{"gname":"Oregon Health & Science University","grp_id":"22","rels":[{"rel_title":"The \"Weekend Warrior\" Physical Activity Pattern and Cardiometabolic Health: A Pooled Harmonized Individual Participant Analysis of the ProPASS Consortium","rel_doi":"10.64898\/2026.07.21.26358626","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358626","rel_abs":"Background While weekend warrior (WW) physical activity (PA) pattern has been associated with cardiovascular benefits, most existing evidence is based on self-reported PA. Evidence using harmonized, thigh-worn accelerometry to examine associations between the weekend warrior phenotype and comprehensive cardiometabolic profiles remains limited. Methods We pooled harmonized individual-participant data from six cohorts in the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. In this cross-sectional analysis, participants were classified as inactive (<150 min\/week MVPA), weekend warriors (150 min\/week with 50% accumulated on 1-2 days), or regularly active 150 min\/week but not meeting the WW criterion). A composite cardiometabolic score averaged eight standardized indicators: triglycerides, HDL cholesterol, total cholesterol, HbA1c, body mass index, waist circumference, systolic blood pressure, and diastolic blood pressure. Generalized linear models were used to estimate associations between PA patterns and both composite and individual cardiometabolic outcomes, adjusted for age, sex, smoking, alcohol intake, self-rated health, CVD history, medication use, blood biomarker fasting status, and cohort. Results Among 13,904 adults (mean age 54.3{+\/-}9.5 years; 54.7% women), 61.8% were inactive, 24.5% weekend warriors, and 13.7% regularly active. Compared with inactivity, both active patterns were associated with more favorable composite cardiometabolic scores (WW: = -0.118 (95% CI: -0.142, -0.095); regularly active: = -0.111 (95% CI: -0.141, -0.081)), with negative values indicating better cardiometabolic health. Weekend warriors and regularly active adults showed broadly similar associations across individual markers, including lower adiposity (BMI and waist circumference) and more favorable metabolic biomarkers (higher HDL cholesterol; lower triglycerides and HbA1c), with no meaningful differences between the two active patterns for the composite score or any individual outcome. Associations with total cholesterol and blood pressure were small. Conclusions Both active patterns were associated with more favorable cardiometabolic profiles than inactivity, and profiles were broadly comparable whether MVPA was concentrated on 1-2 most active days (weekend warrior) or accumulated more regularly across the week. Keywords: weekend warrior; physical activity; accelerometry; cardiometabolic health","rel_num_authors":28,"rel_authors":[{"author_name":"Shan Jiang","author_inst":"The Education University of Hong Kong"},{"author_name":"- The ProPASS Collaborators","author_inst":"-"},{"author_name":"Matthew N Ahmadi","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Nicholas A. Koemel","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Amy S. Ha","author_inst":"The Education University of Hong Kong"},{"author_name":"Raaj Kishore Biswas","author_inst":"University of Sydney"},{"author_name":"Joanna M Blodgett","author_inst":"Institute of Sport Exercise and Health"},{"author_name":"John Mitchell","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Borja del Pozo Cruz","author_inst":"Universidad Europea de Madrid SLU"},{"author_name":"Richard Pulsford","author_inst":"University of Exeter Faculty of Health and Life Sciences"},{"author_name":"Kristin Suorsa","author_inst":"Department of Public Health, University of Turku and Turku University Hospital, Turku, Finland; 2 Centre for Population Health Research, University of Turku and"},{"author_name":"Dick H.J. Thijssen","author_inst":"Radboud University Medical Centre"},{"author_name":"Esm\u00e9e A. Bakker","author_inst":"Radboud universitair medisch centrum"},{"author_name":"Carlos A. Celis-Morales","author_inst":"University of Glasgow Library"},{"author_name":"Peter J Johansson","author_inst":"Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University"},{"author_name":"Pasan Hettiarachchi","author_inst":"Department of Medical Sciences, Uppsala University"},{"author_name":"Sari Stenholm","author_inst":"Department of Public Health, University of Turku and Turku University Hospital"},{"author_name":"Gita D. Mishra","author_inst":"The University of Queensland"},{"author_name":"Sarah Keadle","author_inst":"California Polytechnic State University"},{"author_name":"Vegar Rangul","author_inst":"HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU)"},{"author_name":"Nidhi Gupta","author_inst":"National Research Centre for the Working Environment"},{"author_name":"Stavros Kyriakidis","author_inst":"The National Research Centre for the Working Environment"},{"author_name":"Marvin Y. Chong","author_inst":"Universiteit Maastricht"},{"author_name":"Annemarie Koster","author_inst":"Maastricht University"},{"author_name":"Andrew Atkin","author_inst":"School of Health Sciences and Norwich Epidemiology Centre, University of East Anglia"},{"author_name":"I-Min Lee","author_inst":"Harvard Medical School"},{"author_name":"Mark Hamer","author_inst":"University College London"},{"author_name":"Emmanuel Stamatakis","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"The \"Weekend Warrior\" Physical Activity Pattern and Cardiometabolic Health: A Pooled Harmonized Individual Participant Analysis of the ProPASS Consortium","rel_doi":"10.64898\/2026.07.21.26358626","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358626","rel_abs":"Background While weekend warrior (WW) physical activity (PA) pattern has been associated with cardiovascular benefits, most existing evidence is based on self-reported PA. Evidence using harmonized, thigh-worn accelerometry to examine associations between the weekend warrior phenotype and comprehensive cardiometabolic profiles remains limited. Methods We pooled harmonized individual-participant data from six cohorts in the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. In this cross-sectional analysis, participants were classified as inactive (<150 min\/week MVPA), weekend warriors (150 min\/week with 50% accumulated on 1-2 days), or regularly active 150 min\/week but not meeting the WW criterion). A composite cardiometabolic score averaged eight standardized indicators: triglycerides, HDL cholesterol, total cholesterol, HbA1c, body mass index, waist circumference, systolic blood pressure, and diastolic blood pressure. Generalized linear models were used to estimate associations between PA patterns and both composite and individual cardiometabolic outcomes, adjusted for age, sex, smoking, alcohol intake, self-rated health, CVD history, medication use, blood biomarker fasting status, and cohort. Results Among 13,904 adults (mean age 54.3{+\/-}9.5 years; 54.7% women), 61.8% were inactive, 24.5% weekend warriors, and 13.7% regularly active. Compared with inactivity, both active patterns were associated with more favorable composite cardiometabolic scores (WW: = -0.118 (95% CI: -0.142, -0.095); regularly active: = -0.111 (95% CI: -0.141, -0.081)), with negative values indicating better cardiometabolic health. Weekend warriors and regularly active adults showed broadly similar associations across individual markers, including lower adiposity (BMI and waist circumference) and more favorable metabolic biomarkers (higher HDL cholesterol; lower triglycerides and HbA1c), with no meaningful differences between the two active patterns for the composite score or any individual outcome. Associations with total cholesterol and blood pressure were small. Conclusions Both active patterns were associated with more favorable cardiometabolic profiles than inactivity, and profiles were broadly comparable whether MVPA was concentrated on 1-2 most active days (weekend warrior) or accumulated more regularly across the week. Keywords: weekend warrior; physical activity; accelerometry; cardiometabolic health","rel_num_authors":28,"rel_authors":[{"author_name":"Shan Jiang","author_inst":"The Education University of Hong Kong"},{"author_name":"- The ProPASS Collaborators","author_inst":"-"},{"author_name":"Matthew N Ahmadi","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Nicholas A. Koemel","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"},{"author_name":"Amy S. Ha","author_inst":"The Education University of Hong Kong"},{"author_name":"Raaj Kishore Biswas","author_inst":"University of Sydney"},{"author_name":"Joanna M Blodgett","author_inst":"Institute of Sport Exercise and Health"},{"author_name":"John Mitchell","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Borja del Pozo Cruz","author_inst":"Universidad Europea de Madrid SLU"},{"author_name":"Richard Pulsford","author_inst":"University of Exeter Faculty of Health and Life Sciences"},{"author_name":"Kristin Suorsa","author_inst":"Department of Public Health, University of Turku and Turku University Hospital, Turku, Finland; 2 Centre for Population Health Research, University of Turku and"},{"author_name":"Dick H.J. Thijssen","author_inst":"Radboud University Medical Centre"},{"author_name":"Esm\u00e9e A. Bakker","author_inst":"Radboud universitair medisch centrum"},{"author_name":"Carlos A. Celis-Morales","author_inst":"University of Glasgow Library"},{"author_name":"Peter J Johansson","author_inst":"Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University"},{"author_name":"Pasan Hettiarachchi","author_inst":"Department of Medical Sciences, Uppsala University"},{"author_name":"Sari Stenholm","author_inst":"Department of Public Health, University of Turku and Turku University Hospital"},{"author_name":"Gita D. Mishra","author_inst":"The University of Queensland"},{"author_name":"Sarah Keadle","author_inst":"California Polytechnic State University"},{"author_name":"Vegar Rangul","author_inst":"HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU)"},{"author_name":"Nidhi Gupta","author_inst":"National Research Centre for the Working Environment"},{"author_name":"Stavros Kyriakidis","author_inst":"The National Research Centre for the Working Environment"},{"author_name":"Marvin Y. Chong","author_inst":"Universiteit Maastricht"},{"author_name":"Annemarie Koster","author_inst":"Maastricht University"},{"author_name":"Andrew Atkin","author_inst":"School of Health Sciences and Norwich Epidemiology Centre, University of East Anglia"},{"author_name":"I-Min Lee","author_inst":"Harvard Medical School"},{"author_name":"Mark Hamer","author_inst":"University College London"},{"author_name":"Emmanuel Stamatakis","author_inst":"Faculty of Medicine,Nursing and Health Sciences,Monash University"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Village-level surveillance of neonatal disease with integrated real-time dashboards and quality-control in Uganda","rel_doi":"10.64898\/2026.07.21.26358401","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358401","rel_abs":"Introduction Neonatal mortality remains disproportionately high in sub-Saharan Africa, where an estimated 27 neonatal deaths per 1,000 live births occur annually. Infections, including sepsis and meningitis, account for a substantial proportion of these deaths, while neural tube defects (NTDs) contribute significantly to both neonatal mortality and long-term disability. Existing surveillance systems in the region are predominantly facility-based, missing the substantial proportion of births and deaths that occur in the community. Population-based surveillance platforms that capture community-level data are urgently needed to generate accurate incidence estimates, identify modifiable risk factors, and guide evidence-based interventions. Cohort Description The Consortium to Reduce Infant Mortality (CONRIM) is a multi-institutional partnership among Ugandan physicians and scientists, Yale University, Penn State University, Boston Children's Hospital\/Harvard Medical School, and Uganda's National Planning Authority. CONRIM conducts prospective, community-based neonatal surveillance within the Busoga Kingdom in eastern Uganda. A network of 813 trained Village Health Team members conducts household-level visits using a structured Open Data Kit (ODK)-based mobile questionnaire to capture every birth, assess for danger signs of possible serious bacterial infection (pSBI), screen for NTDs, and record maternal nutrition and folic acid use, water, sanitation and hygiene (WASH) conditions, and health care utilization. Findings to Date Since surveillance began in June 2025, the platform has registered approximately 22,200 household submissions and over 5,700 newborn encounters across the Jinja District (population 660,000). Early data have identified higher than expected rates of infants with NTDs including encephalocele and spina bifida; documented folic acid non-use in before and during most pregnancies; characterized WASH conditions in birthplaces; and mapped geospatial hotspots of neonatal infection risk in northeastern rural subcounties. Prospective 28-day follow-up of all live births has demonstrated a neonatal mortality rate of 21.5 per 1000 live births. A real-time data quality monitoring system with 21 automated quality control flags maintains a 99% clean-record rate. Future Plans Ongoing and planned activities include laboratory-based confirmation of neonatal sepsis via blood culture and cerebrospinal fluid analysis with polymerase chain reaction capacity, portable neuroimaging for NTDs, environmental sampling, genomic studies of folate metabolism pathway genes, linkage with facility-based records at Jinja Regional Referral Hospital and Mulago National Referral Hospital, and community-level interventions informed by surveillance findings.","rel_num_authors":41,"rel_authors":[{"author_name":"Joseph N. Paulson","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Andrew J. Whalen","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Starlin Tindimwebwa","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda"},{"author_name":"Justice Hansen","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Davis Natukwatsa","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda"},{"author_name":"Steven Kalifuba","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Moses Ochora","author_inst":"Department of Paediatrics and Child Health, Soroti University, Soroti, Uganda; National Planning Authority, Kampala, Uganda"},{"author_name":"Ronnie Mulondo","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Edith Mbabazi-Kabachelor","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Kamron Ramelmeier","author_inst":"University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Brian Kaaya Nsubuga","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda"},{"author_name":"Philip O. Omadi","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Joshua Magombe","author_inst":"Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda"},{"author_name":"Carmit Cohen","author_inst":"BGU-FOR (Food Systems, One Health & Resilience) Research Center, Ben Gurion University of the Negev, Beer Sheba, Israel"},{"author_name":"Norbert Muzahura","author_inst":"Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda"},{"author_name":"Justin Onen","author_inst":"Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda"},{"author_name":"Peter Ssenyonga","author_inst":"Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda"},{"author_name":"James R. Broach","author_inst":"Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, USA"},{"author_name":"Sarah U. Morton","author_inst":"Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, USA"},{"author_name":"Marwan Osman","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA"},{"author_name":"Moses Joloba","author_inst":"Makerere University Biomedical Research Center, Kampala, Uganda"},{"author_name":"Edgar Kigozi","author_inst":"Makerere University Biomedical Research Center, Kampala, Uganda"},{"author_name":"Andrew Katabalwa","author_inst":"Makerere University Biomedical Research Center, Kampala, Uganda"},{"author_name":"Julian Apako","author_inst":"Makerere University Biomedical Research Center, Kampala, Uganda"},{"author_name":"Hilda Amutuhaire","author_inst":"Department of Agricultural Production, College of Agricultural and Environmental Sciences, Makerere University, P.O. Box, 7062, Kampala, Uganda"},{"author_name":"John Baptist Tumuhairwe","author_inst":"Department of Agricultural Production, College of Agricultural and Environmental Sciences, Makerere University, P.O. Box, 7062, Kampala, Uganda"},{"author_name":"Agatha Kayemba","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Josephine Namyalo","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Henry Masengere","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Harriet Nambuya","author_inst":"Regional Referral Hospital of Jinja, Jinja, Uganda"},{"author_name":"Agatha Namutosi","author_inst":"Regional Referral Hospital of Jinja, Jinja, Uganda"},{"author_name":"Sophia Kasuswa","author_inst":"Regional Referral Hospital of Jinja, Jinja, Uganda"},{"author_name":"Emma Omo","author_inst":"Regional Referral Hospital of Jinja, Jinja, Uganda"},{"author_name":"Ivan Tibenkana","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Alfred Yayi","author_inst":"National Planning Authority, Kampala, Uganda"},{"author_name":"Joseph Muvawala","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda; National Planning Authority, Kampala, Uganda"},{"author_name":"William Nadiope IV","author_inst":"Kingdom of Busoga, Bugembe, Uganda"},{"author_name":"Abraham Muwanguzi","author_inst":"Busoga Kingdom Health Department \/ CONRIM Uganda Field Team, Jinja, Uganda; National Planning Authority, Kampala, Uganda"},{"author_name":"Elias Kumbakumba","author_inst":"Department of Pediatrics, Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Jessica E. Ericson","author_inst":"Division of Pediatric Infectious Disease, Pennsylvania State University College of Medicine, Hershey, PA, USA"},{"author_name":"Steven J. Schiff","author_inst":"Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA; Department of Epidemiology of Microbial Diseases, Yale University School of"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Community leaders as vaccine champions and the lessons from the COVID-19 pandemic in Papua New Guinea","rel_doi":"10.64898\/2026.07.21.26358216","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358216","rel_abs":"The lessons learned from the COVID-19 pandemic are essential for implementing substantive changes and present a significant opportunity to strengthen the resilience of health systems on both national and global scales in responding to future public health crises. It is widely acknowledged that COVID-19 vaccination represents one of the most effective strategies to contain the pandemic. Nonetheless, vaccine hesitancy continues to evoke fear and uncertainty, particularly in contexts such as Papua New Guinea (PNG), a nation characterised by one of the lowest COVID-19 vaccination rates worldwide. Insights from previous public health interventions in PNG emphasise the critical role that community leaders play in ensuring the success of such initiatives. This publication reports on a study investigating the influence of community leaders on COVID-19 vaccine uptake in PNG. Qualitative research was carried out across seven provinces between July and November 2021, involving interviews with 131 participants, including healthcare professionals, key informants, community leaders, and primary health service clients. There was considerable support for community-led strategies, with participants advocating for awareness programs to be delivered by community leaders. The advantages of locally driven approaches include the trust communities place in their leaders and shared lived experiences, which enable them to address their specific needs effectively while respecting and building upon local beliefs and customs. The effectiveness of place-based vaccine champions was also endorsed, recognising the importance of collaborations between health systems, governments, and community leaders to promote COVID-19 vaccination. These findings underscore the importance of sustained support and  bottom-up strategies to empower community leaders in fostering community ownership of health promotion initiatives and building resilient health systems, not only for COVID-19 vaccine distribution but also for future health interventions.","rel_num_authors":11,"rel_authors":[{"author_name":"Katrina Shen","author_inst":"UNSW Medicne Kirby Institute: The Kirby Institute"},{"author_name":"Jamee Newland","author_inst":"UNSW Medicne Kirby Institute: The Kirby Institute"},{"author_name":"Nalisa Neuendorf","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Ruthy Boli-Neo","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Lisa  Michelle Vallely","author_inst":"UNSW Medicne Kirby Institute: The Kirby Institute"},{"author_name":"Agnes Mek","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Anna Maalsen","author_inst":"World Health Organization"},{"author_name":"Leanne  J. Robinson","author_inst":"Burnet Institute"},{"author_name":"William Pomat","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Moses Laman","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Angela Kelly-Hanku","author_inst":"UNSW Medicne Kirby Institute: The Kirby Institute"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Pembrolizumab in advanced acral lentiginous melanoma: final results of a single-centre, open-label, phase II trial in an East Asian population","rel_doi":"10.64898\/2026.07.22.26358641","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358641","rel_abs":"Background: Acral lentiginous melanoma (ALM) is the predominant melanoma subtype in East Asian populations, accounting for roughly 50 to 58% of cases, compared with 2 to 3% in populations of European ancestry. ALM is genomically and biologically distinct from sun-exposed cutaneous melanoma, and East Asian and acral patients were markedly under-represented in the pivotal antiPD1 registration trials. At the time this study was designed, no prospective trial had evaluated a checkpoint inhibitor specifically in ALM. We conducted a phase II trial to estimate the activity of pembrolizumab in this population. Methods. In this single centre, single arm, open label phase II trial, adults with metastatic or locoregionally advanced inoperable ALM who were naive to antiPD1 or antiPDL1 therapy received pembrolizumab 200 mg intravenously every 3 weeks until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints included duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety (CTCAE v4.0). A Simon minimax two-stage design (P0=0.10, P1=0.30, power=80%) planned enrolment of up to 28 patients. Results. Between February 2017 and June 2019, 9 patients were enrolled before recruitment was halted for slow accrual, the interval availability of reimbursed pembrolizumab, and a low observed response signal. Median age was 72 years (range 48 to 78); 6 (67%) were male; all had ECOG performance status 0 and metastatic disease; 7 (78%) had received prior therapy. One patient achieved a partial response (ORR 11.1%, 95% CI 0.0 to 31.6%), with a DoR of 19 months; 3 had stable disease and 4 progressed. CBR (response or stable disease greater than or equal to 12 weeks) was 44.4% (95% CI 12.0 to 76.9). At a median follow-up of 7.6 months, median PFS was 3.4 months (95% CI 1.4 to 21.3) and median OS was 7.6 months (95% CI 2.0 to 34.3). Two grade 3 adverse events occurred, both assessed as unrelated to study drug; no treatment-related grade 3 or above events were recorded. In an exploratory analysis, an LDH to upper limit of normal ratio >1.5 was associated with worse OS (median 4.3 vs 26.5 months; HR 4.58, 95% CI 0.82 to 25.7; log-rank p=0.06). Conclusions. Recruitment was constrained by disease rarity and a shifting reimbursement landscape, and the trial closed before completing stage 1. Within these limitations, single-agent pembrolizumab showed only modest activity in advanced ALM, consistent with the limited efficacy subsequently reported in larger contemporary acral melanoma cohorts. The exploratory association between elevated LDH ratio and poorer survival warrants prospective evaluation.","rel_num_authors":12,"rel_authors":[{"author_name":"Herbert H Loong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Winnie Yeo","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Candy Yuen","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Frankie Mo","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Tung Ching Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kirsty W C Lee","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chiu Yan Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Ashley C Y Wong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kenneth W C Wong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Daisy C M Lam","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Joanna Tong","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Carlos Wong","author_inst":"University of Hong Kong"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Resolving the classification rates and molecular architecture of early-onset chronic kidney disease with NephVar","rel_doi":"10.64898\/2026.07.22.26358680","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358680","rel_abs":"The genetic architecture of early-onset chronic kidney disease (CKD) is caused by more than 200 monogenic genes, where their common diagnostic classes include congenital anomalies of the kidney and urinary tract, steroid-resistant nephrotic syndrome, nephronophthisis-related ciliopathies, chronic glomerulonephritis, and urinary stone disease. While advancements in whole-exome and whole-genome sequencing have enabled identification of disease-causing variants, their rates of classification have remained unknown. Likewise, the molecular effects of these pathogenic variants remain unresolved, which is essential for improving personalized treatment approaches. In this study, we collected clinical and biophysical data from 117,373 genetic variants across 129 monogenic genes causing early-onset CKD. This data established the NephVar registry, which aims to be a molecular dictionary for nephrologists to classify variants and resolve their unique molecular effects. Through NephVar, we estimated 1-15% of alleles are reclassified and the time to reclassification per variant is 2-12 years in early-onset CKD. Furthermore, NephVar identified the molecular effects of all variant types, emphasizing missense variants. Our analyses indicate that intrinsically disordered regions of proteins are protective against disease-causing missense alleles across most diagnostic classes, but often occur through a buried loss-of-function (LoF) mechanism. Additionally, we show that the mode of inheritance for these monogenic genes influences clustering patterns of genetic variants, where autosomal dominant (AD) genes are more clustered than those of autosomal recessive (AR) genes. This data accurately predicted the non-LoF effects in INF2, PAX2, GATA3, ACTN4, and LMX1B causing inherited nephrotic syndromes. We demonstrate that variant effect prediction is effective for downgrading variants of unknown significance and classifying