author_name":"Nobuya Inagaki","author_inst":"Department of Diabetes, Endocrinology and Nutrition, Kyoto University, Kyoto, Japan"},{"author_name":"Frank Reimann","author_inst":"Institute of Metabolic Science & MRC Metabolic Disease Unit, University of Cambridge, Cambridge, United Kingdom"},{"author_name":"Fiona M Gribble","author_inst":"Institute of Metabolic Science & MRC Metabolic Disease Unit, University of Cambridge, Cambridge, United Kingdom"},{"author_name":"Ben Jones","author_inst":"Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK"},{"author_name":"Daniel I Brierley","author_inst":"Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom"},{"author_name":"Stefan Trapp","author_inst":"Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom"},{"author_name":"Zachary A Knight","author_inst":"Howard Hughes Medical Institute, University of California, San Francisco, USA"},{"author_name":"Alice E Adriaenssens","author_inst":"Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Genomic compartmentalization of pervasive sex-biased gene expression in the vine mealybug Planococcus ficus","rel_doi":"10.64898\/2026.07.01.735863","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735863","rel_abs":"The vine mealybug, Planococcus ficus, is a globally invasive pest of grapevine and a vector of leafroll viruses. Like other mealybugs, it reproduces through paternal genome elimination, a sex-determination system that operates without sex chromosomes and is associated with extreme sexual dimorphism. To characterize genome organization and sex-biased expression in this species, we generated a long-read reference genome spanning 369 Mb with 23,489 annotated genes and macrosynteny conserved with the citrus mealybug, Planococcus citri. Resequencing of four California field individuals yielded a first whole-genome estimate of nucleotide diversity and 132 microsatellite markers for population monitoring. Among 2,129 candidate secreted proteins, a conserved core is shared with P. citri, but each species carries a distinct set of lineage-specific effectors. Comparing adult male and female transcriptomes, we found sex-biased expression to be pervasive and skewed toward females: 41% of tested genes differed between the sexes, with female-biased genes both more numerous and showing larger fold changes. These female-biased genes were not randomly distributed but concentrated in discrete blocks of coordinately expressed, tandemly duplicated gene families, a pattern not previously described in a mealybug. Male- and female-biased secreted proteins also differed in origin, with male-biased proteins drawn from a conserved repertoire shared with P. citri and female-biased proteins spanning a more lineage-specific pool. Together, these results reveal a female-skewed, spatially clustered architecture of sex-biased expression in a mealybug that lacks sex chromosomes, and provide genomic resources for managing an invasive vineyard pest.","rel_num_authors":7,"rel_authors":[{"author_name":"Dario Cantu","author_inst":"University of California Davis"},{"author_name":"Rosa Figueroa-Balderas","author_inst":"University of California Davis"},{"author_name":"Mark Sisterson","author_inst":"USDA-ARS"},{"author_name":"Andrea Minio","author_inst":"University of California Davis"},{"author_name":"Noe Cochetel","author_inst":"University of California Davis"},{"author_name":"Rachel Naegele","author_inst":"USDA-ARS"},{"author_name":"Lindsey Burbank","author_inst":"USDA-ARS"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"ScaleSurfer: multi-scale anatomical segmentation and parcellation of the human brain","rel_doi":"10.64898\/2026.07.01.735927","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735927","rel_abs":"Human brain magnetic resonance imaging (MRI) revolutionized our ability to non-invasively probe individual differences in neuroanatomy. These anatomical scans, in turn, also allow us to accurately localize functional MRI (fMRI) activity. However, extracting anatomical labels and structural characteristics, such as cortical surface area or thickness, is a computationally demanding task, taking on the order of hours per brain volume. This is an intrinsically multi-scale problem given that local image structure defines fine boundaries, whereas accurate assignments depend on broader anatomical context. Here, we introduce ScaleSurfer, a three-dimensional convolutional vision transformer model based on multi-scale learning. Convolution blocks capture local anatomical detail and a transformer bottleneck integrates the distributed spatial context. This approach provides rapid, whole-brain morphometric feature estimation, including volume, cortical thickness, surface area, and curvature. Importantly, ScaleSurfer accomplishes this nearly five orders of magnitude faster than current pipelines, taking 150-500 ms instead of ~5 hours. We validated ScaleSurfer on multiple datasets, showing stable learning across heterogeneous MRI collections, and demonstrate feasibility by training an interpretable Alzheimer's disease classifier that identifies reductions in primarily medial temporal lobe subregions compared to healthy controls. ScaleSurfer positions multi-scale representation learning as a practical route toward faster, anatomically faithful structural MRI processing, whose speed paves the way for nearly real-time anatomical quality control during scanning.","rel_num_authors":3,"rel_authors":[{"author_name":"Ryan P Hammonds","author_inst":"University of California, San Diego"},{"author_name":"Cindy Chen","author_inst":"University of California, San Diego"},{"author_name":"Bradley Voytek","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Topological data analysis captures complex behavioral dynamics during naturalistic social interaction between domestic ferrets","rel_doi":"10.64898\/2026.07.01.735818","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735818","rel_abs":"Capturing naturalistic behavioral dynamics is essential for understanding social interaction in ecologically valid settings. Existing investigations of naturalistic social interaction rely on time-aggregated analysis methods better suited for task-based experiments, which lose the complex, moment-to-moment dynamics exhibited in naturalistic settings. The emerging field of topological data analysis (TDA) provides new tools to characterize fine-grained dynamics in time-series data that cannot be captured by time-averaged methods. The present work utilizes Temporal Mapper, a recently developed TDA specifically tailored to analyzing dynamical systems. Temporal Mapper characterizes complex temporal dynamics as transition networks, where nodes are stable states and edges are transitions between states. Originally designed for human neural time series analysis, here we demonstrate the utility of Temporal Mapper to capture rich animal postural dynamics during naturalistic social interaction. We utilized an existing dataset with 12 video recording sessions of two domestic ferrets (Mustela putorius furo) during naturalistic interaction and tracked the postures of animals during social interaction. Ferrets were chosen due to their strong social-cognitive skills and rich postural dynamics for investigating social behavior via posture estimation. Temporal Mapper was then used to represent the postural dynamics as transition networks for each recording session. Here, we found that posture states are significantly smaller and more widespread during active social interaction compared to non-social activities. Additionally, the number of sequential postural states before transitioning to new behaviors is more consistent during active social interaction than non-social activities. Together, our findings suggest that social activity has a broad range of unstable postural states arranged in consistent sequences. Our method, Temporal Mapper, allows for network structure analysis of complex naturalistic data, applicable for characterizing rich dynamics in different species, scales, and paradigms.","rel_num_authors":5,"rel_authors":[{"author_name":"Jared Reiling","author_inst":"Michigan State University"},{"author_name":"Nancy Padilla-Coreano","author_inst":"University of Florida"},{"author_name":"Dhruvi Patel","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Flavio Frohlich","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mengsen Zhang","author_inst":"Michigan State University"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Recommendations for the ethical and accurate use of population descriptors: a trainee-led survey of early-career researchers","rel_doi":"10.64898\/2026.07.01.735829","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735829","rel_abs":"Despite the importance of population descriptors in human genomics research, many scientists struggle to translate evolving ethical guidelines into their computational workflows. To characterize this gap between recommendations and implementation, we conducted a mixed-methods survey of early-career researchers to assess how they understand and implement the landmark 2023 NASEM report on the use of population descriptors in human genetics research. We show that while exposure to the report fosters ethical awareness, fundamental misconceptions about race and ancestry persist across academic disciplines, and trainees face structural bottlenecks, including legacy data constraints and a lack of technical confidence. To address this gap, we offer actionable, stakeholder-specific recommendations across the research lifecycle ranging from decision-support tools to \"bring-your-own-data\" workshops to leadership from academic journals, scientific societies, and trainee mentors. Ultimately, we argue that to promote scientific rigor and reduce bias in genetic discoveries, the scientific ecosystem must invest in the infrastructure necessary to empower the next generation of researchers.","rel_num_authors":11,"rel_authors":[{"author_name":"Jayati Sharma","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Betzaida Maldonado","author_inst":"University of Colorado Anschutz"},{"author_name":"Rachel Allison Ungar","author_inst":"Stanford University"},{"author_name":"Alvina Adimoelja","author_inst":"Stanford University"},{"author_name":"JP Flores","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Tamara Gjorgjieva","author_inst":"Stanford University"},{"author_name":"Krystin Jones","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Alyna Khan","author_inst":"Pennsylvania State University"},{"author_name":"Diane Xue","author_inst":"University of Pennsylvania"},{"author_name":"Roshni Patel","author_inst":"University of Oregon"},{"author_name":"Christa Caggiano","author_inst":"Icahn School of Medicine at Mt. Sinai"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Molecular Clock Dating of Ancient Environmental DNA Reveals Damage Beyond Deamination","rel_doi":"10.64898\/2026.07.03.735781","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.735781","rel_abs":"Ancient environmental DNA (aeDNA) from permafrost, lake, cave, and marine sediments provides a rich source of genetic data that captures broad perspectives of past biodiversity. Accurate dating is crucial for discovering ecologically relevant patterns from aeDNA, and molecular clock dating would allow for sample ages to be estimated from the recovered genetic material itself instead of the geological components. However, the fragmented and damaged nature of short-read ancient DNA (aDNA) from multiple taxonomic sources poses significant challenges and has limited this dating approach for aeDNA. Here we developed ratePlacer, a phylogeny-based method for analyzing aeDNA that can combine information from many short reads in a sample while accounting for DNA damage to provide maximum likelihood estimates of sample ages. Simulations demonstrate that ratePlacer accurately dates samples even under the fragmented, damaged conditions characteristic of aeDNA and outperforms Bayesian tip-dating approaches for taxonomically mixed samples commonly found in aeDNA. Yet age estimates from re-dating Kap Kobenhavn varied across taxa, highlighting the difficulty of molecular clock dating in aeDNA. This dating also revealed elevated G[-&gt;]T and C[-&gt;]A mismatches consistent with oxidative damage. These patterns reveal aDNA damage beyond deamination and that remains understudied, suggesting that aeDNA should be carefully evaluated in genomic and evolutionary analyses. The new dating method, ratePlacer, extends molecular clock dating of aDNA from single-specimen to pooled environmental DNA data, where traditional methods struggle.","rel_num_authors":4,"rel_authors":[{"author_name":"Maya Lemmon-Kishi","author_inst":"University of California, Berkeley"},{"author_name":"Lenore Pipes","author_inst":"University of Hawai'i at Manoa"},{"author_name":"Bianca De Sanctis","author_inst":"University of Cambridge"},{"author_name":"Rasmus Nielsen","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Structural Mechanism of Filamentation Induced Dampening of GTP Inhibition of Glutamate Dehydrogenase","rel_doi":"10.64898\/2026.07.06.736867","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736867","rel_abs":"Glutamate dehydrogenase (GDH) is a highly regulated key enzyme that catalyzes the reversible oxidative deamination of glutamate to alpha-ketoglutarate, positioning it at a critical hub linking amino acid catabolism to energy production while supplying ammonia for urea synthesis and other nitrogen pathways. Early investigations have shown that bovine GDH (bGDH), which shares 98% sequence identity with its human homolog, assembles into polymeric filaments with altered allosteric responses. Filamentation has only relatively recently been appreciated as a widespread mechanism of enzyme regulation, prompting a reevaluation of these early observations in GDH. Here, we use high resolution cryogenic electron microscopy (cryo EM) to show that bGDH hexamers assemble via reciprocal antenna interactions that oppose the conformational changes associated with GTP inhibition, revealing how filamentation reshapes GDH allostery and with implications for the treatment of human disease.","rel_num_authors":6,"rel_authors":[{"author_name":"Zelin Shan","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Noura I Darwish","author_inst":"The University of Arizona"},{"author_name":"Andres Rivero-Gamez","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Timothy C Strutzenberg","author_inst":"The Salk Institute for Biological Studies and the University of California, San Diego"},{"author_name":"Dmitry Lyumkis","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Nancy C Horton","author_inst":"University of Arizona"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Selective convergence and graded divergence of hippocampal and amygdala subregions using functional connectivity","rel_doi":"10.64898\/2026.07.06.736898","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736898","rel_abs":"The hippocampus and amygdala are neighboring medial temporal lobe structures linked to memory and affect, yet how their subregions are jointly embedded within distributed isocortical systems remains unclear. Using resting-state fMRI from 722 Human Connectome Project Young Adult participants, we mapped hippocampal and amygdalar subregions within a unified cortex-wide framework, quantifying subregion-to-cortex connectivity via Pearson correlation (broad co-fluctuation) and GLASSO partial correlation (relatively more direct functional association). We introduced two count-based metrics: dominance (relative hippocampal vs. amygdalar representation) and sharedness (balanced co-representation). Direct associations showed both structures sharing coupling with paralimbic areas and, more modestly, default mode regions, while broader co-fluctuations extended into somatomotor and paralimbic networks. Divergence patterns depended on the estimator: hippocampal subregions preferentially coupled with default-mode and visual networks under direct association, while amygdalar nuclei favored ventral attention and limbic networks; broader co-fluctuations additionally implicated somatomotor cortex for amygdala and visual cortex for hippocampus. These principles held at the subfield\/nucleus level, varying along the hippocampal long axis and identifying the paralaminar nucleus as the most hippocampus-like amygdalar subregion. Data-driven connectivity gradients confirmed both systems' separation and fine-scale interdigitation. Hippocampal and amygdalar subregions are thus embedded in cortex not as discrete systems, but through structured, spatially organized co-representation.","rel_num_authors":10,"rel_authors":[{"author_name":"Doruk Yi\u011fit Erig\u00fc\u00e7","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Mylla Marsiglia","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Alexandra John","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"\u015eeyma Bayrak","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Bin Wan","author_inst":"University of Geneva"},{"author_name":"Anton Jakov\u010di\u0107","author_inst":"University of Zagreb"},{"author_name":"Jordan DeKraker","author_inst":"Brain and Mind Institute, Imaging Research Laboratories, Robarts Research Institute, Graduate Progra"},{"author_name":"Jessica Royer","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Boris Bernhardt","author_inst":"McGill University"},{"author_name":"Sofie L. Valk","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Dosimetric Characterization and Workflow Optimization of the FLASH-SARRP for Reliable Preclinical Radiobiological Studies","rel_doi":"10.64898\/2026.07.06.736680","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736680","rel_abs":"Objective: Preclinical small-animal irradiators such as the FLASH-SARRP can support the advancement of photon-FLASH toward the clinic. This study aimed at characterizing the FLASH-SARRP and established a robust quality assurance (QA) workflow to enable accurate and reproducible preclinical experiments. Approach: Custom 3D-printed spacers were designed to ensure reproducible X-ray tube alignment, sample positioning and mounting of the dosimetric tools. Beam characteristics were evaluated using a combined dosimetric approach. High spatially resolved dose distributions were obtained from Gafchromic films, whereas a plastic scintillating fiber was employed to monitor in real-time the temporal pulse structure and synchronization between the two X-ray tubes. Day-to-day variability of the delivery was evaluated over several sessions. Main results: The FLASH-SARRP achieved dose-rates of around 80 Gy\/s when both tubes were used simultaneously and provided a homogeneous irradiation field suitable for small-animal studies. A desynchronization between the two tubes was observed with an average delay of 10 ms, resulting in temporal dose-rate heterogeneity. Additionally, a substantial inter-session variability (~11%) was found, whereas the intra-session variability was relatively low (~4%). Inter-session variability was reduced to 5%, approaching the intra-session variability, by adding Gafchromic films\/scintillator-based quality assurance (QA) workflow into the irradiation routine. Significance: This work highlights the importance of temporal dosimetry for preclinical FLASH studies. Additionally, a practical QA framework is proposed integrating real-time monitoring with reference dosimetry. The proposed work enables adaptive dose delivery, thereby enhancing the reproducibility of the irradiations, which is crucial for reliable preclinical studies on the FLASH effect.","rel_num_authors":10,"rel_authors":[{"author_name":"Michele Knol","author_inst":"UNIGE"},{"author_name":"Patrik Goncalves Jorge","author_inst":"HUG"},{"author_name":"Louis V Kunz","author_inst":"UNIGE"},{"author_name":"Pierre Korysko","author_inst":"CERN"},{"author_name":"Benoit Petit","author_inst":"UNIGE"},{"author_name":"Andre Durham","author_inst":"HUG"},{"author_name":"Vozenin Marie-catherine","author_inst":"HUG"},{"author_name":"Pelagia Tsoutsou","author_inst":"HUG"},{"author_name":"Nikolaos Koutsouvelis","author_inst":"HUG"},{"author_name":"Julie Lascaud","author_inst":"LMU"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Cysteine-mediated bortezomib resistance is governed by \u03b1-ketoacid availability","rel_doi":"10.64898\/2026.07.06.736827","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736827","rel_abs":"Dissecting how metabolite availability impacts drug sensitivity is critical for understanding therapy resistance. While proteasome inhibitors like the boronic acid proteasome inhibitor bortezomib are cornerstones of therapy for multiple myeloma, the clinical utility of these drugs is often limited by development of resistance, the metabolic drivers of which remain poorly understood. In this study, we find that -ketoacids, including pyruvate, increase sensitivity to boronic acid proteasome inhibitors independent of their conventional roles in metabolism. Instead, -ketoacids directly react with intracellular cysteine to form thiazolidines, sequestering cysteine away from forming conjugates with boronic acid proteasome inhibitors and detoxifying these drugs. Preventing cysteine-mediated detoxification through -ketoacid supplementation increases the efficacy of boronic acid proteasome inhibitors, leading to greater proteasome inhibition and cytotoxicity that is reversed by cysteine supplementation. These findings suggest that modulating available cysteine through -ketoacid interactions can impact effective levels of some drugs in cells, and represent a potential strategy to overcome resistance and maximize the efficacy of boronic acid proteasome inhibitors.","rel_num_authors":16,"rel_authors":[{"author_name":"Jennifer A Brain","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Sarah M Chang","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Maximilian Kobiesa","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Leah G Rector","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Michele Ceribelli","author_inst":"National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA"},{"author_name":"Sky H Kim","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Zhaoqi Li","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Brian T Do","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Kelli J Che","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"David T Holland","author_inst":"National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA"},{"author_name":"Samuel Block","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Reneee Chang","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Gillian E Oaks","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Craig J Thomas","author_inst":"National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA"},{"author_name":"Matthew G Vander Heiden","author_inst":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Lucas B Sullivan","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Metallothionein loss in cancer cells contributes to increased mutations through defective DNA repair and metabolic imbalance","rel_doi":"10.64898\/2026.07.06.736843","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736843","rel_abs":"Understanding which genes are involved in mutagenesis is essential for developing cancer prevention and treatment strategies; establishing protectors of the genome has revolutionized cancer biology. Here, we describe metallothionein (MT) proteins as previously uncharacterized protectors against mutagenesis. MT is a heavy metal binding protein essential for zinc homeostasis and protection against heavy metal cytotoxicity. Because zinc binds approximately 10-15% of the proteome and is critical for processes such as DNA repair and mitochondrial health, MT loss is expected to disrupt these processes. We hypothesized that MT loss induces genomic instability by impairing DNA repair and mitochondrial function. In this study, the consequences of MT deficiency in high-grade serous ovarian cancer (HGSC) were investigated by knockdown of the most highly expressed MT, MT2A. Loss of MT2A resulted in the impaired DNA repair pathway base excision repair (BER), leading to increased mutagenesis. MT2A deficiency produced mitochondrial dysfunction, characterized by a decrease in mitochondrial membrane potential, glycolysis, oxidative phosphorylation, amino acids, and an imbalance of nucleobases. Together, these defects reflect cellular states associated with increased cancer aggressiveness. These findings identify MT as a fundamental hub maintaining genomic and metabolic integrity.","rel_num_authors":30,"rel_authors":[{"author_name":"Mirna Mina-Abouda","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA; Hollings Cancer Center, Medical University o"},{"author_name":"Amy C Rees","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Della Evans","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Evan Villamor","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"George Fullbright","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Heather R Ghent","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Madison A Clark","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Wendy Y Zhang","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA; Hollings Cancer Center, Medical University o"},{"author_name":"Isabel Koehler","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Isabella Berry","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Sydney Oesch","author_inst":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Obstetrics and Gynecology, Medical University of South C"},{"author_name":"Robert Hutchinson","author_inst":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Obstetrics and Gynecology, Medical University of South C"},{"author_name":"Davide Delisi","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Christopher de Solis","author_inst":"Mutagentech, San Francisco, CA, 94107, USA; Matter Bio, San Francisco, CA, 94107, USA"},{"author_name":"Alexander Y Maslov","author_inst":"Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA"},{"author_name":"Christopher Bradley","author_inst":"Mutagentech, San Francisco, CA, 94107, USA; Matter Bio, San Francisco, CA, 94107, USA"},{"author_name":"Samim Sharifi","author_inst":"Mutagentech, San Francisco, CA, 94107, USA; Matter Bio, San Francisco, CA, 94107, USA"},{"author_name":"Rosemarie Elloisa P Acero","author_inst":"Department of Chemistry, Texas A&M University, College Station, TX 77843, USA; Department of Biochemistry and Biophysics, Texas A&M University, College Station,"},{"author_name":"Yuri K Peterson","author_inst":"Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Jie Zhang","author_inst":"Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Zhiwei Ye","author_inst":"Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Tori C Rodrick","author_inst":"Department of Radiation Oncology, NYU Grossman School of Medicine, New York, NY, USA; Department of Biochemistry, NYU Grossman School of Medicine, New York, NY,"},{"author_name":"Danyelle M Townsend","author_inst":"Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Saverio Gentile","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA"},{"author_name":"Brian Orr","author_inst":"Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Obstetrics and Gynecology, Medical University of South C"},{"author_name":"Drew Jones","author_inst":"Department of Radiation Oncology, NYU Grossman School of Medicine, New York, NY, USA; Department of Biochemistry, NYU Grossman School of Medicine, New York, NY,"},{"author_name":"Jessica H Hartman","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA; Hollings Cancer Center, Medical University o"},{"author_name":"David T Long","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA; Hollings Cancer Center, Medical University o"},{"author_name":"Jonathan T Sczepanski","author_inst":"Department of Chemistry, Texas A&M University, College Station, TX 77843, USA; Department of Biochemistry and Biophysics, Texas A&M University, College Station,"},{"author_name":"Joe R Delaney","author_inst":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA; Hollings Cancer Center, Medical University o"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"In situ identification of substrates of the protein tyrosine phosphatase PTP1B using site-specific photo-crosslinking","rel_doi":"10.64898\/2026.07.06.736850","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736850","rel_abs":"Protein tyrosine phosphorylation is critical for cellular function, and aberrant phosphorylation is tied to a wide range of human diseases. Identifying the substrates of protein tyrosine phosphatases, the enzymes that erase this modification, is critical to understanding human biology and disease states. The state-of-the-art method for tyrosine phosphatase substrate identification requires the use of mutations that modestly increase the lifetime of enzyme-substrate complexes by kill catalytic activity. While these substrate-trapping mutants are useful tools, they work best for high-affinity or abundant substrates that remain phosphatase-bound through cell lysis and enrichment. Here, we use site-specific photo-crosslinking to covalently capture the substrates of tyrosine phosphatases in situ. We identify eight different positions around the active site of the phosphatase PTP1B where photo-crosslinker amino acids can be incorporated via amber codon suppression without dramatically disrupting catalytic activity. We then conduct photo-crosslinking experiments in mammalian cells and identify crosslinked proteins by mass spectrometry proteomics, revealing that our approach can capture known PTP1B interactors and substrates. We then show that PTP1B photo-crosslinking in situ is sensitive to enzyme localization and identify new PTP1B substrates that regulate contacts between the endoplasmic reticulum and plasma membrane. We also demonstrate that photo-crosslinking can capture signal-dependent interactions. For example, we observe PTP1B crosslinking to the epidermal growth factor (EGF) receptor, a known substrate, in an EGF stimulation-dependent manner, and we identify other potential EGF-dependent substrates. Overall, our approach reveals previously unknown roles of PTP1B in signaling systems and could be readily extended to other tyrosine phosphatases in the same family.","rel_num_authors":8,"rel_authors":[{"author_name":"Andrew C Johns","author_inst":"Columbia University"},{"author_name":"Yethmie S Goonatilleke","author_inst":"Columbia University"},{"author_name":"David C Cabanero","author_inst":"Columbia University"},{"author_name":"Yanhze Ma","author_inst":"Columbia University"},{"author_name":"Minhee Lee","author_inst":"Columbia University"},{"author_name":"Anne E van Vlimmeren","author_inst":"Columbia University"},{"author_name":"Marko Jovanovic","author_inst":"Columbia University"},{"author_name":"Neel H Shah","author_inst":"Columbia University"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Efficient Endogenous Tagging in the Sea Urchin, Lytechinus pictus, Using CRISPR\/Cas9-mediated Split-Fluorescent Protein Knock-In","rel_doi":"10.64898\/2026.07.06.736833","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736833","rel_abs":"Precise knock-in of fluorescent reporters is a powerful tool for studying the dynamic cellular and molecular processes of embryogenesis. However, conventional CRISPR-Cas9 knock-in of large inserts, such as full-length fluorescent proteins, is inefficient. This has limited its application in many emerging model systems, including sea urchins. Here, we overcome this barrier using a transgenic Lytechinus pictus line that constitutively and ubiquitously expresses a large fragment of mNeonGreen (mNG3K1-10). In this line, fluorescence is only reconstituted when CRISPR-mediated knock-in delivers mNG211, the 11th beta strand of the fluorescent protein, to complement the constitutively expressed fragment. Because this strategy requires integrating only the short 11th-strand, together with short homology arms (~130 nt total), by homology directed repair, it circumvents the size constraints that limit conventional full-length reporter knock-ins using CRISPR. Using this approach, we achieved integration efficiencies of 14-22%, roughly an order of magnitude higher than those obtained with full-length fluorescent protein knock-ins. This provides a streamlined, scalable method for endogenous protein visualization in echinoderm embryos and a valuable resource for studying gene function, morphogenesis, and toxicant response in this classic developmental model.","rel_num_authors":7,"rel_authors":[{"author_name":"Yoon Lee","author_inst":"University of California, San Diego"},{"author_name":"Chloe Jenniches","author_inst":"University of California, San Diego"},{"author_name":"Svenja Kling","author_inst":"UC San Diego"},{"author_name":"Evan Tjeerdema","author_inst":"University of California, San Diego"},{"author_name":"Elliot Jackson","author_inst":"University of California, San Diego"},{"author_name":"Alexandre Paix","author_inst":"EMBL Heidelberg"},{"author_name":"Amro Hamdoun","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Striatal activity during contextual word learning is influenced by children's reading ability","rel_doi":"10.64898\/2026.07.06.736136","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736136","rel_abs":"Contextual word learning is a fundamental mechanism for vocabulary acquisition during childhood. In adults, successful inference of word meaning from context is intrinsically rewarding, and is associated with greater enjoyment and greater activity in reward-related brain regions. Whether similar reward mechanisms support word learning in children, and whether they differ as a function of ability, remains unknown. We used functional magnetic resonance imaging (fMRI) to examine neural responses during contextual word learning in 25 children aged 11-13 years with typical reading skills and in 20 age-matched children with dyslexia. Neurotypical readers showed enhanced activation in core reward-processing regions, including the ventral striatum, when successfully learning the meanings of novel words. In contrast, children with dyslexia did not exhibit comparable reward-related responses despite performing the same task. Crucially, this group difference was specific to word learning, as no significant group differences were observed in ventral striatal responses during a non-linguistic monetary reward task. In addition, to confirm the behavioural relevance of these neural findings, we examined an age-matched, independent sample of children. We found that stronger reading skills were associated with greater enjoyment during successful word learning. Together, these results suggest that interactions between reward and language systems during contextual word learning is influenced by reading proficiency. Reduced intrinsic reward responses to successful language learning may contribute to differences in reading development and have implications for the design of more engaging and effective reading interventions for struggling readers.","rel_num_authors":8,"rel_authors":[{"author_name":"Nilgoun Bahar","author_inst":"University of California, San Francisco"},{"author_name":"Desislava Arabadzhiyska","author_inst":"Department of Psychology, Royal Holloway, University of London"},{"author_name":"Hannah Jones","author_inst":"Division of Psychology and Language Sciences, University College London"},{"author_name":"Sonia Singh","author_inst":"Division of Psychology and Language Sciences, University College London"},{"author_name":"Miykael Davis","author_inst":"Division of Psychology and Language Sciences, University College London"},{"author_name":"Jessie Ricketts","author_inst":"Department of Psychology, Royal Holloway, University of London"},{"author_name":"Pablo Ripolles","author_inst":"Department of Psychology, New York University"},{"author_name":"Saloni Krishnan","author_inst":"Division of Psychology and Language Sciences, University College London"}],"rel_date":"2026-07-07","rel_site":"biorxiv"},{"rel_title":"Validation of aEEG-CSA Neonatal Seizure Detection Algorithm on Hypothermia Treated Infants with HIE","rel_doi":"10.64898\/2026.07.02.26356964","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356964","rel_abs":"ObjectiveTo validate a neonatal seizure detection algorithm that is based on extracted clinical features of the aEEG and CSA on a cohort of cooled neonatal patients with hypoxic ischemic encephalopathy.\n\nMethodsA seizure detection algorithm was designed using aEEG margin features, CSA features, trained on a public dataset of 79 neonatal EEGs with three supervised machine learning classifiers. It was subsequently tested on an inhouse cohort of 23 neonates with asphyxia whose EEGs were collected during cooling therapy.\n\nResultsThe trained Random Forest, Support Vector Machines and Artificial Neural Network classifiers had an AUC of 0.76, 0.77, and 0.77 and an average accuracy of 0.85, 0.86, and 0.85 respectively. Finally, the average AUC across the 10 seizure patients included was 0.85.\n\nConclusionA neonatal seizure detection algorithm that uses a combination of aEEG and CSA clinical features can capture seizures in HIE patients. Performance across seizure patients is not correlated with seizure duration.","rel_num_authors":5,"rel_authors":[{"author_name":"Sylvia Edoigiawerie","author_inst":"Cook County Hospital"},{"author_name":"Julia Henry","author_inst":"AdventHealth for Children"},{"author_name":"Brett Beaulieu-Jones","author_inst":"University of Chicago"},{"author_name":"Henry David","author_inst":"University of Chicago"},{"author_name":"Naoum Issa","author_inst":"University of Chicago"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"GLP Medications and Severe Post-COVID-19 Outcomes Among Individuals with Type 2 Diabetes Mellitus","rel_doi":"10.64898\/2026.07.03.26357246","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357246","rel_abs":"Background: Glucagon-like peptide-1 receptor agonist-based therapies (GLP) have recently emerged as promising treatments across a wide range of health conditions. These medications may have protective effects against severe long-term consequences of COVID-19 by promoting weight loss, exerting antihyperglycemic and anti-inflammatory effects, and providing cardiovascular and endothelial protection. Methods: We evaluated electronic health record data from a retrospective cohort of individuals in the National Clinical Cohort Collaborative. We included individuals with type 2 diabetes mellitus and comorbid COVID-19 who were prescribed either GLP (treatment) or a sodium-glucose co-transporter 2 inhibitor (SGLT2i) and subsequently developed acute COVID-19 between October 1, 2021, and April 1, 2023. We compared the 12-month cumulative incidence of mortality and Long COVID (Long COVID diagnosis and probable Long COVID via computational phenotype) between groups. We applied targeted maximum likelihood estimation to compare outcome risks by exposure status, controlling for covariates of interest. Results: We analyzed data from 14,215 individuals with COVID-19 and comorbid type 2 diabetes (mean age, 60 years; mean BMI, 37). Compared to SGLT2i, a prescription for GLP medication was associated with a lower risk of mortality (adjusted risk ratio [aRR] 0.71; 95% CI 0.53, 0.95), but not Long COVID diagnosis (aRR 1.01; 95% CI 0.80, 1.27) or probable Long COVID (aRR 0.94; 95% CI 0.88, 1.01). Conclusions: We found that among individuals with type 2 diabetes and comorbid COVID-19, a prescription for GLP vs. SGLT2i medications was associated with a lower risk of mortality, but not Long COVID.","rel_num_authors":14,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John B. Buse","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Steven Johnson","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Jane Reusch","author_inst":"University of Colorado, Anschutz, Aurora, CO, USA"},{"author_name":"Carolyn Bramante","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Rachel Wong","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Cardiovascular events in individuals with small\/medium LDL particle discordance","rel_doi":"10.64898\/2026.06.25.26356542","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356542","rel_abs":"AimsDespite similar LDL-C levels, size and composition of LDL particles (LDL-P) varies widely. Among the metabolically perturbed, or those with altered function of lipid regulatory proteins, LDL-C levels mask elevated atherogenic small-medium LDL-P (S\/M LDL-P). We assessed the contribution of such discordance in S\/M LDL-P on major adverse cardiovascular event risk (MACE).\n\nMethods and resultsUK Biobank participants with Nightingale NMR metabolomics (487,521 participants), were classified as high or low cardiometabolic burden. S\/M LDL-P discordance was defined as the difference between LDL-C predicted S\/M LDL-P and observed S\/M LDL-P. Genetic variants encoding cholesterol ester transfer protein (CETP), which regulates cholesterol-triglyceride exchange and the production of small LDL particles, were identified via whole genome sequencing. Adjusted Cox proportional hazard regression was used to estimate MACE associations. S\/M LDL-P discordance showed an LDL-C and Apo-B independent association with MACE (47,935 cases), which differed by cardiometabolic burden group: hazard ratio (HR) per standard deviation 1.09 (95%CI 1.05; 1.13) and HR 1.24 (95%CI 1.21; 1.27) for low\/high burden, respectively. Loss of function (LoF) CETP variants were strongly associated with lower levels of both S\/M LDL-P and S\/M LDL-P discordance. For example, the S\/M LDL-P discordance effect of CETP LoF carriership for low\/high metabolic burden, respectively, was -4.62 nmol\/L (95%CI -8.40; -0.83) compared to -11.10 nmol\/L (95%CI -15.57; -6.63).\n\nConclusionS\/M LDL-P discordance (overabundance) is strongly associated with MACE risk, especially in people with high cardiometabolic burden. S\/M LDL-P discordance is modified by CETP genetic variation, suggesting a role for CETP-mediated lipid remodelling beyond LDL-C changes.\n\nTranslational perspectiveConventional lipid parameters such as LDL-C and apolipoprotein B may underestimate the atherogenic burden conferred by an overabundance of small and medium LDL particles, particularly in patients with diabetes, obesity, or established atherosclerotic disease. We introduce a novel measure of small\/medium LDL particle (S\/M LDL-P) discordance, quantifying the excess of S\/M LDL-P beyond what is predicted by LDL-C alone. S\/M LDL-P discordance is independently associated with time to incident MACE, especially in people with increased cardiometabolic burden. Genetic loss of function in cholesteryl ester transfer protein (CETP), which regulates cholesterol-triglyceride exchange and the production of small LDL particles, reduced S\/M LDL-P discordance, in particular among those with metabolically perturbed states where discordance was otherwise high. Taken together, these findings provide support for the potential role of CETP inhibition, as a therapeutic strategy that may lower cardiovascular risk in part through reduction of S\/M LDL-P discordance. This hypothesis is currently being evaluated with obicetrapib in the PREVAIL trial.","rel_num_authors":10,"rel_authors":[{"author_name":"Amand Floriaan Schmidt","author_inst":"University College London"},{"author_name":"Nikita Hukerikar","author_inst":"University College London"},{"author_name":"Sam Quill","author_inst":"University College London"},{"author_name":"Marion van Vugt","author_inst":"Amsterdam University Medical Centers"},{"author_name":"Mathijs de Kleer","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Marc Ditmarsch","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Michael Szarek","author_inst":"University of Colorado School of Medicine"},{"author_name":"John J. Kastelein","author_inst":"NewAmsterdam Pharma B.V."},{"author_name":"Kausik K. Ray","author_inst":"Imperial College London"},{"author_name":"Michael H. Davidson","author_inst":"University of Chicago"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Association of Neutrophil-to-Lymphocyte Ratio and Systemic Immune-Inflammation Index With Mortality in Patients With Pericarditis: A Retrospective Dual-Cohort Study Using Two Independent Databases","rel_doi":"10.64898\/2026.06.25.26356550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356550","rel_abs":"BackgroundRisk stratification in pericarditis relies mainly on clinical presentation, suspected etiology, imaging findings, and conventional inflammatory biomarkers. Whether complete blood count-derived inflammatory indices are associated with mortality in pericarditis and reproducible across independent real-world datasets remains unclear.\n\nMethodsWe conducted a retrospective dual-cohort study of hospitalized adults with pericarditis using a Hong Kong cohort from the Clinical Data Analysis and Reporting System (CDARS) as the primary analysis cohort and the Medical Information Mart for Intensive Care IV (MIMIC-IV) cohort as an independent reproducibility cohort. Baseline neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) were analyzed as continuous variables and cohort-specific tertiles. The primary outcome was long-term all-cause mortality in the Hong Kong cohort. Secondary and reproducibility outcomes included 90-day mortality in the Hong Kong cohort and 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Cox models were adjusted for age, sex, renal disease, diabetes mellitus, hypertension, ischemic heart disease, and malignancy.\n\nResultsAmong 504 patients in the Hong Kong cohort and 464 patients in MIMIC-IV, all-cause mortality occurred in 241 and 113 patients during cohort-specific follow-up, respectively. In the Hong Kong cohort, higher NLR was associated with long-term all-cause mortality after full adjustment. Compared with NLR tertile 1, the adjusted hazard ratio was 1.60 for tertile 3. Higher SII was also associated with long-term mortality, with an adjusted hazard ratio of 1.55 for tertile 3 versus tertile 1. NLR and SII showed directionally consistent associations with 90-day mortality in the Hong Kong cohort and with 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Sensitivity analyses yielded broadly consistent findings.\n\nConclusionsIn two independent real-world cohorts of hospitalized patients with pericarditis, higher baseline NLR and SII were associated with increased all-cause mortality, with NLR showing the more consistent prognostic signal. These complete blood count-derived indices may provide simple adjunctive information for mortality risk stratification, although prospective validation is needed before incorporation into formal management algorithms.","rel_num_authors":5,"rel_authors":[{"author_name":"Lingyu Mi","author_inst":"Chinese Academy of Medical Sciences & Peking Union Medical College"},{"author_name":"Ishan Lakhani","author_inst":"Chinese University of Hong Kong"},{"author_name":"Wing Tak Wong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Gary Tse","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Fang Fang","author_inst":"Chinese Academy of Medical Sciences & Peking Union Medical College"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Diagnostic accuracy and acceptability of self- and health worker-collected tongue swabs for Mycobacterium tuberculosis complex detection in adults in South Africa","rel_doi":"10.64898\/2026.07.04.26357275","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357275","rel_abs":"Tongue swabs (TSs) are a non-invasive specimen type for the detection of Mycobacterium tuberculosis complex (MTBC) and can expand access to testing for individuals unable to produce sputum. This study evaluated the diagnostic performance and user acceptability of self-collected and health worker (HW)-collected tongue swabs using the Xpert MTB\/RIF Ultra (Ultra) assay and assessed participant perspectives on self-collection.\n\nIn this prospective, cross-sectional study, symptomatic and asymptomatic adults under investigation for TB were enrolled from a high HIV prevalence setting. Each participant provided both a self-collected and a HW-collected TS, which were tested using Ultra. Ultra TS results were compared to liquid culture as the reference standard and sputum Ultra as a comparator. Participant perspectives on self-collection were captured via questionnaires.\n\nSensitivity on Ultra for both self- and HW-collected TSs was 68% (95% CI:51.9-81.9), compared to liquid culture. This sensitivity was significantly higher than that of sputum smear microscopy (46%, 95% CI: 30.7-62.6; McNemars p = 0.003). Tongue swab sensitivity was lower than sputum Ultra (80.5%; p<0.001) and decreased with low bacillary loads. Importantly, TSs enabled MTBC detection in six participants unable to produce sputum. Most participants (>90%) found self-collection instructions easy to follow, reporting high confidence and comfort, and trust in results from self-collected TSs.\n\nThis study demonstrates that self-collected TSs perform comparably to those collected by health workers for TB detection using Ultra and are both feasible and acceptable in a high TB\/HIV burden setting. To maximize impact, clear training instructions and robust linkage to care remain critical priorities.\n\nImportanceThis study supports the use of tongue swabs (TSs) as a non-invasive alternative for tuberculosis diagnosis, particularly for individuals unable to produce sputum. When tested on the Xpert MTB\/RIF Ultra assay, self-collected TSs performed comparably to health worker-collected swabs, yielding a 68% sensitivity (95% CI: 51.9-81.9) relative to liquid culture. This sensitivity was significantly higher than that of sputum smear microscopy (46%, 95% CI: 30.7-62.6; McNemars p = 0.003). Importantly, TSs successfully detected Mycobacterium tuberculosis complex in six patients who could not provide sputum, underscoring their clinical utility in expanding diagnostic access. Furthermore, high user acceptability (>90%) confirms that self-collection is both feasible and trusted by patients in high TB\/HIV burden settings. To maximize real-world impact, implementing clear training instructions and establishing robust linkage to care, especially following negative results, remain critical programmatic priorities.","rel_num_authors":10,"rel_authors":[{"author_name":"Anura David","author_inst":"University of the Witwatersrand Faculty of Health Sciences"},{"author_name":"Yeonsoo Baik","author_inst":"Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Lesley Scott","author_inst":"University of the Witwatersrand Johannesburg Faculty of Health Sciences"},{"author_name":"Griffiths Kubeka","author_inst":"The Aurum Institute for Health Research, Parktown, Johannesburg, South Africa"},{"author_name":"Adelaide Benoit","author_inst":"Johns Hopkins University School of Public Health, Maryland, USA"},{"author_name":"Lyndel Singh","author_inst":"Wits Diagnostics Innovation Hub, Wits Health Consortium (PTY) Ltd, Johannesburg, South Africa"},{"author_name":"Pedro da Silva","author_inst":"National Priority Programmes, National Health Laboratory Services, Johannesburg, South Africa"},{"author_name":"Wendy Stevens","author_inst":"Wits Diagnostics Innovation Hub, Health Sciences Research Office, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg"},{"author_name":"Gregory P Bisson","author_inst":"Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA"},{"author_name":"Salome Charalambous","author_inst":"The Aurum Institute"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"NEXIM: A Nash Equilibrium-Based Framework for Stable Explainable AI in Medical Applications","rel_doi":"10.64898\/2026.06.25.26356568","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356568","rel_abs":"Reliable explanations are important for trustworthy medical applications of artificial intelligence (AI), but attribution-based explanations can vary across model randomization and small analytic changes. We present NEXIM (Nash Equilibrium-based Explainability and Interpretability Model), implemented here as an accuracy-constrained, equilibrium-inspired model-selection framework that jointly evaluates held-out prediction error, explanation stability, and cross-model connectivity. The implementation evaluated ten GradientBoosting Regressor models per prediction horizon, differing only by random seed (0-9), using a fixed 75\/25 patient split. Kernel SHAP attribution vectors were compared using Spearman rank correlation, and graph connectivity summarized whether each model belonged to a dense explanation-similarity region. Candidate models within 0.02 Montreal Cognitive Assessment points of the best root mean squared error (RMSE) were ranked using a multiplicative Explanation Equilibrium Score. In longitudinal Parkinsons Progression Markers Initiative data, NEXIM selected the RMSE-optimal model at the one- and three-year horizons. At the two-year horizon, it selected Model 4 rather than the RMSE-only Model 8, increasing scaled stability from 0.8757 to 0.8847 and normalized graph connectivity from 0.889 to 1.000 while increasing RMSE by only 0.0014. The two models retained the same top-20 feature set but differed modestly in feature order, illustrating that NEXIM primarily acted as a reproducibility screen rather than identifying clinically contradictory explanations. Stability and consensus are treated as reproducibility criteria, not evidence of causal faithfulness, clinical usefulness, or improved patient outcomes. NEXIM may therefore serve as a governance checkpoint for model refresh and documentation, but external validation, stronger model-family baselines, and prospective clinical evaluation remain necessary.","rel_num_authors":4,"rel_authors":[{"author_name":"Dipak P Upadhyaya","author_inst":"Case Western Reserve University"},{"author_name":"Satya S Sahoo","author_inst":"Case Western Reserve University"},{"author_name":"Katrina Prantzalos","author_inst":"Case Western Reserve University"},{"author_name":"Pedram Golnari","author_inst":"Case Western Reserve University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Tacrolimus variability and creatinine predict readmission after liver transplantation","rel_doi":"10.64898\/2026.07.02.26357106","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357106","rel_abs":"Unplanned readmissions after liver transplantation occur in over 30% of recipients, yet no validated prediction models exist, and prior observational studies suffer from immortal time bias. The optimal readmission window for outcome prediction and the feasibility of early risk stratification remain undefined.  This study is a retrospective analysis of 922 adult liver transplant recipients (August 2018-August 2025) at a single center. Time-varying Cox regression evaluated 14-, 30-, and 90-day readmission windows as predictors of 1-year mortality, correcting for immortal time bias. Gradient-boosted machine learning models leveraging 528,400 laboratory measurements (28 analytes) predicted 90-day readmission using either complete hospitalization data or data restricted to postoperative day 7. Feature importance was quantified by gain, and clinical utility was assessed through risk stratification.  Among 902 hospital survivors, 342 (37.9%) experienced an unplanned readmission within 90 days of initial discharge.  Only the 90-day readmission window predicted 1-year mortality in time-varying analysis (HR 1.73, 95% CI 1.17-2.57, p=0.006).  The model for readmission using complete data achieved AUC 0.614 (95% CI 0.576-0.652); the postoperative day 7 restricted model achieved AUC 0.615 (95% CI 0.577-0.652), with no meaningful performance difference. The tacrolimus coefficient of variation x peak creatinine interaction was the dominant predictor in both the complete model (17.3% importance, rank 1) and the day 7 restricted model (20.4% importance, rank 2). This interaction stratified patients into high-risk (tacrolimus CV >0.3 and creatinine >2.0 mg\/dL; 49.8% readmission) versus low-risk (24.8% readmission) groups (risk ratio 2.01, p<0.001).  These results identify a modifiable biological determinant of readmission and establish a framework for targeted interventions to reduce unplanned readmission and improve post-transplant outcomes.","rel_num_authors":1,"rel_authors":[{"author_name":"Kevin  Marc Korenblat","author_inst":"Washington University School of Medicine in Saint Louis: Washington University in St Louis School of Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Expanding the Pediatric Heart Donor Pool: National Outcomes of Donation After Circulatory Death Versus Donation After Brain Death Heart Transplantation","rel_doi":"10.64898\/2026.07.03.26357254","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357254","rel_abs":"BackgroundDonation after circulatory death (DCD) is an increasingly accepted strategy to expand the adult heart donor pool, but its use in children remains limited and incompletely characterized. We compared national characteristics and post-transplant outcomes of pediatric DCD versus donation after brain death (DBD) heart transplantation.\n\nMethodsWe performed a retrospective cohort study of the Organ Procurement and Transplantation Network (OPTN) registry, including patients younger than 18 years who underwent primary isolated heart transplantation between January 1993 and March 2025. Recipients were stratified by donor type (DCD vs DBD). Continuous variables were compared with the Mann-Whitney U test and categorical variables with the {chi}2 or Fisher exact test. Survival was estimated by the Kaplan-Meier method and compared using the log-rank test and Cox proportional hazards regression.\n\nResultsOf 10,671 pediatric heart transplant recipients, 33 (approximately 0.3%) received DCD allografts. The first DCD transplant was recorded in 2004, with a marked increase in 2023-2024. Compared with DBD recipients, DCD recipients were more frequently infants (<1 year, 51.5% vs 28.4%) and more often had congenital heart disease (69.7% vs 47.6%; P=0.033); DCD donors were younger (median 0 vs 6 years; P=0.038) and more frequently died of anoxia (72.7% vs 37.0%; P<0.001). Donor and recipient left ventricular mass were lower in the DCD group (P<0.05), but predicted left ventricular mass matching was similar. DCD recipients had longer hospital stays (median 31.5 vs 19 days; P=0.023); rates of treated rejection, dialysis, stroke, and pacemaker implantation were comparable. Early survival did not differ (30-day, 90-day, and 1-year), and Kaplan-Meier survival through 5 years was not significantly different (hazard ratio 1.17; 95% CI 0.49-2.81; log-rank P=0.73). More than 90% of DCD transplants were performed in four UNOS regions (11, 4, 5, and 8).\n\nConclusionsIn this national analysis, pediatric DCD heart transplantation was uncommon but expanding rapidly, concentrated in a few regions, and used preferentially in infants and children with congenital heart disease. Early post-transplant outcomes were not significantly different from DBD, supporting cautious expansion of DCD as a means of enlarging the pediatric donor pool. The small number of DCD recipients and limited follow-up warrant confirmation in larger, longer-term studies.","rel_num_authors":9,"rel_authors":[{"author_name":"Bilal Khan Mohammed","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Rohit Ganduboina","author_inst":"NRI Institute of Medical Sciences"},{"author_name":"Omar Abdel Kerim","author_inst":"University of Miami Miller School of Medicine, Miami"},{"author_name":"Gayatri Muley","author_inst":"Grant Medical College and Sir J.J. Group of Hospitals"},{"author_name":"Palak Dutta","author_inst":"University of Illinois College of Medicine"},{"author_name":"Nitya Krishna Arumugam","author_inst":"Kasturba Medical College, Manipal"},{"author_name":"John Karamichalis","author_inst":", Columbia University Irving Medical Center"},{"author_name":"Yahiya Pasha Quadri Syed","author_inst":"UW Health Swedish American Hospital"},{"author_name":"Sandeep Sainathan","author_inst":"University of Miami Miller School of Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Saliva cell-free mitochondrial DNA (cf-mtDNA) response during physical and cognitive stress","rel_doi":"10.64898\/2026.07.02.26356953","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356953","rel_abs":"Emerging evidence suggests that saliva cell-free mitochondrial DNA (cf-mtDNA) increases in response to psychosocial and physical stress. Here, we quantified saliva cf-mtDNA changes in response to acute physical and cognitive stressors as well as identifying potential predictors of these responses, while also exploring the potential modulatory effects of transcranial infrared laser stimulation (TILS). In a crossover design, a total of 47 participants (53% female, ages 18-30) underwent up to three experimental sessions, including an exercise stress task and two cognitive stress tasks. Repeated saliva samples were collected for cf-mtDNA and cell-free nuclear DNA (cf-nDNA) quantification, alongside continuous measurement of heart rate, oxygen consumption, and blood pressure. Our results show that average cf-mtDNA levels increased by 90% after baseline during exercise experiments, and in cognitive stress experiments peaked 160% above average baseline levels during the stress task. Inter-individual differences in response trajectories were associated with differences in factors such as fitness, sleep quality, and stress perception. Notably, participants with higher cf-mtDNA elevations during the exercise experiment reported fewer recent stressful incidents, drank alcohol less frequently, had higher maximum VO2 during exercise, and had lower BMI. More dynamic responses to cognitive stress were observed in participants with poorer sleep quality and greater blood pressure reactivity. These findings provide a foundation for larger studies by highlighting the dynamic behavior of saliva cf-mtDNA following physical and cognitive stressors, and by suggesting potential drivers of individual differences in saliva cf-mtDNA stress reactivity.","rel_num_authors":7,"rel_authors":[{"author_name":"Caroline Trumpff","author_inst":"Columbia University"},{"author_name":"David Shire","author_inst":"Columbia University"},{"author_name":"Tian Wang","author_inst":"Columbia University"},{"author_name":"Shuang Wang","author_inst":"Columbia University"},{"author_name":"Temmie Yu","author_inst":"Columbia University"},{"author_name":"Martin Picard","author_inst":"Columbia University"},{"author_name":"Annie T. Ginty","author_inst":"Baylor University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Maternal Extracellular Vesicles During Pregnancy and Autism Risk in Children","rel_doi":"10.64898\/2026.06.25.26355526","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26355526","rel_abs":"BackgroundDifferences in extracellular vesicles (EVs), bioactive nanoparticles involved in intercellular signaling, have been reported in those with autism. However, little is known about the association between maternal EVs during pregnancy and the likelihood of autism in offspring. This study evaluated the association of the concentration and cargo material of EVs in prenatal maternal plasma with childhood autism likelihood.\n\nMethodsParticipants in the Nulliparous Pregnancy Outcomes Study provided maternal plasma at 15-23 weeks gestational age. EVs were isolated by ultracentrifugation, and concentration, mean size, CD63 levels, and RNA cargo were assessed by nanoparticle tracking analysis, ELISA, and small RNA sequencing. At 4.5-6 years of age, parents completed the Social Communication Questionnaire. Thirty-one children at high-risk for autism were matched to 31 low-risk children on sex, age, and gestational age. Differential RNA transcript analysis and over representation analysis were performed.\n\nResultsThere were no group differences in CD63 levels, mean particle size, or EV concentration (p>0.1). Nominal bin-level differences were observed at 280-290 nm and 430-440 nm before multiple-comparison correction. One hundred forty-five RNAs, including protein-coding RNAs, piRNAs, lncRNAs, miRNAs, snoRNAs, snRNAs, and tRNAs, were differentially contained, most of them downregulated in those at high risk of autism. These RNAs mapped to pathways involved in immune\/inflammatory signaling, intracellular trafficking, protein turnover, and neurodevelopment. Six of the 62 (9.7%) differentially contained protein-coding RNAs overlapped with genes in the SFARI Gene database.\n\nLimitationsLarge studies involving individuals diagnosed with autism are needed to evaluate the role of prenatal EVs in the pathogenesis of the condition. Additionally, prenatal sampling of EVs across multiple timepoints and subsequent deconvolution to determine the source of the EVs will strengthen interpretability and veracity of our findings.\n\nConclusionsThese findings provide preliminary evidence that maternal prenatal EV RNA cargo is associated with childhood autism likelihood.","rel_num_authors":13,"rel_authors":[{"author_name":"Delia McGowan","author_inst":"Barnard College, Columbia University, New York, NY, United States"},{"author_name":"Serena Nencini","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"William Yakah","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Claire-Marie Vacher","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Helene Lacaille","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"David M Haas","author_inst":"Department of Obstetrics and Gynecology, School of Medicine, Indiana University, Indianapolis, IN, United States"},{"author_name":"William A Grobman","author_inst":"Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, United States"},{"author_name":"Robert M Silver","author_inst":"Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, United States"},{"author_name":"Uma M Reddy","author_inst":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States"},{"author_name":"Ronald J Wapner","author_inst":"Department of Obstetrics and Gynecology, Columbia University Irving Medical Center New York, NY, United States"},{"author_name":"William P Fifer","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States; Department of Psychiatry, Columbia University Irving Medical C"},{"author_name":"Anna A Penn","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Morgan R Firestein","author_inst":"Department of Pediatrics, Child Health Institute of New Jersey, Brain Health Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United St"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Maternal Extracellular Vesicles During Pregnancy and Autism Risk in Children","rel_doi":"10.64898\/2026.06.25.26355526","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26355526","rel_abs":"BackgroundDifferences in extracellular vesicles (EVs), bioactive nanoparticles involved in intercellular signaling, have been reported in those with autism. However, little is known about the association between maternal EVs during pregnancy and the likelihood of autism in offspring. This study evaluated the association of the concentration and cargo material of EVs in prenatal maternal plasma with childhood autism likelihood.