AR genes, but challenging for pathogenic alleles in AD genes. Lastly, we propose standards and guidelines for determining non-LoF effects, including gain-of-function and dominant negative, in inherited nephrotic syndrome. Overall, the NephVar renal registry has important implications for defining the molecular architecture and estimating the progress of molecular diagnostics for early-onset CKD.","rel_num_authors":2,"rel_authors":[{"author_name":"Joshua P Pillai","author_inst":"University of California, San Diego"},{"author_name":"John A Sayer","author_inst":"Newcastle University"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Changes in disability status and oral healthcare affordability among working-age Australians","rel_doi":"10.64898\/2026.07.21.26358621","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358621","rel_abs":"Importance: Oral healthcare is often financed outside universal medical coverage, leaving working-age adults exposed to out-of-pocket costs. People with long-term disability may face added financial, physical, and service barriers to care, but longitudinal evidence on disability and oral healthcare unaffordability is limited. Objective: To estimate the effect of time-varying long-term disability on oral healthcare unaffordability among working-age adults in Australia. Design: Longitudinal cohort study using Household, Income and Labour Dynamics in Australia survey data from waves 18 to 22 (2018-2022), analysed with targeted maximum likelihood estimation for longitudinal modified treatment policies. Setting: Nationally representative household panel survey in Australia. Participants: Adults aged 25 to 65 years at wave 18 who could validly contribute to the longitudinal analysis (identified using HILDA longitudinal weights) and had complete baseline covariate data. Exposure: Time-varying self-reported disability at waves 18 to 21 (2018-2022), defined as any long-term health condition, impairment, or disability restricting everyday activities and lasting, or likely to last, for at least 6 months. Hypothetical interventions comprised 50% and 25% reductions in the odds of disability at each wave, and deterministic sustained disability and no disability regimes. Main Outcome and Measure: Self-reported avoidance of dental treatment because of cost at wave 22 (2022). Results: The analytic sample included 9635 adults; 4901 (50.9%) were female, mean age was 44 (SD=12) years, and 2419 (25.1%) reported disability at baseline. A total of 399 participants (4.1%) reported oral healthcare unaffordable at wave 22 follow-up. Compared with the natural course, sustained disability increased the risk of unaffordability (risk ratio [RR], 1.60; 95% CI, 1.15-2.22). No disability at any time point reduced the risk (RR, 0.59; 95% CI, 0.45-0.77). Reducing the odds of disability by 50% and 25% also reduced the risk of oral healthcare unaffordability by 28% (RR, 0.72; 95% CI, 0.65-0.81) and 17% (RR, 0.83; 95% CI, 0.78-0.89), respectively. Conclusions and Relevance: Under the study assumptions, long-term disability was estimated to increase experienced unaffordability of oral healthcare among working-age Australians. Population level policy responses should address both the upstream conditions that shape disability trajectories and the downstream exclusion of adult dental care from routine financial protection.","rel_num_authors":7,"rel_authors":[{"author_name":"Upul Cooray","author_inst":"The University of Sydney"},{"author_name":"Gagandeep Kaur","author_inst":"The University of Sydney"},{"author_name":"Saman Khalatbari-Soltani","author_inst":"The University of Sydney"},{"author_name":"Barbara Janssens","author_inst":"Ghent University"},{"author_name":"George Disney","author_inst":"University of Melbourne"},{"author_name":"Ruby Cole","author_inst":"The University of Sydney"},{"author_name":"Ankur Singh","author_inst":"The University of Sydney"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Palliative Care among People with Advanced Heart Failure: Between Hospital Variation in the US Veterans Administration","rel_doi":"10.64898\/2026.07.22.26358645","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.22.26358645","rel_abs":"Background: Palliative care is recommended by clinical practice guidelines for patients with advanced heart failure (aHF), yet specialty palliative care (SPC) remains substantially underutilized in this population. We sought to quantify between-facility variation in SPC receipt among people with aHF and determine how much variation is explained by patient case mix and facility structural characteristics versus residual unmeasured factors. Methods: This retrospective cohort study included 23,991 Veterans with prevalent aHF identified through administrative data across 133 VA Medical Centers (VAMCs) with [&ge;]20 aHF cases, from January 2022 to December 2023. Variation was assessed using multilevel logistic regression with facility random intercepts, the intraclass correlation coefficient (ICC), and the adjusted median odds ratio (aMOR). Facility-specific risk-standardized SPC rates were used to estimate SPC encounters attributable to facility performance better or worse than the national rate. Results: Of the sample, the mean patient age was 72.3 years (SD = 10.0), and 97.6% were male. The national observed rate of SPC was 17.5%, with risk-adjusted rates varying approximately 14-fold across facilities (3.3% to 45.6%). The adjusted ICC was 11.5%, and aMOR was 1.87 (95% Confidence Intervals 1.70-2.06). Measured patient case-mix and facility structural characteristics explained only 18.9% of between-facility variation (proportional reduction in the ICC, fully adjusted vs. null model). Facilities performing better than the national rate delivered 791 more SPC encounters than expected (17.8%), while those performing worse than the national rate delivered 480 fewer encounters than expected (10.8%). Conclusions: In the context of a national mean rate of SPC that reflects substantial underuse, delivery varied 14-fold across VAMCs, with most variation unexplained by patient complexity or measured facility resources. These findings suggest that potentially modifiable organizational factors, beyond patient preferences or facility structures alone, may contribute to current utilization gaps and represent actionable targets for quality improvement.","rel_num_authors":14,"rel_authors":[{"author_name":"Shelli Feder","author_inst":"Yale University"},{"author_name":"Na Ouyang","author_inst":"Yale"},{"author_name":"Ling Han","author_inst":"Yale"},{"author_name":"Erica Abel","author_inst":"VA"},{"author_name":"Eric DeRycke","author_inst":"VA"},{"author_name":"Daniel Kinder","author_inst":"VA"},{"author_name":"Nancy Redeker","author_inst":"University of Connecticut"},{"author_name":"Leslie A. Curry","author_inst":"Yale School of Public Health and Yale Global Health Leadership Institute"},{"author_name":"Carol Lurhs","author_inst":"VA"},{"author_name":"Cari Levy","author_inst":"VA"},{"author_name":"Jennifer Ibarra","author_inst":"VA"},{"author_name":"Dio Kavalieratos","author_inst":"Emory University"},{"author_name":"Kathleen Akgun","author_inst":"VA"},{"author_name":"Larry A Allen","author_inst":"University of Colorado School of Medicine, Aurora, CO"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Circulating protein profiling identifies prognostic biomarkers in amyotrophic lateral Sclerosis","rel_doi":"10.64898\/2026.07.20.26354798","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26354798","rel_abs":"In the pathologically and clinically heterogeneous neurodegenerative disorder amyotrophic lateral sclerosis (ALS), objective biochemical predictors of survival are essential to handle complexity in clinical trials, enrich clinical decision-making and interrogate the biology of disease progression. In this longitudinal study, we performed high-depth proximity extension assay proteomics using 1,095 samples of serum (N=851) and CSF (N=244) from 426 people with ALS, with orthogonal replication in an external cohort of 349 people with ALS. Age- and sex-adjusted Cox analysis identified 57 proteins in serum, including neurofilament light chain (NEFL) and peripherin, as well as five proteins in CSF, including tropomyosin 3 (TPM3) that were associated with survival (FDR-adjusted p<0.05). Penalised Cox regression identified a panel of 9 serum proteins - including NEFL, peripherin, TNF receptor superfamily member 27 (EDA2R) and calcitonin - that reflect the extent of disease as well as the progression rate, improving survival prediction compared with models using clinical parameters and NEFL. Joint modelling identified associations between the longitudinal trajectories of serum EDA2R and calcitonin with survival, highlighting their potential role in measuring disease progression. This work indicates the utility of multiple proteins reflecting diverse biological pathways in refining survival stratification and highlights systemic factors in ALS progression.","rel_num_authors":23,"rel_authors":[{"author_name":"Hadar Klimovski","author_inst":"Weizmann Institute of Science"},{"author_name":"Marcel Weinreich","author_inst":"University of Sheffield"},{"author_name":"Andrew Strange","author_inst":"University of Sheffield"},{"author_name":"Iddo Magen","author_inst":"Weizmann Institute of Science"},{"author_name":"Elham Alhathli","author_inst":"University of Sheffield"},{"author_name":"Yahel Cohen","author_inst":"Weizmann Institute of Science"},{"author_name":"Dganit Melamed-Kadosh","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"David G Lester","author_inst":"University of Oxford"},{"author_name":"Avigail Taylor","author_inst":"University of Oxford"},{"author_name":"Yuhan Zhou","author_inst":"University of Oxford"},{"author_name":"Tamar Ziv","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Beatrice Abramovich","author_inst":"Sourasky Medical Center"},{"author_name":"Anand Subramanian","author_inst":"Tel Aviv University"},{"author_name":"Eran Perlson","author_inst":"Tel Aviv University"},{"author_name":"Vivian Drory","author_inst":"Tel-Aviv University"},{"author_name":"Arie Admon","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Pamela Shaw","author_inst":"University of Sheffield"},{"author_name":"Andrea Malaspina","author_inst":"University College London"},{"author_name":"Martin R Turner","author_inst":"University of Oxford"},{"author_name":"Kevin Talbot","author_inst":"University of Oxford"},{"author_name":"Johnathan Cooper-Knock","author_inst":"University of Sheffield"},{"author_name":"Alexander G Thompson","author_inst":"University of Oxford"},{"author_name":"Eran Hornstein","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Circulating protein profiling identifies prognostic biomarkers in amyotrophic lateral Sclerosis","rel_doi":"10.64898\/2026.07.20.26354798","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26354798","rel_abs":"In the pathologically and clinically heterogeneous neurodegenerative disorder amyotrophic lateral sclerosis (ALS), objective biochemical predictors of survival are essential to handle complexity in clinical trials, enrich clinical decision-making and interrogate the biology of disease progression. In this longitudinal study, we performed high-depth proximity extension assay proteomics using 1,095 samples of serum (N=851) and CSF (N=244) from 426 people with ALS, with orthogonal replication in an external cohort of 349 people with ALS. Age- and sex-adjusted Cox analysis identified 57 proteins in serum, including neurofilament light chain (NEFL) and peripherin, as well as five proteins in CSF, including tropomyosin 3 (TPM3) that were associated with survival (FDR-adjusted p<0.05). Penalised Cox regression identified a panel of 9 serum proteins - including NEFL, peripherin, TNF receptor superfamily member 27 (EDA2R) and calcitonin - that reflect the extent of disease as well as the progression rate, improving survival prediction compared with models using clinical parameters and NEFL. Joint modelling identified associations between the longitudinal trajectories of serum EDA2R and calcitonin with survival, highlighting their potential role in measuring disease progression. This work indicates the utility of multiple proteins reflecting diverse biological pathways in refining survival stratification and highlights systemic factors in ALS progression.","rel_num_authors":23,"rel_authors":[{"author_name":"Hadar Klimovski","author_inst":"Weizmann Institute of Science"},{"author_name":"Marcel Weinreich","author_inst":"University of Sheffield"},{"author_name":"Andrew Strange","author_inst":"University of Sheffield"},{"author_name":"Iddo Magen","author_inst":"Weizmann Institute of Science"},{"author_name":"Elham Alhathli","author_inst":"University of Sheffield"},{"author_name":"Yahel Cohen","author_inst":"Weizmann Institute of Science"},{"author_name":"Dganit Melamed-Kadosh","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"David G Lester","author_inst":"University of Oxford"},{"author_name":"Avigail Taylor","author_inst":"University of Oxford"},{"author_name":"Yuhan Zhou","author_inst":"University of Oxford"},{"author_name":"Tamar Ziv","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Beatrice Abramovich","author_inst":"Sourasky Medical Center"},{"author_name":"Anand Subramanian","author_inst":"Tel Aviv University"},{"author_name":"Eran Perlson","author_inst":"Tel Aviv University"},{"author_name":"Vivian Drory","author_inst":"Tel-Aviv University"},{"author_name":"Arie Admon","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Pamela Shaw","author_inst":"University of Sheffield"},{"author_name":"Andrea Malaspina","author_inst":"University College London"},{"author_name":"Martin R Turner","author_inst":"University of Oxford"},{"author_name":"Kevin Talbot","author_inst":"University of Oxford"},{"author_name":"Johnathan Cooper-Knock","author_inst":"University of Sheffield"},{"author_name":"Alexander G Thompson","author_inst":"University of Oxford"},{"author_name":"Eran Hornstein","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Greater Mental Health Benefits Following Contemplative-Based Social Resilience Training Among Young Adults with Early-Life Adversity","rel_doi":"10.64898\/2026.07.21.26358618","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358618","rel_abs":"Emerging evidence suggests that adults with a history of early life adversity (ELA), while more susceptible to psychopathology, may also be particularly sensitive to the benefits of contemplative practices. In the present study, we examined whether ELA was associated with greater mental health benefits following a contemplative-based social resilience training program, administered as a university elective course across all ten campuses of the University of California (n = 321; median age = 21 years; 74% female). While significant improvements in mental health were observed for all participants, those with higher ELA exhibited greater reductions in mental distress (3.5-fold larger, p = .007) and greater increases in well-being (2.5-fold larger, p = .010) relative to those with lower ELA. Replication in future studies and further research on the mechanisms underlying this enhanced benefit may improve our understanding of how adults with a history of ELA recover and may ultimately thrive.","rel_num_authors":8,"rel_authors":[{"author_name":"Aaron M Eisen","author_inst":"University of California, San Francisco"},{"author_name":"Philippe Goldin","author_inst":"University of California, Davis"},{"author_name":"Jyoti Mishra","author_inst":"University of California, San Diego"},{"author_name":"Elena Fromer","author_inst":"University of California, San Francisco"},{"author_name":"Lucy Kho","author_inst":"University of California, San Francisco"},{"author_name":"Aric A Prather","author_inst":"University of California, San Francisco"},{"author_name":"Elissa S Epel","author_inst":"University of California, San Francisco"},{"author_name":"- UC Climate Resilience Consortium","author_inst":""}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Greater Mental Health Benefits Following Contemplative-Based Social Resilience Training Among Young Adults with Early-Life Adversity","rel_doi":"10.64898\/2026.07.21.26358618","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358618","rel_abs":"Emerging evidence suggests that adults with a history of early life adversity (ELA), while more susceptible to psychopathology, may also be particularly sensitive to the benefits of contemplative practices. In the present study, we examined whether ELA was associated with greater mental health benefits following a contemplative-based social resilience training program, administered as a university elective course across all ten campuses of the University of California (n = 321; median age = 21 years; 74% female). While significant improvements in mental health were observed for all participants, those with higher ELA exhibited greater reductions in mental distress (3.5-fold larger, p = .007) and greater increases in well-being (2.5-fold larger, p = .010) relative to those with lower ELA. Replication in future studies and further research on the mechanisms underlying this enhanced benefit may improve our understanding of how adults with a history of ELA recover and may ultimately thrive.","rel_num_authors":8,"rel_authors":[{"author_name":"Aaron M Eisen","author_inst":"University of California, San Francisco"},{"author_name":"Philippe Goldin","author_inst":"University of California, Davis"},{"author_name":"Jyoti Mishra","author_inst":"University of California, San Diego"},{"author_name":"Elena Fromer","author_inst":"University of California, San Francisco"},{"author_name":"Lucy Kho","author_inst":"University of California, San Francisco"},{"author_name":"Aric A Prather","author_inst":"University of California, San Francisco"},{"author_name":"Elissa S Epel","author_inst":"University of California, San Francisco"},{"author_name":"- UC Climate Resilience Consortium","author_inst":""}],"rel_date":"2026-07-23","rel_site":"medrxiv"},{"rel_title":"Conformational dynamics of exopolysaccharides underlie biofilm matrix mechanics in Vibrio cholerae","rel_doi":"10.64898\/2026.07.22.739955","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739955","rel_abs":"Polysaccharides remain the least understood biomacromolecules, particularly in terms of the relationship between their chemical structure and physical properties. On the other hand, polysaccharides often serve as the main structural components in biofilms: surface-attached aggregates of bacterial cells encased within a mechanically resilient extracellular matrix. The large chemical space explored by bacteria within biofilms provides excellent opportunities to establish the structure-function relationship for polysaccharides. In this paper, we systematically characterize various polymer properties of Vibrio polysaccharide (VPS), the major exopolysaccharide in biofilms formed by Vibrio cholerae, the causative agent of pandemic cholera. Using a combination of shear rheology, dynamic and static light scattering, and small-angle X-ray scattering, we measure the viscosity, molecular weight, persistence length, radius of gyration, and hydrodynamic radius of this chemically unique biopolymer. Combining all-atom and coarse-grained simulations, we show how the conformational flexibility of a single glycosidic linkage within each VPS monomer can lead to dramatic compaction of the entire polymer chain and nonclassical entanglement behavior. Our comprehensive quantification represents a rare endeavor for bacterial biofilms, whose matrix composition and physical properties remain largely nebulous; it also represents a significant step towards a detailed understanding of the molecular origins of biofilm mechanics.","rel_num_authors":16,"rel_authors":[{"author_name":"Kee-Myoung Nam","author_inst":"Yale University"},{"author_name":"Nathan Fowler","author_inst":"Yale University"},{"author_name":"Rajan Kandel","author_inst":"University of Georgia"},{"author_name":"Yongqi Zhu","author_inst":"Yale University"},{"author_name":"Yuchu Liu","author_inst":"Yale University"},{"author_name":"Yi-Jhen Lai","author_inst":"University of Connecticut - Storrs"},{"author_name":"Muhammad Faheem Hassan","author_inst":"University of Connecticut - Storrs"},{"author_name":"Emma Gerace","author_inst":"Wesleyan University"},{"author_name":"Merrill Asp","author_inst":"Yale University"},{"author_name":"Rich Olson","author_inst":"Wesleyan University"},{"author_name":"Ying Li","author_inst":"University of Wisconsin - Madison"},{"author_name":"Mu-Ping Nieh","author_inst":"University of Connecticut - Storrs"},{"author_name":"Mingjiang Zhong","author_inst":"Yale University"},{"author_name":"Robert J Woods","author_inst":"University of Georgia"},{"author_name":"Alexis Moreau","author_inst":"United Arab Emirates University"},{"author_name":"Jing Yan","author_inst":"Yale University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Widely used GWAS methods can be poorly suited to SNP-level localization under diffuse polygenic architecture in livestock","rel_doi":"10.64898\/2026.07.20.739621","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739621","rel_abs":"In livestock populations, genome-wide association studies (GWAS) can produce strong, apparently localized associations even when no truly discrete nearby causal effect exists. This occurs because small effective population sizes, strong family structure, long-range linkage disequilibrium (LD), and diffuse polygenic architecture can cause the effects of many variants to accumulate and be captured jointly across broad genomic intervals, making variant-level associations difficult to interpret biologically. Using real Duroc pig genotypes, we constructed a benchmark in which phenotypes were simulated under diffuse polygenic architecture across a genome partitioned into alternating effect and null windows, with central-null regions (at least 1 Mb away from effect-containing regions) positioned to detect long-range LD-driven signal propagation. We evaluated nine configurations of six GWAS methods (BOLT-LMM, REGENIE, fastGWA, FarmCPU, BLINK, and SLEMM) under this architecture. The central finding is that strong associations, of the kind normally read as evidence of nearby moderate- or large-effect variants, are produced by many of these methods even though the simulated signal is distributed across many tiny effects and cannot be localized to any single variant. The methods differed sharply in the extent of locus-level spillover: several produced large numbers of genome-wide significant loci within central-null regions, whereas the full-GRM mixed-model benchmark (SLEMM) suppressed this spillover almost entirely. These results show that, under a highly polygenic architecture with livestock-like LD, GWAS tool choice has major consequences for biological interpretation. When the goal is to localize biologically meaningful signals rather than to flag association peaks that may merely reflect tiny effects accumulated through LD across a broad block, methods that control long-range LD spillover should be prioritized.","rel_num_authors":7,"rel_authors":[{"author_name":"Xuesong Wang","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Junjian Wang","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Francesco Tiezzi","author_inst":"Department of Agriculture, Food, Environment and Forestry (DAGRI)"},{"author_name":"Yijian Huang","author_inst":"Smithfield Premium Genetics"},{"author_name":"Wen Huang","author_inst":"Michigan State University"},{"author_name":"Christian Maltecca","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Jicai Jiang","author_inst":"Department of Animal Science, North Carolina State University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Widely used GWAS methods can be poorly suited to SNP-level localization under diffuse polygenic architecture in livestock","rel_doi":"10.64898\/2026.07.20.739621","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739621","rel_abs":"In livestock populations, genome-wide association studies (GWAS) can produce strong, apparently localized associations even when no truly discrete nearby causal effect exists. This occurs because small effective population sizes, strong family structure, long-range linkage disequilibrium (LD), and diffuse polygenic architecture can cause the effects of many variants to accumulate and be captured jointly across broad genomic intervals, making variant-level associations difficult to interpret biologically. Using real Duroc pig genotypes, we constructed a benchmark in which phenotypes were simulated under diffuse polygenic architecture across a genome partitioned into alternating effect and null windows, with central-null regions (at least 1 Mb away from effect-containing regions) positioned to detect long-range LD-driven signal propagation. We evaluated nine configurations of six GWAS methods (BOLT-LMM, REGENIE, fastGWA, FarmCPU, BLINK, and SLEMM) under this architecture. The central finding is that strong associations, of the kind normally read as evidence of nearby moderate- or large-effect variants, are produced by many of these methods even though the simulated signal is distributed across many tiny effects and cannot be localized to any single variant. The methods differed sharply in the extent of locus-level spillover: several produced large numbers of genome-wide significant loci within central-null regions, whereas the full-GRM mixed-model benchmark (SLEMM) suppressed this spillover almost entirely. These results show that, under a highly polygenic architecture with livestock-like LD, GWAS tool choice has major consequences for biological interpretation. When the goal is to localize biologically meaningful signals rather than to flag association peaks that may merely reflect tiny effects accumulated through LD across a broad block, methods that control long-range LD spillover should be prioritized.","rel_num_authors":7,"rel_authors":[{"author_name":"Xuesong Wang","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Junjian Wang","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Francesco Tiezzi","author_inst":"Department of Agriculture, Food, Environment and Forestry (DAGRI)"},{"author_name":"Yijian Huang","author_inst":"Smithfield Premium Genetics"},{"author_name":"Wen Huang","author_inst":"Michigan State University"},{"author_name":"Christian Maltecca","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Jicai Jiang","author_inst":"Department of Animal Science, North Carolina State University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"The Metabarcoding Analysis Pipeline (MAP): Simple, accurate, and flexible metabarcoding","rel_doi":"10.64898\/2026.07.22.740107","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740107","rel_abs":"Current metabarcoding pipelines are inflexible with respect to study design and are poorly suited to long-read sequence data. To address these limitations, we developed MAP, the Metabarcoding Analysis Pipeline, which is a sequence-to-answer workflow supporting the analysis of amplicons from highly multiplexed and replicated study designs. Although MAP can analyze amplicons of any length from any genetic marker, it includes several features tailored to long-read COI metabarcoding. MAP installs from a Docker container and requires only sequence data, a parameters file, and a