\n\nMethodsParticipants in the Nulliparous Pregnancy Outcomes Study provided maternal plasma at 15-23 weeks gestational age. EVs were isolated by ultracentrifugation, and concentration, mean size, CD63 levels, and RNA cargo were assessed by nanoparticle tracking analysis, ELISA, and small RNA sequencing. At 4.5-6 years of age, parents completed the Social Communication Questionnaire. Thirty-one children at high-risk for autism were matched to 31 low-risk children on sex, age, and gestational age. Differential RNA transcript analysis and over representation analysis were performed.\n\nResultsThere were no group differences in CD63 levels, mean particle size, or EV concentration (p>0.1). Nominal bin-level differences were observed at 280-290 nm and 430-440 nm before multiple-comparison correction. One hundred forty-five RNAs, including protein-coding RNAs, piRNAs, lncRNAs, miRNAs, snoRNAs, snRNAs, and tRNAs, were differentially contained, most of them downregulated in those at high risk of autism. These RNAs mapped to pathways involved in immune\/inflammatory signaling, intracellular trafficking, protein turnover, and neurodevelopment. Six of the 62 (9.7%) differentially contained protein-coding RNAs overlapped with genes in the SFARI Gene database.\n\nLimitationsLarge studies involving individuals diagnosed with autism are needed to evaluate the role of prenatal EVs in the pathogenesis of the condition. Additionally, prenatal sampling of EVs across multiple timepoints and subsequent deconvolution to determine the source of the EVs will strengthen interpretability and veracity of our findings.\n\nConclusionsThese findings provide preliminary evidence that maternal prenatal EV RNA cargo is associated with childhood autism likelihood.","rel_num_authors":13,"rel_authors":[{"author_name":"Delia McGowan","author_inst":"Barnard College, Columbia University, New York, NY, United States"},{"author_name":"Serena Nencini","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"William Yakah","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Claire-Marie Vacher","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Helene Lacaille","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"David M Haas","author_inst":"Department of Obstetrics and Gynecology, School of Medicine, Indiana University, Indianapolis, IN, United States"},{"author_name":"William A Grobman","author_inst":"Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, United States"},{"author_name":"Robert M Silver","author_inst":"Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, United States"},{"author_name":"Uma M Reddy","author_inst":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States"},{"author_name":"Ronald J Wapner","author_inst":"Department of Obstetrics and Gynecology, Columbia University Irving Medical Center New York, NY, United States"},{"author_name":"William P Fifer","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States; Department of Psychiatry, Columbia University Irving Medical C"},{"author_name":"Anna A Penn","author_inst":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States"},{"author_name":"Morgan R Firestein","author_inst":"Department of Pediatrics, Child Health Institute of New Jersey, Brain Health Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United St"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Comparative efficacy and acceptability of cognitive-behavioural therapy for insomnia and its abbreviated versions: a systematic review and network meta-analysis","rel_doi":"10.64898\/2026.07.04.26357278","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357278","rel_abs":"ObjectiveTo assess the comparative efficacy and acceptability of cognitive behavioural therapy for insomnia (CBT-I), its abbreviated versions and control conditions.\n\nDesignSystematic review and network meta-analysis.\n\nMethodsScreening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Frequentist, random-effects network meta-analyses estimated odds ratios (ORs) or mean differences with 95% confidence intervals (CIs). The primary outcome was insomnia remission post-treatment. Secondary outcomes included dropout and subjective sleep continuity measures. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA).\n\nData sourcesWe searched MEDLINE, Embase, PsycINFO and Cochrane CENTRAL from inception to December 15, 2025, with a medical information specialist.\n\nEligibility criteria for selecting studiesRandomized -controlled trials (RCTs) comparing CBT-I and its abbreviated versions with each other or with control conditions, in adults with insomnia, with or without comorbidities. To reduce clinical heterogeneity related to treatment intensity and adherence, we restricted inclusion to in-person delivery.\n\nResultsWe identified 11,379 records and included 77 RCTs (5,731 participants; mean age 52.2 years; 3,473 female). CBT-I (number of arms k = 53; number of participants n = 2,002), sleep restriction and stimulus control therapy (SRT&SCT; k = 16; n = 549), sleep restriction therapy (SRT; k = 5; n = 196) and stimulus control therapy (SCT; k = 7; n = 144) were associated with higher remission than sleep hygiene, relaxation therapy and other control conditions. These interventions were also effective in improving subjective sleep continuity measures. Cognitive therapy for insomnia (CT-I) was more beneficial than relaxation therapy. Dropout did not differ meaningfully between interventions and controls. Confidence in evidence was moderate for CBT-I, low for SRT&SCT and SRT, very low for SCT. Given the weighted mean proportion of insomnia remission among sleep hygiene arms of 20%, CBT-I probably leads to a remission rate of 41% (95% CI, 34%; 48%), SRT&SCT may lead to a remission rate of 40% (30%; 52%), SCT 43% (25%; 63%), and SRT 41% (26%; 57%).\n\nConclusionsCBT-I doubles the absolute insomnia remission compared with sleep hygiene, and its abbreviated behavioural therapies, namely, SRT&SCT, SCT and SRT may offer similar benefits with lower resource requirements, but evidence is less certain. CT-I needs further investigations. Relaxation therapy was inferior to these therapies. Implementation decisions should consider resource requirements and evidence certainty.\n\nWhat is already known on this topic- Insomnia is prevalent and disabling, and cognitive behavioural therapy for insomnia (CBT-I) is recommended as the first-line treatment.\n\n- CBT-I and its abbreviated versions are recommended in guidelines, but their comparative efficacy and acceptability remain uncertain.\n\nWhat this study adds- CBT-I and its core behavioural components (sleep restriction and stimulus control) probably achieve similar remission rates, offering scalable options where full CBT-I is not available.\n\n- Relaxation therapy was inferior to cognitive behavioural therapy for insomnia, its abbreviated, behavioural interventions, and cognitive therapy for insomnia.\n\n- Dissemination and implementation attempts should balance the confidence in the evidence and simplicity of abbreviated versions.","rel_num_authors":21,"rel_authors":[{"author_name":"Masatsugu Sakata","author_inst":"Department of Neurodevelopmental Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan"},{"author_name":"Shino Kikuchi","author_inst":"Center for Psycho-Oncology and Palliative Care, Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan"},{"author_name":"Masami Ito","author_inst":"Department of Health Promotion and Behavioral Sciences, Kyoto University Graduate School of Medicine\/School of Public Health, Kyoto, Japan"},{"author_name":"Rie Toyomoto","author_inst":"Department of Health Promotion and Behavioral Sciences, Kyoto University Graduate School of Medicine\/School of Public Health, Kyoto, Japan"},{"author_name":"Hikari N Takashina","author_inst":"Awarefy Mental Research Institute, Awarefy Inc., Japan"},{"author_name":"Shintaro Hara","author_inst":"Graduate School of Education, Joetsu University of Education, Joetsu, Japan"},{"author_name":"Ryuichiro Yamamoto","author_inst":"Department of Psychology and Humanities, Edogawa University, Nagareyama, Japan"},{"author_name":"Shun Nakajima","author_inst":"International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba Institute for Advanced Research (TIAR), University of Tsukuba, Ibaraki, Japan"},{"author_name":"Hiroku Noma","author_inst":"International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba Institute for Advanced Research (TIAR), University of Tsukuba, Ibaraki, Japan"},{"author_name":"Kota Imai","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"},{"author_name":"Shunici Sato","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"},{"author_name":"Daiki Nagaoka","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"},{"author_name":"Yusuke Takahashi","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"},{"author_name":"Keita Kawai","author_inst":"Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany."},{"author_name":"Seina Shinno","author_inst":"Department of Medical Education,Graduate School of Medicine, University of Toyama Toyama, Japan"},{"author_name":"Azusa Ishii","author_inst":"International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba Institute for Advanced Research (TIAR), University of Tsukuba, Ibaraki, Japan"},{"author_name":"Michael Perlis","author_inst":"University of Pennsylvania, PA, US"},{"author_name":"Cagdas Turkmen","author_inst":"Department for Research and Development, St. Olavs Hospital PH, Trondheim, Norway"},{"author_name":"Elisabeth Hertenstein","author_inst":"Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland"},{"author_name":"Annemieke van Straten","author_inst":"Department of Clinical, Neuro and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands"},{"author_name":"Yuki Furukawa","author_inst":"Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Post-vaccination expansion of extrafollicular Th10 and regulatory Tfr cells distinguishes strong from weak influenza vaccine responses in older adults","rel_doi":"10.64898\/2026.07.02.26357118","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357118","rel_abs":"Despite the superior efficacy of high-dose influenza vaccines, over one-third of older adults fail to respond. Yet, the mechanisms underlying this impaired vaccine responsiveness remain poorly understood. Here, we performed longitudinal profiling of older adults (n=60) receiving high-dose influenza vaccination to identify immune programs associated with vaccine responsiveness. Strong responders exhibited a primed baseline immune state characterized by elevated plasma cytokines and chemokines, followed by enhanced IFN-{gamma} responses and coordinated transcriptional and epigenetic activation of cDC2 cells at day 1. By day 7, CD4 T-cell trajectories diverged: strong responders preferentially expanded influenza-specific activated cTfh1 (CXCR5+ CXCR3+ ICOS+ CD38+) and influenza-specific Th10 (CXCR5- CXCR3+ PD1+ IL10) cells, whereas weak responders expanded regulatory cTfr (CXCR5 FOXP3) cells. Th10 expansion correlated with plasmablast and antibody responses and was independently validated in a larger influenza vaccination cohort, including younger adults. Functionally, Th10 cells promoted memory B-cell differentiation into plasmablasts and production of influenza-specific IgGs. TCR analyses revealed minimal clonal overlap between Th10 and cTfh1 cells. Together, these findings identify divergent helper and regulatory CD4 T cell programs associated with vaccine responsiveness and establish Th10 cells as a previously unrecognized component of vaccine-induced humoral immunity.","rel_num_authors":19,"rel_authors":[{"author_name":"Avinash S Mahajan","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Sathyabaarathi Ravichandran","author_inst":"The Jackson laboratory for Genomic Medicine"},{"author_name":"Radu Marches","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Yilmaz Yucehan Yazici","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Sean Nelson","author_inst":"Gale and Ira Drukier Institute for Childrens Health and Department of Pediatrics, Weill Cornell Medicine"},{"author_name":"Teresa Aydillo Gomez","author_inst":"Icahn School of Medicine of Mount Sinai Hospital"},{"author_name":"Kshitija Kshitija","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Amaya Rojo Fernandez","author_inst":"Icahn School of Medicine at Mount Sinai Hospital"},{"author_name":"Djamel Nehar-Belaid","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Lisa Kenyon Pesce","author_inst":"UCONN Center on Aging"},{"author_name":"Daniel Klimes","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Haebeen Jung","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Peter T Sage","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Virginia Pascual","author_inst":"Gale and Ira Drukier Institute for Childrens Health and Department of Pediatrics, Weill Cornell Medicine"},{"author_name":"Patrick Wilson","author_inst":"Weill Cornell Medicine"},{"author_name":"Adolfo Garcia Sastre","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jacques Banchereau","author_inst":"Immunoledge LLC"},{"author_name":"George A Kuchel","author_inst":"UCONN Center on Aging"},{"author_name":"Duygu Ucar","author_inst":"The Jackson Laboratory for Genomic Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Feature Selection with Quantum Annealing for Biomedical Machine Learning Applications","rel_doi":"10.64898\/2026.07.02.26357174","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357174","rel_abs":"Feature selection is a commonly used method in biomedical artificial intelligence and machine learning to identify a subset of high-quality variables that can be used to train downstream predictive models. It has been suggested that quantum feature selection (QFS), which takes advantage of the properties of quantum computers, may better identify variables that are correlated with the outcome while simultaneously reducing redundancy between selected variables. However, there are a limited number of studies evaluating their performance, particularly in real-world data sets. Here, we assess the performance of two QFS methods compared to random forest (RF) feature selection based on feature stability and the performance of a downstream classification algorithm when used to predict urinary tract infections in the emergency department from 211 original features extracted from the electronic health record. We found that a quantum binary quadratic model (BQM) and constrained quadratic model (CQM) had similar performance to RF feature selection (median F1 score of 0.60, 0.61, and 0.61 respectively) when 10 features were selected for an XGBoost classification model. The BQM and RF also had similar feature stability (0.91 and 0.94, respectively) while the CQM had lower stability (0.72). These findings show that QFS can be used with large, clinical data sets to identify features with high stability and predictive performance. As the capacity and quality of quantum computers continue to increase, these methods may offer additional benefits to classical feature selection methods.","rel_num_authors":8,"rel_authors":[{"author_name":"Sarah N. Dudgeon","author_inst":"Yale University"},{"author_name":"Seung Joo Lee","author_inst":"Yale University"},{"author_name":"Thomas JS Durant","author_inst":"Yale University"},{"author_name":"Brent Nelson","author_inst":"Newport Healthcare"},{"author_name":"H. Patrick Young","author_inst":"Yale University"},{"author_name":"Lucila Ohno-Machado","author_inst":"Yale University"},{"author_name":"R. Andrew Taylor","author_inst":"Yale University"},{"author_name":"Wade L. Schulz","author_inst":"Yale University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Cross-Domain Knowledge Transfer from Expert-Annotated Gated CT via Synthetic Ungated CT Improves Coronary Artery Calcium Scoring on CT Attenuation Correction Scans","rel_doi":"10.64898\/2026.07.02.26356002","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356002","rel_abs":"BackgroundCoronary artery calcium (CAC) is an established measure of coronary atherosclerosis from computed tomography (CT). While deep learning (DL) can quantify CAC from non-dedicated CT, the accuracy is limited by image quality.\n\nPurposeWe derived and validated a novel method for DL CAC segmentation on ultra-low dose CT attenuation correction (CTAC) scans that is trained with synthetic low-dose, ungated images.\n\nMaterials and MethodsModels were trained using one center and externally tested in two other centers. Synthetic, ungated CT scans were generated so that expert segmentations from dedicated CAC scans could be used as ground truth for perfectly registered synthetic images through knowledge adaptation (KAD-CAC). We evaluated agreement between CAC scoring methods vs expert readers on a per-patient and per-vessel basis, as well as associations with the primary outcome of death or myocardial infarction (MI).\n\nResultsThe DL models were externally tested on 5969 patients with a median age of 64 (IQR 56 - 73), of whom 50.2% were male. The KAD-CAC model had higher Cohens kappa K (0.86, 95% CI 0.85 - 0.87) compared to previous convolutional LSTM model (K 0.78, 95% CI 0.76 - 0.80, p<0.01), or models trained with only gated images (K 0.81, 95% CI 0.80 - 0.82, p<0.01). Net reclassification improvement for CAC stratified risk of death or MI, was greatest for the KAD-CAC model over baseline including age, sex, hypertension, diabetes, dyslipidemia, family history, smoking, stress total perfusion deficit, and left ventricular ejection fraction.\n\nConclusionWe use paired synthetic ungated scans to transfer expert gated CAC annotations into the ungated domain, resulting in substantially better vessel-level CAC scoring and improved risk stratification.\n\nSummary StatementBy transferring information from expert-annotated gated CT to synthetic ungated CT, a knowledge-adapted deep learning model substantially improved coronary artery calcium assessment on low-dose attenuation correction CT.\n\nKey ResultsIn external testing using 5969 patients from two sites, the proposed model had improved agreement with expert segmentation and provided the greatest net reclassification improvement for CAC stratified risk of death or MI over baseline including age, sex, hypertension, diabetes, dyslipidemia, family history, smoking, stress total perfusion deficit, and Left Ventricular Ejection Fraction.","rel_num_authors":16,"rel_authors":[{"author_name":"Aakash Shanbhag","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Robert JH Miller","author_inst":"University of Calgary"},{"author_name":"Aditya Killekar","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Anna M Marcinkiewicz","author_inst":"National Medical Institute of the Ministry of the Interior and Administration"},{"author_name":"Jianhang Zhou","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Mark Lemley","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Assiata Kamagate","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Serge D Van Kriekinge","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Paul B. Kavanagh","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Attila Feher","author_inst":"Yale University School of Medicine"},{"author_name":"Edward J Miller","author_inst":"Yale University School of Medicine"},{"author_name":"Joanna X Liang","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Daniel S Berman","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Damini Dey","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Richard M Leahy","author_inst":"University of Southern California"},{"author_name":"Piotr Slomka","author_inst":"Cedars-Sinai Medical Center"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts","rel_doi":"10.64898\/2026.07.02.26357108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357108","rel_abs":"Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ({beta}diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohens d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.","rel_num_authors":97,"rel_authors":[{"author_name":"Kimberly V Blake","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Jonathan C Ipser","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Alyssa R Amod","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Tobias Kaufmann","author_inst":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"author_name":"Yair Bar-Haim","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Jochen Bauer","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ali Bayram","author_inst":"Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey"},{"author_name":"Katja Beesdo-Baum","author_inst":"Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany"},{"author_name":"Laura Blanco-Hinojo","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Tiana Borgers","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Robin B\u00fclow","author_inst":"Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Marta Cano","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Narcis Cardoner","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Christopher R.K Ching","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Soo-Hee Choi","author_inst":"Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea"},{"author_name":"Udo Dannlowski","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christopher G Davey","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexander G. G Doruyter","author_inst":"Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Kira Flinkenfl\u00fcgel","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Gregory A Fonzo","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA"},{"author_name":"Tomas Furmark","author_inst":"Department of Psychology, Uppsala University, Uppsala, Sweden"},{"author_name":"Dominik Grotegerd","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Hans J Grabe","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Tim Hahn","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ben J Harrison","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexandre Heeren","author_inst":"Psychological Science Research Institute, Universit\u00e9 Catholique de Louvain, Louvain-la-Neuve, Belgium"},{"author_name":"Kevin Hilbert","author_inst":"Department of Psychology, HMU Health and Medical University Erfurt, Germany"},{"author_name":"Yoshiyuki Hirano","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Joy Hirsch","author_inst":"Departments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"David Hofmann","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Yuko Isobe","author_inst":"Department of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Hamidreza Jamalabadi","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Alec J Jamieson","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Andreas Jansen","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Jaehyun Edmund Kim","author_inst":"Seoul National University, Seoul, Republic of Korea"},{"author_name":"Tilo Kircher","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Hitomi Kitagawa","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Anna Luisa Klahn","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Saskia B. J Koch","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Axel Krug","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Harald Kugel","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Dasom Lee","author_inst":"Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea"},{"author_name":"Elisabeth J Leehr","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christine Lochner","author_inst":"SAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Ulrike Lueken","author_inst":"Department of Psychology, Humboldt-Universit\u00e4t zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany"},{"author_name":"Amirhossein Manzouri","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Kristoffer N. T M\u00e5nsson","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Koji Matsumoto","author_inst":"Department of Radiology, Chiba University Hospital, Chiba, Japan"},{"author_name":"Susanne Meinert","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Alicia Menze","author_inst":"Medical Faculty M\u00fcnster, University Hospital M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Markus Muehlhan","author_inst":"Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Igor Nenadi\u0107","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Ziphozihle Ntwatwa","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Hyuntaek Oh","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Spiro P Pantazatos","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Martin P Paulus","author_inst":"Laureate Institute for Brain Research, Tulsa, OK, USA"},{"author_name":"Jutta Peterburs","author_inst":"Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Jesus Pujol","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Karin Roelofs","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Ramiro Salas","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Franklin R Schneier","author_inst":"New York State Psychiatric Institute, New York, NY, USA"},{"author_name":"Elisabeth Schrammen","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Eiji Shimizu","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Lisa Sindermann","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Theresa M Slump","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Jair C Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Benjamin Straube","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Thomas Straube","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Murray B Stein","author_inst":"Department of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Ardesheer Talati","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Florian Thomas-Odenthal","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Ra\u015fit T\u00fckel","author_inst":"Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey"},{"author_name":"Anna Tyborowska","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Marie-Jos\u00e9 Van Tol","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"},{"author_name":"Dick J Veltman","author_inst":"Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands"},{"author_name":"Roman A. Vogler","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Inge Volman","author_inst":"National Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Henry V\u00f6lzke","author_inst":"Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"P. Michiel Westenberg","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Katharina Wittfeld","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Noga Yair","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Tokiko Yoshida","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Chen Zhang","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Xi Zhu","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Giovana B Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Peter Zwanzger","author_inst":"Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany"},{"author_name":"Daniel S Pine","author_inst":"National Institute of Mental Health, Emotion and Development Branch, USA"},{"author_name":"Moji Aghajani","author_inst":"Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Nic J.A. van der Wee","author_inst":"Leiden Institute for Brain and Cognition, Leiden, the Netherlands"},{"author_name":"Dan J Stein","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Janna Marie Bas-Hoogendam","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Nynke A Groenewold","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts","rel_doi":"10.64898\/2026.07.02.26357108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357108","rel_abs":"Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ({beta}diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohens d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.","rel_num_authors":97,"rel_authors":[{"author_name":"Kimberly V Blake","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Jonathan C Ipser","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Alyssa R Amod","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Tobias Kaufmann","author_inst":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"author_name":"Yair Bar-Haim","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Jochen Bauer","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ali Bayram","author_inst":"Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey"},{"author_name":"Katja Beesdo-Baum","author_inst":"Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany"},{"author_name":"Laura Blanco-Hinojo","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Tiana Borgers","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Robin B\u00fclow","author_inst":"Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Marta Cano","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Narcis Cardoner","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Christopher R.K Ching","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Soo-Hee Choi","author_inst":"Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea"},{"author_name":"Udo Dannlowski","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christopher G Davey","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexander G. G Doruyter","author_inst":"Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Kira Flinkenfl\u00fcgel","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Gregory A Fonzo","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA"},{"author_name":"Tomas Furmark","author_inst":"Department of Psychology, Uppsala University, Uppsala, Sweden"},{"author_name":"Dominik Grotegerd","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Hans J Grabe","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Tim Hahn","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ben J Harrison","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexandre Heeren","author_inst":"Psychological Science Research Institute, Universit\u00e9 Catholique de Louvain, Louvain-la-Neuve, Belgium"},{"author_name":"Kevin Hilbert","author_inst":"Department of Psychology, HMU Health and Medical University Erfurt, Germany"},{"author_name":"Yoshiyuki Hirano","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Joy Hirsch","author_inst":"Departments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"David Hofmann","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Yuko Isobe","author_inst":"Department of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Hamidreza Jamalabadi","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Alec J Jamieson","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Andreas Jansen","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Jaehyun Edmund Kim","author_inst":"Seoul National University, Seoul, Republic of Korea"},{"author_name":"Tilo Kircher","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Hitomi Kitagawa","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Anna Luisa Klahn","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Saskia B. J Koch","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Axel Krug","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Harald Kugel","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Dasom Lee","author_inst":"Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea"},{"author_name":"Elisabeth J Leehr","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christine Lochner","author_inst":"SAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Ulrike Lueken","author_inst":"Department of Psychology, Humboldt-Universit\u00e4t zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany"},{"author_name":"Amirhossein Manzouri","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Kristoffer N. T M\u00e5nsson","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Koji Matsumoto","author_inst":"Department of Radiology, Chiba University Hospital, Chiba, Japan"},{"author_name":"Susanne Meinert","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Alicia Menze","author_inst":"Medical Faculty M\u00fcnster, University Hospital M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Markus Muehlhan","author_inst":"Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Igor Nenadi\u0107","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Ziphozihle Ntwatwa","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Hyuntaek Oh","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Spiro P Pantazatos","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Martin P Paulus","author_inst":"Laureate Institute for Brain Research, Tulsa, OK, USA"},{"author_name":"Jutta Peterburs","author_inst":"Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Jesus Pujol","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Karin Roelofs","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Ramiro Salas","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Franklin R Schneier","author_inst":"New York State Psychiatric Institute, New York, NY, USA"},{"author_name":"Elisabeth Schrammen","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Eiji Shimizu","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Lisa