reference library. It produces intuitive reports, enabling users to evaluate their data immediately after analysis. We validate MAP by showing that it generates biodiversity estimates that correspond closely to a ground-truth dataset of single-specimen DNA barcode data and by demonstrating that it outperforms alternative platforms for COI metabarcoding. MAP is free, open-source, and available from: https:\/\/github.com\/cbg-innov\/MAP.","rel_num_authors":8,"rel_authors":[{"author_name":"Sean WJ Prosser","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Nicholas W Bard","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Ken A Thompson","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Robin A Floyd","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Sameer Padhye","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Emine Ozsahin","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Saeideh Jafarpour","author_inst":"Centre for Biodiversity Genomics, University of Guelph"},{"author_name":"Paul D. N. Hebert","author_inst":"Centre for Biodiversity Genomics, University of Guelph"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Antibody evasion and receptor binding of SARS-CoV-2 variants PQ.16.1.1 and RK.1","rel_doi":"10.64898\/2026.07.21.739818","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739818","rel_abs":"The recent global expansion of the SARS-CoV-2 variant NB.1.8.1 has driven the emergence of sublineages PQ.16.1.1 and RK.1, which independently acquired the D420N mutation in their receptor-binding domains and and now dominate the Asia-Pacific region. Evaluations utilizing surface plasmon resonance and pseudovirus assays demonstrate that these sublineages exhibit significantly reduced human ACE2 receptor engagement compared to their parental strain. However, this functional cost is offset by a marked ability to evade humoral immunity, specifically demonstrating profound resistance to Class 1 neutralizing monoclonal antibodies and convalescent plasma from Wuhan-Hu-1-primed individuals. This convergent evolution exemplifies a classical viral trade-off, sacrificing receptor binding efficiency to escape population-level immune pressure. Consequently, these findings suggest these variants will soon spread globally and emphasize the critical need for ongoing surveillance to monitor D420N-carrying lineages.","rel_num_authors":8,"rel_authors":[{"author_name":"Peizhuo He","author_inst":"Changping Laboratory"},{"author_name":"Yunwen Song","author_inst":"Changping Laboratory"},{"author_name":"Caiwan Guo","author_inst":"Changping Laboratory"},{"author_name":"Lingling Yu","author_inst":"Changping Laboratory"},{"author_name":"Yuanling Yu","author_inst":"Changping Laboratory"},{"author_name":"Fanchong Jian","author_inst":"Peking University"},{"author_name":"Fei Shao","author_inst":"Changping Laboratory"},{"author_name":"Yunlong Cao","author_inst":"Peking University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Symmetry-breaking flow bifurcation as an under-recognised haemodynamic factor in valve-associated thrombosis","rel_doi":"10.64898\/2026.07.20.739554","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739554","rel_abs":"Venous thrombosis commonly develops in the vicinity of venous valve pockets, where disturbed haemodynamics, xreduced washout, and endothelial dysfunction promote thrombus initiation. While previous studies have focused on conventional flow descriptors such as velocity, shear stress, recirculation, and residence time, the influence of valve mechanics on flow organisation remains poorly understood. Here, we combine a biomimetic vein-on-a-chip platform with computational fluid dynamics, fluid-structure interaction simulations, Ghost Particle Velocimetry (GPV), whole-blood flow measurements, and particle transport experiments to investigate the interplay between valve biomechanics and venous haemodynamics. Movable venous valve leaflets fabricated by in situ photopolymerisation of poly(ethylene glycol) diacrylate (PEGDA) enabled independent control of leaflet stiffness under physiologically relevant steady and pulsatile flow conditions. Previous experiments demonstrated that leaflet flexibility governs thrombus localisation, with symmetric leaflet stiffness promoting clot formation at the valve tips, while asymmetric stiffness shifts thrombus formation towards the valve sinus. In addition, we identify a previously undescribed Reynolds-number-dependent symmetry-breaking transition in post-valve flow. Above a critical flow condition, an initially symmetric jet spontaneously develops into a stable asymmetric flow pattern. This behaviour was consistently reproduced experimentally using GPV and confirmed by Fluid-structure simulations. Valve compliance delayed the onset of the transition by increasing the effective leaflet opening, whereas valves with a small geometric offset promoted earlier asymmetry through higher local flow velocities within the valve gap. The resulting asymmetric flow generated persistent lateral bias in the transport of red blood cell-sized particles, suggesting enhanced platelet accumulation and prolonged residence within one valve sinus. These findings demonstrate that venous valve mechanics regulate not only local flow fields but also particle transport relevant to thrombosis. The discovery of a stable symmetry-breaking flow state provides a new haemodynamic mechanism linking valve stiffness, asymmetric particle transport, and the preferential localisation of thrombus formation, offering new insight into the mechanobiology of deep vein thrombosis.","rel_num_authors":2,"rel_authors":[{"author_name":"Yuxin Chen","author_inst":"THE UNIVERSITY OF SYDNEY"},{"author_name":"Daniele Vigolo","author_inst":"The University of Sydney"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Pulsed priming with the FAK inhibitor narmafotinib enhances both gemcitabine\/Abraxane and FOLFIRINOX chemotherapy response in pancreatic cancer","rel_doi":"10.64898\/2026.07.23.740234","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.740234","rel_abs":"Background: Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with few treatment options available. Extensive remodelling of extracellular matrix (ECM) generates a highly fibrotic tumour landscape, which impairs therapeutic response. Objective: We investigated whether stromal priming via the highly specific Focal Adhesion Kinase (FAK) inhibitor narmafotinib (AMP945) in combination with the two major standard-of-care chemotherapies in PDAC, gemcitabine\/Abraxane and FOLFIRINOX, reduces fibrosis and enhances treatment efficacy. Design: 3D organotypic matrices, intravital imaging, and in vivo subcutaneous and orthotopic PDAC models were used to provide a rationale for a first-line priming regimen of narmafotinib prior to chemotherapy. Results: Neoadjuvant chemotherapy induces fibrosis in PDAC indicating a need for upfront first-line priming of the ECM to normalise the stroma for optimal treatment response. Narmafotinib is a new potent small molecule FAK inhibitor. Phase I safety data shows excellent safety, tolerability, and pharmacokinetics following oral administration in humans. We reveal that narmafotinib treatment during early ECM remodelling (priming) reduces fibrosis, while limiting subsequent PDAC invasion. Moreover, intravital imaging demonstrates real-time FAK inactivation and cell cycle stalling, leading to improved chemotherapeutic efficacy upon narmafotinib priming in vivo. Long-term assessment in patient-derived models shows that narmafotinib priming prior to gemcitabine\/Abraxane or FOLFIRINOX reduces PDAC progression and extends survival in both chemotherapy settings. Conclusions: Our results using these Phase II-ready drug combinations strongly support the clinical assessment of narmafotinib in PDAC. Narmafotinib is currently in Phase Ib\/IIa trials, assessing a pulsed dosing regimen prior to gemcitabine\/Abraxane, and warrants further clinical assessment in combination with FOLFIRINOX.","rel_num_authors":67,"rel_authors":[{"author_name":"Kendelle J Murphy","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Cecilia R Chambers","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Daniel A Reed","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Lily M Channon","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Niamh EP Mills","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Sophie E McKay","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Victoria Lee","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Anna E Howell","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Alice MH Tran","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Max Nobis","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Astrid Magenau","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Janett Stoehr","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Brooke A Pereira","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Nadia Kuepper","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Shona Ritchie","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Katie Gordon","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Michael Trpceski","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Victoria M Tyma","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Shanna Hafiz","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Vrinda Johri","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Alexis Ang","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Deborah S Barkauskas","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Claire Vennin","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Xiao Q Wang","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Marjan M Naeini","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Braydon Meyer","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Amelia L Parker","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Sriram Gummadi","author_inst":"Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia."},{"author_name":"Sai V Chitti","author_inst":"Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia."},{"author_name":"Diego Chacon Fajardo","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Anaiis Zaratzian","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Michael Tayao","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Andrew Da Silva","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"- Australian Pancreatic Genome Initiative (APGI)","author_inst":""},{"author_name":"- Australian Pancreatic Matrix Atlas (APMA)","author_inst":""},{"author_name":"Anthony J Cesare","author_inst":"Childrens Medical Research Institute, University of Sydney, Sydney, New South Wales 2145, Australia."},{"author_name":"Suresh Mathivanan","author_inst":"Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia."},{"author_name":"Clare Stirzaker","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Sharissa L Latham","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"David R Croucher","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"George Sharbeen","author_inst":"School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia."},{"author_name":"Phoebe A Phillips","author_inst":"School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia."},{"author_name":"Leonard D Goldstein","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Ruth J Lyons","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Adnan Nagrial","author_inst":"Westmead Hospital Sydney, NSW Australia."},{"author_name":"Nick Pavlakis","author_inst":"Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Anthony J Gill","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; Royal North Shore Hospital, The University of Sydney, Sydney, "},{"author_name":"Andrew V Biankin","author_inst":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G"},{"author_name":"Jaswinder Samra","author_inst":"Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Catherine E Caldon","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Thomas RJ Evans","author_inst":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G"},{"author_name":"Lorraine Chantrill","author_inst":"NSW Health, Department of Medical Oncology, Illawarra Shoalhaven Local Health District, NSW, Australia."},{"author_name":"Lisa G Horvath","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006,"},{"author_name":"Owen J Sansom","author_inst":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G"},{"author_name":"Jennifer P Morton","author_inst":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G"},{"author_name":"Tri G Phan","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Yingxiao Wang","author_inst":"Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles 90089-1112, California, USA."},{"author_name":"Terrie-Anne Cock","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"Sarah A Kinkel","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"Anthony Bishop","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"Mark Devlin","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"John Lambert","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"Thomas R Cox","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Marina Pajic","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Christopher J Burns","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"David Herrmann","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Paul Timpson","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Pulsed priming with the FAK inhibitor narmafotinib enhances both gemcitabine\/Abraxane and FOLFIRINOX chemotherapy response in pancreatic cancer","rel_doi":"10.64898\/2026.07.23.740234","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.740234","rel_abs":"Background: Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with few treatment options available. Extensive remodelling of extracellular matrix (ECM) generates a highly fibrotic tumour landscape, which impairs therapeutic response. Objective: We investigated whether stromal priming via the highly specific Focal Adhesion Kinase (FAK) inhibitor narmafotinib (AMP945) in combination with the two major standard-of-care chemotherapies in PDAC, gemcitabine\/Abraxane and FOLFIRINOX, reduces fibrosis and enhances treatment efficacy. Design: 3D organotypic matrices, intravital imaging, and in vivo subcutaneous and orthotopic PDAC models were used to provide a rationale for a first-line priming regimen of narmafotinib prior to chemotherapy. Results: Neoadjuvant chemotherapy induces fibrosis in PDAC indicating a need for upfront first-line priming of the ECM to normalise the stroma for optimal treatment response. Narmafotinib is a new potent small molecule FAK inhibitor. Phase I safety data shows excellent safety, tolerability, and pharmacokinetics following oral administration in humans. We reveal that narmafotinib treatment during early ECM remodelling (priming) reduces fibrosis, while limiting subsequent PDAC invasion. Moreover, intravital imaging demonstrates real-time FAK inactivation and cell cycle stalling, leading to improved chemotherapeutic efficacy upon narmafotinib priming in vivo. Long-term assessment in patient-derived models shows that narmafotinib priming prior to gemcitabine\/Abraxane or FOLFIRINOX reduces PDAC progression and extends survival in both chemotherapy settings. Conclusions: Our results using these Phase II-ready drug combinations strongly support the clinical assessment of narmafotinib in PDAC. Narmafotinib is currently in Phase Ib\/IIa trials, assessing a pulsed dosing regimen prior to gemcitabine\/Abraxane, and warrants further clinical assessment in combination with FOLFIRINOX.","rel_num_authors":67,"rel_authors":[{"author_name":"Kendelle J Murphy","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Cecilia R Chambers","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Daniel A Reed","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Lily M Channon","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Niamh EP Mills","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Sophie E McKay","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Victoria Lee","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Anna E Howell","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Alice MH Tran","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Max Nobis","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Astrid Magenau","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Janett Stoehr","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Brooke A Pereira","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Nadia Kuepper","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Shona Ritchie","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Katie Gordon","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Michael Trpceski","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Victoria M Tyma","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Shanna Hafiz","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Vrinda Johri","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Alexis Ang","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Deborah S Barkauskas","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Claire Vennin","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Xiao Q Wang","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Marjan M Naeini","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Braydon Meyer","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Amelia L Parker","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Sriram Gummadi","author_inst":"Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia."},{"author_name":"Sai V Chitti","author_inst":"Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia."},{"author_name":"Diego Chacon Fajardo","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Anaiis Zaratzian","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Michael Tayao","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Andrew Da Silva","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"- Australian Pancreatic Genome Initiative (APGI)","author_inst":""},{"author_name":"- Australian Pancreatic Matrix Atlas (APMA)","author_inst":""},{"author_name":"Anthony J Cesare","author_inst":"Childrens Medical Research Institute, University of Sydney, Sydney, New South Wales 2145, Australia."},{"author_name":"Suresh Mathivanan","author_inst":"Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia."},{"author_name":"Clare Stirzaker","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Sharissa L Latham","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"David R Croucher","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"George Sharbeen","author_inst":"School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia."},{"author_name":"Phoebe A Phillips","author_inst":"School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia."},{"author_name":"Leonard D Goldstein","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Ruth J Lyons","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia."},{"author_name":"Adnan Nagrial","author_inst":"Westmead Hospital Sydney, NSW Australia."},{"author_name":"Nick Pavlakis","author_inst":"Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Anthony J Gill","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; Royal North Shore Hospital, The University of Sydney, Sydney, "},{"author_name":"Andrew V Biankin","author_inst":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G"},{"author_name":"Jaswinder Samra","author_inst":"Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia."},{"author_name":"Catherine E Caldon","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Thomas RJ Evans","author_inst":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G"},{"author_name":"Lorraine Chantrill","author_inst":"NSW Health, Department of Medical Oncology, Illawarra Shoalhaven Local Health District, NSW, Australia."},{"author_name":"Lisa G Horvath","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006,"},{"author_name":"Owen J Sansom","author_inst":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G"},{"author_name":"Jennifer P Morton","author_inst":"School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G"},{"author_name":"Tri G Phan","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Yingxiao Wang","author_inst":"Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles 90089-1112, California, USA."},{"author_name":"Terrie-Anne Cock","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"Sarah A Kinkel","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"Anthony Bishop","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"Mark Devlin","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"John Lambert","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"Thomas R Cox","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Marina Pajic","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Christopher J Burns","author_inst":"Amplia Therapeutics Limited, VIC 3000, Melbourne, Australia."},{"author_name":"David Herrmann","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "},{"author_name":"Paul Timpson","author_inst":"Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia; St. Vincents Clinical School, Faculty of Health and Medicine, "}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Noncanonical Circular RNAs and Potential Functions","rel_doi":"10.64898\/2026.07.23.740256","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.23.740256","rel_abs":"Circular RNAs (circRNAs) are ubiquitous in eukaryotes; dysregulated circRNA expression is linked to diseases, including lung cancer. In contrast to canonical circRNAs arising from exon-intron boundaries, noncanonical circRNAs originating within exonic, intronic, and intergenic regions have typically been dismissed as transcriptional noise or technical artifacts. To explore circRNA diversity and appreciate their functions, we developed an algorithm to identify both canonical and noncanonical circRNAs without relying on genome annotation, enabling the identification of circRNAs of all types and in newly sequenced or poorly annotated species. Results from lung cancer cells revealed that noncanonical circRNAs constituted over two-thirds of the circRNA population and were expressed more abundantly than canonical circRNAs, and genes with fewer and shorter exons were hotspots for noncanonical circRNA and circRNA isoform production. Further analyses showed that many noncanonical circRNAs were indeed endogenous circRNAs transcribed within cells rather than experimental artifacts, were potentially translated into proteins or peptides, and were conserved across species. Moreover, we validated 65 noncanonical circRNAs in NCI-H23 cells using multiple bioassays and demonstrated that both exonic and intergenic noncanonical circRNAs influenced cell viability. CircRNA profiles in tumor and tumor-adjacent tissues of lung cancer patients revealed tissue-specific expression and differentially expressed canonical and noncanonical circRNAs from cognate genes involved in cancer-related pathways, indicating their potential clinical relevance. This study confirmed the authenticity of noncanonical circRNAs and provided the first experimental evidence that noncanonical circRNAs influence cancer cell phenotypes. These findings broaden our understanding of circRNA biology, highlighting their widespread genomic distribution, diverse functions, and potential clinical relevance.","rel_num_authors":14,"rel_authors":[{"author_name":"Kang Li","author_inst":"The Hongkong Polytechnic University"},{"author_name":"Weixu Wang","author_inst":"The Hongkong Polytechnic University"},{"author_name":"Abebe Edao Negesso","author_inst":"The Hongkong Polytechnic University"},{"author_name":"Jing Deng","author_inst":"The Hongkong Polytechnic University"},{"author_name":"Haoning Qin","author_inst":"The Hongkong Polytechnic University"},{"author_name":"Jiahao Jiang","author_inst":"The Hongkong Polytechnic University"},{"author_name":"Ke Ma","author_inst":"The Hongkong Polytechnic University"},{"author_name":"Jie Zhang","author_inst":"The Hongkong Polytechnic University"},{"author_name":"Ping Wei","author_inst":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China"},{"author_name":"Dawei Li","author_inst":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China"},{"author_name":"Feng-Ming Spring Kong","author_inst":"Department of Clinical Oncology, HKU Shenzhen Hospital, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China"},{"author_name":"William C. Cho","author_inst":"Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong"},{"author_name":"Shulan Qiu","author_inst":"The Hongkong Polytechnic University"},{"author_name":"weixong zhang","author_inst":"The Hongkong Polytechnic University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"A multimodal interrogation of Broca's area in the pediatric and adult human brain","rel_doi":"10.64898\/2026.07.22.739934","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739934","rel_abs":"Language is a defining trait of our species, and disruptions in language acquisition can have profound consequences to the individuals affected. Uncovering the neurodevelopmental basis of this complex trait requires detailed molecular and cellular insights into the neocortical areas that support linguistic abilities. Here we performed joint gene expression and chromatin accessibility profiling at single-nucleus resolution (10x Genomics Single cell Multiome) and spatial transcriptomic profiling (Xenium high-plex in situ spatial transcriptomics) of Broca's area alongside adjacent motor cortical areas. We profiled individuals from different ancestries (European and African) and developmental stages (infancy, childhood, adolescence, and adulthood). We provide a high-resolution dissection of the cellular and molecular architecture of Broca's and motor cortical areas across early life stages and anchor the trajectories to the cellular states found in the adult human brain. We identify distinct area- and stage-specific cellular signatures, including a prominent role of glia populations and interneuron subtypes contributing to cytoarchitectonic specializations. Using longitudinal single cell spatial transcriptomic profiling, we orthogonally validate our consensus cell taxonomy and spatially resolve layer enrichment of neuronal and astrocyte subtypes that distinguish Broca's area and motor cortex. We also uncover cell type-specific molecular signatures that distinguish cell developmental trajectories in these cortical areas, including an early molecular code established by differential expression of cadherin genes that might contribute to area-specific intercellular communication. We also identify cell type-specific vulnerabilities to language-related neurodevelopmental and neuropsychiatric disorders, with selective susceptibility of particular somatostatin-positive interneuron subtypes to ASD\/ADHD. Finally, evolutionary analysis of differentially accessible regions between Broca's area and motor cortex suggests that genetic mutations that might have contributed to the emergence of linguistic abilities accumulated over the course of million years following the divergence of human and chimpanzee lineages. Together, our study provides a comprehensive molecular, cellular and spatial definition of Broca's area and motor cortex, laying the groundwork for investigations into unique aspects of human cognition and related neurodevelopmental and neuropsychiatric disorders.","rel_num_authors":36,"rel_authors":[{"author_name":"Juan Moriano","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Tanzila Mukhtar","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Jimmy Tsz Hang Lee","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Fani Memi","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Jonathan Augustin","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Rachel Leonard","author_inst":"Department of Anatomy, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Joseph Asfouri","author_inst":"Department of Anatomy, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"I-Ling Lu","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Pediatrics, Univer"},{"author_name":"Clara Siebert","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Jennifer Ja-Yoon Choi","author_inst":"Department of Pathology, University of California San Francisco, San Francisco, CA, USA; Department of Pathology and Immunology, Washington University School of"},{"author_name":"Guolong Zuo","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Yinshui Chang","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Stanislaw Makarchuk","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Elina Jin","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Martin Prete","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Shaohui Wang","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Qiuli Bi","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Yuhan Hao","author_inst":"Department of Neurological Surgery, University of California, San Francisco, CA, USA"},{"author_name":"Liz Tuck","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Katy Tudor","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Vanessa B. Pereira","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Hon Man Chan","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Jasmine Halliwell","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Benjamin Rumney","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Holly Anderson","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Arren Ramsey","author_inst":"Department of Pathology, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Fabian Theis","author_inst":"Institute of Computational Biology, Helmholtz Munich, Munich, Germany; TUM School of Computation, Information and Technology, Technical University of Munich, Ge"},{"author_name":"Mercedes Paredes","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Xianhua Piao","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Departments of Pediatrics and Ne"},{"author_name":"Elizabeth Crouch","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Pediatrics, Univer"},{"author_name":"Arturo Alvarez-Buylla","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Neurological Surge"},{"author_name":"David Rowitch","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Pediatrics, Univer"},{"author_name":"Eric J. Huang","author_inst":"Department of Pathology, University of California San Francisco, San Francisco, CA, USA; Department of Pathology and Immunology, Washington University School of"},{"author_name":"Tomasz J. Nowakowski","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Anatomy, Universit"},{"author_name":"Omer J. Bayraktar","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Arnold Kriegstein","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"A multimodal interrogation of Broca's area in the pediatric and adult human brain","rel_doi":"10.64898\/2026.07.22.739934","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739934","rel_abs":"Language is a defining trait of our species, and disruptions in language acquisition can have profound consequences to the individuals affected. Uncovering the neurodevelopmental basis of this complex trait requires detailed molecular and cellular insights into the neocortical areas that support linguistic abilities. Here we performed joint gene expression and chromatin accessibility profiling at single-nucleus resolution (10x Genomics Single cell Multiome) and spatial transcriptomic profiling (Xenium high-plex in situ spatial transcriptomics) of Broca's area alongside adjacent motor cortical areas. We profiled individuals from different ancestries (European and African) and developmental stages (infancy, childhood, adolescence, and adulthood). We provide a high-resolution dissection of the cellular and molecular architecture of Broca's and motor cortical areas across early life stages and anchor the trajectories to the cellular states found in the adult human brain. We identify distinct area- and stage-specific cellular signatures, including a prominent role of glia populations and interneuron subtypes contributing to cytoarchitectonic specializations. Using longitudinal single cell spatial transcriptomic profiling, we orthogonally validate our consensus cell taxonomy and spatially resolve layer enrichment of neuronal and astrocyte subtypes that distinguish Broca's area and motor cortex. We also uncover cell type-specific molecular signatures that distinguish cell developmental trajectories in these cortical areas, including an early molecular code established by differential expression of cadherin genes that might contribute to area-specific intercellular communication. We also identify cell type-specific vulnerabilities to language-related neurodevelopmental and neuropsychiatric disorders, with selective susceptibility of particular somatostatin-positive interneuron subtypes to ASD\/ADHD. Finally, evolutionary analysis of differentially accessible regions between Broca's area and motor cortex suggests that genetic mutations that might have contributed to the emergence of linguistic abilities accumulated over the course of million years following the divergence of human and chimpanzee lineages. Together, our study provides a comprehensive molecular, cellular and spatial definition of Broca's area and motor cortex, laying the groundwork for investigations into unique aspects of human cognition and related neurodevelopmental and neuropsychiatric disorders.","rel_num_authors":36,"rel_authors":[{"author_name":"Juan Moriano","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Tanzila Mukhtar","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Jimmy Tsz Hang Lee","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Fani Memi","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Jonathan Augustin","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Rachel Leonard","author_inst":"Department of Anatomy, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Joseph Asfouri","author_inst":"Department of Anatomy, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"I-Ling Lu","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Pediatrics, Univer"},{"author_name":"Clara Siebert","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Jennifer Ja-Yoon Choi","author_inst":"Department of Pathology, University of California San Francisco, San Francisco, CA, USA; Department of Pathology and Immunology, Washington University School of"},{"author_name":"Guolong Zuo","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Yinshui Chang","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Stanislaw Makarchuk","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Elina Jin","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Martin Prete","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Shaohui Wang","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Qiuli Bi","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Yuhan Hao","author_inst":"Department of Neurological Surgery, University of California, San Francisco, CA, USA"},{"author_name":"Liz Tuck","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Katy Tudor","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Vanessa B. Pereira","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Hon Man Chan","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Jasmine Halliwell","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Benjamin Rumney","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Holly Anderson","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Arren Ramsey","author_inst":"Department of Pathology, University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Fabian Theis","author_inst":"Institute of Computational Biology, Helmholtz Munich, Munich, Germany; TUM School of Computation, Information and Technology, Technical University of Munich, Ge"},{"author_name":"Mercedes Paredes","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"},{"author_name":"Xianhua Piao","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Departments of Pediatrics and Ne"},{"author_name":"Elizabeth Crouch","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Pediatrics, Univer"},{"author_name":"Arturo Alvarez-Buylla","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Neurological Surge"},{"author_name":"David Rowitch","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Pediatrics, Univer"},{"author_name":"Eric J. Huang","author_inst":"Department of Pathology, University of California San Francisco, San Francisco, CA, USA; Department of Pathology and Immunology, Washington University School of"},{"author_name":"Tomasz J. Nowakowski","author_inst":"Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA; Department of Anatomy, Universit"},{"author_name":"Omer J. Bayraktar","author_inst":"Wellcome Sanger Institute, Hinxton, Cambridge, UK"},{"author_name":"Arnold Kriegstein","author_inst":"Department of Neurology, University of California, San Francisco, CA, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Univers"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Single-cell foundation models predict durable CAR T response despite imperfect cell annotation","rel_doi":"10.64898\/2026.07.22.740224","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740224","rel_abs":"CD19 targeted chimeric antigen receptor (CAR) T cell therapy achieves high initial response rates in B cell acute lymphoblastic leukemia (B ALL), yet half of patients relapse within one year. Pre-infusion product composition decoded by single-cell RNA sequencing (scRNA-seq) carries information predictive of long term CAR T persistence, but extracting this information from individual patients typically requires highly sophisticated bioinformatics expert annotation, limiting clinical translation. Here, we evaluate whether single cell foundation models (scFMs) can extract clinically actionable information from engineered CAR T products. We applied four scFMs (scGPT, scFoundation, CellPLM and UCE), including fine-tuned versions of scGPT and scFoundation, to paired basal and CD19 stimulated preinfusion CAR T products from 33 pediatric patients with B ALL. Although annotation accuracy declined relative to healthy peripheral blood references, scFM derived cell composition stratified patients with long-duration B-cell aplasia with a leave one out cross validated area under the receiver operating characteristic curve of 0.879 (95% confidence interval, 0.742 to 0.986). Notably, foundation-model-identified cell proportion analysis matched or exceeded expert annotations for several predictive features, demonstrating that accurate clinical prediction may not require perfect per-cell annotation to begin with. CD8+XCL1\/2+ cells were further identified as the biomarker consistently associated with durable CAR T persistence across models under CD19 stimulation, whereas other candidate populations showed limited reproducibility. Finally, we translate these findings into a locally deployable decision-support AI agent that predicts the probability of sustained CAR T persistence from pre-infusion CAR T scRNA seq data.","rel_num_authors":5,"rel_authors":[{"author_name":"Leo Shen","author_inst":"Yale University"},{"author_name":"Zhiliang Bai","author_inst":"Yale University"},{"author_name":"Mingyu Yang","author_inst":"Yale University"},{"author_name":"Na Li","author_inst":"Harvard University"},{"author_name":"Rong Fan","author_inst":"Yale University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Extreme cooling enables survival in extreme heat","rel_doi":"10.64898\/2026.07.22.740203","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740203","rel_abs":"Complex, multicellular extremophiles face intense challenges in coordinating their cells, tissues, and organs to function in harsh environments. Tidestromia oblongifolia is a desert plant that thrives in Death Valley, where air temperatures exceed 50{degrees}C. Using natural collections of T. oblongifolia seed, we identified individuals that survive in daily air temperature regimens at the eukaryotic upper thermal limit of 60{degrees}C. Genome-wide association testing revealed genetic variation for survival in extreme heat, and transcriptomics identified pathways regulating physiological cooling. High-throughput infrared imaging showed that survival was enabled by extreme leaf cooling, a physiological mechanism not previously reported in a thermophilic organism. These discoveries provide insights into mechanisms of extreme heat adaptation in a complex organism that could be leveraged to engineer heat-resilient crops.","rel_num_authors":5,"rel_authors":[{"author_name":"Joanna M Feehan","author_inst":"Michigan State University"},{"author_name":"Mark C Bitter","author_inst":"Stanford University"},{"author_name":"David Lowry","author_inst":"Michigan State University"},{"author_name":"Thomas David Sharkey","author_inst":"Michigan State University"},{"author_name":"Seung Y Rhee","author_inst":"Michigan State University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"DROSOPHILA PRICKLE MUTANTS DISPLAY COMORBID NEUROLOGICAL PHENOTYPES AND PROVIDE A GENETIC LINK BETWEEN EPILEPSY AND AUTISM SPECTRUM DISORDER","rel_doi":"10.64898\/2026.07.20.739611","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739611","rel_abs":"Epilepsy affects approximately 30% of individuals with autism spectrum disorder (ASD). Consistent with these observations, while PRICKLE mutations are primarily linked with epilepsy, there is an enrichment of pathogenic DNA sequence variants in PRICKLE genes carried by individuals with ASD. Nonetheless, a connection between PRICKLE function and ASD warrants further investigation. Here, we show that a seizure-prone Drosophila prickle mutant (prickle-spiny-legs, or pksple) exhibits learning and memory deficits, increased pain sensitivity, both communication and social interaction difficulties, and restrictive repetitive grooming behaviors, all of which are strongly correlated with ASD, while a non-seizure prone prickle mutant (prickle-prickle, or pkpk) does not, thereby providing a direct genetic connection between epilepsy and ASD through prickle. Comparing headed versus headless pksple mutants, we also show that the excessive grooming requires higher level cognitive processing from the brain. Finally, both pksple and pkpk mutants exhibit circadian rhythm defects, another feature correlated with ASD, as well as distinct yet overlapping neurological anomalies in processes that include innate immune response, oxidative stress response, neuronal cell death, neurodegeneration, motor dysfunction and reduced lifespan, likely reflecting the unique isoform expression patterns observed in the developing CNS. Collectively, this study highlights the broadscale effects of PRICKLE mutations that extend beyond the primary clinical features of epilepsy to include several of the core features of ASD.","rel_num_authors":11,"rel_authors":[{"author_name":"Krishna M. Nukala","author_inst":"University of Iowa"},{"author_name":"Brady Williquett","author_inst":"University of Iowa"},{"author_name":"Anthony J. Lilienthal","author_inst":"University of Iowa"},{"author_name":"Dakota M. Thompson","author_inst":"University of Iowa"},{"author_name":"Josephine N. Massingham","author_inst":"University of Sydney"},{"author_name":"Shu Hui Lye","author_inst":"University of Alabama"},{"author_name":"Avery Yu","author_inst":"University of Iowa"},{"author_name":"Bridget C. Lear","author_inst":"University of Iowa"},{"author_name":"G. Gregory Neely","author_inst":"University of Sydney"},{"author_name":"Stanislava Chtarbanova","author_inst":"University of Alabama"},{"author_name":"J. Robert Manak","author_inst":"University of Iowa"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"DROSOPHILA PRICKLE MUTANTS DISPLAY COMORBID NEUROLOGICAL PHENOTYPES AND PROVIDE A GENETIC LINK BETWEEN EPILEPSY AND AUTISM SPECTRUM DISORDER","rel_doi":"10.64898\/2026.07.20.739611","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739611","rel_abs":"Epilepsy affects approximately 30% of individuals with autism spectrum disorder (ASD). Consistent with these observations, while PRICKLE mutations are primarily linked with epilepsy, there is an enrichment of pathogenic DNA sequence variants in PRICKLE genes carried by individuals with ASD. Nonetheless, a connection between PRICKLE function and ASD warrants further investigation. Here, we show that a seizure-prone Drosophila prickle mutant (prickle-spiny-legs, or pksple) exhibits learning and memory deficits, increased pain sensitivity, both communication and social interaction difficulties, and restrictive repetitive grooming behaviors, all of which are strongly correlated with ASD, while a non-seizure prone prickle mutant (prickle-prickle, or pkpk) does not, thereby providing a direct genetic connection between epilepsy and ASD through prickle. Comparing headed versus headless pksple mutants, we also show that the excessive grooming requires higher level cognitive processing from the brain. Finally, both pksple and pkpk mutants exhibit circadian rhythm defects, another feature correlated with ASD, as well as distinct yet overlapping neurological anomalies in processes that include innate immune response, oxidative stress response, neuronal cell death, neurodegeneration, motor dysfunction and reduced lifespan, likely reflecting the unique isoform expression patterns observed in the developing CNS. Collectively, this study highlights the broadscale effects of PRICKLE mutations that extend beyond the primary clinical features of epilepsy to include several of the core features of ASD.","rel_num_authors":11,"rel_authors":[{"author_name":"Krishna M. Nukala","author_inst":"University of Iowa"},{"author_name":"Brady Williquett","author_inst":"University of Iowa"},{"author_name":"Anthony J. Lilienthal","author_inst":"University of Iowa"},{"author_name":"Dakota M. Thompson","author_inst":"University of Iowa"},{"author_name":"Josephine N. Massingham","author_inst":"University of Sydney"},{"author_name":"Shu Hui Lye","author_inst":"University of Alabama"},{"author_name":"Avery Yu","author_inst":"University of Iowa"},{"author_name":"Bridget C. Lear","author_inst":"University of Iowa"},{"author_name":"G. Gregory Neely","author_inst":"University of Sydney"},{"author_name":"Stanislava Chtarbanova","author_inst":"University of Alabama"},{"author_name":"J. Robert Manak","author_inst":"University of Iowa"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Towards interoperable modeling of toehold-mediated strand exchange circuits across DNA nanotechnology and engineering biology","rel_doi":"10.64898\/2026.07.22.739222","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739222","rel_abs":"Originally developed for DNA nanotechnology, toehold-mediated strand exchange (TMSE) circuits are gaining traction in synthetic biology due to their high programmability, seamless integration with biological components, and robust operation across diverse environments and cell types. However, while forward-engineering in synthetic biology has benefited from automated genetic circuit modeling pipelines, there is currently a lack of accessible, automated tools for the mechanistic modeling of TMSE circuits integrated with these systems, hindering the development of new biotechnologies. The TMSE-BioCRNpyler Library allows TMSE molecules to be transcribed RNAs or fixed-concentration nucleic acids while leveraging existing BioCRNpyler features, such as upstream transcription regulation and downstream gene regulation. We demonstrate this library`s applicability by modeling published applications of TMSE circuits spanning a wide range of applications, including simple in vitro reactions, cell-free biosensors, and in vivo microbial and mammalian systems. Additionally, we validated that models compiled using the TMSE-BioCRNpyler Library produced results with < 0.2 % relative error compared to multiple models of TMSE previously developed in the literature. Finally, to streamline interoperability with existing models, we developed txt2biocrnpyler. This accompanying tool converts chemical reaction networks from the literature into a BioCRNpyler-ready source script and a Systems Biology Markup Language XML file -- a standard data format for sharing and simulating biological models. The TMSE-BioCRNpyler Library serves as a powerful new resource for the rational, automated design of molecular information processing systems.","rel_num_authors":3,"rel_authors":[{"author_name":"Zoila Jurado","author_inst":"National Institute of Standards and Technology"},{"author_name":"Geoffrey Taghon","author_inst":"National Institute of Standards and Technology; Johns Hopkins University"},{"author_name":"Samuel W. Schaffter","author_inst":"National Institute of Standards and Technology"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Programming protein shape as an explicit design layer via CAD blueprint-guided diffusion","rel_doi":"10.64898\/2026.07.22.740177","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740177","rel_abs":"In engineering, industrial design principles link geometric form with function. In nature, global protein shape, curvature, and chirality similarly drive critical processes like membrane remodeling and cellular motility. However, explicitly programming these global features remains a challenge for generative AI. Here, we integrate computer-aided design (CAD) blueprints with diffusion models, establishing protein shape as an explicit, programmable layer. We engineered diverse, tunable architectures, including single-chain shapes, scaffolds with unusual twist handedness, and superhelical assemblies, structurally validating 31 of 59 designs via X-ray crystallography or electron microscopy. To demonstrate shape-encoded function, we coupled fluid-flow-optimized helical propellers to an F1-ATPase rotor, yielding a prototype ATP-dependent molecular swimmer. This framework translates industrial design principles to the molecular scale, enabling the programmable engineering of biomimetic architecture with emergent functions.","rel_num_authors":10,"rel_authors":[{"author_name":"Yilun Qi","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Guoxun Zhang","author_inst":"Department of Pharmaceutical Chemistry, University of California, San Francisco; San Francisco, CA, USA"},{"author_name":"Klaus Yserentant","author_inst":"Department of Pharmaceutical Chemistry, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Sonya Lee","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Artem Lyubimov","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Kyrellos Ibrahim","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Giuseppe Cimicata","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"James S Fraser","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Bo Huang","author_inst":"Department of Pharmaceutical Chemistry, University of California, San Francisco; SanFrancisco, CA, USA."},{"author_name":"Tanja Kortemme","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Programming protein shape as an explicit design layer via CAD blueprint-guided diffusion","rel_doi":"10.64898\/2026.07.22.740177","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740177","rel_abs":"In engineering, industrial design principles link geometric form with function. In nature, global protein shape, curvature, and chirality similarly drive critical processes like membrane remodeling and cellular motility. However, explicitly programming these global features remains a challenge for generative AI. Here, we integrate computer-aided design (CAD) blueprints with diffusion models, establishing protein shape as an explicit, programmable layer. We engineered diverse, tunable architectures, including single-chain shapes, scaffolds with unusual twist handedness, and superhelical assemblies, structurally validating 31 of 59 designs via X-ray crystallography or electron microscopy. To demonstrate shape-encoded function, we coupled fluid-flow-optimized helical propellers to an F1-ATPase rotor, yielding a prototype ATP-dependent molecular swimmer. This framework translates industrial design principles to the molecular scale, enabling the programmable engineering of biomimetic architecture with emergent functions.","rel_num_authors":10,"rel_authors":[{"author_name":"Yilun Qi","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Guoxun Zhang","author_inst":"Department of Pharmaceutical Chemistry, University of California, San Francisco; San Francisco, CA, USA"},{"author_name":"Klaus Yserentant","author_inst":"Department of Pharmaceutical Chemistry, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Sonya Lee","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Artem Lyubimov","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Kyrellos Ibrahim","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Giuseppe Cimicata","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"James S Fraser","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."},{"author_name":"Bo Huang","author_inst":"Department of Pharmaceutical Chemistry, University of California, San Francisco; SanFrancisco, CA, USA."},{"author_name":"Tanja Kortemme","author_inst":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco; San Francisco, CA, USA."