Sindermann","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Theresa M Slump","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Jair C Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Benjamin Straube","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Thomas Straube","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Murray B Stein","author_inst":"Department of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Ardesheer Talati","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Florian Thomas-Odenthal","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Ra\u015fit T\u00fckel","author_inst":"Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey"},{"author_name":"Anna Tyborowska","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Marie-Jos\u00e9 Van Tol","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"},{"author_name":"Dick J Veltman","author_inst":"Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands"},{"author_name":"Roman A. Vogler","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Inge Volman","author_inst":"National Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Henry V\u00f6lzke","author_inst":"Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"P. Michiel Westenberg","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Katharina Wittfeld","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Noga Yair","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Tokiko Yoshida","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Chen Zhang","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Xi Zhu","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Giovana B Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Peter Zwanzger","author_inst":"Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany"},{"author_name":"Daniel S Pine","author_inst":"National Institute of Mental Health, Emotion and Development Branch, USA"},{"author_name":"Moji Aghajani","author_inst":"Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Nic J.A. van der Wee","author_inst":"Leiden Institute for Brain and Cognition, Leiden, the Netherlands"},{"author_name":"Dan J Stein","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Janna Marie Bas-Hoogendam","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Nynke A Groenewold","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts","rel_doi":"10.64898\/2026.07.02.26357108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357108","rel_abs":"Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ({beta}diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohens d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.","rel_num_authors":97,"rel_authors":[{"author_name":"Kimberly V Blake","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Jonathan C Ipser","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Alyssa R Amod","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Tobias Kaufmann","author_inst":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"author_name":"Yair Bar-Haim","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Jochen Bauer","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ali Bayram","author_inst":"Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey"},{"author_name":"Katja Beesdo-Baum","author_inst":"Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany"},{"author_name":"Laura Blanco-Hinojo","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Tiana Borgers","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Robin B\u00fclow","author_inst":"Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Marta Cano","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Narcis Cardoner","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Christopher R.K Ching","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Soo-Hee Choi","author_inst":"Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea"},{"author_name":"Udo Dannlowski","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christopher G Davey","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexander G. G Doruyter","author_inst":"Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Kira Flinkenfl\u00fcgel","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Gregory A Fonzo","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA"},{"author_name":"Tomas Furmark","author_inst":"Department of Psychology, Uppsala University, Uppsala, Sweden"},{"author_name":"Dominik Grotegerd","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Hans J Grabe","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Tim Hahn","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ben J Harrison","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexandre Heeren","author_inst":"Psychological Science Research Institute, Universit\u00e9 Catholique de Louvain, Louvain-la-Neuve, Belgium"},{"author_name":"Kevin Hilbert","author_inst":"Department of Psychology, HMU Health and Medical University Erfurt, Germany"},{"author_name":"Yoshiyuki Hirano","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Joy Hirsch","author_inst":"Departments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"David Hofmann","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Yuko Isobe","author_inst":"Department of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Hamidreza Jamalabadi","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Alec J Jamieson","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Andreas Jansen","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Jaehyun Edmund Kim","author_inst":"Seoul National University, Seoul, Republic of Korea"},{"author_name":"Tilo Kircher","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Hitomi Kitagawa","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Anna Luisa Klahn","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Saskia B. J Koch","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Axel Krug","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Harald Kugel","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Dasom Lee","author_inst":"Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea"},{"author_name":"Elisabeth J Leehr","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christine Lochner","author_inst":"SAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Ulrike Lueken","author_inst":"Department of Psychology, Humboldt-Universit\u00e4t zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany"},{"author_name":"Amirhossein Manzouri","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Kristoffer N. T M\u00e5nsson","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Koji Matsumoto","author_inst":"Department of Radiology, Chiba University Hospital, Chiba, Japan"},{"author_name":"Susanne Meinert","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Alicia Menze","author_inst":"Medical Faculty M\u00fcnster, University Hospital M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Markus Muehlhan","author_inst":"Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Igor Nenadi\u0107","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Ziphozihle Ntwatwa","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Hyuntaek Oh","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Spiro P Pantazatos","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Martin P Paulus","author_inst":"Laureate Institute for Brain Research, Tulsa, OK, USA"},{"author_name":"Jutta Peterburs","author_inst":"Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Jesus Pujol","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Karin Roelofs","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Ramiro Salas","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Franklin R Schneier","author_inst":"New York State Psychiatric Institute, New York, NY, USA"},{"author_name":"Elisabeth Schrammen","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Eiji Shimizu","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Lisa Sindermann","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Theresa M Slump","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Jair C Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Benjamin Straube","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Thomas Straube","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Murray B Stein","author_inst":"Department of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Ardesheer Talati","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Florian Thomas-Odenthal","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Ra\u015fit T\u00fckel","author_inst":"Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey"},{"author_name":"Anna Tyborowska","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Marie-Jos\u00e9 Van Tol","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"},{"author_name":"Dick J Veltman","author_inst":"Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands"},{"author_name":"Roman A. Vogler","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Inge Volman","author_inst":"National Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Henry V\u00f6lzke","author_inst":"Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"P. Michiel Westenberg","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Katharina Wittfeld","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Noga Yair","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Tokiko Yoshida","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Chen Zhang","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Xi Zhu","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Giovana B Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Peter Zwanzger","author_inst":"Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany"},{"author_name":"Daniel S Pine","author_inst":"National Institute of Mental Health, Emotion and Development Branch, USA"},{"author_name":"Moji Aghajani","author_inst":"Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Nic J.A. van der Wee","author_inst":"Leiden Institute for Brain and Cognition, Leiden, the Netherlands"},{"author_name":"Dan J Stein","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Janna Marie Bas-Hoogendam","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Nynke A Groenewold","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts","rel_doi":"10.64898\/2026.07.02.26357108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357108","rel_abs":"Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ({beta}diagnosis (SE)=0.70 (0.37) years, p=0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohens d=0.23, pFDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.","rel_num_authors":97,"rel_authors":[{"author_name":"Kimberly V Blake","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Jonathan C Ipser","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Alyssa R Amod","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Tobias Kaufmann","author_inst":"Department of Psychiatry and Psychotherapy, University of T\u00fcbingen, T\u00fcbingen, Germany"},{"author_name":"Yair Bar-Haim","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Jochen Bauer","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ali Bayram","author_inst":"Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey"},{"author_name":"Katja Beesdo-Baum","author_inst":"Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany"},{"author_name":"Laura Blanco-Hinojo","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Tiana Borgers","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Robin B\u00fclow","author_inst":"Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Marta Cano","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Narcis Cardoner","author_inst":"Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"},{"author_name":"Christopher R.K Ching","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Soo-Hee Choi","author_inst":"Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea"},{"author_name":"Udo Dannlowski","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christopher G Davey","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexander G. G Doruyter","author_inst":"Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Kira Flinkenfl\u00fcgel","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Gregory A Fonzo","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA"},{"author_name":"Tomas Furmark","author_inst":"Department of Psychology, Uppsala University, Uppsala, Sweden"},{"author_name":"Dominik Grotegerd","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Hans J Grabe","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Tim Hahn","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Ben J Harrison","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Alexandre Heeren","author_inst":"Psychological Science Research Institute, Universit\u00e9 Catholique de Louvain, Louvain-la-Neuve, Belgium"},{"author_name":"Kevin Hilbert","author_inst":"Department of Psychology, HMU Health and Medical University Erfurt, Germany"},{"author_name":"Yoshiyuki Hirano","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Joy Hirsch","author_inst":"Departments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"David Hofmann","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Yuko Isobe","author_inst":"Department of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Hamidreza Jamalabadi","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Alec J Jamieson","author_inst":"Department of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia"},{"author_name":"Andreas Jansen","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Jaehyun Edmund Kim","author_inst":"Seoul National University, Seoul, Republic of Korea"},{"author_name":"Tilo Kircher","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Hitomi Kitagawa","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Anna Luisa Klahn","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Saskia B. J Koch","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Axel Krug","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Harald Kugel","author_inst":"University Clinic for Radiology, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Dasom Lee","author_inst":"Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea"},{"author_name":"Elisabeth J Leehr","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Christine Lochner","author_inst":"SAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa"},{"author_name":"Ulrike Lueken","author_inst":"Department of Psychology, Humboldt-Universit\u00e4t zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany"},{"author_name":"Amirhossein Manzouri","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Kristoffer N. T M\u00e5nsson","author_inst":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"},{"author_name":"Koji Matsumoto","author_inst":"Department of Radiology, Chiba University Hospital, Chiba, Japan"},{"author_name":"Susanne Meinert","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Alicia Menze","author_inst":"Medical Faculty M\u00fcnster, University Hospital M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Markus Muehlhan","author_inst":"Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Igor Nenadi\u0107","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Ziphozihle Ntwatwa","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Hyuntaek Oh","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Spiro P Pantazatos","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Martin P Paulus","author_inst":"Laureate Institute for Brain Research, Tulsa, OK, USA"},{"author_name":"Jutta Peterburs","author_inst":"Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany"},{"author_name":"Jesus Pujol","author_inst":"MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain"},{"author_name":"Karin Roelofs","author_inst":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"author_name":"Ramiro Salas","author_inst":"The Menninger Clinic, Houston, TX, USA"},{"author_name":"Franklin R Schneier","author_inst":"New York State Psychiatric Institute, New York, NY, USA"},{"author_name":"Elisabeth Schrammen","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Eiji Shimizu","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Lisa Sindermann","author_inst":"Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany"},{"author_name":"Theresa M Slump","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Jair C Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Benjamin Straube","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Thomas Straube","author_inst":"Institute of Medical Psychology and Systems Neuroscience, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Murray B Stein","author_inst":"Department of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Ardesheer Talati","author_inst":"Department of Psychiatry, Columbia University Medical Center, New York, NY, USA"},{"author_name":"Florian Thomas-Odenthal","author_inst":"Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Ra\u015fit T\u00fckel","author_inst":"Istanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey"},{"author_name":"Anna Tyborowska","author_inst":"Donders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Marie-Jos\u00e9 Van Tol","author_inst":"Center for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"},{"author_name":"Dick J Veltman","author_inst":"Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands"},{"author_name":"Roman A. Vogler","author_inst":"Institute for Translational Psychiatry, University of M\u00fcnster, M\u00fcnster, Germany"},{"author_name":"Inge Volman","author_inst":"National Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands"},{"author_name":"Henry V\u00f6lzke","author_inst":"Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"P. Michiel Westenberg","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Katharina Wittfeld","author_inst":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Noga Yair","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Tokiko Yoshida","author_inst":"Research Center for Child Mental Development, Chiba University, Chiba, Japan"},{"author_name":"Chen Zhang","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Xi Zhu","author_inst":"The University of Texas at Arlington, Arlington, USA"},{"author_name":"Giovana B Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA"},{"author_name":"Peter Zwanzger","author_inst":"Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany"},{"author_name":"Daniel S Pine","author_inst":"National Institute of Mental Health, Emotion and Development Branch, USA"},{"author_name":"Moji Aghajani","author_inst":"Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA"},{"author_name":"Nic J.A. van der Wee","author_inst":"Leiden Institute for Brain and Cognition, Leiden, the Netherlands"},{"author_name":"Dan J Stein","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"},{"author_name":"Janna Marie Bas-Hoogendam","author_inst":"Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands"},{"author_name":"Nynke A Groenewold","author_inst":"Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"its2s: a Python package for two-stage interrupted time series analysis using machine learning","rel_doi":"10.64898\/2026.07.02.26357175","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357175","rel_abs":"1When randomized controlled trials are infeasible, researchers may leverage natural experiments for causal inference. Interrupted time-series (ITS) designs compare observed post-event trends to counterfactual predictions from pre-event data. Two-stage ITS designs use flexible models to generate optimized counterfactual predictions in the first stage, then estimate intervention effects by comparing observed to predicted outcomes in the second stage. Fitting high-dimensional versions of these models is challenging, requiring systematic infrastructure to ensure rigor and reproducibility. In response, we developed its2s, an open-source Python package implementing the two-stage ITS design with machine learning. its2s allows users to specify an intervention date and training\/testing periods, select among built-in model architectures (e.g., Prophet-XGBoost, NeuralProphet), and generate confidence intervals via moving block bootstrap, preserving temporal autocorrelation in residuals. its2s layers defaults, configuration files, and runtime overrides to support workflows ranging from rapid default implementations to highly tailored analyses. We validated its2s using two case studies: a simulation with a 12% policy effect, recovering the true effect as 11.77%, and an analysis of the 2021 Pacific Northwest heat dome, finding 53% excess injury mortality over the following three weeks. its2s provides a flexible, reproducible framework for ITS-based quasi-experimental research, lowering barriers to rigorous machine learning-based counterfactual modeling.","rel_num_authors":7,"rel_authors":[{"author_name":"Lauren Wilner","author_inst":"University of Washington"},{"author_name":"Joan A Casey","author_inst":"University of Washington"},{"author_name":"Stephen J Mooney","author_inst":"University of Washington"},{"author_name":"Vivian Do","author_inst":"Scripps Institution of Oceanography, University of California San Diego"},{"author_name":"Yiqun Ma","author_inst":"Scripps Institution of Oceanography, University of California San Diego"},{"author_name":"Tarik Benmarhnia","author_inst":"Scripps Institution of Oceanography, University of California San Diego"},{"author_name":"Arnab K Dey","author_inst":"Scripps Institution of Oceanography, University of California San Diego"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Association between glycated hemoglobin A1c and automated abdominal aortic calcification: the UK Biobank Imaging Study","rel_doi":"10.64898\/2026.07.02.26357193","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357193","rel_abs":"BackgroundPoor glycemic control is associated with cardiovascular disease (CVD) risk. However, it is unknown whether glycemic control is related to abdominal aortic calcification (AAC), a marker of subclinical CVD. We investigated the association between glycated hemoglobin (HbA1c) and moderate-to-high automated AAC among middle-aged to older adults from the general population.\n\nMethodsWe included UK Biobank Imaging Study participants free of atherosclerotic CVD at baseline. HbA1c was measured at baseline (2006-2010) and categorized as normoglycemia (<39.0 mmol\/mol), prediabetes (39.0-47.9 mmol\/mol), undiagnosed diabetes (HbA1c [&ge;]48 mmol\/mol) and diagnosed diabetes. Machine learning derived AAC24 (ML-AAC24) scores were estimated using a validated automated algorithm applied to dual-energy X-ray absorptiometry lateral spine images (2014-2022). The associations of HbA1c with Moderate-to-high ML-AAC24 (defined as a score [&ge;]2) were assessed using logistic regression adjusting for cardiovascular risk factors.\n\nResultsOf the included 48,912 participants (mean {+\/-} SD age 55 {+\/-} 7.6 years, 52% women), 9.7% had prediabetes (HbA1c 39.0-47.9 mmol\/mol [5.7-6.4%]), 0.4% had undiagnosed diabetes and 2.7% diagnosed diabetes. Each 1-SD increase in log-transformed HbA1c was associated with higher odds of moderate-to-high ML-AAC24 (adjusted odds ratio [aOR] 1.12, 95%CI: 1.09-1.16). Amongst individuals with normal HbA1c this association was consistent but somewhat weaker for each 1-SD increase in log-transformed HbA1c (aOR 1.07, 95%CI 1.03-1.10). Compared to participants with normal HbA1c, those with prediabetes (aOR 1.19, 95%CI: 1.08-1.30) or diagnosed diabetes (1.64, 95%CI: 1.39-1.94) had higher odds of moderate-to-high ML-AAC24. These associations were consistent in stratified analyses by sex, age groups, body mass index, smoking status and total cholesterol\n\nConclusionsLinear associations between HbA1c levels and ML-AAC24 were observed in UK adults, even in those with normal HbA1c level. These findings indicate that AAC may develop early in the dysglycemic continuum, supporting earlier cardiometabolic risk assessment even amongst people with \"normal\" levels.","rel_num_authors":14,"rel_authors":[{"author_name":"Haftom Niguse Abraha","author_inst":"Edith Cowan University School of Medical and Health Sciences"},{"author_name":"Abadi Kahsu Gebre","author_inst":"Edith Cowan University School of Medical and Health Sciences"},{"author_name":"Cassandra Smith","author_inst":"Edith Cowan University School of Medical and Health Sciences"},{"author_name":"Lakshini Y. Herat","author_inst":"The University of Western Australia"},{"author_name":"James Webster","author_inst":"University of Oxford"},{"author_name":"Afsah Saleem","author_inst":"Edith Cowan University"},{"author_name":"Zulqarnain Gilani","author_inst":"Edith Cowan University"},{"author_name":"Christian M. Girgis","author_inst":"The University of Sydney"},{"author_name":"Nicklas H. Rasmussen","author_inst":"Aalborg Universitetshospital"},{"author_name":"William D. Leslie","author_inst":"University of Manitoba"},{"author_name":"John T. Schousboe","author_inst":"HealthPartners Institute"},{"author_name":"Nicholas C Harvey","author_inst":"MRC lifecourse Epidemiology unit"},{"author_name":"Marc Sim","author_inst":"Edith Cowan University"},{"author_name":"Joshua Richard Lewis","author_inst":"Edith Cowan University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Efficacy and safety of triple versus dual combinations of antihypertensive drugs: A systematic review and meta-analysis of double-blind randomized clinical trials","rel_doi":"10.64898\/2026.07.03.26356990","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26356990","rel_abs":"We evaluated the blood pressure (BP)-lowering efficacy and safety of triple vs dual therapy of antihypertensive drug (AHTD) combinations, among adults with hypertension. Seventeen randomized, double-blind trials (41 comparisons and 13,461 participants) comparing triple versus dual therapy for [&ge;]3 weeks identified by multiple literature databases searches including PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) until October 2024 were included in the meta-analysis.\n\nTriple therapy achieved a greater reduction in systolic BP (SBP) compared with dual therapy (26.9 vs. 21.7 mmHg, mean difference 5.4 mmHg [95% CI, 4.7-6.2]). Among patients receiving dual therapy at submaximal and maximal doses, the addition of a third drug further reduced SBP by 7.5 and 3.6 mmHg, respectively. BP control was significantly better with triple therapy (60% vs. 47%, RR=1.34 [1.27-1.41]). Withdrawal due to adverse events was slightly higher in the triple therapy group (4% vs. 3%, RR=1.5 [1.2-1.8]). Triple AHTD therapy provides superior BP reduction and is well-tolerated compared to dual therapy.","rel_num_authors":6,"rel_authors":[{"author_name":"Rupasvi Dhurjati","author_inst":"The George Institute for Global Health"},{"author_name":"Rashmi Pant","author_inst":"The George Institute for Global Health"},{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Anshika Mittal","author_inst":"The George Institute for Global Health"},{"author_name":"Anthony Rodgers","author_inst":"School of Population Health, UNSW Sydney, Sydney, NSW, Australia"},{"author_name":"Abdul Salam","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; The George Institute for Global Health, University of New South Wales, Sydney, New South Wa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Efficacy and safety of triple versus dual combinations of antihypertensive drugs: A systematic review and meta-analysis of double-blind randomized clinical trials","rel_doi":"10.64898\/2026.07.03.26356990","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26356990","rel_abs":"We evaluated the blood pressure (BP)-lowering efficacy and safety of triple vs dual therapy of antihypertensive drug (AHTD) combinations, among adults with hypertension. Seventeen randomized, double-blind trials (41 comparisons and 13,461 participants) comparing triple versus dual therapy for [&ge;]3 weeks identified by multiple literature databases searches including PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) until October 2024 were included in the meta-analysis.\n\nTriple therapy achieved a greater reduction in systolic BP (SBP) compared with dual therapy (26.9 vs. 21.7 mmHg, mean difference 5.4 mmHg [95% CI, 4.7-6.2]). Among patients receiving dual therapy at submaximal and maximal doses, the addition of a third drug further reduced SBP by 7.5 and 3.6 mmHg, respectively. BP control was significantly better with triple therapy (60% vs. 47%, RR=1.34 [1.27-1.41]). Withdrawal due to adverse events was slightly higher in the triple therapy group (4% vs. 3%, RR=1.5 [1.2-1.8]). Triple AHTD therapy provides superior BP reduction and is well-tolerated compared to dual therapy.","rel_num_authors":6,"rel_authors":[{"author_name":"Rupasvi Dhurjati","author_inst":"The George Institute for Global Health"},{"author_name":"Rashmi Pant","author_inst":"The George Institute for Global Health"},{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Anshika Mittal","author_inst":"The George Institute for Global Health"},{"author_name":"Anthony Rodgers","author_inst":"School of Population Health, UNSW Sydney, Sydney, NSW, Australia"},{"author_name":"Abdul Salam","author_inst":"The George Institute for Global Health, Hyderabad, Telangana, India; The George Institute for Global Health, University of New South Wales, Sydney, New South Wa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Comparing cutaneous NO-dependent vasodilation between young males and females","rel_doi":"10.64898\/2026.07.02.26357121","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357121","rel_abs":"BackgroundDespite the common use of local heating and intradermal microdialysis perfusion of acetylcholine (ACh) to probe cutaneous endothelium and nitric oxide (NO)-dependent dilation, sex differences in microvascular responsiveness to these stimuli in healthy young adults remain incompletely understood.\n\nMethodsCutaneous vasodilation was assessed in response to local heating to 39{degrees}C and 42{degrees}C and graded perfusion of ACh (10-10 to 10-1 mol\/L) alone or concurrently with 15 mM NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) using laser-Doppler flowmetry coupled with intradermal microdialysis in 80 young adults (40 females).\n\nResultsLocal heating to 42{degrees}C elicited greater endothelium- and NO-dependent dilation than heating to 39{degrees}C in both groups (p<0.001), but no sex differences were observed at either temperature (p=0.65). ACh-induced endothelium-dependent dilation also was not different between sexes (p=0.08), but the NO-dependent component was greater in females than in males (p=0.01). In young females, menstrual cycle day (range: day 2-33) was not associated with endothelium- or NO-dependent dilation in response to any stimulus (all p[&ge;]0.19), regardless of hormonal contraceptive use.\n\nConclusionsTaken together, these findings suggest that sex differences in microvascular NO bioavailability in healthy young adults depend on the stimulus used to elicit cutaneous vasodilation and, in females, microvascular endothelium- and NO-dependent dilation are not meaningfully influenced by menstrual cycle phase.","rel_num_authors":5,"rel_authors":[{"author_name":"Madison G Evering","author_inst":"University of Delaware"},{"author_name":"Kelsey S. Schwartz","author_inst":"The University of Iowa"},{"author_name":"Claire E. Goebel","author_inst":"The University of Iowa"},{"author_name":"Anna E. Stanhewicz","author_inst":"The University of Iowa"},{"author_name":"Jody L. Greaney","author_inst":"University of Delaware"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Microvascular responses to common endothelial stimuli are not related in humans","rel_doi":"10.64898\/2026.07.02.26357129","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357129","rel_abs":"BackgroundCutaneous microvascular responses to local heating and acetylcholine perfusion are widely used to assess nitric oxide (NO)-mediated endothelium-dependent dilation in human health and disease. Despite the increasingly common usage of these approaches, no studies have directly compared responses to these stimuli within individuals. Therefore, we assessed endothelium- and NO-dependent dilation in 80 young adults (40 males\/40 females; 22{+\/-}3 years) to determine the extent to which microvascular responses to these endothelium-dependent stimuli are comparable within an individual.\n\nMethodsWe examined cutaneous vascular conductance responses to (1) standardized local heating protocols to 39{degrees}C and 42{degrees}C, and (2) graded infusions of acetylcholine (10-10-10-1 M) alone or with 15 mM NG-nitro-l-arginine methyl ester (L-NAME; NO synthase inhibitor). Endothelium- and NO-dependent dilation were calculated and expressed in multiple ways based on commonly published analyses to allow for a thorough comparison within and between each stimulus.\n\nResultsLocal heating-induced endothelium- and NO-dependent dilation were lower at 39{degrees}C compared with 42{degrees}C (P<0.001). The magnitude of local heating-induced endothelium-dependent dilation was significantly related to the NO-dependent contribution of that response at 39{degrees}C (R2= 0.79) and 42{degrees}C (R2= 0.56). Local heating-induced NO-dependent dilation at 39{degrees}C was not related to that at 42{degrees}C (P>0.05). Acetylcholine-induced endothelium- and NO-dependent dilation were not related to local heating-induced responses (all P>0.05).