}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Proprotein convertase activity regulates cumulus-oocyte-complex matrix integrity and cumulus cell migration during ovulation via a GDF9-dependent mechanism","rel_doi":"10.64898\/2026.07.22.738304","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.738304","rel_abs":"Cumulus cells have well-established roles early in ovulation but the key molecules that drive their behavior in later stages, leading to follicle rupture, remain underexplored. Here, we observed that inhibition of proprotein convertases (PCSKs) via a pan-inhibitor (PCI) impaired follicular rupture and disrupted the cumulus matrix integrity within intact follicles. Reduced cumulus cell adherence to the cumulus-oocyte-complex (COC) matrix was also observed in isolated COCs and notably occurred late during the maturation window without affecting oocyte maturation. Visualization of PCSK transcript and protein expression, as well as selective inhibition of specific PCSKs, determined that the observed phenotype in COCs is likely attributed to PCSK5A inhibition. We conducted bulk RNA-sequencing and proteomics of PCI-treated COCs which revealed that PCSK inhibition caused dysregulation of extracellular matrix organization, cell migration\/adhesion, and TGF-b signaling pathways. Subsequent validation showed that this inhibition translated to disrupted matrix organization and altered migratory and adhesive behaviors in cumulus cells. The TGF-b ligand GDF9 has a predicted PCSK cleavage site, and supplementation with GDF9 rescued matrix integrity suggesting its role as a downstream substrate of PCSKs to regulate matrix organization. Altogether, this study identified PCSK5A and GDF9 as key regulators of COC matrix integrity and cumulus cell migration during late ovulation. These findings highlight novel factors required for follicle rupture which can be leveraged for the development of fertility therapeutics and contraceptives.","rel_num_authors":15,"rel_authors":[{"author_name":"Caroline E Kratka","author_inst":"Northwestern University"},{"author_name":"Ruixu Huang","author_inst":"Dartmouth College"},{"author_name":"Jeffrey Pea","author_inst":"Northwestern University"},{"author_name":"Robin M Skory","author_inst":"University of Pennsylvania"},{"author_name":"Christina D King","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Jiyang Zhang","author_inst":"Rutgers University"},{"author_name":"Pawat Pattarawat","author_inst":"Rutgers University"},{"author_name":"Caroline M Milner","author_inst":"University of Manchester"},{"author_name":"Anthony J Day","author_inst":"University of Manchester"},{"author_name":"Nicolas Plachta","author_inst":"University of Pennsylvania"},{"author_name":"Shuo Xiao","author_inst":"Rutgers University"},{"author_name":"Birgit Schilling","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Darryl L Russell","author_inst":"University of Adelaide"},{"author_name":"Brittany A Goods","author_inst":"University of Melbourne"},{"author_name":"Francesca E Duncan","author_inst":"Northwestern University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Morphomechanically-Informed Spatial Curvature Sequencing in Prostate Cancer","rel_doi":"10.64898\/2026.07.22.740088","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740088","rel_abs":"Morphological changes in prostate glands, assessed by Gleason grading, remain the gold standard for diagnosing prostate cancer, yet molecular biomarkers associated with gland shape are not well understood. Here, we introduce CurvSeq, a mechanomorphology-informed framework for spatial sequencing data, and CurvSee, its complementary version for proteomic and imaging datasets. These methods integrate gland boundary curvature, pocket architecture, microenvironmental composition, and molecular profiles to study morphomechanical relationships in prostate adenocarcinoma. Using five independent spatial transcriptomic and multiplexed imaging datasets, we segmented individual prostate glands, extracted gland contours, quantified local curvature and pocket-like concavities, and projected these features onto spatially resolved gene and protein measurements. In Xenium data, CurvSeq distinguished benign and GG1 glands, identifying cancer-associated genes such as PCA3 and AMACR in GG1 glands and basal, basement membrane, and mechanotransduction-associated programs in benign glands. In Visium data, a diffusion-based morphomechanical score ordered benign glands by area, circularity, pocket number, smooth muscle abundance, immune-cell proximity, and remodeling-associated genes including MMP7. In GG4 glands, CurvSeq identified neuroendocrine-like boundary regions associated with MMP7 expression, COL1A1-rich adjacent stroma, and immune-cell accumulation. Finally, CurvSee extended this framework to multiplexed protein imaging, where combined morphology and protein-expression features distinguished Gleason-associated gland states. Together, CurvSeq and CurvSee provide a quantitative framework for linking gland architecture, local microenvironment, and molecular state, showing that prostate gland morphology can be integrated with spatial omics to identify morphomechanical niches associated with cancer progression.","rel_num_authors":13,"rel_authors":[{"author_name":"Ivan Kordic","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; George W. Woodruff School of Mechanical Engineering,"},{"author_name":"Felix G. Rivera Moctezuma","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; George W. Woodruff School of Mechanical Engineering,"},{"author_name":"Hoseyn A. Amiri","author_inst":"George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA"},{"author_name":"Alan Liu","author_inst":"Optics11 Life Inc., Boston, MA, USA"},{"author_name":"Shuangyi Cai","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA"},{"author_name":"Mehdia Nadeem Rajab Ali","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA"},{"author_name":"Lourdes Brea","author_inst":"Department of Urology, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"author_name":"Abhijeet Venkataraman","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Parker H. Petit Institute for Bioengineering and Bio"},{"author_name":"Hongshun Shi","author_inst":"Department of Urology, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"author_name":"Lara Harik","author_inst":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Todd A Sulchek","author_inst":"George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Wallace H. Coulter Department of Biomedical Engineering,"},{"author_name":"Jindan Yu","author_inst":"Department of Urology, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"author_name":"Ahmet F. Coskun","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; School of Electrical and Computer Engineering, Georg"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Harmonized nucleoside mass spectrometry enables reproducible cross-platform RNA modification quantification","rel_doi":"10.64898\/2026.07.17.739095","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.17.739095","rel_abs":"RNA modification analysis by LC-MS\/MS is central to epitranscriptomics, yet quantitative comparison across laboratories and instrument platforms remains poorly standardized. Here, we performed a community-driven benchmarking study during the first Human RNome Pro-ject workshop to systematically evaluate cross-platform reproducibility of ribonucleoside mass spectrometry workflows. Using the same analytical column and gradient, standardized RNA samples, and shared reagents, we compared nucleoside quantification across quadru-pole, time-of-flight, and orbitrap-based LC-MS platforms employing distinct acquisition strategies. While chromatographic separation was highly reproducible across systems, nucleoside-specific MS response behavior differed substantially between platforms and limited direct comparability of relative signal intensities. These response differences varied across ana-lytes and concentration ranges, demonstrating that harmonized chromatography alone is in-sufficient for transferable quantitative analysis. Stable isotope-labeled internal standard (SILIS) normalization substantially reduced platform- and method-dependent response and im-proved agreement for most evaluated modifications. External calibration improved agreement between qTOF and Orbitrap workflows for a subset of modifications but did not fully resolve residual intersystem differences. Based on these findings, we establish benchmark-derived recommendations for harmonized relative and absolute RNA modification quantification, including guidance for calibration de-sign, quality control, and data reporting. Together, this work provides a methodological framework for reproducible nucleoside LC-MS\/MS workflows and establishes a foundation for large-scale comparative epitranscriptomic studies.","rel_num_authors":36,"rel_authors":[{"author_name":"Jan Felix Dalwigk","author_inst":"Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany"},{"author_name":"Kira Kerkhoff","author_inst":"Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany"},{"author_name":"Oskar Knittelfelder","author_inst":"Bruker Daltonics GmbH & Co. KG, Fahrenheitstr. 4, 28359 Bremen, Germany"},{"author_name":"Robert Ross","author_inst":"Thermo Fisher Scientific, 10 Maguire Ave., Lexington, MA 01450"},{"author_name":"Maria Cristina Petrella","author_inst":"Centre for Genomic Regulation (CRG), The Barcelona Institue of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain"},{"author_name":"Anna Kusnierczyk","author_inst":"University of Bern, Swiss RNA Mass Spectrometry Platform, Department of Chemistry, Biochemistry and Pharmaceutical Sciences, Freiestrasse 3, 3012 Bern, Switzerl"},{"author_name":"Tulsi Bhandari","author_inst":"University of Cincinnati, Cincinnati, OH 45221, United States"},{"author_name":"Aurore Attina","author_inst":"Plateforme Proteoomique Clinique, IRBM CHU St.-Eloi, Montpellier, France"},{"author_name":"Alicia Burkard","author_inst":"Johannes Gutenberg-Universitaet, Institute of Pharmaceutical and Biomedical Sciences, Staudingerweg 5, 55128 Mainz, Germany"},{"author_name":"Carolina Bras-Costa","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States"},{"author_name":"Michael S. DeMott","author_inst":"Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA 02139, United States"},{"author_name":"Kitty Johnson","author_inst":"Phillips University Marburg, Department of Pharmacy, Institute for Pharmaceutical Biology and Biotechnology, 35037 Marburg, Germany"},{"author_name":"Xenia Kerkhoff-Bernaciak","author_inst":"TU Dortmund University, Department of Mathematics, Vogelpothsweg 87, 44227 Dortmund, Germany"},{"author_name":"Jennifer Kist","author_inst":"University of Cincinnati, Cincinnati, OH 45221, United States"},{"author_name":"Ken Koegel","author_inst":"Ludwigs-Maximilians-University Munich, Department of Chemistry, Institute of Chemical Epigenetics, Butenadt Strasse 5-13, 81377 Munich Germany"},{"author_name":"Martina Kraemer","author_inst":"Johannes Gutenberg-Universitaet, Institute of Pharmaceutical and Biomedical Sciences, Staudingerweg 5, 55128 Mainz, Germany"},{"author_name":"Ricardo Moreno-Ballesteros","author_inst":"University of Dundee, School of Life Sciences, Protein Phosphorylation and Ubiquitylation Unit, Dow Street, DD1 5EH Dundee, United Kingdom"},{"author_name":"Ganna Podoprygorina","author_inst":"Johannes Gutenberg-Universitaet, Institute of Pharmaceutical and Biomedical Sciences, Staudingerweg 5, 55128 Mainz, Germany"},{"author_name":"Kaley Simcox","author_inst":"University of Michigan, Department of Molecular, Cellular, and Developmental Biology, Ann Arbor, MI 48109, United States"},{"author_name":"Oezge Simsir","author_inst":"Ludwigs-Maximilians-University Munich, Department of Chemistry, Institute of Chemical Epigenetics, Butenadt Strasse 5-13, 81377 Munich Germany"},{"author_name":"Anton Skriba","author_inst":"Institute of Organic Chemistry and Biochemistry of the CAS, Flemingovo namesti 542\/2, Prague 6, Czech Republik"},{"author_name":"Sam Wein","author_inst":"University of Tuebingen, Department of Computer Science, Maria-von-Linden-Strasse 6, 72076 Tuebingen"},{"author_name":"Hana Cahova","author_inst":"Institute of Organic Chemistry and Biochemistry of the CAS, Flemingovo namesti 542\/2, Prague 6, Czech Republik"},{"author_name":"Benjamin A. Garcia","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States"},{"author_name":"Mark Helm","author_inst":"Johannes Gutenberg-Universitaet, Institute of Pharmaceutical and Biomedical Sciences, Staudingerweg 5, 55128 Mainz, Germany"},{"author_name":"David Alexandre","author_inst":"Plateforme Proteomique Clinique, IRBM  CHU St.-Eloi, Montpellier, France"},{"author_name":"Katharina Hoefer","author_inst":"Phillips University Marburg, Department of Pharmacy, Institute for Pharmaceutical Biology and Biotechnology, 35037 Marburg, Germany"},{"author_name":"Sebastian Leidel","author_inst":"University of Bern, Swiss RNA Mass Spectrometry Platform, Department of Chemistry, Biochemistry and Pharmaceutical Sciences, Freiestrasse 3, 3012 Bern, Switzerl"},{"author_name":"Patrick A Limbach","author_inst":"University of Cincinnati, Cincinnati, OH 45221, United States"},{"author_name":"Eva Novoa","author_inst":"Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain"},{"author_name":"Eduard Sabido","author_inst":"Centre for Genomic Regulation (CRG), The Barcelona Institue of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain"},{"author_name":"Sabine Schneider","author_inst":"Ludwigs-Maximilians-University Munich, Department of Chemistry, Institute of Chemical Epigenetics, Butenandtstrasse 5-13, 81377 Munich Germany"},{"author_name":"Philippe Wolff","author_inst":"Universite de Strasbourg, CNRS, Architecture et Reactivite de lARN, 67084 Strasbourg, France"},{"author_name":"Peter Dedon","author_inst":"Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA 02139, United States"},{"author_name":"Vivian Cheung","author_inst":"Brown University. Department of Molecular Biology, Cell Biology and Biochemistry, 70 Ship Street, Providence, RI 02903, United States"},{"author_name":"Stefanie Kaiser","author_inst":"Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Harmonized nucleoside mass spectrometry enables reproducible cross-platform RNA modification quantification","rel_doi":"10.64898\/2026.07.17.739095","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.17.739095","rel_abs":"RNA modification analysis by LC-MS\/MS is central to epitranscriptomics, yet quantitative comparison across laboratories and instrument platforms remains poorly standardized. Here, we performed a community-driven benchmarking study during the first Human RNome Pro-ject workshop to systematically evaluate cross-platform reproducibility of ribonucleoside mass spectrometry workflows. Using the same analytical column and gradient, standardized RNA samples, and shared reagents, we compared nucleoside quantification across quadru-pole, time-of-flight, and orbitrap-based LC-MS platforms employing distinct acquisition strategies. While chromatographic separation was highly reproducible across systems, nucleoside-specific MS response behavior differed substantially between platforms and limited direct comparability of relative signal intensities. These response differences varied across ana-lytes and concentration ranges, demonstrating that harmonized chromatography alone is in-sufficient for transferable quantitative analysis. Stable isotope-labeled internal standard (SILIS) normalization substantially reduced platform- and method-dependent response and im-proved agreement for most evaluated modifications. External calibration improved agreement between qTOF and Orbitrap workflows for a subset of modifications but did not fully resolve residual intersystem differences. Based on these findings, we establish benchmark-derived recommendations for harmonized relative and absolute RNA modification quantification, including guidance for calibration de-sign, quality control, and data reporting. Together, this work provides a methodological framework for reproducible nucleoside LC-MS\/MS workflows and establishes a foundation for large-scale comparative epitranscriptomic studies.","rel_num_authors":36,"rel_authors":[{"author_name":"Jan Felix Dalwigk","author_inst":"Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany"},{"author_name":"Kira Kerkhoff","author_inst":"Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany"},{"author_name":"Oskar Knittelfelder","author_inst":"Bruker Daltonics GmbH & Co. KG, Fahrenheitstr. 4, 28359 Bremen, Germany"},{"author_name":"Robert Ross","author_inst":"Thermo Fisher Scientific, 10 Maguire Ave., Lexington, MA 01450"},{"author_name":"Maria Cristina Petrella","author_inst":"Centre for Genomic Regulation (CRG), The Barcelona Institue of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain"},{"author_name":"Anna Kusnierczyk","author_inst":"University of Bern, Swiss RNA Mass Spectrometry Platform, Department of Chemistry, Biochemistry and Pharmaceutical Sciences, Freiestrasse 3, 3012 Bern, Switzerl"},{"author_name":"Tulsi Bhandari","author_inst":"University of Cincinnati, Cincinnati, OH 45221, United States"},{"author_name":"Aurore Attina","author_inst":"Plateforme Proteoomique Clinique, IRBM CHU St.-Eloi, Montpellier, France"},{"author_name":"Alicia Burkard","author_inst":"Johannes Gutenberg-Universitaet, Institute of Pharmaceutical and Biomedical Sciences, Staudingerweg 5, 55128 Mainz, Germany"},{"author_name":"Carolina Bras-Costa","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States"},{"author_name":"Michael S. DeMott","author_inst":"Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA 02139, United States"},{"author_name":"Kitty Johnson","author_inst":"Phillips University Marburg, Department of Pharmacy, Institute for Pharmaceutical Biology and Biotechnology, 35037 Marburg, Germany"},{"author_name":"Xenia Kerkhoff-Bernaciak","author_inst":"TU Dortmund University, Department of Mathematics, Vogelpothsweg 87, 44227 Dortmund, Germany"},{"author_name":"Jennifer Kist","author_inst":"University of Cincinnati, Cincinnati, OH 45221, United States"},{"author_name":"Ken Koegel","author_inst":"Ludwigs-Maximilians-University Munich, Department of Chemistry, Institute of Chemical Epigenetics, Butenadt Strasse 5-13, 81377 Munich Germany"},{"author_name":"Martina Kraemer","author_inst":"Johannes Gutenberg-Universitaet, Institute of Pharmaceutical and Biomedical Sciences, Staudingerweg 5, 55128 Mainz, Germany"},{"author_name":"Ricardo Moreno-Ballesteros","author_inst":"University of Dundee, School of Life Sciences, Protein Phosphorylation and Ubiquitylation Unit, Dow Street, DD1 5EH Dundee, United Kingdom"},{"author_name":"Ganna Podoprygorina","author_inst":"Johannes Gutenberg-Universitaet, Institute of Pharmaceutical and Biomedical Sciences, Staudingerweg 5, 55128 Mainz, Germany"},{"author_name":"Kaley Simcox","author_inst":"University of Michigan, Department of Molecular, Cellular, and Developmental Biology, Ann Arbor, MI 48109, United States"},{"author_name":"Oezge Simsir","author_inst":"Ludwigs-Maximilians-University Munich, Department of Chemistry, Institute of Chemical Epigenetics, Butenadt Strasse 5-13, 81377 Munich Germany"},{"author_name":"Anton Skriba","author_inst":"Institute of Organic Chemistry and Biochemistry of the CAS, Flemingovo namesti 542\/2, Prague 6, Czech Republik"},{"author_name":"Sam Wein","author_inst":"University of Tuebingen, Department of Computer Science, Maria-von-Linden-Strasse 6, 72076 Tuebingen"},{"author_name":"Hana Cahova","author_inst":"Institute of Organic Chemistry and Biochemistry of the CAS, Flemingovo namesti 542\/2, Prague 6, Czech Republik"},{"author_name":"Benjamin A. Garcia","author_inst":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States"},{"author_name":"Mark Helm","author_inst":"Johannes Gutenberg-Universitaet, Institute of Pharmaceutical and Biomedical Sciences, Staudingerweg 5, 55128 Mainz, Germany"},{"author_name":"David Alexandre","author_inst":"Plateforme Proteomique Clinique, IRBM  CHU St.-Eloi, Montpellier, France"},{"author_name":"Katharina Hoefer","author_inst":"Phillips University Marburg, Department of Pharmacy, Institute for Pharmaceutical Biology and Biotechnology, 35037 Marburg, Germany"},{"author_name":"Sebastian Leidel","author_inst":"University of Bern, Swiss RNA Mass Spectrometry Platform, Department of Chemistry, Biochemistry and Pharmaceutical Sciences, Freiestrasse 3, 3012 Bern, Switzerl"},{"author_name":"Patrick A Limbach","author_inst":"University of Cincinnati, Cincinnati, OH 45221, United States"},{"author_name":"Eva Novoa","author_inst":"Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain"},{"author_name":"Eduard Sabido","author_inst":"Centre for Genomic Regulation (CRG), The Barcelona Institue of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain"},{"author_name":"Sabine Schneider","author_inst":"Ludwigs-Maximilians-University Munich, Department of Chemistry, Institute of Chemical Epigenetics, Butenandtstrasse 5-13, 81377 Munich Germany"},{"author_name":"Philippe Wolff","author_inst":"Universite de Strasbourg, CNRS, Architecture et Reactivite de lARN, 67084 Strasbourg, France"},{"author_name":"Peter Dedon","author_inst":"Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA 02139, United States"},{"author_name":"Vivian Cheung","author_inst":"Brown University. Department of Molecular Biology, Cell Biology and Biochemistry, 70 Ship Street, Providence, RI 02903, United States"},{"author_name":"Stefanie Kaiser","author_inst":"Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Toxoplasma GRA8 engages the host ESCRT accessory protein ALG-2 and is necessary for parasite metabolic integrity","rel_doi":"10.64898\/2026.07.20.739547","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739547","rel_abs":"The endosomal sorting complex required for transport (ESCRT) is a hetero-multimeric membrane-remodeling machinery essential for endosomal sorting, intraluminal vesicle formation, cytokinetic abscission, and membrane repair. ESCRT is also hijacked by some pathogens including the protozoan Toxoplasma gondii, which subverts it at the parasitophorous vacuole membrane to support parasite ingestion of host cytosolic proteins. Although the ESCRT accessory protein, ALG-2 is recruited to the parasitophorous vacuole, nothing was known about how this happens. Herein we identify the dense granule protein TgGRA8 as a key effector that recruits ALG-2 and ALIX to the parasitophorous vacuole. We show that TgGRA8 directly binds ALG-2 via conserved ALG-2-binding elements like those found in other ALG-2 interacting proteins including ALIX and SEC31A. Biochemical assays show high-affinity, Ca2+-dependent TgGRA8-ALG-2 binding, and structural modeling suggests TgGRA8 may assemble multivalently to coordinate multiple ALG-2 dimers, stabilizing ALG-2\/ALIX recruitment through a non-canonical bridging mechanism. Conservation of these motifs among tissue cyst-forming coccidians implies a lineage-linked adaptation that supports infection by these parasites. Metabolomics further indicates that TgGRA8 loss disrupts amino acid, purine, and central carbon metabolism, like those seen in other ingestion deficient mutants. Together, these findings uncover a conserved, multivalent strategy by which Toxoplasmaengages host ALG-2 to organize ESCRT at the parasitophorous vacuole, thereby coupling nutrient acquisition to metabolic fitness and exposing a novel agent for probing ESCRT biology.","rel_num_authors":13,"rel_authors":[{"author_name":"Hargobinder Kaur","author_inst":"University of Michigan Medical School"},{"author_name":"Rebekah  B. Guevara","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Yolanda Rivera-Cuevas","author_inst":"University of Michigan Medical School"},{"author_name":"Einar  B. Olafsson","author_inst":"University of Michigan Medical School"},{"author_name":"Joshua Mayoral","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Leonardo Augusto","author_inst":"University of Nebraska Medical Center"},{"author_name":"Alfredo  J. Guerra","author_inst":"University of Michigan Medical School"},{"author_name":"Romir Patel","author_inst":"University of Michigan Medical School"},{"author_name":"Kevin  P. Bohannon","author_inst":"University of Michigan Medical School"},{"author_name":"Jonathon  Z. Sexton","author_inst":"University of Michigan College of Pharmacy"},{"author_name":"Phyllis  I. Hanson","author_inst":"University of Michigan Medical School"},{"author_name":"Louis  M. Weiss","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Vern  B. Carruthers","author_inst":"University of Michigan"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"An immune-stimulating antibody conjugate spatiotemporally targeting CD47 and TLR9 elicits macrophage-dependent tumor clearance and durable anti-cancer adaptive immunity","rel_doi":"10.64898\/2026.07.22.739359","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739359","rel_abs":"Cluster of differentiation 47 (CD47) blockade promotes tumor cell phagocytosis; however, transitioning this initial innate immune event into durable anti-cancer adaptive immunity and tumor control remains a critical challenge. To address this translational gap, we have engineered aCD47-CpG, a novel immune-stimulating antibody conjugate (ISAC) coupling a CD47-blocking antibody (aCD47) to a Toll-like receptor 9 agonist, unmethylated CpG, to enable synchronized deployment of co-stimulatory signals during tumor engulfment. This ISAC, aCD47-CpG, but not the parent aCD47, reprograms macrophages toward an anti-tumor M1-like phenotype, enhances antigen cross-presentation, and promotes robust CD8+ T cell priming. We found that systemically administered aCD47-CpG drove macrophage-dependent tumor suppression in a human lymphoma xenograft model. In parallel, the treatment in immunocompetent syngeneic models of lymphoma and highly immunosuppressive triple-negative breast cancer resulted in profound tumor regression, metastasis inhibition, and durable anti-cancer immune memory. These effects were accompanied by remodeling of the immunosuppressive tumor microenvironment toward an immune-permissive state, characterized by M2-to-M1 macrophage repolarization, intratumoral infiltration of cytotoxic and memory T cells, and depletion of regulatory T cells. This spatiotemporally coordinated immunotherapy platform offers a promising strategy to bridge innate and adaptive immunity, thereby advancing the translational potential of CD47-targeted cancer therapies.","rel_num_authors":5,"rel_authors":[{"author_name":"Jung Soo Suk","author_inst":"University of Maryland School of Medicine"},{"author_name":"Byoungjae Kong","author_inst":"University of Maryland School of Medicine"},{"author_name":"Seung Woo Chung","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Daiheon Lee","author_inst":"University of Maryland School of Medicine"},{"author_name":"Gijung Kwak","author_inst":"University of Maryland School of Medicine"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Nuclear size and physical properties of the nucleoplasm are determined by colloid osmotic pressure at the nuclear envelope","rel_doi":"10.64898\/2026.07.21.739918","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739918","rel_abs":"The size of the nucleus scales with cell size, suggesting a universal scaling rule. Yet the biophysical determinants of nuclear size and the significance and consequences of altered nuclear-to-cell (N\/C) ratios, which are observed across diverse pathological states and cell-fate transitions, remain poorly understood. Recent theoretical models propose that nuclear size arises from a balance of colloid osmotic pressures generated by macromolecules in the nucleoplasm and cytoplasm. Here we demonstrate that altering this osmotic balance through massive overexpression of an exogenous protein targeted to either the nucleoplasm or cytoplasm produces predictable changes in the N\/C ratio in S. pombe. These quantitative perturbations show that nuclear size is set primarily by the number of proteins in the nucleus and cytoplasm, providing strong support for a pure osmotic pressure mechanism. Furthermore, cells with altered N\/C ratios display tunable changes in nucleoplasmic crowding, nuclear condensate formation, nucleolar scaling and heterochromatin organization, establishing a causal link between nuclear size and gene regulatory processes. These findings reveal how cells exploit osmotic forces to set organelle dimensions, with broad implications for understanding how nuclear size shapes gene expression and cell identity in health and disease.","rel_num_authors":3,"rel_authors":[{"author_name":"Jo\u00ebl Lemi\u00e8re","author_inst":"UCSF"},{"author_name":"Zhidong Tan","author_inst":"UCSF"},{"author_name":"Fred Chang","author_inst":"UCSF"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"iG6PSnFR: A genetically encoded fluorescent sensor for observing glucose-6-phosphate dynamics in living preparations","rel_doi":"10.64898\/2026.07.22.740099","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740099","rel_abs":"Glucose-6-phosphate (G6P) is a key intermediate in multiple energetic and anabolic pathways, and quantifying its dynamics is essential for understanding cellular physiology. We have previously developed a syndicate of intensity-based, genetically encoded sensors based on the insertion of circularly permuted GFP into a Venus-flytrap-like analyte-binding protein. Here we use the same approach to develop an intensity-based G6P Sensing Fluorescent Reporter (iG6PSnFR). We present two variants: a G6P-activated sensor that increases fluorescence and a G6P-inactivated sensor that decreases fluorescence. We validate performance across progressively more complex preparations, including purified protein in vitro, immortalized and primary neuronal cultures, isolated pancreatic islets, in an intravital liver model, and finally in vivo in C. elegans neurons. In each context, iG6PSnFR reports G6P changes consistent with expected responses to physiological perturbations.","rel_num_authors":12,"rel_authors":[{"author_name":"Jonathan S Marvin","author_inst":"HHMI - Janelia Research Campus"},{"author_name":"Anastasia Tsives","author_inst":"Department of Neuroscience and Department of Cell Biology, Yale University School of Medicine; New Haven, CT, USA"},{"author_name":"Shih Ming Huang","author_inst":"Yale University"},{"author_name":"Zhanat Koshenov","author_inst":"Department of Biochemistry & Biophysics, Weill Cornell Medicine, New York, NY, USA"},{"author_name":"Raghabendra Adhikari","author_inst":"Janelia Research Campus, Howard Hughes Medical Institute"},{"author_name":"Aaron D Wolfe","author_inst":"Yale University"},{"author_name":"Ian J Gonzalez","author_inst":"Department of Neuroscience and Department of Cell Biology, Yale University School of Medicine; New Haven, CT, USA"},{"author_name":"Daniel Feliciano","author_inst":"Janelia Research Campus\/HHMI"},{"author_name":"Timothy A Ryan","author_inst":"Weill Cornell Medical College"},{"author_name":"Matthew J Merrins","author_inst":"Yale University"},{"author_name":"Daniel Col\u00f3n-Ramos","author_inst":"Yale University"},{"author_name":"Timothy A Brown","author_inst":"Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"A de novo designed enzyme for photo-proximity labeling of E3 ligase neighborhoods in live cells","rel_doi":"10.64898\/2026.07.22.739993","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739993","rel_abs":"Photocatalytic proximity labeling proteomics (photo-PLP) has emerged as a powerful technology for rapid capture of protein interactomes in situ. Typically, photo-PLP relies on chemical conjugation of the photocatalyst to the target of interest which creates practical challenges for derivatized photocatalyst synthesis and bioconjugation specificity. Integrating the precision of genetically encodable enzymes with the versatility of chemically defined photocatalysts provides a modular approach to further expand the scope of neighborhood mapping. Here, we present EYClamp, a de novo designed proximity labeling enzyme harnessing the off-the-shelf photocatalyst Eosin Y (EY) as a cofactor. Using a domain-swapped dimer architecture, we designed a scaffold that binds EY with high affinity (Kd = 10 nM) and lengthens its triplet excited-state lifetime by 29-fold. EYClamp enables efficient, multi-scale photocatalytic proximity labeling in live cells with aryl-diazirine-, aryl-azide- and phenol-biotin. We genetically fused EYClamp to a panel of six important E3 ligases. Using EYClamp, we identified over 1,500 candidate neighbors for KEAP1, MDM2, ASB7 and STUB1, providing a broad and unbiased view of these important neighborhoods. Critical functional networks were revealed including ASB7 engagement with HP1a\/CUL5 complex for heterochromatin remodeling. Our EYClamp provides a genetically encodable plug-and-play solution for photo-PLP interactome discovery of the large family of E3 ligases and establishes domain-swapping as a promising strategy for de novo photoenzyme design.","rel_num_authors":9,"rel_authors":[{"author_name":"Nam Hyeong Kim","author_inst":"University of California San Francisco"},{"author_name":"Zhi Lin","author_inst":"University of California, San Francisco"},{"author_name":"Sangwon Nam","author_inst":"Duke University"},{"author_name":"Danielle Swaney","author_inst":"University of California San Francisco"},{"author_name":"Nevan Krogan","author_inst":"University of California San Francisco"},{"author_name":"Yong Ho Kim","author_inst":"Sungkyunkwan University"},{"author_name":"Michael J Therien","author_inst":"Duke University"},{"author_name":"William F DeGrado","author_inst":"University of California San Francisco"},{"author_name":"James A. Wells","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"A de novo designed enzyme for photo-proximity labeling of E3 ligase neighborhoods in live cells","rel_doi":"10.64898\/2026.07.22.739993","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739993","rel_abs":"Photocatalytic proximity labeling proteomics (photo-PLP) has emerged as a powerful technology for rapid capture of protein interactomes in situ. Typically, photo-PLP relies on chemical conjugation of the photocatalyst to the target of interest which creates practical challenges for derivatized photocatalyst synthesis and bioconjugation specificity. Integrating the precision of genetically encodable enzymes with the versatility of chemically defined photocatalysts provides a modular approach to further expand the scope of neighborhood mapping. Here, we present EYClamp, a de novo designed proximity labeling enzyme harnessing the off-the-shelf photocatalyst Eosin Y (EY) as a cofactor. Using a domain-swapped dimer architecture, we designed a scaffold that binds EY with high affinity (Kd = 10 nM) and lengthens its triplet excited-state lifetime by 29-fold. EYClamp enables efficient, multi-scale photocatalytic proximity labeling in live cells with aryl-diazirine-, aryl-azide- and phenol-biotin. We genetically fused EYClamp to a panel of six important E3 ligases. Using EYClamp, we identified over 1,500 candidate neighbors for KEAP1, MDM2, ASB7 and STUB1, providing a broad and unbiased view of these important neighborhoods. Critical functional networks were revealed including ASB7 engagement with HP1a\/CUL5 complex for heterochromatin remodeling. Our EYClamp provides a genetically encodable plug-and-play solution for photo-PLP interactome discovery of the large family of E3 ligases and establishes domain-swapping as a promising strategy for de novo photoenzyme design.","rel_num_authors":9,"rel_authors":[{"author_name":"Nam Hyeong Kim","author_inst":"University of California San Francisco"},{"author_name":"Zhi Lin","author_inst":"University of California, San Francisco"},{"author_name":"Sangwon Nam","author_inst":"Duke University"},{"author_name":"Danielle Swaney","author_inst":"University of California San Francisco"},{"author_name":"Nevan Krogan","author_inst":"University of California San Francisco"},{"author_name":"Yong Ho Kim","author_inst":"Sungkyunkwan University"},{"author_name":"Michael J Therien","author_inst":"Duke University"},{"author_name":"William F DeGrado","author_inst":"University of California San Francisco"},{"author_name":"James A. Wells","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"P95-HER2 promotes metastatic progression by biasing MRTFA dependent signaling","rel_doi":"10.64898\/2026.07.22.739975","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739975","rel_abs":"Naturally occurring isoforms of the proto-oncogene Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2, HER2) incite unique pathways of tumor progression in mouse models of breast cancer. Although each isoform has been shown to progress to metastasis, the N-terminally truncated isoform (p95) was previously shown to be biased toward early distant dissemination prior to detection. Here we show how HER2 isoforms differentially promote go-or-grow phenotypes through biased utilization of tyrosine autophosphorylation sites in the intracellular tail of HER2. Fluorescently barcoded humanized full-length HER2 (WT), exon-16 splice HER2 isoform (d16), and p95 expressing tumor cell lines were derived from HER2 Crainbow mice, then utilized for a series of functional assays including proliferation, tumor growth rate, cell motility, collective cell migration, cellular morphology, and invasive potential. Quantitative analysis reveals biased tumor cell behaviors across each genotype. WT tumor cells are biased toward proliferation and collective migration, d16 cells are biased toward proliferation and individual motility, and p95 tumor cells are biased toward individual motility and invasion. Single cell analysis reveals a myogenic-like state transition in p95 cells accompanied by an increased nuclear translocation of the Myocardin Related Transcription Factor A (MRTFA). MRTFA knockdown, as well as knockdown of a downstream effector, Transforming growth factor beta 1 induced transcript 1 (TGFB1I1), both inhibit the p95 invasive phenotype. Furthermore, intracellular residue tyrosine 1139 (Y1139) is necessary for MRTFA translocation, and when edited in p95 cells (Y1139F) invasion and motility phenotypes are subsequently lost. Our data illustrate the importance of functionally selective signaling in HER2 and highlight the need for therapeutics that intercept metastasis by targeting HER2 biased signaling.","rel_num_authors":15,"rel_authors":[{"author_name":"Joseph D Fernandes","author_inst":"Duke University"},{"author_name":"Erin Bresnahan","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Hillary Zawada","author_inst":"Duke University"},{"author_name":"Joshua D Ginzel","author_inst":"Duke University"},{"author_name":"H Kim Lyerly","author_inst":"Duke University"},{"author_name":"Bruce Rogers","author_inst":"Duke University"},{"author_name":"Shyam M Kavuri","author_inst":"Baylor College of Medicine"},{"author_name":"Allison J Introne","author_inst":"North Carolina State University"},{"author_name":"Melanie R Sadecki","author_inst":"North Carolina State University"},{"author_name":"Hidetoshi Mori","author_inst":"University of California - San Francisco School of Medicine"},{"author_name":"Glenn Doherty","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Alexander D Borowsky","author_inst":"University of California - San Francisco School of Medicine"},{"author_name":"Kevin B Flores","author_inst":"North Carolina State University"},{"author_name":"Jose Javier Bravo-Cordero","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Joshua C. Snyder","author_inst":"Duke University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"P95-HER2 promotes metastatic progression by biasing MRTFA dependent signaling","rel_doi":"10.64898\/2026.07.22.739975","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739975","rel_abs":"Naturally occurring isoforms of the proto-oncogene Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2, HER2) incite unique pathways of tumor progression in mouse models of breast cancer. Although each isoform has been shown to progress to metastasis, the N-terminally truncated isoform (p95) was previously shown to be biased toward early distant dissemination prior to detection. Here we show how HER2 isoforms differentially promote go-or-grow phenotypes through biased utilization of tyrosine autophosphorylation sites in the intracellular tail of HER2. Fluorescently barcoded humanized full-length HER2 (WT), exon-16 splice HER2 isoform (d16), and p95 expressing tumor cell lines were derived from HER2 Crainbow mice, then utilized for a series of functional assays including proliferation, tumor growth rate, cell motility, collective cell migration, cellular morphology, and invasive potential. Quantitative analysis reveals biased tumor cell behaviors across each genotype. WT tumor cells are biased toward proliferation and collective migration, d16 cells are biased toward proliferation and individual motility, and p95 tumor cells are biased toward individual motility and invasion. Single cell analysis reveals a myogenic-like state transition in p95 cells accompanied by an increased nuclear translocation of the Myocardin Related Transcription Factor A (MRTFA). MRTFA knockdown, as well as knockdown of a downstream effector, Transforming growth factor beta 1 induced transcript 1 (TGFB1I1), both inhibit the p95 invasive phenotype. Furthermore, intracellular residue tyrosine 1139 (Y1139) is necessary for MRTFA translocation, and when edited in p95 cells (Y1139F) invasion and motility phenotypes are subsequently lost. Our data illustrate the importance of functionally selective signaling in HER2 and highlight the need for therapeutics that intercept metastasis by targeting HER2 biased signaling.","rel_num_authors":15,"rel_authors":[{"author_name":"Joseph D Fernandes","author_inst":"Duke University"},{"author_name":"Erin Bresnahan","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Hillary Zawada","author_inst":"Duke University"},{"author_name":"Joshua D Ginzel","author_inst":"Duke University"},{"author_name":"H Kim Lyerly","author_inst":"Duke University"},{"author_name":"Bruce Rogers","author_inst":"Duke University"},{"author_name":"Shyam M Kavuri","author_inst":"Baylor College of Medicine"},{"author_name":"Allison J Introne","author_inst":"North Carolina State University"},{"author_name":"Melanie R Sadecki","author_inst":"North Carolina State University"},{"author_name":"Hidetoshi Mori","author_inst":"University of California - San Francisco School of Medicine"},{"author_name":"Glenn Doherty","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Alexander D Borowsky","author_inst":"University of California - San Francisco School of Medicine"},{"author_name":"Kevin B Flores","author_inst":"North Carolina State University"},{"author_name":"Jose Javier Bravo-Cordero","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Joshua C. Snyder","author_inst":"Duke University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"A continuum of CAM phenotypes in the carnivorous plant genus Pinguicula (Lentibulariaceae)","rel_doi":"10.64898\/2026.07.22.740078","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740078","rel_abs":"Premise Pinguicula are carnivorous plants occupying a wide range of habitats, from wetlands to barren rock cliffs, where CAM photosynthesis was recently discovered in several species. This ecological and physiological diversity makes the genus a promising system for exploring the environmental drivers and evolutionary transitions underlying variation in CAM. Here, we present a physiological survey of CAM with a particular focus on the Mexican Clade, which contains the recently identified CAM species. Methods We conducted a carbon isotope survey of live and herbarium specimens to identify candidate CAM species. We then measured diurnal gas-exchange patterns and changes in leaf titratable acidity to quantify CAM activity. Results Pinguicula species exhibited a variety of photosynthetic phenotypes. Pinguicula vulgaris showed no detectable evidence of CAM, whereas P. cyclosecta and P. moranensis demonstrated a C3-CAM physiology with most net assimilation via C3. Pinguicula martinezii also showed the same C3-CAM physiology under well-watered conditions but had strong facultative induction of CAM with drought. Pinguicula agnata displayed net assimilation via CAM. Titratable acidity had a positive correlation with {delta}13C within the species we sampled. Conclusions Our results support the existence of a CAM physiological continuum within Pinguicula. Notably, closely related species encompass physiologies that span the large variation of CAM. This diversity provides a rare opportunity for future studies to investigate the evolution of CAM in closely related species, including differences and similarities between differing states across the continuum.","rel_num_authors":3,"rel_authors":[{"author_name":"Daniel Wah Lai Mok","author_inst":"Michigan State University"},{"author_name":"Robert VanBuren","author_inst":"Michigan State University"},{"author_name":"Kadeem Jamal Gilbert","author_inst":"Michigan State University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Coral Guard substrates accelerate growth and fragment fusion for coral restoration","rel_doi":"10.64898\/2026.07.21.739923","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739923","rel_abs":"Coral reefs are declining globally, creating an urgent need for scalable technologies that improve the efficiency and effectiveness of active reef restoration. Coral reef restoration is increasingly constrained by algal overgrowth, which suppresses coral growth, survival, and restoration efficiency. Building on the recently developed Coral Guard platform, we evaluate its restoration performance under long-term in situ coral nursery conditions and introduce Fusion Guard Tiles, a geometry-optimized Coral Guard design that accelerates microfragment fusion. We evaluated Coral Guard Plugs using the branching coral Stylophora pistillata under complementary ex situ conditions and Fusion Guard Tiles using the massive reef-building coral Porites evermanni in in situ coral nurseries. In P. evermanni, Fusion Guard Tiles increased lateral tissue growth 2.6-fold and three-dimensional tissue surface area growth by >2.7-fold after 6 months compared with conventional substrates. After 12 months, colony height and volume were approximately 4.0-fold and 2.2-fold greater, respectively, while complete fragment fusion occurred only on Fusion Guard Tiles. In S. pistillata, Coral Guard Plugs increased lateral tissue growth by ~1.7-fold. Microcomputed tomography revealed 10-13% higher skeletal density in both species. In P. evermanni, Fusion Guard Tiles also increased symbiont density by 70% and tissue protein content by ~2.5-fold relative to controls. Together, these findings demonstrate that Coral Guard substrates suppress algal competition while accelerating coral growth, skeletal development, and microfragment fusion, providing a scalable, low-maintenance technology to enhance coral nursery productivity and reef restoration.","rel_num_authors":14,"rel_authors":[{"author_name":"Stefan Kolle","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Nathaniel Kramer","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Christopher Suchocki","author_inst":"Hawaii Institute of Marine Biology University of Hawaii at Manoa"},{"author_name":"Joshua L Kuailani","author_inst":"Hawaii Institute of Marine Biology University of Hawaii at Manoa"},{"author_name":"Lindsey Badder","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Natalie Levy","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Sofia PC Martin","author_inst":"Department of Earth Sciences, University of Hawaii at Manoa"},{"author_name":"Aiden Beaupain","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Alexander Perez","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Samapti Kundu","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Eric Schuster","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Chris B Wall","author_inst":"Department of Earth Sciences, University of Hawaii at Manoa"},{"author_name":"Rob Toonen","author_inst":"Hawaii Institute of Marine Biology, University of Hawaii at Manoa"},{"author_name":"Daniel Wangpraseurt","author_inst":"University of California San Diego Scripps Institution of Oceanography"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Structural and functional heterogeneity in cardiac RyR signalling nanodomains revealed with quantitative single molecule mapping toolkit","rel_doi":"10.64898\/2026.07.22.740006","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740006","rel_abs":"The nanoscale organisation of ryanodine receptor type-2 (RyR2) channels and junctophilin-2 (JPH2) shapes cardiac calcium release, but how this relationship is remodelled in right ventricular failure remains unclear. We developed an integrated analysis pipeline building on multiplexed DNA-PAINT data to quantify RyR2 and JPH2 abundance, stoichiometry of co-clustering, and spatial organisation within individual subsarcolemmal calcium release nanodomains. Applied to cardiomyocytes from control rats with pulmonary hypertension-induced right ventricular failure, the approach revealed reduced co-localisation between RyR2 and JPH2 within peripheral junctions and greater variability in their co-clustering stoichiometry across the cell. A subvariogram analysis further showed divergent remodelling of JPH2 expression patterns across subcellular length scales, indicating that disease alters both local molecular composition and cell-wide spatial heterogeneity. Experimentally derived RyR2\/JPH2 maps were then used to model as two-dimensional templates for stochastic reaction diffusion of calcium release. Simulations of spontaneous calcium waves from failing cells showed up to 25% wave propagation. Maps from failing cells supported faster transverse and longitudinal calcium dependent release, consistent with the emergence, that support the likelihood of heterogeneous modulation and coupling of RyR resulting from the RyR redistribution and heterogeneous JPH2 expression in the failing cell. Together, these findings identify spatially heterogeneous RyR2-JPH2 remodelling as a potential substrate for dysregulated calcium signalling in right ventricular failure and establish a transferable toolkit for linking molecular nanostructure to cellular function.","rel_num_authors":4,"rel_authors":[{"author_name":"Ralf K\u00f6hler","author_inst":"EMBL Australia Node in Single Molecule Science, Department of Molecular Medicine, School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sy"},{"author_name":"Miriam E Hurley","author_inst":"School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom"},{"author_name":"Edward White","author_inst":"School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom"},{"author_name":"Izzy Jayasinghe","author_inst":"EMBL Australia Node in Single Molecule Science, Department of Molecular Medicine, School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sy"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Aging disrupts cumulus-oocyte NAD homeostasis","rel_doi":"10.64898\/2026.07.22.739977","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739977","rel_abs":"The age-related decline in oocyte nicotinamide adenine dinucleotide (NAD) is associated with reduced developmental potential and female infertility. Despite the extraordinary longevity of the female germline, the mechanism for maintaining oocyte NAD remains unresolved. Here, we used stable isotope tracing to identify a new mechanism for shared, intercellular NAD biosynthesis, whereby somatic-germline metabolic coupling between the oocyte and its surrounding cumulus cells is critical to maintain oocyte NAD homeostasis. We show that this coupling deteriorates with reproductive aging, identifying altered NAD metabolism in cumulus cells from mice and women of advancing reproductive age. This cumulus-oocyte metabolic coupling of NAD biosynthesis contributes to protection against the age-related increases in oocyte reactive oxygen species (ROS). In intact complexes, restoring NAD through supplementation with the precursor nicotinamide mononucleotide (NMN) increased glutathione, reduced ROS and improved mitochondrial membrane potential in oocytes from aged mice and in oocytes exposed to oxidative insult. Importantly, the ability of NMN to resolve elevated ROS depends on the presence of cumulus cells. Together, this new model of somatic-germline metabolic coupling of NAD biosynthesis places an age-related deterioration in cumulus cell-mediated metabolic support as a key driver of impaired oocyte NAD levels and redox dysregulation with aging.","rel_num_authors":10,"rel_authors":[{"author_name":"Bettina P Mihalas","author_inst":"University of New South Wales"},{"author_name":"Denise Lin","author_inst":"University of New South Wales"},{"author_name":"Sonia Bustamante","author_inst":"University of New South Wales"},{"author_name":"Russell Pickford","author_inst":"University of New South Wales"},{"author_name":"Emily R Frost","author_inst":"University of New South Wales"},{"author_name":"Ananya Vuyyuru","author_inst":"University of New South Wales"},{"author_name":"Derek Y Wong","author_inst":"University of New South Wales"},{"author_name":"Michael J Bertoldo","author_inst":"University of New South Wales"},{"author_name":"Lindsay E Wu","author_inst":"University of New South Wales"},{"author_name":"Robert B Gilchrist","author_inst":"University of New South Wales"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"HSC70 prevents TDP-43 nuclear puncta formation and toxicity in a novel nuclear puncta cell model for ALS","rel_doi":"10.64898\/2026.07.21.739729","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739729","rel_abs":"Amyotrophic lateral sclerosis (ALS) is categorized by TDP-43 proteinopathy, however, the nuclear pathological events remain poorly defined. While cytoplasmic TDP-43 inclusions dominate the late disease stages, accumulating evidence indicates that nuclear TDP-43 assemblies arise earlier and impair RNA splicing. Here, we characterized a single RRM-proximal TDP-43 variant, G148V, designed to disrupt nucleic-acid engagement without altering canonical RNA-binding residues. Structural and biophysical analyses revealed conformational changes and loss of DNA\/RNA binding. In mammalian cells, TDP-43 G148V robustly formed nuclear puncta with high penetrance, exhibiting solid-like properties, pathological phosphorylation, splicing dysfunction, and toxicity. Furthermore, we identified molecular chaperone HSC70 as an important regulator of the nuclear puncta assembly. HSC70 redistributed into G148V nuclear puncta to modulate their material state, whereas HSC70 depletion significantly promoted puncta solidification, increased insoluble TDP-43 accumulation, and enhanced cytotoxicity. Disease-associated K181E and K263E mutants also formed nuclear puncta and induced HSC70 nuclear redistribution. These findings establish G148V as a model of early nuclear TDP-43 pathology and highlight HSC70-mediated regulation as a key factor of TDP-43 nuclear assembly.","rel_num_authors":4,"rel_authors":[{"author_name":"Jeng Jung Wu","author_inst":"Academia Sinica"},{"author_name":"Shin-Yu Fan","author_inst":"National Taiwan University"},{"author_name":"Tien-Hsien Chang","author_inst":"Academia Sinica"},{"author_name":"Yun-Ru Chen","author_inst":"Academia Sinica"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"HSC70 prevents TDP-43 nuclear puncta formation and toxicity in a novel nuclear puncta cell model for ALS","rel_doi":"10.64898\/2026.07.21.739729","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739729","rel_abs":"Amyotrophic lateral sclerosis (ALS) is categorized by TDP-43 proteinopathy, however, the nuclear pathological events remain poorly defined. While cytoplasmic TDP-43 inclusions dominate the late disease stages, accumulating evidence indicates that nuclear TDP-43 assemblies arise earlier and impair RNA splicing. Here, we characterized a single RRM-proximal TDP-43 variant, G148V, designed to disrupt nucleic-acid engagement