\n\nConclusionsThese data demonstrate that while local heating and acetylcholine perfusion produce robust endothelium- and NO-dependent cutaneous vasodilation, these responses are not comparable within an individual.\n\nClinical Trial RegistrationURL: https:\/\/www.clinicaltrials.gov\/ Unique identifier: NCT06499844\n\nNovelty and RelevanceO_ST_ABSWhat Is New?C_ST_ABSO_LILocal thermal heating and acetylcholine perfusion each produce robust endothelium- and nitric oxide-dependent cutaneous vasodilation. However, these responses are not directly comparable within an individual.\nC_LI\n\nWhat Is Relevant?O_LIChanges in microvascular function precede and predict adverse changes in conduit vessels and are reversible before the onset of overt vascular disease and target organ damage.\nC_LI\n\nClinical\/Pathophysiological Implications?O_LIThese approaches are widely used by investigators to interrogate mechanisms of microvascular function and dysfunction in humans. Selection of the appropriate approach should be based on the specific research question and pathophysiological mechanism under investigation.\nC_LI","rel_num_authors":5,"rel_authors":[{"author_name":"Kelsey S. Schwartz","author_inst":"The University of Iowa"},{"author_name":"Madison G Evering","author_inst":"University of Delaware"},{"author_name":"Claire E. Goebel","author_inst":"The University of Iowa"},{"author_name":"Jody L. Greaney","author_inst":"University of Delaware"},{"author_name":"Anna E. Stanhewicz","author_inst":"The University of Iowa"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Anti-HBsAg antibody mAb19-LS enhances antiviral immunity in humans with chronic hepatitis B","rel_doi":"10.64898\/2026.07.03.26357226","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357226","rel_abs":"Chronic infection with hepatitis B virus (HBV) is characterized by persistent expression of hepatitis B surface antigen (HBsAg), which is associated with profound immune tolerance. Although nucleos(t)ide analogue therapy effectively suppresses viral replication, it neither eliminates HBV nor reverses virus-specific immune dysfunction. Here, we report the results of two parallel first-in-human, dose-escalation studies evaluating a single infusion of mAb19-LS, a long-acting IgG1 monoclonal antibody targeting HBsAg, in individuals with chronic HBV infection receiving nucleos(t)ide analogue therapy. mAb19-LS was generally safe and well tolerated and induced a mean 11-fold increase in antigen clearance. The magnitude and duration of HBsAg suppression were dependent on both baseline antigen levels and mAb19-LS dose, with suppression maintained for more than 36 weeks in individuals receiving the highest dose. Reduction of circulating HBsAg was associated with uptake of HBsAg-IgG immune complexes by monocytes and dendritic cells and inflammatory reprogramming of these antigen-presenting cells. Notably, proliferation of both CD4+ and CD8+ T cells, as well as interferon-{gamma} and TNF- production in response to HBV antigens, were significantly increased 24 weeks after infusion. Together, these findings demonstrate that mAb19-LS is generally safe and effectively accelerates HBsAg clearance while activating antigen presenting cells and enhancing antiviral T cell responses.","rel_num_authors":41,"rel_authors":[{"author_name":"Zijun Wang","author_inst":"The Rockefeller University"},{"author_name":"Mary Tenuta","author_inst":"The Rockefeller University"},{"author_name":"Han Ngoc Le","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Siri Nana Halling Scensgaard","author_inst":"Aarhus University Hospital"},{"author_name":"Gabriela S Silva Santos","author_inst":"The Rockefeller University"},{"author_name":"Daniel B Reeves","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Gaelle Breton","author_inst":"The Rockefeller University"},{"author_name":"Vanessa Igbokwe","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Andre Moraes Nicola","author_inst":"The Rockefeller University"},{"author_name":"Katrina Millard","author_inst":"The Rockefeller University"},{"author_name":"Sidsel Dahl Winther Andersen","author_inst":"Aarhus University Hospital"},{"author_name":"Henriette Graversen","author_inst":"Aarhus University Hospital"},{"author_name":"Caroline Zollner","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Martin Kluge","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Rachel Scheck","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Nina Weis","author_inst":"Copenhagen University Hospital - Amager and Hvidovre"},{"author_name":"Isik Johansen","author_inst":"Odense University Hospital"},{"author_name":"Deanna Dong","author_inst":"The Rockefeller University"},{"author_name":"Brianna Hernandez","author_inst":"The Rockefeller University"},{"author_name":"Irina Shimeliovich","author_inst":"The Rockefeller University"},{"author_name":"Juan Dizon","author_inst":"The Rockefeller University"},{"author_name":"Valeska Viera","author_inst":"The Rockefeller University"},{"author_name":"Frank Fabris","author_inst":"The Rockefeller University"},{"author_name":"Magdalena Schwarzmuller","author_inst":"Aarhus University Hospital"},{"author_name":"Pinkus Tober-Lau","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"David Hillus","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Munevver Demir","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Anna Gazumyan","author_inst":"The Rockefeller University"},{"author_name":"Frank Tacke","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Leif Erik Sander","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Florian Kurth","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Thomas Rasmussen","author_inst":"Aarhus University Hospital"},{"author_name":"Hector Ye","author_inst":"Medical Procare PLC"},{"author_name":"Calvin Pan","author_inst":"New York University Langone Health"},{"author_name":"Ira Jacobson","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Qiao Wang","author_inst":"The Rockefeller University"},{"author_name":"Jesper Damsgaard Gunst","author_inst":"Aarhus University Hospital"},{"author_name":"Christian Gaebler","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Ole S Sogaard","author_inst":"Aarhus University Hospital"},{"author_name":"Marina Caskey","author_inst":"The Rockefeller University"},{"author_name":"Michel Nussenzweig","author_inst":"The Rockefeller University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Anti-HBsAg antibody mAb19-LS enhances antiviral immunity in humans with chronic hepatitis B","rel_doi":"10.64898\/2026.07.03.26357226","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357226","rel_abs":"Chronic infection with hepatitis B virus (HBV) is characterized by persistent expression of hepatitis B surface antigen (HBsAg), which is associated with profound immune tolerance. Although nucleos(t)ide analogue therapy effectively suppresses viral replication, it neither eliminates HBV nor reverses virus-specific immune dysfunction. Here, we report the results of two parallel first-in-human, dose-escalation studies evaluating a single infusion of mAb19-LS, a long-acting IgG1 monoclonal antibody targeting HBsAg, in individuals with chronic HBV infection receiving nucleos(t)ide analogue therapy. mAb19-LS was generally safe and well tolerated and induced a mean 11-fold increase in antigen clearance. The magnitude and duration of HBsAg suppression were dependent on both baseline antigen levels and mAb19-LS dose, with suppression maintained for more than 36 weeks in individuals receiving the highest dose. Reduction of circulating HBsAg was associated with uptake of HBsAg-IgG immune complexes by monocytes and dendritic cells and inflammatory reprogramming of these antigen-presenting cells. Notably, proliferation of both CD4+ and CD8+ T cells, as well as interferon-{gamma} and TNF- production in response to HBV antigens, were significantly increased 24 weeks after infusion. Together, these findings demonstrate that mAb19-LS is generally safe and effectively accelerates HBsAg clearance while activating antigen presenting cells and enhancing antiviral T cell responses.","rel_num_authors":41,"rel_authors":[{"author_name":"Zijun Wang","author_inst":"The Rockefeller University"},{"author_name":"Mary Tenuta","author_inst":"The Rockefeller University"},{"author_name":"Han Ngoc Le","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Siri Nana Halling Scensgaard","author_inst":"Aarhus University Hospital"},{"author_name":"Gabriela S Silva Santos","author_inst":"The Rockefeller University"},{"author_name":"Daniel B Reeves","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Gaelle Breton","author_inst":"The Rockefeller University"},{"author_name":"Vanessa Igbokwe","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Andre Moraes Nicola","author_inst":"The Rockefeller University"},{"author_name":"Katrina Millard","author_inst":"The Rockefeller University"},{"author_name":"Sidsel Dahl Winther Andersen","author_inst":"Aarhus University Hospital"},{"author_name":"Henriette Graversen","author_inst":"Aarhus University Hospital"},{"author_name":"Caroline Zollner","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Martin Kluge","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Rachel Scheck","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Nina Weis","author_inst":"Copenhagen University Hospital - Amager and Hvidovre"},{"author_name":"Isik Johansen","author_inst":"Odense University Hospital"},{"author_name":"Deanna Dong","author_inst":"The Rockefeller University"},{"author_name":"Brianna Hernandez","author_inst":"The Rockefeller University"},{"author_name":"Irina Shimeliovich","author_inst":"The Rockefeller University"},{"author_name":"Juan Dizon","author_inst":"The Rockefeller University"},{"author_name":"Valeska Viera","author_inst":"The Rockefeller University"},{"author_name":"Frank Fabris","author_inst":"The Rockefeller University"},{"author_name":"Magdalena Schwarzmuller","author_inst":"Aarhus University Hospital"},{"author_name":"Pinkus Tober-Lau","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"David Hillus","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Munevver Demir","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Anna Gazumyan","author_inst":"The Rockefeller University"},{"author_name":"Frank Tacke","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Leif Erik Sander","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Florian Kurth","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Thomas Rasmussen","author_inst":"Aarhus University Hospital"},{"author_name":"Hector Ye","author_inst":"Medical Procare PLC"},{"author_name":"Calvin Pan","author_inst":"New York University Langone Health"},{"author_name":"Ira Jacobson","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Qiao Wang","author_inst":"The Rockefeller University"},{"author_name":"Jesper Damsgaard Gunst","author_inst":"Aarhus University Hospital"},{"author_name":"Christian Gaebler","author_inst":"Charite-Universitatsmedizin Berlin"},{"author_name":"Ole S Sogaard","author_inst":"Aarhus University Hospital"},{"author_name":"Marina Caskey","author_inst":"The Rockefeller University"},{"author_name":"Michel Nussenzweig","author_inst":"The Rockefeller University"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Clinical Impact, Diagnostic Performance, and Prognostic Implications of Plasma Metagenomic Next-Generation Sequencing in Solid Organ Transplant Recipients","rel_doi":"10.64898\/2026.07.02.26357172","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357172","rel_abs":"IntroductionPlasma metagenomic next-generation sequencing (mNGS) may detect pathogens in solid organ transplant (SOT) recipients, but optimal patient selection and result interpretation remain uncertain.\n\nMethodsIn a retrospective cohort study, physicians reviewed SOT recipients with first-instance clinical plasma mNGS testing (Karius, Inc.) and determined microbiological diagnoses, clinical impact of results, diagnostic yield, and clinical outcome. mNGS results were compared to microbiological diagnoses. A HIPAA-compliant large language model (GPT-4) was used to analyze electronic medical record (EMR) data and predict risk of infection with atypical bacteria, invasive fungi, mycobacteria, or parasites (collectively: pre-specified organisms of presumed significance, POPS) and identify patients with positive-impact mNGS testing.\n\nResultsOf 145 SOT recipients, 119 (82.1%) had positive tests, 42 (29.0%) had [&ge;] 1 POPS organism, and 27 (19.1%) had [&ge;] 1 organism causing positive clinical impact. Positive impact was highly correlated with POPS status, with 24 (88.9%) of 27 positive-impact organisms categorized as POPS (P<0.001). GPT-4 scores accurately identified patients with POPS diagnoses (AUC 0.86), and assigned higher scores to patients with positive-impact tests (P=0.001). mNGS testing had highest sensitivity for atypical bacteria (82.4% sensitivity) and lower sensitivity for Aspergillus spp (53.3% sensitivity). Detection of greater numbers of organisms by mNGS was associated with increased mortality (odds ratio 1.32 per organism detected).\n\nDiscussionPlasma mNGS is a valuable clinical tool in SOT recipients. Positive clinical impact is associated with detection of atypical bacteria, fungi, mycobacteria, or parasites. GPT-4 analysis of EMR data identifies patients at risk of infection from these organisms and most likely to benefit from mNGS testing.\n\nSummaryThe optimal use of plasma mNGS in solid organ transplant recipients remains uncertain. We demonstrate that mNGS is most impactful when atypical bacteria, fungi, or parasites are detected, and create an artificial intelligence tool to identify patients with those infections.","rel_num_authors":9,"rel_authors":[{"author_name":"Natasha Spottiswoode","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Pedro S Marra","author_inst":"University of California San Francisco School of Medicine, San Francisco, CA, USA"},{"author_name":"Emily C Lydon","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Victoria T Chu","author_inst":"University of California San Francisco"},{"author_name":"Nathan Radakovich","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Julieta Rodriguez","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Hoang Van Phan","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Charles R Langelier","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Monica Fung","author_inst":"Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Romosozumab Safely Restores Bone Mass in Multiple Myeloma via Osteoblast Reprogramming: A Phase IIa Study","rel_doi":"10.64898\/2026.07.02.26357196","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357196","rel_abs":"Multiple myeloma causes devastating osteolytic bone disease. Current antiresorptive therapies slow bone loss but fail to rebuild the skeleton. Consequently, patients continue to fracture and suffer the associated morbidity and mortality. Targeting the Wnt inhibitor sclerostin, with romosozumab, increases bone mass in osteoporosis but has not been leveraged in cancer. We hypothesised that romosozumab would safely restore bone mass in multiple myeloma. In a murine model of myeloma, romosozumab was safe, demonstrating no impact on tumour progression while significantly increasing bone density. We subsequently conducted a Phase IIa proof-of-concept study in 12 multiple myeloma patients refractory to bisphosphonate therapy. Romosozumab was safe, it was well-tolerated and did not promote clinical or clonal myeloma progression. Treatment induced an early, significant rise in serum bone formation markers whilst resorption remained unchanged. This was coupled with significant gains in bone mineral density throughout the skeleton. Additionally, we observed radiological evidence of repair to pre-existing osteolytic lesions and, critically, a reduction in the skeletal morbidity rate from 2.5 to 0.11 events per patient-year. Longitudinal single-cell transcriptomics revealed that romosozumab transiently reprograms the osteoblast lineage to upregulate matrix synthesis and mineralisation programmes. These findings demonstrate that sclerostin inhibition safely rebuilds bone, providing clinical and mechanistic rationale for further randomised studies to restore bone health in myeloma patients.","rel_num_authors":22,"rel_authors":[{"author_name":"Betty Gration","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Ryan C. Chai","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Shelley G. Young","author_inst":"Garvan Institute of Medical Research"},{"author_name":"C. Marcelo Sergio","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Elena Skorokhodova","author_inst":"Garvan Institute of Medical Research"},{"author_name":"James T. Smith","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Ariel Castro-Martinez","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Alessandra Bray","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Xufeng Lin","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Calysta Yan","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Joanna Kao","author_inst":"St Vincent's Hospital Sydney"},{"author_name":"Jacinta Perram","author_inst":"St Vincent's Hospital Sydney"},{"author_name":"Sam Lai","author_inst":"St Vincent's Hospital Sydney"},{"author_name":"Louis Lau","author_inst":"St Vincent's Hospital Sydney"},{"author_name":"Katherine N. Weilbaecher","author_inst":"Washington University"},{"author_name":"John Moore","author_inst":"St Vincent's Hospital Sydney"},{"author_name":"Nicholas Pocock","author_inst":"St Vincent's Hospital Sydney"},{"author_name":"Christine L. Chaffer","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Jackie Center","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Tri Giang Phan","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Georgia McCaughan","author_inst":"St Vincent's Hospital Sydney"},{"author_name":"Peter I. Croucher","author_inst":"Garvan Institute of Medical Research"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"RenalTransLSTM: Multi-Horizon Prediction of Acute Kidney Injury in ICU Patients using a Hybrid LSTM-Transformer Architecture","rel_doi":"10.64898\/2026.07.02.26357177","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357177","rel_abs":"ObjectiveAcute kidney injury (AKI) affects a large proportion of patients in the intensive care unit (ICU) and is a major contributor to morbidity, mortality, and cost. Although electronic health records (EHRs) capture rich longitudinal data, many predictive models fail to detect AKI early enough for effective intervention. Non-temporal methods such as logistic regression and XGBoost treat patient history as aggregated risk factors, discarding the temporal evolution of clinical state. A recent trend is to employ temporal models, such as recurrent neural networks, to capture sequential patterns, but these models struggle with irregular sampling and limited long-range contextual awareness. To address the challenge, we propose RenalTransLSTM, a hybrid temporal deep learning framework for early, multi-horizon AKI prediction and identification of modifiable risk factors.\n\nMethodsRenalTransLSTM integrates Long Short-Term Memory (LSTM) networks with Transformer encoders to model both local temporal dynamics and global contextual depen-dencies in ICU time-series data. Using 48-hour patient histories from MIMIC-IV (61,735 admissions), the model predicts AKI at 6-, 12-, and 24-hour lead times. We benchmark the model against SVM, XGBoost, LSTM, TG-LSTM, and a Transformer, and apply Integrated Gradients and counterfactual analysis to identify modifiable risk factors.\n\nResultsRenalTransLSTM outperforms all baselines across most horizons and metrics, achiev-ing AUROC above 0.90 and F1-scores reaching 0.85 while maintaining balanced precision and recall on imbalanced data. Ablation studies confirm that combining LSTM and Transformer components improved robustness and predictive performance. Counterfactual analysis identifies clinically meaningful, modifiable risk factors associated with AKI progression.\n\nConclusionRenalTransLSTM offers an effective, interpretable framework for early AKI prediction in the ICU, supporting proactive intervention and clinical decision support.","rel_num_authors":7,"rel_authors":[{"author_name":"S M Saiful Islam Badhon","author_inst":"University of North Texas"},{"author_name":"Mohammad Adibuzzaman","author_inst":"Oregon Health & Science University"},{"author_name":"Abu Saleh Mohammad Mosa","author_inst":"University of Alabama Birmingham"},{"author_name":"Serdar Bozdag","author_inst":"University of North Texas"},{"author_name":"Ana D Cleveland","author_inst":"University of North Texas"},{"author_name":"Junhua Ding","author_inst":"University of North Texas"},{"author_name":"K S M Tozammel Hossain","author_inst":"University of North Texas"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Toward Clinical Implementation of Polygenic Scores for Substance Use Disorders: A Multi-Ancestry Study","rel_doi":"10.64898\/2026.07.03.26357210","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357210","rel_abs":"ObjectiveTo develop and validate clinically relevant polygenic scores (PGS) for alcohol (AUD), cannabis (CanUD), opioid (OUD), tobacco (TUD), and polysubstance use disorders (polySUD) across African (AA), European (EA), and Latinx (LA) ancestry populations.\n\nMethodsUsing multiple genome-wide association study summary statistics and PGS methods, substance use disorder PGS were developed and evaluated in Indiana Biobank samples (IB, N: 1,356-24,989), then top-performing PGS were validated in All of Us Research Program samples (AOU, N: 62,389-209,952). Case and controls were defined using ICD-9\/10 codes. All participants were aged 18 years or older (>=21 years for AUD controls). Clinical relevance was defined as an odds ratio (OR) >=2 for individuals with the highest PGS determined based on disorder prevalence compared to everyone else.\n\nResultsIn EA and LA, all PGS achieved clinically relevant performance in both IB and AOU (ORs: 2.00-9.10; P <= 3.87E-4). In AA, PGS met this threshold in IB (ORs: 2.02-2.71; P <= 2.20E-4) but not in AOU (ORs: 1.28-1.56; P <=0.03). Overall, OUD PGS showed the strongest associations in most analyses, followed by CanUD and polySUD. Generally, compared to female PGS, male PGS had higher or comparable ORs, but the differences were not significant except AUD PGS in AOU LA.\n\nConclusionsPGS demonstrated clinically meaningful risk prediction for substance use disorders in EA and LA, supporting the feasibility of future clinical implementation for population-level screening. However, reduced performance in AA underscores the urgent need for more genetic studies in that population.","rel_num_authors":13,"rel_authors":[{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Michael Zhang","author_inst":"Indiana University School of Medicine"},{"author_name":"Tae-Hwi Schwantes-An","author_inst":"Indiana University School of Medicine"},{"author_name":"Marcus R. Breese","author_inst":"Indiana University School of Medicine"},{"author_name":"Karen Chartier","author_inst":"Virginia Commonwealth University"},{"author_name":"Christina M. Sheerin","author_inst":"Virginia Commonwealth University"},{"author_name":"Martin H. Plawecki","author_inst":"Indiana University School of Medicine"},{"author_name":"Changyong Guo","author_inst":"Indiana University School of Medicine"},{"author_name":"Yao-Ying Ma","author_inst":"Indiana University School of Medicine"},{"author_name":"Zhiping P. Pang","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Tatiana Foroud","author_inst":"Indiana University School of Medicine"},{"author_name":"Yunlong Liu","author_inst":"Indiana University School of Medicine"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"In silico clinical trials of BiTE expression by oncolytic viruses reveal the impact of patient heterogeneity on dosage protocol","rel_doi":"10.64898\/2026.07.02.26357107","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357107","rel_abs":"Immunotherapies have become a transformative therapeutic strategy for many cancer types in recent years. Bispecific T-cell engagers (BiTEs) are one promising immunotherapy that enhances cellular antitumour immunity by redirecting T cells towards cancer cells. Recent evidence suggests that BiTE efficacy can be augmented by encoding BiTEs in oncolytic measles virus vectors (MV-BiTE). Infection of cancer cells with MV-BiTE causes the local production of BiTEs and has shown safety and efficacy in murine tumour models. However, whether the observed efficacy of this treatment will translate to a heterogeneous human population is unknown. In this work, we generate an in silico clinical trial of MV-BiTE therapy using a system of ordinary differential equations. We capture potential heterogeneity of individual patients using variability in in vivo tumour volume and change in baseline (%) measurements from a Phase II clinical trial. In lieu of human MV-BiTE data, we use the oncolytic virus talimogene laherparepvec (T-VEC) as a surrogate oncolytic virus carrying an immunostimulatory payload. Our predictions imply that the main drivers of heterogeneity are the underlying effector T cell killing rate and BiTE pharmacokinetics. Furthermore, we find that if individuals are classified as non-responders to the Phase II T-VEC clinical protocol, they may respond to more frequent administration of lower dosages. This work highlights how in silico clinical trials can provide predictions for novel therapeutics to generate hypotheses and guide the design of treatment schedules for clinical translation.\n\nAuthor summaryThe immune system has the ability to kill cancer cells; however, cancer cells are able to resist immune cell-mediated killing. A new therapy uses modified measles viruses to activate the immune system against cancer. These viruses are modified with bispecific T-cell engagers (BiTEs) which assist immune cells in targeting and removing cancer cells. While the potential success of this treatment has been demonstrated in mouse models, it is yet to be verified in a human cohort. In this work, we use mathematical and computational simulations to examine how patient-to-patient variability might affect the success of this treatment. We compare our model predictions to data from a clinical trial and find that virtual individuals in the simulation that are classified as non-responders to the standard protocol would likely respond better to more frequent administrations of lower dosages. The work presented here generates hypotheses for how individuals in a human cohort may respond, however, more work is required to verify these results in humans.","rel_num_authors":6,"rel_authors":[{"author_name":"Adrianne L Jenner","author_inst":"Queensland University of Technology"},{"author_name":"Robyn P. Araujo","author_inst":"University of Melbourne"},{"author_name":"Noa L Levi","author_inst":"University of Melbourne"},{"author_name":"Guy Ungerechts","author_inst":"German Cancer Research Centre"},{"author_name":"Christine E Engeland","author_inst":"Fraunhofer Institute for Cell Therapy and Immunology"},{"author_name":"Johannes P.W. Heidbuechel","author_inst":"German Cancer Research Center"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Effect of fortified balanced energy-protein supplementation during pregnancy and lactation on infant neurodevelopment: a community-based randomized controlled trial in rural Nepal","rel_doi":"10.64898\/2026.07.02.26357185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357185","rel_abs":"IntroductionInfant neurodevelopment is associated with maternal nutritional status, yet few studies have evaluated the effects of balanced energy-protein (BEP) supplementation during pregnancy and\/or lactation.\n\nMethodsThe Maternal Infant Nutrition Trial (NCT03668977) was a 2x2 factorial, household randomized, unblinded, efficacy trial conducted in Sarlahi District, Nepal. Pregnant women were randomized to daily fortified BEP supplementation or no supplementation, and those with a live birth were re-randomized after delivery to supplementation or not until 6-months postpartum. The first 100 infants in each of the four intervention groups were enrolled in a neurodevelopment substudy. At 6-months, these infants underwent a cognitive, motor, language, and socioemotional assessment using the Bayley Scales of Infant and Toddler Development, fourth edition.\n\nResultsBaseline characteristics were similar across the four trial groups. A significant interaction (p< 0.05) between pregnancy and lactation supplementation groups was observed in the language domain only. Infants born to mothers who received BEP supplementation during pregnancy did not differ in standard scores for cognitive (mean difference (MD): 2.0, 95% confidence interval (CI): -0.29, 4.29), motor (MD: 0.98, 95% CI: -1.41, 3.36), or socioemotional (MD: -2.35, 95% CI: -5.27, 0.57) domains compared to the pregnancy control group. Similarly, for these three domains, there were no significant differences among infants whose mothers received BEP in lactation period vs. not. Infants born to mothers supplemented in both pregnancy and lactation had significantly higher mean language standard scores of 2.12 (95% CI: 0.16, 4.08; p-interaction = 0.015), driven by the expressive communication subtest, compared to those with no BEP supplementation in either period.\n\nConclusionBEP supplementation during pregnancy and\/or lactation was not associated with improvements in cognitive, motor, or socioemotional domains at 6 months; however, infants of women supplemented in pregnancy and lactation had significant improvements in the language domain. Evaluation at later ages is warranted.","rel_num_authors":8,"rel_authors":[{"author_name":"Tsering  Pema Lama","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Rita Shrestha","author_inst":"Nepal Nutrition Intervention Project - Sarlahi"},{"author_name":"Parul Christian","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"James  M Tielsch","author_inst":"George Washington University School of Public Health and Health Services: The George Washington University Milken Institute of Public Health"},{"author_name":"Joanne Katz","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Subarna  K Khatry","author_inst":"Nepal Nutrition Intervention Project - Sarlahi"},{"author_name":"Steven  C LeClerq","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Daniel  Joseph Erchick","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Hemispheric Asymmetry Features and Interpretable Machine Learning for Focal Cortical Dysplasia Classification in Drug-Resistant Epilepsy","rel_doi":"10.64898\/2026.07.02.26357180","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357180","rel_abs":"Focal cortical dysplasia (FCD) is a principal cause of pharmacoresistant focal epilepsy, yet its structural MRI signature, subtle cortical thickening, blurring of the gray-white matter junction, is frequently undetected even by experienced neuroradiologists, delaying or precluding referral for curative surgical resection. Here we develop a machine learning pipeline for FCD detection that prioritizes mechanistic interpretability over model complexity. In a subsample of 50 subjects (25 FCD, 25 age-matched controls) drawn from a public structural MRI cohort, we register all scans to a common stereotactic template and derive hemispheric asymmetry features across 48 cortical regions, exploiting the characteristic unilaterality of FCD pathology. Among four classifiers evaluated under leave-one-out cross-validation, an L1-regularized logistic regression achieves the highest accuracy (78%, permutation p=0.02), substantially outperforming tree-based ensembles, which perform at or below chance in this feature-to-sample regime. The fitted model selects a sparse subset of 21 of 96 features, with the largest-magnitude contributions localized to inferior and middle frontal gyri and temporal pole and superior temporal gyrus, regions consistent with the known anatomical distribution of FCD. These findings indicate that hemispheric asymmetry, combined with a sufficiently regularized, interpretable classifier, captures a modest but statistically robust and anatomically grounded signal for FCD detection, offering a transparent complement to existing deep learning approaches for presurgical evaluation.","rel_num_authors":2,"rel_authors":[{"author_name":"Aleena Iraqui","author_inst":"Broad Institute"},{"author_name":"Hoang Dang","author_inst":"MIT"}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"Poor sleep is robustly correlated with accelerated aging but the evidence for causation is mixed","rel_doi":"10.64898\/2026.07.02.26357135","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357135","rel_abs":"SIGNIFICANCE STATEMENTPoor sleep increases with age and is correlated with increased risk of many different age-related diseases. This has led many to claim that poor sleep causes aging to accelerate. In our study, we tested this claim using data from over 64,000 people. We found clear evidence that poor sleep is correlated with faster aging during young, middle, and late adulthood. However, we found mixed evidence that poor sleep may cause aging to accelerate. Slowing aging by improving sleep warrants further research as causal claims are not consistently supported by the existing data.