without altering canonical RNA-binding residues. Structural and biophysical analyses revealed conformational changes and loss of DNA\/RNA binding. In mammalian cells, TDP-43 G148V robustly formed nuclear puncta with high penetrance, exhibiting solid-like properties, pathological phosphorylation, splicing dysfunction, and toxicity. Furthermore, we identified molecular chaperone HSC70 as an important regulator of the nuclear puncta assembly. HSC70 redistributed into G148V nuclear puncta to modulate their material state, whereas HSC70 depletion significantly promoted puncta solidification, increased insoluble TDP-43 accumulation, and enhanced cytotoxicity. Disease-associated K181E and K263E mutants also formed nuclear puncta and induced HSC70 nuclear redistribution. These findings establish G148V as a model of early nuclear TDP-43 pathology and highlight HSC70-mediated regulation as a key factor of TDP-43 nuclear assembly.","rel_num_authors":4,"rel_authors":[{"author_name":"Jeng Jung Wu","author_inst":"Academia Sinica"},{"author_name":"Shin-Yu Fan","author_inst":"National Taiwan University"},{"author_name":"Tien-Hsien Chang","author_inst":"Academia Sinica"},{"author_name":"Yun-Ru Chen","author_inst":"Academia Sinica"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Water stress adaptive responses in plants require movement of ABA and AB-aldehyde from vascular to target tissues","rel_doi":"10.64898\/2026.07.22.739638","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739638","rel_abs":"Vascular plants rapidly coordinate root and shoot responses to water stress. Abscisic acid (ABA) mediates these adaptations; however, it remains unclear which cells produce ABA, whether ABA synthesis shifts during stress, and whether ABA movement is required for its adaptive functions. Here, we map ABA biosynthesis at cellular resolution in Arabidopsis and report that water-stress adaptive responses in roots and shoots require movement of ABA and its precursor AB-aldehyde from vascular tissues to target cells. We suggest that ABA accumulation arises from two parallel routes: (i) ABA synthesized in the vasculature via ABA2 and AAO3, then moving to guard cells, and (ii) phloem-derived AB-aldehyde being converted to ABA in the epidermis or bundle sheath by AAO1 and AAO2. Finally, we predict that tightly packed cells beneath leaf veins facilitate efficient ABA delivery to guard cells, an anatomical arrangement that has enabled angiosperms to evolve the use of ABA to rapidly close stomata.","rel_num_authors":25,"rel_authors":[{"author_name":"Moran Anfang","author_inst":"Tel Aviv University"},{"author_name":"Kristian B Kiradjiev","author_inst":"University of Nottingham"},{"author_name":"Shir Ben Yaakov","author_inst":"Tel Aviv University"},{"author_name":"Dan Gothilf","author_inst":"Tel Aviv University"},{"author_name":"Christa Kanstrup","author_inst":"University of Copenhagen"},{"author_name":"Barak Bitman","author_inst":"Tel Aviv University"},{"author_name":"Jacob M Jepson","author_inst":"University of Nottingham"},{"author_name":"Liat Fellus-Alyagor","author_inst":"Weizmann Institute of Science"},{"author_name":"Dana Hirsch","author_inst":"Weizmann Institute of Science"},{"author_name":"Vadim E Galperin","author_inst":"Tel Aviv University"},{"author_name":"Shunsuke Watanabe","author_inst":"Yasuda Womens University"},{"author_name":"Masanori Okamoto","author_inst":"RIKEN Center for Sustainable Resource Science"},{"author_name":"Roshan Kumar","author_inst":"University of Nottingham"},{"author_name":"Christoph Crocoll","author_inst":"University of Copenhagen"},{"author_name":"Sara Morghen","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Thorsten Hamann","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Yariv Brotman","author_inst":"Tel Aviv University"},{"author_name":"Mitsunori Seo","author_inst":"University of the Ryukyus"},{"author_name":"Hussam Hassan Nour-Eldin","author_inst":"University of Copenhagen"},{"author_name":"Craig J Sturrock","author_inst":"University of Nottingham"},{"author_name":"Poonam Mehra","author_inst":"University of Nottingham"},{"author_name":"Malcolm J Bennett","author_inst":"University of Nottingham"},{"author_name":"James H Rowe","author_inst":"University of Sheffield"},{"author_name":"Leah R Band","author_inst":"University of Nottingham"},{"author_name":"Eilon Shani","author_inst":"Tel Aviv University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Water stress adaptive responses in plants require movement of ABA and AB-aldehyde from vascular to target tissues","rel_doi":"10.64898\/2026.07.22.739638","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739638","rel_abs":"Vascular plants rapidly coordinate root and shoot responses to water stress. Abscisic acid (ABA) mediates these adaptations; however, it remains unclear which cells produce ABA, whether ABA synthesis shifts during stress, and whether ABA movement is required for its adaptive functions. Here, we map ABA biosynthesis at cellular resolution in Arabidopsis and report that water-stress adaptive responses in roots and shoots require movement of ABA and its precursor AB-aldehyde from vascular tissues to target cells. We suggest that ABA accumulation arises from two parallel routes: (i) ABA synthesized in the vasculature via ABA2 and AAO3, then moving to guard cells, and (ii) phloem-derived AB-aldehyde being converted to ABA in the epidermis or bundle sheath by AAO1 and AAO2. Finally, we predict that tightly packed cells beneath leaf veins facilitate efficient ABA delivery to guard cells, an anatomical arrangement that has enabled angiosperms to evolve the use of ABA to rapidly close stomata.","rel_num_authors":25,"rel_authors":[{"author_name":"Moran Anfang","author_inst":"Tel Aviv University"},{"author_name":"Kristian B Kiradjiev","author_inst":"University of Nottingham"},{"author_name":"Shir Ben Yaakov","author_inst":"Tel Aviv University"},{"author_name":"Dan Gothilf","author_inst":"Tel Aviv University"},{"author_name":"Christa Kanstrup","author_inst":"University of Copenhagen"},{"author_name":"Barak Bitman","author_inst":"Tel Aviv University"},{"author_name":"Jacob M Jepson","author_inst":"University of Nottingham"},{"author_name":"Liat Fellus-Alyagor","author_inst":"Weizmann Institute of Science"},{"author_name":"Dana Hirsch","author_inst":"Weizmann Institute of Science"},{"author_name":"Vadim E Galperin","author_inst":"Tel Aviv University"},{"author_name":"Shunsuke Watanabe","author_inst":"Yasuda Womens University"},{"author_name":"Masanori Okamoto","author_inst":"RIKEN Center for Sustainable Resource Science"},{"author_name":"Roshan Kumar","author_inst":"University of Nottingham"},{"author_name":"Christoph Crocoll","author_inst":"University of Copenhagen"},{"author_name":"Sara Morghen","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Thorsten Hamann","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Yariv Brotman","author_inst":"Tel Aviv University"},{"author_name":"Mitsunori Seo","author_inst":"University of the Ryukyus"},{"author_name":"Hussam Hassan Nour-Eldin","author_inst":"University of Copenhagen"},{"author_name":"Craig J Sturrock","author_inst":"University of Nottingham"},{"author_name":"Poonam Mehra","author_inst":"University of Nottingham"},{"author_name":"Malcolm J Bennett","author_inst":"University of Nottingham"},{"author_name":"James H Rowe","author_inst":"University of Sheffield"},{"author_name":"Leah R Band","author_inst":"University of Nottingham"},{"author_name":"Eilon Shani","author_inst":"Tel Aviv University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Area-level context and functional brain organization across the lifespan","rel_doi":"10.64898\/2026.07.21.739899","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739899","rel_abs":"The neighborhoods children grow up in are associated with cognitive and mental health outcomes across the lifespan. Yet how neighborhood-level factors are quantified, and how they relate to large-scale functional brain connectivity, remains an emerging area of investigation. This scoping review synthesizes empirical evidence on associations between area-level factors and resting-state functional brain connectivity and network organization. We included studies assessing resting-state fMRI functional connectivity or rs-fMRI-derived intrinsic activity in relation to validated area-level deprivation indices guided by Trinidad et al.'s (2022) inventory, the Opportunity Atlas, or geocoded crime exposure from the Uniform Crime Reporting program. Of the 28 studies meeting inclusion criteria, the evidence base was unevenly distributed across the lifespan; 25 of 28 (89.3%) examined perinatal, childhood, or adolescent samples, while only one examined adults exclusively. The literature was also methodologically non-independent, over half drew on the Adolescent Brain and Cognitive Development (ABCD) Study, and the Area Deprivation Index was the most commonly used measure (k = 16, 57.1%). Therefore, apparent convergence partly reflects shared data and instruments rather than independent replication. Where directions could be compared, higher area-level disadvantage was associated predominantly with lower within-network connectivity in association and control systems and higher connectivity in somatomotor systems, with several findings attenuating once area-level exposure was isolated from household socioeconomic status. Geographic resolution varied but was rarely justified. Progress will require greater theoretical intentionality in selecting area-level measures, transparent justification of geographic resolution, treatment of dataset and measure non-independence, and investment in understudied developmental periods and non-US contexts.","rel_num_authors":8,"rel_authors":[{"author_name":"Jocelyn A Ricard","author_inst":"Stanford University"},{"author_name":"Chase Antonacci","author_inst":"Stanford University"},{"author_name":"Gabriel Reyes","author_inst":"Stanford University"},{"author_name":"Eugenia Giampetruzzi","author_inst":"Stanford University"},{"author_name":"Jivesh Ramduny","author_inst":"Yale University"},{"author_name":"Gracie Grimsrud","author_inst":"Stanford University"},{"author_name":"Monica E Ellwood-Lowe","author_inst":"Stanford University"},{"author_name":"Russell A Poldrack","author_inst":"Stanford University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Unsupervised nonmotor learning in the human cerebellum","rel_doi":"10.64898\/2026.07.22.740142","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.740142","rel_abs":"A core motor function of the cerebellum is error-based learning: it uses prediction errors--mismatches between predicted and actual sensory feedback--to refine actions. One provocative hypothesis is that the cerebellum performs similar computations in cognitive domains. Here, we ask whether error-based learning computations in the cerebellum extend to a passive statistical learning task that requires neither action nor decision-making. Human participants viewed sequences of visual stimuli with varying probabilistic stimulus-stimulus transitions while undergoing fMRI. Subjects reported no explicit knowledge of the transitional probabilities after the scan. Nonetheless, putative cognitive regions of the cerebellum encoded prediction errors during statistical learning. Moreover, error signals in the cerebellum were encoded in a different manner than error signals in the anterior hippocampus, a well-known substrate of statistical learning: cerebellar activity covaried with trial-by-trial prediction errors that evolved slowly over time (echoing cerebellar computations in motor learning), whereas the hippocampus responded in a more fixed manner to the underlying transition structure. Computational modeling formalized this dissociation, with cerebellar activity explained by a delta-rule model that incrementally adjusted predictions based on recent experience, and hippocampal activity characterized as a form of Bayesian updating of a transition distribution held in memory. Our findings demonstrate that the cerebellum encodes prediction errors during passive nonmotor learning, and thus that it likely plays a domain-general role in error-based learning.","rel_num_authors":4,"rel_authors":[{"author_name":"Juliana E. Trach","author_inst":"Yale University"},{"author_name":"Yiran Ou","author_inst":"Yale University"},{"author_name":"Nicholas B. Turk-Browne","author_inst":"Yale University"},{"author_name":"Samuel D. McDougle","author_inst":"Yale University"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Cerebral Encoding of Word Classes is Distributed and Context-Dependent","rel_doi":"10.64898\/2026.07.22.739973","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739973","rel_abs":"Word classes such as nouns, verbs, and adjectives are fundamental units of language, but their neural encoding remains unclear. Here, we investigate whether word classes are processed as invariant, context-independent lexical categories or depend on sentence context during language processing. We analyse source-localized magnetoencephalography (MEG) data from 200 native Dutch participants who read or listened to sentences and their scrambled counterparts (word lists) from the MOUS dataset. Time-resolved encoding models are used to predict neural responses from major word classes (noun, verb, adjective) and other linguistic variables including word frequency, surprisal, entropy, word length, and ordinal position. Across modalities, we observe a significant interaction between word class and context (sentences vs. word lists), manifest as dynamic modulation of neural responses in a widespread cortical network including bilateral perisylvian, frontal, and midline regions previously implicated in lexicosemantic, structural, and pragmatic processing. This interaction emerges early and reappears later in processing, with distinct temporal profiles for reading and listening. Within-condition effects reveal that word class contributes to neural responses at the level of individual words, but this contribution is context-dependent: it is robust in sentences across modalities and in word-list reading, but absent in auditory word lists. These results indicate that word-class encoding is shaped by the interaction between word-level properties and sentence context during real-time language processing.","rel_num_authors":5,"rel_authors":[{"author_name":"Natalia Bekemeier","author_inst":"University of Zurich"},{"author_name":"Marianne Hundt","author_inst":"University of Zurich"},{"author_name":"Zirui Huang","author_inst":"University of Zurich"},{"author_name":"Martina Djordjijevic","author_inst":"University of Geneva"},{"author_name":"Alexis Hervais-Adelman","author_inst":"University of Geneva"}],"rel_date":"2026-07-23","rel_site":"biorxiv"},{"rel_title":"Pathways from inequality to health: Social determinants of health shape the gut microbiome in low-resource U.S. communities","rel_doi":"10.64898\/2026.07.20.26358501","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358501","rel_abs":"The gut microbiome influences cardiovascular and gastrointestinal disease risk, yet the indirect pathways through which structural social determinants of health (SDoH) shape microbial composition remain understudied. We investigated causal pathways linking SDoH - systemic conditions that shape health opportunities - to the gut microbiome in two low-resource, flood-prone U.S. communities. We collected questionnaires, dried blood spots, and fecal samples (n=131; ages 3-79) in Mississippi and Illinois (2022-2023) as part of a longitudinal project on infrastructure and health, identifying bacterial composition via 16S rRNA sequencing. Controlling for covariates, structural equation modeling showed education positively predicted microbiome richness and evenness, partially mediated through income and diet. This suggests that structural inequities in education, food access, and income significantly influence the microbiome. Notably, contrary to established literature, greater consumption of processed and fried foods was associated with increased alpha diversity. Therefore, in this context, diet may covary with environmental vulnerability, such as opportunistic pathogen exposure from frequent flooding. Analysis of beta diversity showed direct effects from education, diet, and CRP; income and homeownership had indirect effects mediated through diet. The taxa driving these relationships likely include Tannerellaceae for diet and a subgroup of Firmicutes for income, based on our differential abundance analysis. These findings indicate that pathways linking SDoH to the microbiome may vary by local infrastructure and environmental context. This research highlights how structural inequality may be biologically embedded, suggesting that public health interventions should target infrastructural inequities linked with environmental racism, rather than individual behavioral change.","rel_num_authors":18,"rel_authors":[{"author_name":"Carlye Chaney","author_inst":"University of Missouri"},{"author_name":"Jennifer Ong","author_inst":"Washington University in St. Louis"},{"author_name":"Leena Kwak","author_inst":"Washington University in St. Louis"},{"author_name":"Kiersten Grathwohl","author_inst":"Washington University in St. Louis"},{"author_name":"Shan Wang","author_inst":"Washington University in St. Louis"},{"author_name":"Kaylaa Betts","author_inst":"Washington University in St. Louis"},{"author_name":"Jade A Beauregard","author_inst":"Washington University in St. Louis"},{"author_name":"Katherine L Nemeth","author_inst":"Washington University in St. Louis"},{"author_name":"Sophie Waimon","author_inst":"Washington University in St. Louis"},{"author_name":"Angela Zhang","author_inst":"Washington University in St. Louis"},{"author_name":"Alex B Shing","author_inst":"Washington University in St. Louis"},{"author_name":"Anna Samsonov","author_inst":"Baylor University"},{"author_name":"Marcela Pfaff-Nash","author_inst":"Baylor University"},{"author_name":"Braveen Ragunanthan","author_inst":"University of Pittsburgh"},{"author_name":"Samuel S Urlacher","author_inst":"Baylor University"},{"author_name":"Tara J Cepon-Robins","author_inst":"University of Colorado Colorado Springs"},{"author_name":"Theresa E Gildner","author_inst":"Washington University in St. Louis"},{"author_name":"Elizabeth K Mallott","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Safety of Tenecteplase in Pediatric Arterial Ischemic Stroke","rel_doi":"10.64898\/2026.07.20.26358531","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358531","rel_abs":"Background: Recent AHA guidelines recommend the use of IV Tenecteplase (TNK) in adult stroke patients, but there is minimal safety and dosing data on TNK in pediatric patients. We performed a safety surveillance study aiming to evaluate risk of symptomatic intracranial hemorrhage (ICH) in children who received TNK for suspected acute ischemic stroke (AIS). Methods: This was a prospective observational cohort surveillance study analyzing responses from a monthly email survey sent to members of two large international pediatric stroke and neurocritical care research consortia querying recent use of TNK in children. Limited demographic, clinical, and outcome data were collected. A Bayesian beta-binomial model for risk of symptomatic ICH with IV TNK was fit using a prior distribution based on the risk level in adults. Results: Between February 2023-June 2026, 44 children received TNK for suspected AIS. Most patients (n=37, 84.1%) were adolescents; no children under 5 received TNK. Twelve patients (27.3%) were ultimately diagnosed with a stroke mimic. Symptomatic ICH was not reported in any children who received IV TNK; 3 had asymptomatic ICH on follow-up imaging. One patient received intra-arterial TNK and experienced symptomatic ICH. No other major bleeding events were reported. Conclusions: IV TNK is being administered to pediatric patients with suspected stroke in clinical practice, and may be safe in older children with AIS. Rigorous prospective studies are needed to better assess risk and outcomes in this unique population.","rel_num_authors":15,"rel_authors":[{"author_name":"Sarah Lee","author_inst":"Stanford University School of Medicine"},{"author_name":"- International Pediatric Stroke Study","author_inst":"-"},{"author_name":"Lisa R Sun","author_inst":"Johns Hopkins School of Medicine, Baltimore, Maryland, USA"},{"author_name":"- Pediatric Neurocritical Care Research Group","author_inst":"-"},{"author_name":"Jacqueline Lee-Eng","author_inst":"Seattle Children's Hospital Foundation"},{"author_name":"Dwight Barry","author_inst":"Seattle Children's Hospital Foundation"},{"author_name":"Jenny L Wilson","author_inst":"Oregon Health & Science University"},{"author_name":"Dana B Harrar","author_inst":"Children's National Hospital"},{"author_name":"Marcela Torres","author_inst":"Cook Children's Medical College, Fort Worth, TX"},{"author_name":"Maria Milagros Galardi","author_inst":"The University of Utah"},{"author_name":"Sahar Mohamed Hassanein","author_inst":"Ain Shams University Faculty of Medicine"},{"author_name":"Megan M Barry","author_inst":"University of Colorado Boulder"},{"author_name":"Michael J. Rivkin","author_inst":"Harvard Medical School"},{"author_name":"Kristin Guilliams","author_inst":"Washington Unviersity"},{"author_name":"Catherine Amlie-Lefond","author_inst":"Seattle Children's Hospital\/University of Washington"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Safety of Tenecteplase in Pediatric Arterial Ischemic Stroke","rel_doi":"10.64898\/2026.07.20.26358531","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358531","rel_abs":"Background: Recent AHA guidelines recommend the use of IV Tenecteplase (TNK) in adult stroke patients, but there is minimal safety and dosing data on TNK in pediatric patients. We performed a safety surveillance study aiming to evaluate risk of symptomatic intracranial hemorrhage (ICH) in children who received TNK for suspected acute ischemic stroke (AIS). Methods: This was a prospective observational cohort surveillance study analyzing responses from a monthly email survey sent to members of two large international pediatric stroke and neurocritical care research consortia querying recent use of TNK in children. Limited demographic, clinical, and outcome data were collected. A Bayesian beta-binomial model for risk of symptomatic ICH with IV TNK was fit using a prior distribution based on the risk level in adults. Results: Between February 2023-June 2026, 44 children received TNK for suspected AIS. Most patients (n=37, 84.1%) were adolescents; no children under 5 received TNK. Twelve patients (27.3%) were ultimately diagnosed with a stroke mimic. Symptomatic ICH was not reported in any children who received IV TNK; 3 had asymptomatic ICH on follow-up imaging. One patient received intra-arterial TNK and experienced symptomatic ICH. No other major bleeding events were reported. Conclusions: IV TNK is being administered to pediatric patients with suspected stroke in clinical practice, and may be safe in older children with AIS. Rigorous prospective studies are needed to better assess risk and outcomes in this unique population.","rel_num_authors":15,"rel_authors":[{"author_name":"Sarah Lee","author_inst":"Stanford University School of Medicine"},{"author_name":"- International Pediatric Stroke Study","author_inst":"-"},{"author_name":"Lisa R Sun","author_inst":"Johns Hopkins School of Medicine, Baltimore, Maryland, USA"},{"author_name":"- Pediatric Neurocritical Care Research Group","author_inst":"-"},{"author_name":"Jacqueline Lee-Eng","author_inst":"Seattle Children's Hospital Foundation"},{"author_name":"Dwight Barry","author_inst":"Seattle Children's Hospital Foundation"},{"author_name":"Jenny L Wilson","author_inst":"Oregon Health & Science University"},{"author_name":"Dana B Harrar","author_inst":"Children's National Hospital"},{"author_name":"Marcela Torres","author_inst":"Cook Children's Medical College, Fort Worth, TX"},{"author_name":"Maria Milagros Galardi","author_inst":"The University of Utah"},{"author_name":"Sahar Mohamed Hassanein","author_inst":"Ain Shams University Faculty of Medicine"},{"author_name":"Megan M Barry","author_inst":"University of Colorado Boulder"},{"author_name":"Michael J. Rivkin","author_inst":"Harvard Medical School"},{"author_name":"Kristin Guilliams","author_inst":"Washington Unviersity"},{"author_name":"Catherine Amlie-Lefond","author_inst":"Seattle Children's Hospital\/University of Washington"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Safety of Tenecteplase in Pediatric Arterial Ischemic Stroke","rel_doi":"10.64898\/2026.07.20.26358531","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358531","rel_abs":"Background: Recent AHA guidelines recommend the use of IV Tenecteplase (TNK) in adult stroke patients, but there is minimal safety and dosing data on TNK in pediatric patients. We performed a safety surveillance study aiming to evaluate risk of symptomatic intracranial hemorrhage (ICH) in children who received TNK for suspected acute ischemic stroke (AIS). Methods: This was a prospective observational cohort surveillance study analyzing responses from a monthly email survey sent to members of two large international pediatric stroke and neurocritical care research consortia querying recent use of TNK in children. Limited demographic, clinical, and outcome data were collected. A Bayesian beta-binomial model for risk of symptomatic ICH with IV TNK was fit using a prior distribution based on the risk level in adults. Results: Between February 2023-June 2026, 44 children received TNK for suspected AIS. Most patients (n=37, 84.1%) were adolescents; no children under 5 received TNK. Twelve patients (27.3%) were ultimately diagnosed with a stroke mimic. Symptomatic ICH was not reported in any children who received IV TNK; 3 had asymptomatic ICH on follow-up imaging. One patient received intra-arterial TNK and experienced symptomatic ICH. No other major bleeding events were reported. Conclusions: IV TNK is being administered to pediatric patients with suspected stroke in clinical practice, and may be safe in older children with AIS. Rigorous prospective studies are needed to better assess risk and outcomes in this unique population.","rel_num_authors":15,"rel_authors":[{"author_name":"Sarah Lee","author_inst":"Stanford University School of Medicine"},{"author_name":"- International Pediatric Stroke Study","author_inst":"-"},{"author_name":"Lisa R Sun","author_inst":"Johns Hopkins School of Medicine, Baltimore, Maryland, USA"},{"author_name":"- Pediatric Neurocritical Care Research Group","author_inst":"-"},{"author_name":"Jacqueline Lee-Eng","author_inst":"Seattle Children's Hospital Foundation"},{"author_name":"Dwight Barry","author_inst":"Seattle Children's Hospital Foundation"},{"author_name":"Jenny L Wilson","author_inst":"Oregon Health & Science University"},{"author_name":"Dana B Harrar","author_inst":"Children's National Hospital"},{"author_name":"Marcela Torres","author_inst":"Cook Children's Medical College, Fort Worth, TX"},{"author_name":"Maria Milagros Galardi","author_inst":"The University of Utah"},{"author_name":"Sahar Mohamed Hassanein","author_inst":"Ain Shams University Faculty of Medicine"},{"author_name":"Megan M Barry","author_inst":"University of Colorado Boulder"},{"author_name":"Michael