\n\nSleep gets worse with age and is correlated with risk for disease and mortality. The possibility that poor sleep causes aging to accelerate has prompted interest in improving sleep to slow aging and prevent disease. However, the existing evidence on the link between poor sleep and accelerated aging is unclear. Here, we tested for correlation and causation between poor sleep and accelerated aging using five independent datasets of adults (total N > 64,000). We found strong evidence for a correlation between poor sleep and fast aging that is consistent across young, middle, and late adulthood and across aging biomarkers derived from different tissues and modalities. We found that this correlation is robust to the influence of chronic disease burden, but not to the influence of shared genetic and early environmental factors among twins. Finally, we found mixed evidence for a causal influence of poor sleep on accelerated aging using Mendelian randomization. Our findings indicate that the correlation between poor sleep and accelerated aging is highly robust; however, the claim that poor sleep causes aging to accelerate is not consistently supported.","rel_num_authors":20,"rel_authors":[{"author_name":"Ethan T. Whitman","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"Aric A. Prather","author_inst":"School of Medicine, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Julian Mutz","author_inst":"Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK"},{"author_name":"Louise Arseneault","author_inst":"Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK"},{"author_name":"David A.A. Baranger","author_inst":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Maxwell L. Elliott","author_inst":"Department of Psychology, University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Helen L. Fisher","author_inst":"Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK"},{"author_name":"David Ireland","author_inst":"Dunedin Multidisciplinary Health and Development Research Unit, Department of Psychology, University of Otago, Dunedin, New Zealand"},{"author_name":"Annchen R. Knodt","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"Christoph Kositzke","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"Yue Leng","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Aaron Reuben","author_inst":"Department of Psychology, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Karen Sugden","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"Benjamin S. Williams","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"J. Kathy Xie","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"Allison Yuan","author_inst":"Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Terrie E. Moffitt","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"Avshalom Caspi","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"Ahmad R. Hariri","author_inst":"Department of Psychology and Neuroscience, Duke University, Durham, NC, USA"},{"author_name":"- the Alzheimer's Disease Neuroimaging Initiative","author_inst":""}],"rel_date":"2026-07-06","rel_site":"medrxiv"},{"rel_title":"SpliSync: Genomic language model-driven splice site correction of long RNA sequencing reads","rel_doi":"10.64898\/2026.07.04.736518","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736518","rel_abs":"Long RNA sequencing reads are rapidly replacing short reads in transcriptomic analyses, enabling full-length transcript sequencing and better identification of isoforms, alternative splicing events, and other transcript variants. However, their higher sequencing error rates can cause misalignments, especially at splice junctions, reducing the accuracy of transcript reconstruction and analysis. We developed SpliSync, a genomic language model-driven method for splice site correction that integrates a pre-trained genomic sequence model (HyenaDNA), alignment data, and a U-net architecture to predict splice sites at nucleotide resolution. SpliSync substantially improved the precision of RNA long-read alignments by 27%-194% across diverse datasets and consistently outperformed competing tools. As a preprocessing step, it increased alternative splicing detection accuracy by 26%-330%. In contrast, its benefit for transcript reconstruction was limited, likely due to the tools' built-in correction mechanisms. The code, developed in Python using the PyTorch package, is freely available at https:\/\/github.com\/splicebox\/SpliSync.","rel_num_authors":2,"rel_authors":[{"author_name":"Wui Wang Lui","author_inst":"Johns Hopkins University"},{"author_name":"Liliana D Florea","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"EDTA v2: enabling scalable TE annotation in animal genomes","rel_doi":"10.64898\/2026.07.01.735963","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735963","rel_abs":"The Extensive de-novo TE Annotator (EDTA) automates transposable element annotation in plant genomes but lacks direct LINE\/SINE detection, limiting its applicability to animal genomes. We present EDTA v2, which integrates LINE and SINE detection, completely rewrites TIR-Learner for deployability and scalability, and accelerates structural detectors by up to two orders of magnitude. Tested in 30 animal genomes from the Vertebrate Genomes Project Phase I, EDTA v2 bridges the non-LTR detection gap that has prevented automated TE annotation in animals.","rel_num_authors":12,"rel_authors":[{"author_name":"Shujun Ou","author_inst":"Department of Molecular Genetics and Center for RNA Biology, Ohio State University, Columbus, OH 43210, USA"},{"author_name":"Tianyu Lu","author_inst":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"},{"author_name":"Hieu Nguyen","author_inst":"Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH 43210, USA"},{"author_name":"Kenji Gerhardt","author_inst":"Department of Molecular Genetics, Ohio State University, Columbus, OH 43210, USA"},{"author_name":"Ning 'Faye' Fang","author_inst":"Department of Molecular Genetics, Ohio State University, Columbus, OH 43210, USA"},{"author_name":"Usman Rashid","author_inst":"New Zealand Institute for Bioeconomy Science Limited, Auckland 1025, NZ"},{"author_name":"Joseph Guhlin","author_inst":"Genomics Aotearoa, Department of Biochemistry, University of Otago, Dunedin 9016, NZ"},{"author_name":"Jacques Dainat","author_inst":"MIVEGEC, University of Montpellier, IRD, CNRS, Montpellier 34394, FR"},{"author_name":"Zhigui Bao","author_inst":"Department of Molecular Biology, Max Planck Institute for Biology Tubingen, Tubingen 72076, DE"},{"author_name":"Philipp E. Bayer","author_inst":"School of Biological Sciences and Centre for Applied Bioinformatics, University of Western Australia, Crawley, WA 6009, AU"},{"author_name":"Yeojung Na","author_inst":"Department of Molecular Genetics, Ohio State University, Columbus, OH 43210, USA"},{"author_name":"Christopher Benson","author_inst":"Department of Molecular Genetics, Ohio State University, Columbus, OH 43210, USA"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Fitness flux in SARS-CoV-2 and influenza H3N2","rel_doi":"10.64898\/2026.07.05.736619","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736619","rel_abs":"The tempo of viral adaptation is usually read indirectly from the composition of mutations, through measures such as dN\/dS. Here we measure it directly from the dynamics of variant frequencies, where we use multinomial logistic regression to estimate a fitness for each co-circulating variant. We aggregate these estimates to derive the rate of change of mean population fitness, referred to as fitness flux. Tracing SARS-CoV-2 from its emergence, we find that it initially adapted rapidly, doubling in fitness every 6 months from Jan 2021 to Jun 2022, but slowing to every 2.4 years from Jul 2022 to Dec 2025. Seasonal influenza H3N2 sustained a slower, steadier pace doubling in fitness every 10.0 years. In both, the rate of fitness gain closely tracks the variance in fitness, matching the 1:1 expectation of Fisher's fundamental theorem. Phylogenetic contrasts between parent and child lineages localize most fitness gain to spike, and within spike to the receptor-binding domain, where a simple count of spike S1 substitutions predicts lineage fitness about as well as deep-learning escape and protein-language-model scores. Measuring fitness directly thus offers a transparent, frequency-based alternative to mutational proxies for tracking and anticipating viral adaptation. The website https:\/\/blab.github.io\/fitness-flux\/ is the intended reading experience of this paper, providing responsive layout and interactive figures.","rel_num_authors":1,"rel_authors":[{"author_name":"Trevor Bedford","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Adaptation of Pseudomonas aeruginosa to the lung allograft environment in cystic fibrosis lung transplant recipients","rel_doi":"10.64898\/2026.07.06.736721","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736721","rel_abs":"Lung transplantation (LT) is the ultimate treatment option for patients suffering from end stage cystic fibrosis (CF). Most LT-patients, colonized pre-LT by Pseudomonas aeruginosa witness colonization of their non-CF allograft within a few days or weeks post-LT, thereby compromising graft and life expectancy. How P. aeruginosa isolates adapted for years to the specific CF lung environment efficiently colonize and survive in the non-CF allograft environment remains unclear. To address this question, we collected sequential isolates from CF LT-recipients and non-CF LT-recipients and performed phenotypic and genetic analyses of pairs of early and late isolates from LT-patients. We found evidence for mutations compatible with a switch from biofilm to planktonic lifestyle as well as loss of mucoid phenotypes. Hypermutators, characteristic of chronic CF-adapted isolates, were also found in four LT-patients. Their persistence in the non-CF allograft environment suggests a continuous seeding from the sinuses. Our results suggest that in CF LT-recipients efficient colonisation by P. aeruginosa of the allograft implies both adaptation and continuous seeding from the sinuses to the lower respiratory tract.","rel_num_authors":10,"rel_authors":[{"author_name":"Thilo Kohler","author_inst":"University of Geneva"},{"author_name":"Lena Falconnet","author_inst":"University of Geneva"},{"author_name":"Alexandre Luscher","author_inst":"University of Geneva"},{"author_name":"Marie Graindorge Beaume","author_inst":"GREENPHAGE"},{"author_name":"Marc Chanson","author_inst":"University of Geneva"},{"author_name":"Gilbert Greub","author_inst":"University of Lausanne"},{"author_name":"Angela Koutsokera","author_inst":"Lausanne University Hospital"},{"author_name":"Gregory Berra","author_inst":"Geneva University Hospitals"},{"author_name":"Paola M Soccal","author_inst":"Geneva University Hospitals"},{"author_name":"Christian van Delden","author_inst":"Geneva University Hospitals"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"First community challenge for automated virus taxonomy","rel_doi":"10.64898\/2026.07.04.736517","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736517","rel_abs":"The rapid rate of virus discovery renders manual curation by taxonomy experts increasingly impractical, creating a need for reliable software that can reproducibly assign viral contigs to taxa at all fifteen ranks of the virus taxonomy. We led an open community challenge for the computational taxonomic classification of viruses and assembled a dataset of virus sequences combining expert-curated and metagenomic sequences. Seventeen teams contributed a total of thirty-four automated, fully reproducible classification pipelines. Most tools correctly assigned viruses belonging to established species, genera, or families, but viruses that are unclassified at those lower ranks remain challenging. This study provides datasets, open-source software, novel approaches, and recommendations to benchmark computational taxonomic classification of viruses, and support organizing the many viruses discovered in big omics data.","rel_num_authors":59,"rel_authors":[{"author_name":"Cedric Lood","author_inst":"Department of Biology, University of Oxford, Oxford, UK"},{"author_name":"Swapnil Doijad","author_inst":"Institute of Biodiversity, Ecology, and Evolution, Faculty of Biological Sciences, Cluster of Excellence Balance of the Microverse, Friedrich Schiller Universit"},{"author_name":"Evelien Adriaenssens","author_inst":"Quadram Institute Bioscience, Norwich Research Park, Norwich, UK"},{"author_name":"Yiming Bao","author_inst":"National Genomics Data Center, China National Center for Bioinformation, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Jakub Barylski","author_inst":"Department of Molecular Virology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland"},{"author_name":"Benjamin Bolduc","author_inst":"Department of Microbiology, Ohio State University, Columbus, OH, USA"},{"author_name":"George Bouras","author_inst":"Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia."},{"author_name":"Rodney J. Brister","author_inst":"National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA."},{"author_name":"Titus C. Brown","author_inst":"Department of Population Health and Reproduction, University of California, Davis, CA, USA"},{"author_name":"Antonio Pedro Camargo","author_inst":"DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Lander De Coninck","author_inst":"Department of Microbiology, Immunology and Transplantation, Laboratory of Viral Metagenomics, KU Leuven, Leuven, Belgium"},{"author_name":"Sebastian Deorowicz","author_inst":"Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Gliwice, Poland"},{"author_name":"Robert Edgar","author_inst":"Unaffiliated (independent scientist)"},{"author_name":"Robert Edwards","author_inst":"Flinders Accelerator for Microbiome Exploration, Flinders University, Bedford Park, SA, Australia"},{"author_name":"Shitao Gong","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"},{"author_name":"Arthur Gruber","author_inst":"Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulon, Brazil"},{"author_name":"Adam Gudys","author_inst":"Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Gliwice, Poland"},{"author_name":"Ernestina Hauptfeld","author_inst":"Theoretical Biology and Bioinformatics, Science4Life, Utrecht University, Utrecht, the Netherlands"},{"author_name":"Anneliek ter Horst","author_inst":"Department of Population Health and Reproduction, University of California, Davis, CA, USA"},{"author_name":"Tianyang Huang","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"},{"author_name":"Jingzhe Jiang","author_inst":"Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research In"},{"author_name":"Lars Kaderali","author_inst":"Institute of Bioinformatics, University Medicine Greifswald, Germany"},{"author_name":"Jaebeom Kim","author_inst":"School of Biological Sciences, Seoul National University, Seoul, Republic of Korea"},{"author_name":"Mart Krupovic","author_inst":"Institut Pasteur, Universite Paris Cite, Cell Biology and Virology of Archaea Unit, Paris, France"},{"author_name":"Jens H. Kuhn","author_inst":"Frederick, Maryland, USA"},{"author_name":"Elliott Lefkowitz","author_inst":"Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Matthieu Leobold","author_inst":"Institut de Recherche sur la Biologie de l'Insecte, UMR 7261 CNRS-Universite de Tours, Tours, France"},{"author_name":"Shuai-Cheng Li","author_inst":"Department of Computer Science, City University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Yiyun Liu","author_inst":"National Genomics Data Center, China National Center for Bioinformation, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Bastiaan F.A. von Meijenfeldt","author_inst":"Department of Marine Microbiology and Biogeochemistry, NIOZ Royal Netherlands Institute for Sea Research, Texel, The Netherlands"},{"author_name":"Uri Neri","author_inst":"DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Judit Penzes","author_inst":"Texas A&M University, Department of Entomology, College Station, TX, USA"},{"author_name":"Tessa Pierce-Ward","author_inst":"Department of Population Health and Reproduction, University of California, Davis, CA, USA"},{"author_name":"Janina Rahlff","author_inst":"Aero-Aquatic Virus Research Group, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Germany"},{"author_name":"Alejandro Reyes Munoz","author_inst":"Departament of Biological Sciences, Universidad de los Andes, Bogota, Colombia"},{"author_name":"Luisa Rubino","author_inst":"Consiglio Nazionale delle Ricerche, Istituto per la Protezione Sostenibile delle Piante, Sede Secondaria di Bari, Bari, Italy"},{"author_name":"Sead Sabanodzovic","author_inst":"Department of Agricultural Science and Plant Protection, Mississippi State University, Mississippi State, MS, USA"},{"author_name":"Jiayu Shang","author_inst":"Department of Information Engineering, Chinese University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Peter Simmonds","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Martin Steinegger","author_inst":"School of Biological Sciences, Seoul National University, Seoul, Republic of Korea"},{"author_name":"Matthew Sullivan","author_inst":"Department of Microbiology, Ohio State University, Columbus, OH, USA"},{"author_name":"Yanni Sun","author_inst":"Department of Electrical Engineering, City University of Hong Kong, Hong Kong SAR, China"},{"author_name":"LIli Tian","author_inst":"National Genomics Data Center, China National Center for Bioinformation, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Yigang Tong","author_inst":"BAICSM, State Key Laboratory of Green Biomanufacturing, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China"},{"author_name":"Robert Turnbull","author_inst":"Melbourne Data Analytics Platform, The University of Melbourne, Parkville, VIC, Australia"},{"author_name":"Dann Turner","author_inst":"School of Applied Sciences, College of Health, Science and Society, University of the West of England, Bristol, UK"},{"author_name":"Arvind Varsani","author_inst":"The Biodesign Center for Fundamental and Applied Microbiomics, School of Life Sciences, Arizona State University, Center of Evolution and Medicine, Tempe, AZ, U"},{"author_name":"Ziye Wang","author_inst":"School of Mathematical Sciences and LPMC, Nankai University, Tianjin, China."},{"author_name":"Yasas Wijesekara","author_inst":"Institute of Bioinformatics, University Medicine Greifswald, Germany"},{"author_name":"Wytamma Wirth","author_inst":"Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia"},{"author_name":"Haolong Xia","author_inst":"School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangdong, China"},{"author_name":"Shuo Yang","author_inst":"Department of Computer Science, City University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Tze-Ching Yeo","author_inst":"Aero-Aquatic Virus Research Group, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Germany"},{"author_name":"Jinbei Zhang","author_inst":"BAICSM, State Key Laboratory of Green Biomanufacturing, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China"},{"author_name":"Xianglilan Zhang","author_inst":"Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Shanfeng Zhu","author_inst":"Institute of Science and Technology for Brain-Inspired Intelligence and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"},{"author_name":"Andrzej Zielezinski","author_inst":"Laboratory of Computational Biology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland"},{"author_name":"Simon Roux","author_inst":"DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA"},{"author_name":"Bas E. Dutilh","author_inst":"Institute of Biodiversity, Ecology, and Evolution, Faculty of Biological Sciences, Cluster of Excellence Balance of the Microverse, Friedrich Schiller Universit"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Model of naturally occurring refractive error (NORE) in mice","rel_doi":"10.64898\/2026.07.01.735855","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735855","rel_abs":"Purpose: Animal models of myopia typically induce monocular refractive shifts via form deprivation (FD) or lens-induced myopia (LIM), modeling susceptibility to myopia, but with potentially limited applicability to childhood myopia. Here we describe a novel, genetically diverse mouse model of naturally occurring refractive error (NORE) with three distinct refractive phenotypes: hyperopic, myopic, and intermediate. Methods: C57BL\/6J mice were mated to 129S2\/SvPasCrl mice to create F1 or F2 offspring. Refractive errors in male and female F1 (N=21) and F2 (N=101) mice were assessed on postnatal days (P) 28 and 42 using photorefractometry. In a subset of mice (N=30 - 40), corneal radius of curvature, axial ocular dimensions, retinal and visual function were assessed. Results: F2 mice were classified as NORE with either hyperopic (RE [&ge;] 0 diopters (D) at P28 and P42), myopic (RE<0D at P28 and P42) or intermediate (RE<0D at P28 and RE [&ge;] 0D at P42) refractions based on individual trajectories. All ocular parameters changed with age, with significantly slower growth in axial length and vitreous chamber depth in the intermediate versus myopic mice (p<0.05). Lens thickness was smaller in the myopic group at P28. Differences in refraction were not attributed to variances in retinal function or dopamine signaling. Conclusions: NORE mice represent a novel, genetically diverse wild-type mouse model that, unlike traditional models, does not require interventions such as FD or LIM to induce myopia. NORE mice provide a valuable tool for future investigations of genetic and environmental mechanisms and targeted therapeutic strategies for refractive errors.","rel_num_authors":8,"rel_authors":[{"author_name":"Melissa R. Bentley-Ford","author_inst":"1) Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; 2) Center for Visual and Neurocognitive Rehabilitation, Joseph Maxwell Cl"},{"author_name":"Teele Palumaa","author_inst":"1) Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; 3) Institute of Genomics, University of Tartu, Tartu, Estonia"},{"author_name":"Linjiang Lou","author_inst":"1) Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Aparna Jonnalagadda","author_inst":"1) Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; 4) Georgia Institute of Technology Undergraduate Neuroscience Program, At"},{"author_name":"Morgan L. Bade","author_inst":"1) Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Shruti Balamurugan","author_inst":"1) Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Reece Mazade","author_inst":"1) Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Machelle T. Pardue","author_inst":"1)Dept. of Ophthalmology, Emory University; 2) Center for Visual and Neurocognitive Rehabilitation, Joseph Maxwell Cleland, Atlanta VA. Medical Center; 5) Dept."}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"A Conserved Chromatin-Driven Checkpoint Defines Late Macrophage Maturation Independent of Tissue Specialization","rel_doi":"10.64898\/2026.07.01.735834","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735834","rel_abs":"Macrophage identity is widely viewed as a product of ontogeny and tissue-specific imprinting. Here, we identify a conserved, chromatin-driven maturation checkpoint that operates independently of initial lineage commitment and broadly across tissue contexts. Using long-term bone marrow-derived macrophage cultures, we uncover a late-stage transition characterized by coordinated transcriptional an epigenomic remodeling. Integration with in vivo developmental, tissue-resident, and monocyte repopulation datasets demonstrates that this program is conserved across ontogenies, tissues, species, and experimental systems, revealing a previously unrecognized stage of macrophage maturation. Functionally, late maturation preserves core macrophage activities while promoting lysosomal expansion and fundamentally rewiring innate immune responsiveness. Mature macrophages display enhanced stimulus-specific responses to interferons and microbial danger signals, coupled to increased metabolic and inflammatory competence while restricting interferon-induced transcriptional memory. Together, our findings identify late macrophage maturation as a conserved regulatory checkpoint that reprograms the logic of innate immune responsiveness through chromatin remodeling shaping innate immune function.","rel_num_authors":13,"rel_authors":[{"author_name":"Djurdja Pasajlic","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"},{"author_name":"Maud Plaschka","author_inst":"St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria"},{"author_name":"Frank P. Assen","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"},{"author_name":"Anna Kusienicka","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"},{"author_name":"Lisa E. Shaw","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"},{"author_name":"Peter Traxler","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"},{"author_name":"Ulrike Mann","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"},{"author_name":"Martin Petrovic","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"},{"author_name":"Jelena Bogdanovic","author_inst":"University of Chicago, Department of Molecular Genetics and Cell Biology, Chicago, Illinois, USA"},{"author_name":"Wolfgang Weninger","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"},{"author_name":"Thomas Decker","author_inst":"University of Vienna, Department of Microbiology, Immunobiology and Genetics, Center for Molecular Biology, Vienna, Austria"},{"author_name":"Florian Halbritter","author_inst":"St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria"},{"author_name":"Matthias Farlik","author_inst":"Medical University of Vienna, Department of Dermatology, Vienna, Austria"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Longitudinal Salivary Immunophenotyping Reveals Distinct Cellular Signatures of Periodontal Disease Activity and Resolution","rel_doi":"10.64898\/2026.07.01.735878","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735878","rel_abs":"AimTo investigate whether salivary immune cell profiling can serve as a non-invasive approach to monitor periodontal disease activity and therapeutic response by characterizing innate and adaptive immune cell dynamics in periodontitis.\n\nMaterials and MethodsThis longitudinal study included systemically healthy adults with periodontitis and healthy controls. Periodontal parameters (PPD, BOP, plaque\/calculus, and radiographic bone loss) were recorded by calibrated examiners ({kappa}=0.85) following established criteria. Stimulated saliva and gingival biopsies were collected before and 4-6 weeks after non-surgical periodontal therapy (NSPT), and from healthy controls. Multiparametric flow cytometry was used to characterize myeloid and lymphoid cell populations and polarization markers. Bacterial transcripts and host inflammatory markers were assessed by qRT-PCR. Statistical analyses were performed using one-way ANOVA.\n\nResultsPeriodontitis subjects exhibited significantly elevated salivary bacterial transcripts, which decreased but did not normalize following NSPT. Both myeloid and lymphoid immune cell populations increased in periodontitis compared with healthy controls and declined after therapy. This was accompanied by a pronounced pro-inflammatory shift with elevated IFN-{gamma}-producing macrophages, dendritic cells, Th1\/Th17 cells, and B cells, including the novel identification of IFN-{gamma}-producing B cells in saliva and mirrors the gingival immune cell profiles. In contrast, anti-inflammatory populations (IL-10-producing myeloid cells, Tr1 cells, and regulatory B cells) were reduced in disease and partially restored following NSPT.\n\nConclusionsSalivary immunophenotyping non-invasively monitors PD activity and therapeutic response by capturing dynamic immune changes that reflect gingival signatures and track post-therapy resolution.\n\nClinical RelevanceO_ST_ABSScientific rationaleC_ST_ABSSalivary immune profiling offers a real-time, non-invasive tool for assessing periodontal disease status and treatment outcomes, with potential applications in precision diagnostics and personalized periodontal care.\n\nPrinciple findingsPeriodontitis was associated with increased salivary bacterial burden and a marked pro-inflammatory immune profile involving both innate and adaptive immune cells, including newly identified IFN-{gamma}-producing B cells. Non-surgical periodontal therapy partially restored anti-inflammatory immune responses and reduced inflammatory cell populations, supporting salivary immunophenotyping as a promising non-invasive biomarker approach for monitoring disease activity and treatment response.\n\nPractical implicationsSalivary immune cell profiling could serve as a simple, non-invasive tool to monitor periodontal disease activity and response to therapy in clinical practice. Identification of specific inflammatory cell subsets may also aid in developing personalized diagnostic and therapeutic strategies for periodontitis.","rel_num_authors":11,"rel_authors":[{"author_name":"Raza Ali Naqvi","author_inst":"University of Illinois Chicago"},{"author_name":"Matt Tokarski","author_inst":"University of Illinois Chicago"},{"author_name":"Kristofer Ceredon","author_inst":"University of Illinois Chicago"},{"author_name":"Joseph Gluck","author_inst":"University of Illinois Chicago"},{"author_name":"Sarah Elshourbagy","author_inst":"University of Illinois Chicago"},{"author_name":"Laura Popa","author_inst":"University of Illinois Chicago"},{"author_name":"Lana Dalbah","author_inst":"University of Illinois Chicago"},{"author_name":"Michael Schmerman","author_inst":"University of Illinois Chicago"},{"author_name":"Joel L Schwartz","author_inst":"University of Illinois Chicago"},{"author_name":"Salvador Nares","author_inst":"University of Illinois Chicago"},{"author_name":"Afsar Naqvi","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Targeting DNMT1 augments anti-tumor CD8\u207a T cell function","rel_doi":"10.64898\/2026.07.03.736412","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736412","rel_abs":"Chronic stimulation of CD8 T cells within the tumor microenvironment (TME) induces a hypofunctional state characterized by diminished cytotoxicity and functionally impaired anti-tumor function, known as exhaustion. Exhaustion is associated with epigenetic changes that remain relatively stable despite interventions like immune checkpoint inhibition (ICI). Although epigenetic changes are potentially reversible, reports of therapeutic strategies to effectively restore function in exhausted CD8 T cells remain limited. Here, we report DNA methyltransferase 1 (DNMT1) inhibition (DNMT1i) in counteracting CD8+ T cell dysfunction during the anti-tumor response. We show that DNMT1i synergizes with ICI to rescue the tumor cell killing activity of chronically stimulated CD8 T cells in a melanoma model. DNMT1i mitigates transcriptional features of exhaustion while inducing a divergent effector program. DNMT1i attenuates the global increase in chromatin accessibility associated with exhaustion and enables epigenetic remodeling of the exhausted chromatin landscape upon restimulation. Finally, DNMT1i enhances the effector function of melanoma patient-derived tumor infiltrating lymphocytes after prolonged ex vivo expansion. These studies establish DNMT1 targeting as a promising strategy to counteract CD8 T cell exhaustion and potentiate ICI efficacy.","rel_num_authors":15,"rel_authors":[{"author_name":"Maya Deshmukh","author_inst":"Yale School of Medicine"},{"author_name":"Danielle Sohai","author_inst":"Yale School of Medicine"},{"author_name":"Kamal Obbad","author_inst":"Stanford University"},{"author_name":"Koonam Park","author_inst":"Yale School of Medicine"},{"author_name":"Simon Milette","author_inst":"Yale School of Medicine"},{"author_name":"Peili Gu","author_inst":"Yale School of Medicine"},{"author_name":"Henna Nam","author_inst":"Yale School of Medicine"},{"author_name":"Andrew Daniels","author_inst":"Yale School of Medicine"},{"author_name":"Krasimir Spasov","author_inst":"Yale School of Medicine"},{"author_name":"Michael Hurwitz","author_inst":"Yale School of Medicine"},{"author_name":"Samuel G Katz","author_inst":"Yale University"},{"author_name":"Richard A Flavell","author_inst":"Yale University"},{"author_name":"Karen Anderson","author_inst":"Yale School of Medicine"},{"author_name":"Marcus Bosenberg","author_inst":"Yale School of Medicine"},{"author_name":"Goran Micevic","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Northward expansion of the barnacle Fistulobalanus albicostatus in Japan","rel_doi":"10.64898\/2026.07.06.736396","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736396","rel_abs":"Fistulobalanus albicostatus Pilsbry, 1916 (Thoracica: Balanidae) is a tropical to temperate species distributed in the NW Pacific. The previously known northernmost record of this species in Japan was from Aomori Prefecture, at the northern end of Honshu Island, Japan. However, field surveys conducted in 2023 and 2026 confirmed the occurrence of F. albicostatus in Hakodate Bay, the southern end of Hokkaido, Japan, across the Tsugaru Strait, thereby extending the northern limit of its known distribution. A line transect survey conducted in May 2026 recorded seven living individuals within an area of 128 m. F. albicostatus was rare on the mid-high shores, accounting for only 2% of all barnacle individuals in a quadrat survey. The basal diameter of the living individuals ranged from 0.76 to 1.23 cm, and all individuals possessed ovaries. Based on characteristics of both morphological and COI gene, the specimens were identified as F. albicostatus, and belonged to the same haplotype of populations that are present in Honshu Island. The establishment of F. albicostatus in Hokkaido suggests an ongoing northward range shift of this warm-water species, with the potential for further expansion under continued ocean warming.","rel_num_authors":3,"rel_authors":[{"author_name":"Masami Matsuno Tamechika","author_inst":"Hokkaido University"},{"author_name":"Adnan Shahdadi","author_inst":"Academia Sinica"},{"author_name":"Benny Kwok Kan Chan","author_inst":"Academia Sinica"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"BoltzMol-1: Towards Reliable Virtual Screening for Fast and Cost-Effective Hit Discovery","rel_doi":"10.64898\/2026.07.04.736485","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736485","rel_abs":"We present BoltzMol-1, a small-molecule hit discovery pipeline, centered on an optimized version of Boltz-2, explicitly adapted for prospective discovery. Reliable hit discovery that generalizes across target classes (rather than only the well-characterized families that dominate existing ligand data) would broaden the range of biology accessible to small-molecule intervention and reduce reliance on resource-intensive high-throughput screening. Towards this goal, the system prioritizes compounds for rapid experimental validation by coupling model-driven ranking with streamlined procurement from commercial catalogs. To improve developability at the point of selection, we introduce a suite of ADMET models for kinetic solubility (logS), lipophilicity (logD), and Caco-2 permeability. These models act as an early triage layer, systematically filtering out compounds with unfavorable physicochemical and absorption properties prior to synthesis or purchase. Across a panel of ten targets (most with no representation in the underlying affinity training data) we observe strong prospective performance on challenging systems. Functional actives or binders were identified for 6 of 10 targets, despite modest experimental budgets of 28-96 compounds per target. These results include successes on receptors and enzymes traditionally considered difficult for structure- or ligand-based approaches. Collectively, this work establishes a practical framework for low-throughput, cost constrained discovery campaigns capable of delivering chemically tractable binders with favorable property profiles.","rel_num_authors":13,"rel_authors":[{"author_name":"Noah Getz","author_inst":"Boltz PBC"},{"author_name":"Geoffrey Smith","author_inst":"Boltz PBC"},{"author_name":"Avene Colgan","author_inst":"Boltz PBC"},{"author_name":"Vincent Fan","author_inst":"Boltz PBC"},{"author_name":"Luca Cavalleri","author_inst":"Boltz PBC"},{"author_name":"Francesco Capponi","author_inst":"Boltz PBC"},{"author_name":"Jeremy Wohlwend","author_inst":"Boltz PBC"},{"author_name":"Anthony Gitter","author_inst":"University of Wisconsin-Madison; Morgridge Institute for Research"},{"author_name":"Joshua Kritzer","author_inst":"Tufts University"},{"author_name":"Madison Maiorano","author_inst":"Tufts University"},{"author_name":"Nathan Wlodarchak","author_inst":"Research Service, Rocky Mountain Regional Veterans Affairs Medical Center"},{"author_name":"Gabriele Corso","author_inst":"Boltz PBC"},{"author_name":"Saro Passaro","author_inst":"Boltz PBC"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Development and Characterisation of a Versatile Single-Domain Antibody Specific for M1-linked Ubiquitin Chains","rel_doi":"10.64898\/2026.07.05.736589","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736589","rel_abs":"Ubiquitin signalling is mediated by structurally distinct polyubiquitin chains that encode discrete cellular functions. Progress in deciphering this ubiquitin code, particularly for the less abundant atypical chain types, has been hindered by limited availability of versatile chain type-specific affinity reagents. Here, we demonstrate that human single-domain antibodies (sdAbs) provide a versatile scaffold for the generation of ubiquitin linkage-specific binders. Using phage display and synthetic human sdAb libraries, we identified 2A6, an sdAb that specifically recognises methionine-1 (M1)-linked ubiquitin chains. To our knowledge, 2A6 represents the first reported sdAb with specificity for a defined homotypic ubiquitin chain linkage. 2A6 bound M1-linked ubiquitin chains with nanomolar affinity and was specific for M1-linked chains at the level of both diubiquitin and long polyubiquitin chains. AlphaFold3 modelling, supported by saturation mutagenesis, predicted that 2A6 recognises the proximal and distal ubiquitin moieties together with the region near the M1 linkage. Functionally, 2A6 enabled specific detection and enrichment of M1-linked ubiquitin across multiple applications, including ELISA, immunoblotting, immunoprecipitation under semi-denaturing conditions, substrate ubiquitination analysis, and immunofluorescence microscopy. The sdAb can be readily produced in E. coli from a single expression plasmid, providing a tractable, cost-effective and versatile reagent for investigating M1-linked ubiquitin signalling. Our work establishes sdAbs as a versatile scaffold for ubiquitin linkage-specific affinity reagents, providing a framework for the development of analogous binders specifically targeting additional ubiquitin linkages or architectures.","rel_num_authors":14,"rel_authors":[{"author_name":"Julian Koch","author_inst":"Technical University of Denmark"},{"author_name":"Shun-Je Bhark","author_inst":"Oregon Health & Science University"},{"author_name":"Verian Bader","author_inst":"Ruhr University Bochum"},{"author_name":"Berthe Katrine Fiil","author_inst":"University of Copenhagen"},{"author_name":"Blanca Lopez-Mendez","author_inst":"University of Copenhagen"},{"author_name":"Josefine Bebe Rasthoej","author_inst":"Technical University of Denmark"},{"author_name":"Dominik Priesmann","author_inst":"Technical University of Denmark"},{"author_name":"Oscar Mejias-Gomez","author_inst":"Technical University of Denmark"},{"author_name":"Marta Braghetto","author_inst":"Technical University of Denmark"},{"author_name":"Guillermo Montoya","author_inst":"University of Copenhagen"},{"author_name":"Mads Gyrd-Hansen","author_inst":"University of Copenhagen"},{"author_name":"Konstanze F Winklhofer","author_inst":"Ruhr University Bochum"},{"author_name":"Steffen Goletz","author_inst":"Technical University of Denmark"},{"author_name":"Rune Busk Damgaard","author_inst":"Technical University of Denmark"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Lack of co-ordination of stomatal, hydraulic and leaf browning traits in 16 perennial Australian grass species of differing climate origins","rel_doi":"10.64898\/2026.07.04.736528","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736528","rel_abs":"Grasslands are vulnerable to increasing drought with global warming, but process-based models lack the mechanistic knowledge required to predict the magnitude of drought impacts. While a plant hydraulics framework has been successful in advancing process understanding of drought responses in trees, and how drought responses vary across rainfall gradients, similar approaches have rarely been applied to grasses. Here, we quantified the progression of key drought response processes in sixteen dominant perennial grasses (seven C3 and nine C4) with differing climatic origins across eastern Australia. We found that stomatal closure, hydraulic impairment and leaf browning occurred concurrently, in contrast to the progressive sequence typically observed in trees. We also found that drought response traits were not correlated with species climate of origin. The early impairment of leaf hydraulic conductance and leaf browning along with the lack of correlation with climate of origin suggest that grasses may employ fundamentally different strategies to adapt to low water availability than trees. These results highlight the need for grass-specific parameterization of drought responses in process-based models.","rel_num_authors":8,"rel_authors":[{"author_name":"Krishnananthaselvan Arjunan","author_inst":"Department of Bio-Science , Faculty of Applied Science, University of Vavuniya, Sri Lanka"},{"author_name":"Vinod Jacob","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Australia"},{"author_name":"Jinyan Yang","author_inst":"CSIRO Environment, Canberra, Australia"},{"author_name":"Brendan Choat","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Australia"},{"author_name":"Elise Pendall","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Australia"},{"author_name":"Sally Power","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Australia"},{"author_name":"David Tissue","author_inst":"Western Sydney University"},{"author_name":"Belinda Medlyn","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Australia"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"The membrane distal domain of CD16a allosterically regulates NK cell ADCC","rel_doi":"10.64898\/2026.07.03.736431","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736431","rel_abs":"Antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells is mediated by the activating IgG receptor CD16a (Fc{gamma}RIIIa), yet the molecular mechanisms governing receptor activation remain poorly understood. We demonstrate that the membrane-distal domain 1 (D1) of CD16a functions as an allosteric checkpoint that controls ADCC independently of IgG-Fc binding. A nanobody, C28, that binds an electronegative patch in D1 dose-dependently blocks NK cell ADCC against multiple therapeutic antibodies without affecting direct cytotoxicity. A second nanobody, C21, binding an adjacent D1 epitope has no such effect. Cryo-EM structures of the CD16a-IgG-nanobody complex reveal that C28 allosterically competes with core-fucosylated IgG and stabilizes a closed D1 conformation resembling unliganded receptor, even when Fc is bound. Molecular dynamics simulations show that occupation of the D1 epitope rigidifies the IgG-binding site, stabilizing CD16a overall in contrast with IgG binding alone. The nanobody C28 restricts CD3{zeta} phosphorylation in both resting and ADCC-activated NK cells, revealing tonic inhibitory control upstream of the signaling cascade. Using MINFLUX nanoscopy, we also show that CD16a forms dimers of [~]9 nm spacing on the NK cell surface, a geometry unaltered by the ADCC-enhancing L48H polymorphism. Drawing on structural parallels with the IgE receptor Fc{varepsilon}RI, which is held inactive as a cholesterol-stabilized dimer, we propose that CD16a dimerization through D1 contacts represents a conserved autoinhibitory mechanism among Fc receptors. Consistent with this model, structure-guided disruption of the C28 epitope in NK-92 cells enhances ADCC potency and killing kinetics, providing a blueprint for engineering improved cellular immunotherapeutics.","rel_num_authors":17,"rel_authors":[{"author_name":"Tania Cid","author_inst":"San Diego Biomedical Research Institute"},{"author_name":"Monica Fernandez-Quintero","author_inst":"Scripps Research"},{"author_name":"Hijab Fatima","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Ema Robinson","author_inst":"Scripps Research"},{"author_name":"Braden Christenson","author_inst":"San Diego Biomedical Research Institute"},{"author_name":"Johannes Loeffler","author_inst":"Scripps Research"},{"author_name":"Daniel P Leaman","author_inst":"Scripps Research"},{"author_name":"Ryan Lin","author_inst":"Scripps Research"},{"author_name":"Kayla Xu","author_inst":"Scripps Research"},{"author_name":"Jessica Matthias","author_inst":"Abberior USA"},{"author_name":"Scott C Henderson","author_inst":"Scripps Research"},{"author_name":"Kathryn Spencer","author_inst":"Scripps Research"},{"author_name":"Joseph Jardine","author_inst":"Scripps Research"},{"author_name":"Michael B Zwick","author_inst":"Scripps Research"},{"author_name":"Andrew B Ward","author_inst":"Scripps Research"},{"author_name":"Emily M Mace","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Charles Daniel Murin","author_inst":"San Diego Biomedical Research Institute"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Representations of active grasp maintenance emerge during reach-grasp-carry learning in mouse motor cortex","rel_doi":"10.64898\/2026.06.30.735546","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735546","rel_abs":"Object manipulation is a dexterous behavior requiring ongoing sensorimotor coordination to establish and maintain a grasp during consecutive movements. Although grasp initiation is known to modulate activity in primary motor cortex (M1), it remains unclear if sustained grasp maintenance is represented in M1, whether it corresponds to an intrinsic M1 state or one that emerges through learning, and how this state contributes to skilled behaviors involving object manipulation. We addressed these questions using two-photon calcium imaging in mice learning a self-initiated, self-paced, reach-grasp-carry task. This task allowed mice to control trial structure and timing, revealing two kinematically similar but functionally distinct carry behaviors: active grasps, in which mice maintained control of a sucrose pellet and received sensory feedback from the held object, and empty grasps, in which mice completed the same carry movement after failing to grasp the pellet. As behavior was refined, empty grasps became less frequent and the M1 representation of active grasp maintenance became more reliable and more distinct from empty grasp. This distinction was evident in single-neuron activity, population activity, and functional connectivity between neurons. These differences were sufficiently robust to support accurate decoding of active and empty grasp state from neural activity and improved encoding of single neuron activity when models incorporated condition-specific functional network coupling. Together, these findings show that learning refines M1 activity into a distinct and reliable representation of active grasp maintenance, revealing sensorimotor integration during object contact as a key neural substrate of learned dexterous behavior.","rel_num_authors":3,"rel_authors":[{"author_name":"Eliza T Wiener","author_inst":"University of Chicago"},{"author_name":"Gabriella Wheeler Fox","author_inst":"University of Chicago"},{"author_name":"Jason N MacLean","author_inst":"University of Chicago"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Frontal Eye Field Leads a Distributed Oculomotor Circuit for Abstract Categorical Decisions","rel_doi":"10.64898\/2026.06.30.735630","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735630","rel_abs":"Flexible decisions require the brain to transform sensory evidence into abstract, task-relevant variables and then into actions. Understanding this process requires identifying how distributed neural populations represent sensory, cognitive, and motor variables, and how interareal interactions mediate transformations between them. We simultaneously recorded population activity in frontal eye field (FEF), lateral intraparietal area (LIP) and superior colliculus (SC) while monkeys performed a flexible yet urgent visual motion-categorization task. Within this network, FEF first encoded abstract categories, followed by SC and then LIP. LIP showed the earliest encoding of visual stimulus features, but a later encoding of upcoming saccades. Single-trial analyses revealed directed information flow from FEF to LIP populations for category- and choice-related signals. Reversible FEF inactivation impaired categorization and saccadic choice, causally implicating FEF in category-guided action. These findings reveal a differentiated FEF-LIP-SC circuit for transforming sensory evidence into abstract categorical decisions and the actions used to report them.","rel_num_authors":8,"rel_authors":[{"author_name":"Ou Zhu","author_inst":"The University of Chicago"},{"author_name":"Vinay Shirhatti","author_inst":"The University of Chicago"},{"author_name":"Maura M Garza","author_inst":"The University of Chicago"},{"author_name":"Yunlong Xu","author_inst":"The University of Chicago"},{"author_name":"Samuel David","author_inst":"The University of Chicago"},{"author_name":"Chris K Hauser","author_inst":"The University of Chicago"},{"author_name":"Brent Doiron","author_inst":"The University of Chicago"},{"author_name":"David J Freedman","author_inst":"The University of Chicago"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Sex differences in brain metabolism assessed with whole-brain magnetic resonance spectroscopic imaging","rel_doi":"10.64898\/2026.06.30.735476","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735476","rel_abs":"Sex differences in brain disorders span age at onset, symptom profiles, disease course and treatment response, and may partly reflect underlying differences in cellular metabolism. Indeed, in vivo evidence of sex-related neurometabolic variation remains sparse, with heterogenous and conflicting findings. Using fast high-resolution whole-brain three-dimensional magnetic resonance spectroscopic imaging, we mapped five brain metabolites in three independent cohorts of healthy participants (total n = 114). In a discovery sample of adolescents scanned at 3 Tesla (3T) (n = 61), males showed higher total N-acetylaspartate (tNAA) across widespread gray matter regions. Regional analyses further revealed opposing sex patterns with a complementary higher total creatine (tCr) observed in females, motivating examination of their ratio as an integrative metabolic index. The tNAA\/tCr ratio was consistently higher in males in the discovery sample and this finding was replicated across two independent young-adult samples (3T, n = 26; 7T, n = 27), with a widespread gray and white matter distribution. This tNAA\/tCr ratio may link neuronal mitochondrial metabolism with cellular energy buffering, positioning it as a potential index of bioenergetic balance relevant for conditions showing both sex differences and altered neurometabolism, notably multiple sclerosis, Alzheimer disease, and psychosis. Together, these findings reveal a reproducible, distributed metabolic sexual dimorphism in the human brain, and underscore the importance of accounting for sex-specific neurometabolic profiles in studies of brain health and disease.","rel_num_authors":23,"rel_authors":[{"author_name":"Edgar C\u00e9l\u00e9reau","author_inst":"Lausanne University Hospital and University of Lausanne"},{"author_name":"Federico Lucchetti","author_inst":"Lausanne University Hospital"},{"author_name":"Pascal Steullet","author_inst":"Lausanne University Hospital"},{"author_name":"Zo\u00e9 Schilliger","author_inst":"Lausanne University Hospital"},{"author_name":"Yasser Alem\u00e1n-G\u00f3mez","author_inst":"Lausanne University Hospital"},{"author_name":"Raoul Jenni","author_inst":"Lausanne University Hospital"},{"author_name":"Teya Petrova","author_inst":"Lausanne University Hospital"},{"author_name":"Silas Forrer","author_inst":"University of Geneva"},{"author_name":"Farnaz Delavari","author_inst":"Lausanne University Hospital"},{"author_name":"Jean-Baptiste Ledoux","author_inst":"Lausanne University Hospital"},{"author_name":"India D'Addona","author_inst":"Lausanne University Hospital"},{"author_name":"Lila Wider","author_inst":"Lausanne University Hospital"},{"author_name":"Maria Fernanda Rueda","author_inst":"Lausanne University Hospital"},{"author_name":"Basilio Giangreco","author_inst":"Lausanne University Hospital"},{"author_name":"Patric Hagmann","author_inst":"Lausanne University Hospital"},{"author_name":"Kerstin Jessica Plessen","author_inst":"Lausanne University Hospital"},{"author_name":"Stephan Eliez","author_inst":"University of Geneva"},{"author_name":"Philippe Conus","author_inst":"Lausanne University Hospital"},{"author_name":"Camille Piguet","author_inst":"University of Geneva"},{"author_name":"Arnaud Merglen","author_inst":"University of Geneva"},{"author_name":"Daniella Dwir","author_inst":"Lausanne University Hospital"},{"author_name":"Antoine Klauser","author_inst":"Siemens Healthineers International AG"},{"author_name":"Paul Klauser","author_inst":"Lausanne University Hospital"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Estimating Body Segment Properties for Adults AcrossDiverse Body Morphologies: A Data-Driven GeometricFramework","rel_doi":"10.64898\/2026.07.03.736346","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736346","rel_abs":"Accurate estimation of body segment inertial properties is essential for biomechanical analyses, yet commonly used scaling methods rely on limited datasets and do not generalize well across diverse adult body morphologies. We developed a data-driven framework that estimates segment lengths, masses, centers of mass, and moments of inertia using regression models trained on large anthropometric datasets (ANSUR II and NHANES) combined with a geometric representation of 16 body segments. The framework uses height, weight, and sex as primary inputs and incorporates waist and hip circumferences or other length and cross-sectional measurements when available to refine body-shape predictions. For individuals with obesity, additional geometric rules redistribute excess mass based on segment-specific volume changes. The resulting models reproduced segment lengths, cross-sectional dimensions, and lumped segment masses within the ranges observed in the training datasets and outperformed published regression equations, particularly at higher body mass index (BMI) values. To promote broad adoption, we provide an open-source API in Python that performs the full parameter estimation using the trained models. This framework offers an accurate and accessible method for estimating adult body segment properties across a wide range of body sizes and shapes, supporting improved motion analysis, musculoskeletal simulation, and clinical biomechanics.","rel_num_authors":6,"rel_authors":[{"author_name":"Onorato \u010f Angelis","author_inst":"Northeastern University"},{"author_name":"Chi Whan Choi","author_inst":"Boston University"},{"author_name":"Hariharan Sureshkumar","author_inst":"Northeastern University"},{"author_name":"Mario Merone","author_inst":"Universita` Campus Bio-Medico di Roma"},{"author_name":"Simone V Gill","author_inst":"Boston University"},{"author_name":"Seungmoon Song","author_inst":"Northeastern University"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Water as a thermal contrast agent for artificial-intelligence-enhanced in vivo mid-infrared thermography","rel_doi":"10.64898\/2026.07.03.736311","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736311","rel_abs":"In vivo infrared thermography is limited by the inherently poor spatial resolution at long wavelengths, low contrast, and the lack of biocompatible contrast agents. Here, we present 3-5 m mid-wave infrared (MWIR) thermography enhanced by an artificial intelligence (AI) network and cold phosphate-buffered saline (PBS) as a thermal contrast agent for noninvasive in vivo imaging with high contrast and resolution. MWIR imaging enabled high thermal sensitivity with microscale spatial resolution, strong relative thermal contrast, and facilitated visualization of the subcutaneous vasculature in the human arm, hand, ankle, the femoral artery and vein in rats, and the femoral vessels in mice, with image contrast further enhanced by AI networks. In a 4T1 tumor-bearing mouse model, AI-enhanced MWIR resolved early-stage tumors of ~2.3 mm and metastases as small as ~1.7 mm. Using cold PBS as a MWIR thermal contrast agent, we achieved precise tumor boundary visualization and real-time imaging-guided tumor resection. AI-enhanced MWIR offers a promising solution for early diagnosis and improved surgical precision.","rel_num_authors":7,"rel_authors":[{"author_name":"Sixin Xu","author_inst":"The University of Hong Kong"},{"author_name":"Yuanhua Liu","author_inst":"The University of Hong Kong"},{"author_name":"Danyang Xu","author_inst":"The University of Hong Kong"},{"author_name":"Zideng Dai","author_inst":"The University of Hong Kong"},{"author_name":"Wentao Ye","author_inst":"The University of Hong Kong"},{"author_name":"Xingzu Zhan","author_inst":"The University of Hong Kong"},{"author_name":"Feifei Wang","author_inst":"The University of Hong Kong"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Stereoselective Covalent Targeting of BTK(C481S) and Kinases with \u03b2-Lactone Electrophiles","rel_doi":"10.64898\/2026.07.03.736436","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736436","rel_abs":"The cysteine to serine mutation at residue 481 of Brutons tyrosine kinase (BTK) is the most common mechanism of clinical resistance against ibrutinib for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. We report small molecule ligands containing chiral {beta}-lactone electrophiles to address this challenge. The asymmetric warhead enabled stereoselective covalent modification of wild-type and ibrutinib-resistant mutant BTK(C481S) through distinct sites of reactivity. Building on these findings, we developed kinase-directed {beta}-lactone probes and demonstrated that individual enantiomers preferentially engage distinct subsets of the kinome. These studies establish {beta}-lactones as stereochemically encodable covalent warheads whose stereochemistry can serve as a selectivity filter in covalent drug discovery.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC=\"FIGDIR\/small\/736436v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (15K):\norg.highwire.dtl.DTLVardef@ec0cc8org.highwire.dtl.DTLVardef@13b2518org.highwire.dtl.DTLVardef@7a79org.highwire.dtl.DTLVardef@168ca0b_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":8,"rel_authors":[{"author_name":"Celine Wang","author_inst":"University of California, Berkeley"},{"author_name":"Polina E Barzova","author_inst":"University of California, Berkeley"},{"author_name":"Julian Robles","author_inst":"University of California, Berkeley"},{"author_name":"Ethan S Toriki","author_inst":"Novartis Biomedical Research"},{"author_name":"Francisco J Garcia","author_inst":"Novartis Biomedical Research"},{"author_name":"Jeffrey M McKenna","author_inst":"Novartis Biomedical Research"},{"author_name":"Markus Schirle","author_inst":"Novartis Biomedical Research"},{"author_name":"Ziyang Zhang","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"'Who Goes There?' Quantifying Scavenger-Carcass Activity at Mass Mortality Events","rel_doi":"10.64898\/2026.07.03.735954","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.735954","rel_abs":"Mass mortality events (MMEs) create sudden pulses of carrion that can alter how vertebrate scavengers use carcass resources, including the frequency, duration, and timing of species-carcass contacts. These changes could have implications for pathogen transmission at the scavenger-carcass interface. We aimed to develop and apply a reproducible analytical framework for using camera-trap data to quantify transmission-relevant vertebrate activity at carcass sites under differing carrion biomass scenarios. We studied experimental carcass plots (single carcass ~43 kg; 'mass mortality' plots [10 carcasses, >350 kg total]; 6 of each) in Australia's alpine ecosystem. The framework integrated descriptive summaries (bipartite network analysis, Kaplan-Meier curves) and marked temporal point-process models to characterise structural and temporal dimensions of species-carcass activity. Mass mortality plots had greater overall visitation duration, occurring as sustained activity (50% of visitation event volume by day 17), compared with intense then rapidly declining activity at single carcasses (50% by day 8). Mass mortality plots also had higher predicted daily arrival probability and contact hours across most species, indicating an extended window for pathogen transmission. This framework provides empirically derived contact parameters for MME-related disease spread models using camera-trap data to identify potential transmission pathways at the scavenger-carcass interface.","rel_num_authors":9,"rel_authors":[{"author_name":"Katie A Barton","author_inst":"Sydney School of Veterinary Science, Faculty of Science, The University of Sydney, NSW, 2006, Australia"},{"author_name":"Patrick B Finnerty","author_inst":"School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Stefanie J Bonat","author_inst":"School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia AND Science for Wildlife Ltd, Blackheath NSW 2785, Austr"},{"author_name":"Beatriz Mart\u00ednez-L\u00f3pez","author_inst":"Center for Animal Disease Modeling and Surveillance (CADMS), School of Veterinary Medicine, University of California at Davis, Davis, 95616, California, USA"},{"author_name":"Niraj Y Meisuria","author_inst":"Sydney School of Veterinary Science, Faculty of Science, The University of Sydney, NSW, 2006, Australia AND School of Life and Environmental Sciences, The Unive"},{"author_name":"Thomas M Newsome","author_inst":"School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia"},{"author_name":"Alison J Peel","author_inst":"Sydney School of Veterinary Science, Faculty of Science, The University of Sydney, NSW, 2006, Australia AND Sydney Infectious Diseases Institute, The University"},{"author_name":"Justine A Smith","author_inst":"Department of Wildlife, Fish, and Conservation Biology, University of California, Davis, Davis, CA, United States"},{"author_name":"Victoria J Brookes","author_inst":"Sydney School of Veterinary Science, Faculty of Science, The University of Sydney, NSW, 2006, Australia AND Sydney Infectious Diseases Institute, The University"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Comparative assessment of gene drive release patterns and spread with a hex-based model for large-scale simulations","rel_doi":"10.64898\/2026.07.04.736481","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736481","rel_abs":"Spatial population genetic and ecological modeling is often necessary to predict outcomes accurately. One example is gene drive, a rapid process involving spread of gene drive alleles through a population, usually to suppress pests or reduce transmission of vector-borne disease. Several existing models have been used to assess gene drive and other spatial processes. However, each of these has limitations, such as high computational cost and limited scalability, difficulty in incorporating environmental factors and complex lifecycles, or potentially simplified spatial structure. To overcome these challenges, we propose a hexagon-based computational framework that is designed to mimic continuous space for rapid genetic wave advances. This allows us to accurately simulate a larger spatial domain with lower computational investment. We implemented this model and compared the wave speeds of different gene drives with those obtained from other models. The results showed good agreement when hexagon width and dispersal were properly calibrated. We then determined optimal circular and linear (along roads) release patterns for a variety of gene drives and Wolbachia bacteria. To demonstrate the application of our framework to a hypothetical scenario, we constructed a model Culex quinquefasciatus mosquitoes on Hainan Island. We then evaluated the outcome of different gene drive release strategies, showing the transgenic insect release level necessary to achieve high gene drive coverage and how this could be further optimized based on mosquito and human distribution. Overall, our hex-based population genetic framework provides a flexible platform for realistic and large-scale models for gene drive and related applications.","rel_num_authors":3,"rel_authors":[{"author_name":"Jiahe Li","author_inst":"Peking University"},{"author_name":"Chengwei Shi","author_inst":"Peking University"},{"author_name":"Jackson Champer","author_inst":"Peking University"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"CatESO: Differentiable Enzyme Sequence Optimization Guided by Substrate-Aware kcat Prediction","rel_doi":"10.64898\/2026.07.04.736506","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736506","rel_abs":"Enzymes drive biological chemistry and offer greener routes to chemicals, materials and medicines, yet their broader use as biocatalysts is often limited by insufficient catalytic turnover. Improving turnover is hard: measured rate constants are scarce and protein sequence space is vast. Deep-learning models now predict the turnover number, Kcat, with growing accuracy, but they are typically applied after sequence generation to score or filter candidates, which separates the kinetic objective from the design itself. To bridge the gap between sequence generation and kinetic evaluation, we introduce CatESO, a differentiable sequence optimizer that enables direct, gradient-guided design of substrate-specific catalytic turnover. By backpropagating through a cross-modal Kcat predictor under continuous sequence relaxation, CatESO co-optimizes predicted catalytic activity, evolutionary plausibility and structural integrity in one end-to-end framework, using ESM-2 and ESMFold to keep designs evolutionarily plausible and foldable. Across seven stringent out-of-distribution enzymes spanning EC classes 1-7, CatESO raised model-predicted Kcat for the vast majority of designs, with a median predicted fold change of 1.52 while every variant retained a pLDDT above 70. Against RFdiffusion3-LigandMPNN pipeline and ZymCtrl, CatESO struck a better balance between predicted activity and structural confidence. By making substrate-conditioned kinetic objectives differentiable, CatESO carries differentiable protein design beyond structure- and binding-centred goals to enzyme catalytic function, giving a general route to function-oriented enzyme engineering.","rel_num_authors":8,"rel_authors":[{"author_name":"Zhenjia Gan","author_inst":"East China Normal University"},{"author_name":"Yuzhi Xu","author_inst":"New York University"},{"author_name":"Junde Xu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Zhihao Wu","author_inst":"Zhejiang University"},{"author_name":"Juping Huang","author_inst":"Fudan University"},{"author_name":"Jiabin Yin","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Guangyong Chen","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences"},{"author_name":"John Z.H. Zhang","author_inst":"Shenzhen University of Advanced Technology"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"An Atlas of Short Linear Motif-Mediated Human Protein-Protein Interactions","rel_doi":"10.64898\/2026.07.03.735260","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.735260","rel_abs":"Short linear motifs (SLiMs) within intrinsically disordered protein regions mediate transient interactions crucial for cell physiology1. However, the global interaction landscape of human SLiMs remains largely uncharted. Here we present the Atlas of SLiM-mediated Human protein-protein Interactions (ASHI), which maps more than 20,000 interactions by screening over 800 human protein domains against a library of one million peptides tiling the human disordered proteome. ASHI expands the SLiM interactome, uncovers novel binding modes for known peptide-binding domains, and reveals unexpected peptide-binding activities in enzymes, chaperones, RNA-binding proteins, and modification-reader domains. Furthermore, intrinsically disordered regions emerge as densely encoded interaction platforms where interaction specificity is governed by diverse mechanisms, including key motif determinants, flanking residues, competition, and multivalency. These data provide an unprecedented foundation for modeling dynamic interaction networks, interpreting disease-associated variants, and decoding the dark proteome.","rel_num_authors":36,"rel_authors":[{"author_name":"Priyanka Madhu","author_inst":"Uppsala University"},{"author_name":"Caroline Benz","author_inst":"Uppsala University"},{"author_name":"Leandro Simonetti","author_inst":"Uppsala University"},{"author_name":"Matthew J. Winters","author_inst":"University of Massachusetts Medical School"},{"author_name":"Mythili S. Subbanna","author_inst":"University of Massachusetts Medical School"},{"author_name":"Johanna Kliche","author_inst":"Uppsala University"},{"author_name":"Lidia Gomez-Lucas","author_inst":"Uppsala University"},{"author_name":"Hazem M. Kotb","author_inst":"The Institute of Cancer Research"},{"author_name":"Izabella Krystkowiak","author_inst":"The Institute of Cancer Research, London"},{"author_name":"Dmitri Segal","author_inst":"University of Toronto"},{"author_name":"William T.P. Darling","author_inst":"Uppsala University"},{"author_name":"Sven Larsen-Ledet","author_inst":"University of Copenhagen"},{"author_name":"Maximilian Vieler","author_inst":"Uppsala University"},{"author_name":"Ana Zupancic","author_inst":"Uppsala University"},{"author_name":"Aimiliani Konstantinou","author_inst":"Uppsala University"},{"author_name":"Filip Mihali\u010d","author_inst":"Uppsala University: Uppsala Universitet"},{"author_name":"Julia K. Varga","author_inst":"Hebrew University"},{"author_name":"Livia Pagano","author_inst":"University of Rome La Sapienza"},{"author_name":"Susanne L\u00fcchow","author_inst":"Uppsala Unviersity"},{"author_name":"Andreas Kraemer","author_inst":"Johann Wolfgang Goethe University"},{"author_name":"Lachlan Ellingboe","author_inst":"The Institute of Cancer Research"},{"author_name":"Kristof G\u00f6rlitz","author_inst":"Uppsala University"},{"author_name":"Germanna L Righetto","author_inst":"Structural Genomics Consortium"},{"author_name":"Christin Kossmann","author_inst":"University of Copenhagen"},{"author_name":"Ruisheng Xiong","author_inst":"Uppsala Unviersity"},{"author_name":"Ora Schueler-Furman","author_inst":"Hebrew University"},{"author_name":"Levon Halabelian","author_inst":"University of Toronto"},{"author_name":"Vijayaratnam Santhakumar","author_inst":"University of Toronto"},{"author_name":"Cheryl Arrowsmith","author_inst":"University of Toronto"},{"author_name":"Stefan Knapp","author_inst":"Goethe-University Frankfurt"},{"author_name":"Mate Erdelyi","author_inst":"Uppsala University"},{"author_name":"Amelie Stein","author_inst":"University of Copenhagen"},{"author_name":"Renaud Vincentelli","author_inst":"AFMB"},{"author_name":"Peter M Pryciak","author_inst":"University of Massachusetts Medical School"},{"author_name":"Norman E Davey","author_inst":"St Jude"},{"author_name":"Ylva Ivarsson","author_inst":"Uppsala University"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"A comparison of sharpening and dampening accounts of the role of expectation in shaping the neural fidelity of early visual representations","rel_doi":"10.64898\/2026.07.05.736624","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736624","rel_abs":"The natural environment is spatiotemporally structured, and the brain exploits this regularity to predict and prepare for upcoming sensory stimuli. Such predictive processing is thought to increase neural efficiency by reducing metabolic expenditure and altering the fidelity with which newly encountered stimuli are encoded. Competing theoretical frameworks propose this is achieved either through sharpening, whereby expected events are encoded more precisely, or dampening, whereby expected events are suppressed and encoded less precisely. Despite clear, opposing predictions, evidence in humans for each account remains mixed due to methodological and analytical inconsistencies. Here we addressed these issues using probabilistic visual paradigm combined with functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). We used population receptive field (pRF) mapping of fMRI data and inverted encoding of EEG data to compare the fidelity and timecourse of activity in visual areas in response to expected, unexpected, and random stimuli. Both methods produced a consistent pattern of results. Post hoc analysis of EEG data revealed that the apparent effect of expectancy was better explained by local spatiotemporal stimulus properties than the global expectancy manipulation. Although this pattern resembled sensory adaptation, it was more consistent with an expectation of temporal stability combined with dampening, in which both the aggregate response to expected features and their representational fidelity are suppressed. Taken together, our findings suggest that predictive processing may operate through dampening, with ecological advantages for high-fidelity encoding of unexpected sensory events.","rel_num_authors":6,"rel_authors":[{"author_name":"Reuben Rideaux","author_inst":"University of Sydney"},{"author_name":"Ziyue Hu","author_inst":"University of Sydney"},{"author_name":"Kali Chidley","author_inst":"University of Queensland"},{"author_name":"Martijn Cloos","author_inst":"Radboud University"},{"author_name":"D. Sam Schwarzkopf","author_inst":"University of Auckland"},{"author_name":"Jason B Mattingley","author_inst":"The University of Queensland, Brisbane, Australia and School of Psychology, The University of Queens"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"Behavior Differentially Shapes Spontaneous Cortical Network Dynamics Across Frequencies","rel_doi":"10.64898\/2026.07.05.736600","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736600","rel_abs":"The rapid and coordinated propagation of neural activity across a network of distributed brain regions underpins complex behavior and cognition. Yet how multiple distributed processes are facilitated in parallel across timescales and behavioral states remains unclear. Using simultaneous fast wide-field voltage and hemodynamic imaging in awake mice, we show that behavior differentially shapes cortical network dynamics across frequencies and signal types. Although static functional connectivity preserved canonical networks across frequencies, the underlying dynamics diverged. Low-frequency and hemodynamic activity were dominated by behavior-dependent persistence of network states, whereas higher-frequency activity exhibited stable network structure with modulation through changes in state expression. Despite these differences, shared network organization was preserved across timescales and signal types. This indicates that similar functional connectivity can arise from distinct temporal dynamics. These findings reveal that cortical networks are governed by frequency-dependent principles through which behavior shapes the persistence and expression of large-scale brain states.","rel_num_authors":3,"rel_authors":[{"author_name":"Lisa Meyer-Baese","author_inst":"Georgia Institute of Technology and Emory University"},{"author_name":"Dieter Jaeger","author_inst":"Emory University"},{"author_name":"Shella Keilholz","author_inst":"Georgia Institute of Technology and Emory University"}],"rel_date":"2026-07-06","rel_site":"biorxiv"},{"rel_title":"The mechanotransduction channel Piezo2 refines axonal projections to the accessory optic system and regulates the optokinetic reflex","rel_doi":"10.64898\/2026.06.30.735567","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735567","rel_abs":"The optokinetic reflex (OKR) is an evolutionarily conserved reflexive behavior that ensures image stabilization on the retina during global motion. It consists of smooth eye tracking movements in the direction of the moving stimulus interspersed with rapid resetting saccades. This reflex is driven by retinal ON direction-selective ganglion cells (oDSGCs), which comprise distinct subtypes tuned either to vertical or horizontal motion. oDSGCs convey directional signals to the brain via precise axonal projections to specific accessory optic system (AOS) nuclei. However, the mechanisms that establish and maintain the specificity of these circuits remain poorly understood. Here, we identify a critical role for the mechanosensitive ion channel Piezo2 in refining AOS circuitry to ensure appropriate eye movement responses. Single-cell transcriptomic profiling revealed selective enrichment of Piezo2 in horizontally-tuned oDSGCs. We show that both loss and hyperactivation of Piezo2 in retinal neurons leads to cross-coupling of horizontal and vertical OKR responses, producing aberrant diagonal eye tracking movements during horizontal optokinetic stimulation. Mechanistically, Piezo2 regulates the developmental refinement of oDSGC axonal projections within the AOS, and disruption of this process results in persistent ectopic innervation that enables aberrant crosstalk between horizontal and vertical motion pathways. These findings reveal a channel activity-dependent mechanism that ensures the functional segregation of directional motion circuits underlying gaze stabilization.\n\nHIGHLIGHTSO_LIPiezo2 is selectively expressed in forward-tuned ON and ON-OFF DSGCs that innervate the accessory optic system\nC_LIO_LIBoth loss and overactivation of Piezo2 induce cross-coupling of horizontal and vertical optokinetic reflexes\nC_LIO_LIPiezo2 function in ON-OFF DSGCs is dispensable for normal optokinetic reflex responses\nC_LIO_LIRetinal Piezo2 refines axonal targeting to the accessory optic system nuclei, ensuring proper optokinetic reflex function\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Natalie R Hamilton","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Victoria N Neckles","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Timour Al-Khindi","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Nitya Donthi","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Shun Mizutori","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Renata Fu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"James K Kiraly","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Bea C Winship","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Alex L Kolodkin","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Karina Chaudhari","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-07-05","rel_site":"biorxiv"},{"rel_title":"Proteomic signatures of cognitive resilience in LOU\/c\/Jall rats converge with inverse hippocampal axes of Alzheimer disease.","rel_doi":"10.64898\/2026.06.30.735140","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735140","rel_abs":"Why some individuals maintain good level of cognitive performances during aging, others dont or even progress toward Alzheimers disease. We profiled the hippocampal proteome of adult LOU\/c\/Jall rats, a strain associated with spontaneous cognitive longevity, and compared this proteomic state with a published human hippocampal Alzheimers disease dataset. Because individual protein changes did not survive proteome-wide correction, interpretation was based on convergent pathway-level, cell-type enrichment and cross-species directional analyses. The LOU hippocampus displayed a structured remodeling of mitochondrial, lysosomal, proteostatic and synaptic systems. Oligodendrocyte-associated nuclear-encoded complex I\/III components were reduced, whereas neuronal mitochondrial aminoacyl-tRNA synthetases, V-ATPase, SNARE-related proteins and inhibitory-transmission markers were increased. CD200 was markedly reduced, but this occurred without accompanying complement, microglial, astrocytic or inflammatory activation signatures. Cross-species overlay indicated that several LOU-associated axes were directionally opposed to late Alzheimers disease, particularly synaptic vesicle and inhibitory-transmission programs, whereas myelin-associated changes occupied a lower-amplitude and non-inflammatory position along an axis altered in early Alzheimers disease. These findings identify a hippocampal proteomic configuration associated with the LOU resilience phenotype and suggest that successful brain aging and Alzheimers disease may involve opposing states of shared hippocampal molecular systems.\n\nGRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC=\"FIGDIR\/small\/735140v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (38K):\norg.highwire.dtl.DTLVardef@8a1a17org.highwire.dtl.DTLVardef@b7023corg.highwire.dtl.DTLVardef@f3ca20org.highwire.dtl.DTLVardef@15b1b29_HPS_FORMAT_FIGEXP  M_FIG C_FIG HIGHLIGHTSO_LIHippocampal proteome of the LOU\/c\/Jall rat at 3 months profiled by DIA-MS\nC_LIO_LICoordinated reduction of complex I\/III subunits in oligodendrocytes\nC_LIO_LINeuronal aminoacyl-tRNA synthetases, V-ATPase and SNARE machinery up-regulated\nC_LIO_LIMarked reduction of CD200 with no inflammatory correlate\nC_LIO_LILate human AD hippocampal transcriptome moves opposite to adult LOU\nC_LI","rel_num_authors":6,"rel_authors":[{"author_name":"Lucas Gephine","author_inst":"University of Caen Normandy"},{"author_name":"Aurelien Badina","author_inst":"University hospitals of geneva"},{"author_name":"Sophie Corvaisier","author_inst":"University of Caen Normandy"},{"author_name":"Benjamin B Tournier","author_inst":"University hospitals of geneva"},{"author_name":"Marianne Leger","author_inst":"University of Caen Normandy"},{"author_name":"Thomas Freret","author_inst":"University of Caen Normandy"}],"rel_date":"2026-07-05","rel_site":"biorxiv"},{"rel_title":"Suprachoroidal Delivery of Anti-Angiogenic Peptide Microparticles Enables Sustained Activity with Favorable Ocular Safety","rel_doi":"10.64898\/2026.06.30.735614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735614","rel_abs":"Retinal and choroidal vascular diseases are major causes of vision loss that require frequent intravitreal anti-VEGF therapy. Anti-angiogenic peptide AXT107 demonstrated efficacy in preclinical studies and was advanced to the clinical stage. To provide for sustained delivery of the peptide and avoid complications with intravitreal injection, we evaluated suprachoroidal delivery of AXT107 microparticles (MP-AXT107). The original, soluble AXT107 formulation was ineffective at inhibiting laser-induced choroidal neovascularization (CNV) in our rat model and was consequently reformulated as microparticles. MP-AXT107 demonstrated high peptide incorporation efficiency, reproducible morphology, and physical and chemical stability for at least 9 months under refrigerated storage. In the rat CNV model, suprachoroidal MP-AXT107 significantly reduced neovascular area by approximately 60% relative to vehicle controls. Safety and durability were evaluated in a 9-month GLP toxicology study in Gottingen minipigs following a single suprachoroidal injection of vehicle or MP-AXT107 (0.125-1.25 mg\/eye). Transient increases in IOP and mild ocular inflammatory findings were observed immediately following administration but resolved rapidly without lasting effects. No treatment-related adverse ocular findings were observed during the remainder of the study, and the highest tested dose (1.25 mg\/eye) was established as the no-observed-adverse-effect level. Bioanalysis at study completion demonstrated persistent AXT107 localization primarily within choroid\/RPE and scleral tissues, with no signs of systemic exposure. Collectively, these findings demonstrate that suprachoroidal delivery of MP-AXT107 enables sustained anti-angiogenic activity with favorable ocular safety and prolonged tissue retention, supporting further clinical development as a durable therapy for retinal and choroidal vascular diseases.","rel_num_authors":8,"rel_authors":[{"author_name":"Adam C Mirando","author_inst":"Johns Hopkins University"},{"author_name":"Raquel Lima e Silva","author_inst":"Johns Hopkins University"},{"author_name":"Jikui Shen","author_inst":"Johns Hopkins University"},{"author_name":"Thomas J Robinson","author_inst":"AsclepiX Therapeutics, Inc."},{"author_name":"Jordan J Green","author_inst":"Johns Hopkins University"},{"author_name":"Peter A Campochiaro","author_inst":"Johns Hopkins University"},{"author_name":"Aleksander S Popel","author_inst":"Johns Hopkins University"},{"author_name":"Niranjan B Pandey","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-05","rel_site":"biorxiv"},{"rel_title":"Inhibition of delta-1 glutamate receptor current by extracellular protons","rel_doi":"10.64898\/2026.06.30.735595","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735595","rel_abs":"Decreases in brain pH are associated with numerous neurological and neuropsychiatric conditions yet the molecular mechanisms linking decreased brain pH with these disorders are incomplete. The ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission in the brain and are inhibited by extracellular protons; however, the proton sensitivity of the delta-glutamate receptor subclass of iGluRs is unknown. Using whole-cell patch-clamp recordings of serotonin neurons in mouse brain slices and activating alpha 1-adrenergic receptors to induce delta 1 glutamate receptor (GluD1R) current, we demonstrated that GluD1R current is inhibited by physiological drops in extracellular pH. Unlike other iGluRs, protons inhibited GluD1R current via a voltage-independent decrease in unitary current. Moreover, mice lacking GluD1R showed impaired behavioral responses to inhalation of CO2. Taken together, this study continues to expand on the growing body of evidence positing GluD1R as functional ion channels and suggests that GluD1R facilitate pH sensing in vivo.","rel_num_authors":4,"rel_authors":[{"author_name":"Andrew G Kain","author_inst":"University of Iowa"},{"author_name":"Joseph P Deuitch","author_inst":"University of Iowa"},{"author_name":"Ayank Maiti","author_inst":"University of Iowa"},{"author_name":"Stephanie C Gantz","author_inst":"University of Iowa"}],"rel_date":"2026-07-05","rel_site":"biorxiv"},{"rel_title":"Sphingosine 1-phosphate lyase expressed in pulmonary epithelial cells potentiates host innate defenses and alleviates influenza pathogenicity in mice","rel_doi":"10.64898\/2026.07.02.736172","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736172","rel_abs":"Influenza viruses circulate in humans, causing a substantial burden on global health. Investigation of influenza-host interactions could identify host factors that regulate influenza pathogenicity. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator and regulates crucial cellular processes. S1P lyase (SPL), an enzyme that mediates S1P degradation, was shown to display anti-influenza activity in a cell culture system. Here, we constructed a mouse model to demonstrate the antiviral function of SPL in respiratory epithelial cells during influenza in vivo. Deletion of SPL from lung epithelial cells exacerbated influenza-induced weight loss and mortality. Influenza virus began to propagate more effectively in the absence of SPL at the innate immune stage. Increased virus titers were sustained during influenza and associated with enhanced accumulation of multiple immune cell types in the lungs. Single-cell RNA sequencing was conducted to further define the function of SPL in lung epithelial cells. SPL deletion increased the proportion of alveolar type 1 (AT1) cells compared to alveolar type 2 (AT2) cells with alteration of the related signaling pathways, suggesting a role of SPL in AT1\/AT2 programming. Importantly, host innate defense pathways were changed in SPL-deficient lung epithelial cells upon infection, which corroborates the antiviral function of SPL. This study elucidates the host protective function of SPL in lung epithelial cells during influenza and provides gene signature profiles critical for SPL-mediated alleviation of influenza pathogenicity. The findings may contribute to development of host-directed therapeutics to better control influenza.","rel_num_authors":8,"rel_authors":[{"author_name":"Kwang Il Jung","author_inst":"University of Missouri"},{"author_name":"Savannah McKenna","author_inst":"University of Missouri"},{"author_name":"Lei Jiang","author_inst":"Univisity of Missouri"},{"author_name":"Hailey Huerter","author_inst":"University of Missouri"},{"author_name":"Ying He","author_inst":"University of Missouri"},{"author_name":"Dong Xu","author_inst":"University of Missouri"},{"author_name":"Julie D Saba","author_inst":"University of California San Francisco"},{"author_name":"Bumsuk Hahm","author_inst":"University of Missouri"}],"rel_date":"2026-07-05","rel_site":"biorxiv"},{"rel_title":"Gut microbiome signatures associated with self-reported allergic symptoms among Finnish adults","rel_doi":"10.64898\/2026.07.03.26357002","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.03.26357002","rel_abs":"BackgroundGrowing evidence suggests that the gut microbiome influences nasal and ocular allergic inflammation through gut-mucosal immune interactions. Yet, its association with Allergic rhinitis (AR) and allergic eye symptoms (AES) remains incompletely understood in large population-based cohorts.\n\nObjectiveTo examine associations between the gut microbiome and self-reported AR and AES in Finnish adults.\n\nMethodsShallow metagenomic sequencing was performed on stool samples from a population-based cohort (FINRISK02; n = 7,231). Microbial taxonomic and functional profiles were compared between individuals with AR (n = 1,950), AES (n = 1,554), combined allergies (AR and\/or AES; n = 2,305), and controls without reported symptoms (n = 3,175).\n\nResultsAllergic groups exhibited lower microbial richness and phylogenetic diversity than controls. Shared microbial and functional signatures were observed across AR and AES, consistent with their high co-occurrence (N = 1,199). Compared with controls, allergic groups showed enrichment of 17 bacterial species, predominantly from the Clostridia class, including taxa previously associated with asthma, chronic obstructive pulmonary disease, and atopic dermatitis. Allergic individuals also exhibited enrichment of pathways related to mucosal carbohydrate processing, shikimate metabolism, histidine turnover, and broader amino acid metabolism. Concurrent enrichment of histidine biosynthesis and degradation suggested altered microbial histidine metabolism.\n\nConclusionsAdult allergic symptoms are associated with gut microbiome taxonomic and functional alterations linked to mucosal barrier function and immune-related metabolism, supporting a shared gut-mucosal immune axis across allergic phenotypes.\n\nClinical ImplicationShared microbial signatures across AR and AES support the concept of a common gut-mucosal immune axis underlying allergic manifestations in adults.\n\nCapsule SummaryThe large population-based study revealed that allergic symptoms in adults are associated with lower richness and phylogenetic diversity of gut microbiome together with taxonomic and functional alterations","rel_num_authors":14,"rel_authors":[{"author_name":"Himmi H Lindgren","author_inst":"University of Turku"},{"author_name":"Ville Vartiainen","author_inst":"University of Helsinki"},{"author_name":"Geraldson Muluh","author_inst":"University of Turku"},{"author_name":"Nitin Bayal","author_inst":"University of Turku"},{"author_name":"Katariina Parnanen","author_inst":"University of Helsinki"},{"author_name":"Guillaume Meric","author_inst":"University of Bath"},{"author_name":"Pekka Jousilahti","author_inst":"Finnish Institute for Health and Welfare"},{"author_name":"Matti Olavi Ruuskanen","author_inst":"University of Turku"},{"author_name":"Rob Knight","author_inst":"University of California San Diego"},{"author_name":"Teemu Niiranen","author_inst":"University of Turku"},{"author_name":"Aki Havulinna","author_inst":"University of Turku"},{"author_name":"Veikko Salomaa","author_inst":"University of Turku"},{"author_name":"Pande Putu Erawijantari","author_inst":"University of Turku"},{"author_name":"Leo Lahti","author_inst":"University of Turku"}],"rel_date":"2026-07-04","rel_site":"medrxiv"},{"rel_title":"Impact of wildfire-related fine particulate matter on tuberculosis notifications in Brazil: a nationwide panel study, 2003-2023","rel_doi":"10.64898\/2026.07.01.26356762","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26356762","rel_abs":"BackgroundWildfire activity and smoke exposure are increasing worldwide because of climate and land-use change. Although fine particulate matter (PM2.5) may impair pulmonary immune defences against tuberculosis (TB), population-level evidence remains limited. We estimated the effect of wildfire-related PM2.5 exposure on TB notification rates in Brazil.\n\nMethodsWe conducted a nationwide panel study linking municipality-level monthly TB notifications from Brazils SINAN system with wildfire-related PM2.5 estimates from GEOS-Chem simulations across 5,545 municipalities (2003-2023). We estimated the impact of high-exposure days (PM2.5>25{micro}g\/m3) on monthly TB notifications using Poisson regression with fixed effects for municipalities, state-by-year, and state-by-month, controlling for time-invariant differences, secular trends, and seasonality. Distributed lag effects were estimated over 1-24 months before notification. Models accounted for meteorological conditions, GeneXpert diagnostic coverage, and spatial correlation using Conley standard errors. We computed attributable fractions among exposed municipality-months (AFE). Sensitivity analyses evaluated alternative PM2.5 thresholds (15, 35{micro}g\/m3), co-pollutants, and agricultural expansion.\n\nFindingsFrom Jan 1, 2003 to Dec 1, 2023, 1,758,982 TB cases were reported. Of these, 353,319 (20.1%) had at least one high-exposure day (PM2.5>25{micro}g\/m3) 1-24 months before notification. An additional 14 high-exposure days over the 24-month lag period was associated with an average monthly increase of 2.9% [95% CI: 0.9-4.9%] in TB notification rates. Effects peaked at 13 months (IQR: 11-14) prior to notification. Results showed a dose-response relationship across PM2.5 thresholds and were robust to controlling for NO2, O3 and agricultural expansion. Overall, wildfire-related PM2.5 exposure accounted for 2.1% [0.7-3.5%] of TB notifications in exposed municipality-months, corresponding to 7,802 [2,612-12,544] attributable cases. The AFE reached 10.7% [7.1-14.0%] in Pantanal and 7.3% [6.1-8.5%] in Amazonia, areas most impacted by wildfires.\n\nInterpretationWildfire-related PM2.5 exposure may represent an increasingly important and modifiable risk factor for TB. As wildfire activity increases across many regions of the world, these findings highlight the need for integrating air quality into climate adaptation and TB control strategies.\n\nFundingNational Institutes of Health K01AI173385; University of Utah 3i Initiative","rel_num_authors":9,"rel_authors":[{"author_name":"Thi Mui Pham","author_inst":"University of Utah"},{"author_name":"Thiago Mendonca","author_inst":"Center for Environment and Public Health Studies, School of Public Policy and Government, Fundacao Getulio Vargas,"},{"author_name":"Yue Zhang","author_inst":"University of Utah"},{"author_name":"Derek Mallia","author_inst":"University of Utah"},{"author_name":"Julio Croda","author_inst":"Oswaldo Cruz Foundation"},{"author_name":"Ted Cohen","author_inst":"Yale University School of Public Health"},{"author_name":"Jason R Andrews","author_inst":"Stanford University"},{"author_name":"Weeberb Requia","author_inst":"Center for Environment and Public Health Studies, School of Public Policy and Government, Fundaco Getulio Vargas,"},{"author_name":"Katharine S. Walter","author_inst":"University of Utah"}],"rel_date":"2026-07-04","rel_site":"medrxiv"},{"rel_title":"Microbial and immune determinants of disease severity and death in pediatric pneumonia.","rel_doi":"10.64898\/2026.07.02.26356561","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26356561","rel_abs":"Pneumonia is a leading cause of death globally and disproportionately affects children in lower- and middle-income countries. To explore microbial and immune correlates of disease and death, we performed metagenomic sequencing of upper respiratory tract (URT) microbiome in 309 children in Mali with pneumonia and 150 age- and season- and site-matched controls. We show that the URT microbiome matures throughout early life and is influenced by breastfeeding. URT microbiome maturation was disrupted during pneumonia resulting in loss of commensal species and expansion of pathobionts, which was linked to disease severity and death. Analysis of serum antibody levels revealed that low levels of passively acquired antibody from mothers, deficient antibody responses to RSV, and persistent autoantibody to cytokines were associated with pneumonia mortality in an age-dependent manner. These findings underscore the complex nature of pneumonia and identify microbial and immune factors for risk stratification and therapeutic interventions in pediatric pneumonia.","rel_num_authors":11,"rel_authors":[{"author_name":"Karen Hanze Villavicencio","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Ceylan Tanes","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Clara Malekshahi","author_inst":"University of Pennsylvania"},{"author_name":"Daniel Cutillo","author_inst":"University of Pennsylvania"},{"author_name":"Maria Deloria Knoll","author_inst":"Johns Hopkins University"},{"author_name":"Christine Prosperi","author_inst":"Johns Hopkins University International Vaccine Access Center"},{"author_name":"Muge Kalaycioglu","author_inst":"Stanford University"},{"author_name":"Marlayna Harris","author_inst":"Stanford University"},{"author_name":"Paul J Utz","author_inst":"Stanford University"},{"author_name":"Lisa Mattei","author_inst":"University of Pennsylvania"},{"author_name":"Daniel Beiting","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-04","rel_site":"medrxiv"},{"rel_title":"A detailed molecular picture of protein folding during active translation","rel_doi":"10.64898\/2026.07.03.736445","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736445","rel_abs":"All proteins can begin to fold on the ribosome, and many proteins critically rely on co-translational folding to attain their native conformation. The molecular details underlying this crucial process, however, remain largely unknown and are not accounted for by structure predictions such as AlphaFold. To probe high-resolution folding during active translation, we develop a novel application of hydrogen-deuterium pulse labeling. We show that two proteins sequentially adopt stable structure during elongation, while a third protein only has time to loosely fold during active elongation. This loose folding kinetically traps the N-terminus and alters the post-translational folding pathway, allowing it to circumvent an aggregation-prone intermediate. These results highlight the crucial non-equilibrium coupling between translation and folding and reveal diverse strategies to promote robust co-translational folding.","rel_num_authors":3,"rel_authors":[{"author_name":"Amir Bitran","author_inst":"University of California Berkeley"},{"author_name":"Carlos Bustamante","author_inst":"University of California, Berkeley"},{"author_name":"Susan Marqusee","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-04","rel_site":"biorxiv"}]}