J. Rivkin","author_inst":"Harvard Medical School"},{"author_name":"Kristin Guilliams","author_inst":"Washington Unviersity"},{"author_name":"Catherine Amlie-Lefond","author_inst":"Seattle Children's Hospital\/University of Washington"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Lessons learned from real-time nowcasting: The 2024 dengue outbreak in Puerto Rico","rel_doi":"10.64898\/2026.07.20.26358497","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358497","rel_abs":"Real-time nowcasting enhances situational awareness by mitigating reporting delays that obscure transmission dynamics. We applied Nowcasting by Bayesian Smoothing (NobBS) to the 2024 dengue outbreak in Puerto Rico (PR), using case surveillance data from the PR Department of Health. The method accurately captured the epidemic trajectory and consistently outperformed a baseline model, although reporting anomalies occasionally reduced performance. We also conducted analyses by dengue virus serotype and health region, as well as previous years. For analyses with few dengue cases, a model in which parameters are jointly estimated across groups generally achieved better performance than the independent one. Historical analyses revealed that years with higher variability in reporting delays generally exhibited higher uncertainty. The findings here underscore key lessons for real-time dengue nowcasting: alternative models may be needed in complex circumstances, but with stable reporting patterns and continuous evaluation, nowcasts can be a reliable and valuable public health tool.","rel_num_authors":12,"rel_authors":[{"author_name":"Quan M Tran","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Ariana L Detmar","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Carol Y Liu","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Zachary J. Madewell","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Dania M Rodriguez","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Jomil Torres Aponte","author_inst":"Puerto Rico Department of Health, San Juan, Puerto Rico"},{"author_name":"Melissa Marzan-Rodriguez","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Gabriela Paz-Bailey","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Laura Adams","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Karen Holcomb","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"},{"author_name":"Michael A Johansson","author_inst":"Bouve College of Health Sciences and Network Science Institute, Northeastern University, Boston, Massachusetts, United States of America"},{"author_name":"Maile Thayer","author_inst":"Centers for Disease Control and Prevention, San Juan, Puerto Rico"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"How does CBT work? Causal discovery modelling locates the mechanisms of change in cognitive behavioural treatment for eating disorders","rel_doi":"10.64898\/2026.07.21.26358524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358524","rel_abs":"Background: Cognitive behavioural therapy (CBT) is the most frequently used and recommended therapy program for mental health conditions, including for eating disorders. Despite decades of use, little is known about how change is produced in CBT across mental illnesses, and there has been no empirical validation of the causal structure of change for CBT treatment of eating disorders. Progress in optimisation of CBT and the development of alternatives particularly for non-responders, has been constrained by a lack of understanding of the mechanisms through which the therapy works. This study aimed to investigate, for the first time, mechanism by mechanism the causal direction of change across a therapeutic CBT package. Methods: Directed acyclical graphs (DAGs) were estimated using causal discovery machine learning methods applied to data from a randomised controlled trial of a digital CBT program in 114 participants with bulimia nervosa. Eating disorder symptoms and psychological distress were assessed at each treatment session across the 10-session intervention in both conditions. Treatment effects were then estimated using the inferred causal structure. Results: The inferred causal structure estimated direct effects of treatment on eating restraint (small to medium), alongside indirect effects upon preoccupation with eating, fear of weight gain, desire for weight loss, binge days, loss of control, over-exercise and fasting (small to medium). Eating restraint emerged as the first and only node that treatment directly affected, suggesting that it is the primary mechanism through which treatment produces subsequent change in other behavioural and cognitive symptoms. Conclusion: These findings provide the first empirical evidence, beyond cross-sectional or correlational analyses, for the long theorised mechanisms underlying CBT for eating disorders. Contrary to the conceptual model which posits CBT acts directly on dietary restraint and shape and weight concerns, our findings suggest treatment acts primarily through reductions in eating restraint, with downstream effects on shape- and weight-related concerns and other symptoms. To build our understanding of the processes by which effective treatments for eating disorders operate, progress personalised medicine, and optimise therapeutic outcomes, the methodology developed here can be applied broadly to examination of causal change structures in both direction and magnitude across different interventions.","rel_num_authors":7,"rel_authors":[{"author_name":"Sarah Barakat","author_inst":"University of Sydney"},{"author_name":"Mathew Varidel","author_inst":"University of Sydney"},{"author_name":"Patrick Eades","author_inst":"University of Sydney"},{"author_name":"Victor An","author_inst":"University of Sydney"},{"author_name":"Ian Hickie","author_inst":"University of Sydney"},{"author_name":"Frank Iorfino","author_inst":"University of Sydney"},{"author_name":"Sarah Maguire","author_inst":"University of Sydney"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Left Atrial Remodeling, Hemodynamic Burden, and Time-Varying Risk of Newly Documented Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction","rel_doi":"10.64898\/2026.07.20.26358547","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358547","rel_abs":"Background: Left atrial volume index (LAVI) reflects atrial remodeling in heart failure with preserved ejection fraction (HFpEF), but its nonlinear, hemodynamic, and time-varying associations with atrial fibrillation (AF) remain uncertain. Objectives: To assess the association of baseline LAVI with documented incident AF in HFpEF. Methods: We studied 764 patients with HFpEF without documented AF in a Hong Kong registry. LAVI was analyzed continuously, by tertiles, and with restricted cubic splines. Incident AF was the first qualifying AF diagnosis or electrocardiographic record after echocardiography. Cause-specific Cox and Fine-Gray models were used, with death before AF as a competing event. A hemodynamic overlap-adjusted model additionally included E\/e' ratio and pulmonary artery systolic pressure. Results: During a median follow-up of 5.81 years, 360 patients developed documented incident AF and 272 died before AF was documented. In the primary clinical model, each 10-mL\/m2 increase in LAVI was associated with incident AF in cause-specific Cox regression (HR, 1.08; 95% CI, 1.06-1.11) and Fine-Gray regression (sHR, 1.06; 95% CI, 1.04-1.09). After hemodynamic overlap adjustment, the continuous association was attenuated. However, the highest LAVI tertile remained associated with incident AF (HR, 1.78; 95% CI, 1.28-2.49; sHR, 1.47; 95% CI, 1.05-2.04). Splines showed nonlinear excess risk at higher LAVI, and period-specific analyses showed the strongest association during the first year. Conclusions: Marked left atrial enlargement identified a structural-hemodynamic phenotype associated with early documented incident AF and may support risk-enriched rhythm surveillance.","rel_num_authors":5,"rel_authors":[{"author_name":"Lingyu Mi","author_inst":"Chinese Academy of Medical Sciences & Peking Union Medical College"},{"author_name":"Jeffrey Shi Kai Chan","author_inst":"The 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":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Learning shared forecast-error structure to improve ensemble forecasts of seasonal respiratory outbreaks","rel_doi":"10.64898\/2026.07.20.26358508","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358508","rel_abs":"Real-time forecasts of seasonal respiratory outbreaks are critical for public health preparedness and healthcare planning. Multi-model ensembles, which combine predictions from individual models, have become a leading approach for operational outbreak forecasting. Their success, however, depends in part on the assumption that component models make sufficiently independent errors. Here, we examined this assumption using archived real-time forecasts for influenza hospitalizations and influenza-like illness (ILI) in the United States. We found that component models with diverse structures and calibration methods shared systematic forecast errors during epidemic growth and around epidemic peaks, reflecting the common challenge of tracking rapid changes in epidemic dynamics from real-time surveillance data. Because such shared errors cannot be fully corrected by ensembling alone, we developed a deep learning framework that learns structured residual errors from historical forecasts and uses them to correct ensemble predictions. This framework improved influenza hospitalization forecasts across horizons and geographic scales, reducing the Weighted Interval Score by up to 20\\% at the national level and 12\\% across states relative to official ensemble forecasts, with the largest improvements at the near-term horizon and during epidemic growth and peak periods. We further showed that learned residual structures transferred across ensembles formed from different component models, making the approach robust to changes in model participation across seasons. The framework also improved ensemble forecasts for ILI, although gains were more modest. These findings reveal a fundamental challenge in ensemble forecasting and provide a generalizable approach for improving real-time epidemic forecasts.","rel_num_authors":3,"rel_authors":[{"author_name":"Yuchen Qin","author_inst":"Department of Systems & Information Engineering, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Hongru Du","author_inst":"Department of Systems & Information Engineering, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Sen Pei","author_inst":"Columbia University Mailman School of Public Health"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Exclusion of the commonest subtype of B-cell leukemia in children acquiring EBV infection in early life","rel_doi":"10.64898\/2026.07.20.26358339","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358339","rel_abs":"In developed countries, the rate of childhood B-cell acute lymphoblastic leukemia (B-ALL), the most common pediatric cancer with a peak incidence at 2-5 years of age, has been rising for several decades. Epidemiological studies suggest that reduced exposure to common infections in early life increases the risk of B-ALL. However, no specific infection capable of protecting against such cancer has been identified. One of the most prevalent infectious agents in humans is Epstein-Barr virus (EBV), a B-cell tropic tumor virus that infects ~95% of the global population by adult age. Paradoxically, recent studies reveal that EBV, through its signaling protein LMP1, elicits potent cytotoxic CD4+ and CD8+ T cell responses against a wide range of tumor-associated antigens (TAAs), which can recognize and attack EBV-unrelated cancer cells via shared TAAs. In developed countries, primary EBV infection is often delayed from early childhood into adolescence or young adulthood. Taken together, we hypothesized that EBV (LMP1)-induced TAA-specific T cells may help protect against some childhood B-ALL by targeting shared TAAs. If so, lack of EBV infection in early life may contribute to the rise of childhood B-ALL seen in developed countries. In this work, EBV serology assessment in pediatric B-ALL patients revealed strong exclusion of the commonest high hyperdiploid (HHD) subtype of B-ALL in children having recent primary EBV infection. Our mouse model studies demonstrated that LMP1-induced T cell immunity can eradicate some B-ALL-like leukemias via shared TAAs during the effector phase. These findings support the notion that EBV-induced anti-tumor immunity may help protect against some childhood B-ALL.","rel_num_authors":17,"rel_authors":[{"author_name":"Jutatip Panaampon","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Zhe Wang","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Il-Kyu Choi","author_inst":"Daegu Gyeongbuk Institute of Science and Technology"},{"author_name":"Jiankun Guan","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Seaman","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Shanna Richard","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Victoria Koch","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Marian H. Harris","author_inst":"Boston Children's Hospital"},{"author_name":"Yael Flamand","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Jerome Ritz","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Michael E. Scheurer","author_inst":"Emory University School of Medicine"},{"author_name":"Lynda M. Vrooman","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Andrew E. Place","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Melissa Burns","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Lewis B. Silverman","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Yana Pikman","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Baochun Zhang","author_inst":"Dana-Farber Cancer Institute"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Contextualizing Womens Birth Experiences at Hospitals in Conflict-Affected Settings in Northeast Nigeria and Eastern Democratic Republic of Congo: A Mixed Methods Comparative Case Study","rel_doi":"10.64898\/2026.07.21.26358548","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358548","rel_abs":"IntroductionIn conflict-affected settings, insecurity, poor health systems, and displacement hinder womens access to timely, quality maternal and newborn care. In Northeastern Nigeria and Eastern DRC, access to quality intrapartum care remains limited, contributing to preventable deaths. This study compares the quality of intrapartum care in rural hospitals in Yobe State (Nigeria) and North and South Kivu (DRC), using, facility assessments, provider perspectives and womens experiences to inform women-centered improvements in maternal health.\n\nMethodsA comparative mixed-methods case study was conducted across three rural public hospitals selected from the most insecure districts in Yobe State and North and South Kivu. Data were collected through facility assessments, semi-structured interviews with providers, and focus group discussions with postpartum women and triangulated for an in-depth understanding of care quality in these settings.\n\nResultsWomens childbirth experiences across the three conflict-affected settings were shaped by a combination of under-resourced but functioning facilities, financial barriers, sociocultural norms, and interactions with health personnel. While structural limitations such as overcrowding, limited privacy and infrastructures, and cost barriers were reported in all settings, the degree of support from external actors and local health governance shaped key differences in experience. Autonomy in birth decisions was often limited, and perceptions of communication, respect, and emotional support varied. Nonetheless, across all contexts, compassionate provider behavior was consistently valued by women and contributed to more positive experiences, even in strained environments.\n\nConclusionsImproving maternal care in these settings requires systemic reforms that combine infrastructure and workforce investment with attention to sociocultural norms, womens autonomy, and equity.","rel_num_authors":17,"rel_authors":[{"author_name":"Sussan Israel-Isah","author_inst":"Institute of Human Virology"},{"author_name":"Meighan Mary","author_inst":"University of Maryland School of Medicine"},{"author_name":"Rosine Bigirinama Nshobole","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Salomine Ekambi","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Christian Chiribagula Zalinga","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Charity  Pring\u2019ar Maina","author_inst":"Institute of Human Virology"},{"author_name":"Kazeem  Olalekan Ayodeji","author_inst":"Institute of Human Virology"},{"author_name":"Rejoice  Helma Abimiku","author_inst":"Institute of Human Virology"},{"author_name":"Shatha Elnakib","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Pacifique Mwene-Batu","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Ghislain Bisimwa Balaluka","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Rifkatu  Sunday Aimu","author_inst":"Institute of Human Virology"},{"author_name":"Gaylord Amani Ngaboyeka","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"George Odonye","author_inst":"Institute of Human Virology"},{"author_name":"Christine Chimanuka Murhima\u2019alika","author_inst":"Universit\u00e9 Catholique de Bukavu: Universite Catholique de Bukavu"},{"author_name":"Emilia Ngozi Iwu","author_inst":"Institute of Human Virology"},{"author_name":"Hannah Tappis","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Indirect and direct effects of doxycycline post-exposure prophylaxis: an observational study in a US healthcare system","rel_doi":"10.64898\/2026.07.21.26358607","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358607","rel_abs":"Importance: Doxycycline post-exposure prophylaxis (doxyPEP) is recommended to prevent bacterial sexually-transmitted infections (bSTIs) among certain men who have sex with men and transgender women. Impacts on bSTI transmission are unknown. Objective: To quantify the impact of doxyPEP implementation on bSTI risk, distinguishing indirect and direct protection. Design: Longitudinal cohort study, January 2022 to June 2025, with a nested test-negative design study among individuals potentially eligible to receive doxyPEP. Setting: Kaiser Permanente Southern California healthcare system. Participants: Individuals aged 16-59 years, including: 'at-risk males' assigned male sex at birth, who were living with HIV or who recently received HIV pre- or post-exposure prophylaxis; other males; and females. The nested test-negative design study included at-risk males who received bSTI testing after doxyPEP implementation. Exposures: Oral doxyPEP prescription dispense, defined as a 30+ dose supply of 200mg doxycycline absent accompanying bSTI diagnoses. Main outcomes and measures: Incident laboratory-confirmed gonorrhea, chlamydia, and syphilis. We quantified indirect effects as incidence rate ratios comparing observed to expected incidence of each bSTI, absent doxyPEP implementation, among doxyPEP non-recipients. We quantified direct effects among recipients via the adjusted odds ratio of recent doxyPEP dispenses among individuals testing positive or negative for each bSTI. Results: Analyses included 30,185 at-risk males, among whom 2,713 (9.0%) received 1+ doxyPEP fill; 1,212,854 other males; and 1,321,363 females. Among all at-risk males, overall doxycycline consumption increased 2.31-fold (95% confidence interval: 1.99-2.64; absolute increase by 18,953 [16,052-21,048] defined daily doses per 1,000 person-years) after doxyPEP implementation, without accompanying changes in consumption among other males or females. Resulting indirect protection was associated with 41.4% (95% confidence interval: 33.0-48.8%) and 29.0% (13.4-41.8%) lower-than-expected incidence of chlamydia and syphilis, respectively, among at-risk males who did not receive doxyPEP. We observed no indirect effect against gonorrhea among at-risk males, and no indirect effect against any bSTI among other males or females. Among 22,937 at-risk males in the nested test-negative design study, direct protection from doxyPEP was associated with 66.8% (47.6-78.7%) and 50.1% (2.1-74.2%) further reductions in chlamydia and syphilis risk, respectively, and no reduction in gonorrhea risk. Among doxyPEP recipients, one case of chlamydia and one case of syphilis was prevented for every 2,785 (1,553-5,491) and 20,001 (5,725-182,569) doses dispensed, respectively. Conclusions and relevance: DoxyPEP implementation conferred indirect as well as direct protection against chlamydia and syphilis among at-risk males. However, substantial volumes of antibiotic use were needed to realize this benefit. Tailoring doxyPEP guidance to circumstances associated with the greatest bSTI risk may be warranted to minimize unnecessary antibiotic use.","rel_num_authors":11,"rel_authors":[{"author_name":"Matan Yechezkel","author_inst":"University of California, Berkeley"},{"author_name":"Banshri Kapadia","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Vennis Hong","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Jue Tao Lim","author_inst":"Nanyang Technological University, Singapore"},{"author_name":"Iris Anne C Reyes","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Magdalena E Pomichowski","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Gregg S Davis","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Isabel Rodriguez Barraquer","author_inst":"University of California, San Francisco"},{"author_name":"Nicola F Mueller","author_inst":"University of California, San Francisco"},{"author_name":"Sara Y Tartof","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Joseph A Lewnard","author_inst":"University of California Berkeley"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Developmental mis-specification of cardiac conduction and structure transcriptome in Brugada syndrome","rel_doi":"10.64898\/2026.07.20.26358469","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358469","rel_abs":"Background and AimsBrugada syndrome (BrS) is an inherited arrhythmia associated with ventricular fibrillation and sudden cardiac death. While pathogenic SCN5A variants account for approximately 20-25% of cases, most patients have no identifiable causal rare variant. Genome-wide association studies have identified common susceptibility variants near transcription factor genes involved in cardiac development, suggesting that developmental abnormalities may contribute to BrS pathogenesis beyond sodium channel dysfunction. We therefore investigated whether genetically distinct forms of BrS exhibit altered developmental transcriptomic trajectories during human cardiogenesis.\n\nMethodsDaily bulk 3' RNA sequencing was performed throughout a 30-day directed cardiac differentiation of hiPSC lines derived from two healthy controls and four BrS patients representing distinct genetic backgrounds: SCN5A haploinsufficiency (BrS-SCN5A and BrS-SCN5A-2), a pathogenic RRAD variant (BrS-RRAD), and a patient without rare pathogenic variants but carrying a high burden of common BrS susceptibility alleles (ACV).\n\nResultsTranscriptomic trajectories markedly differed according to the underlying genetic architecture. While the BrS-SCN5A line remained largely similar to controls throughout differentiation, BrS-RRAD and BrS-ACV lines diverged as early as day 5, corresponding to the onset of cardiac specification. Differential expression analysis identified only 113 dysregulated genes in the BrS-SCN5A line compared with 525 and 383 genes in the BrS-RRAD and BrS-ACV lines, respectively. The BrS-RRAD and BrS-ACV models shared a common developmental signature characterized by early downregulation of key regulators of cardiac conduction system development, including NKX2-5, IRX3 and IRX5, together with upregulation of genes involved in extracellular matrix organization. Interestingly, similarly to the BrS-SCN5A line, the BrS-SCN5A-2 line presented a transcriptomic remodeling that diverge from the BrS-RRAD and BrS-ACV lines. Consistent with these findings, predicted IRX5 regulatory normal interactions were completely lost in both non-SCN5A models, whereas transcriptomic remodeling remained minimal in both the BrS-SCN5A hiPSC line and an independent Scn5a haploinsufficient mouse model.\n\nConclusionBrS associated with SCN5A haploinsufficiency and non-SCN5A genetic backgrounds follows distinct developmental transcriptomic trajectories. Our findings support a model in which non-SCN5A BrS is associated with early dysregulation of developmental transcriptional networks controlling cardiac conduction and extracellular matrix organization, whereas SCN5A-mediated BrS primarily results from sodium channel deficiency with limited developmental remodeling. These results identify developmental heterogeneity as a potential determinant of BrS pathophysiology and clinical variability.","rel_num_authors":12,"rel_authors":[{"author_name":"Thomas Stervinou","author_inst":"Nantes Universite"},{"author_name":"Bastien Cimarosti","author_inst":"Institut du Thorax"},{"author_name":"Robin Canac","author_inst":"Institut du Thorax"},{"author_name":"Aurore Girardeau","author_inst":"Institut du Thorax"},{"author_name":"Loubna Ahmed","author_inst":"Institut du Thorax"},{"author_name":"Agnes Tessier","author_inst":"Institut du Thorax, Inserm UMR1087\/CNRS UMR6291"},{"author_name":"Jeremie Poschmann","author_inst":"CRTI: Centre de recherche en transplantation et immunologie"},{"author_name":"Richard Redon","author_inst":"Inserm"},{"author_name":"Flavien Charpentier","author_inst":"Institut du Thorax INSERM UMR 1087 \/ CNRS UMR 6291"},{"author_name":"Patricia Lemarchand","author_inst":"Institut du Thorax"},{"author_name":"Nathalie Gaborit","author_inst":"Institut du Thorax"},{"author_name":"Guillaume Lamirault","author_inst":"Institut du Thorax"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"ASXL3 truncating patient variants mediate transcriptional gain-of-function and are antisense oligonucleotide-responsive","rel_doi":"10.64898\/2026.07.20.26358515","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358515","rel_abs":"One Sentence SummaryASXL3 patient truncations cause BRS through GOF protein accumulation, not LOF, and ASO-mediated knockdown reverses disease transcriptional signatures.\n\nTruncating variants in the human Additional sex combs (asx) ASXL genes are frequent in clonal hematopoiesis and severe dominant neurodevelopmental syndromes, yet are assumed to represent loss-of-function (LOF) alleles. However, numerous LOF alleles are documented in healthy individuals. Here we show ASXL3 patient truncations in neurodevelopmental condition Bainbridge-Ropers syndrome (BRS), by virtue of their distinct location in the gene body, instead mediates gain-of-function (GOF) by escaping nonsense-mediated decay and Cullin 4-dependent degradation, resulting in aberrant protein accumulation, widespread transcriptional dysregulation, and altered chromatin accessibility. Patient-derived cell lines partnered with CRISPR knock-in of patient versus population truncations excluded simple haploinsufficiency, and instead support this  two-hit GOF mechanism. Deletion mapping identified a broad C-terminal destabilizing region, explaining the 3' clustering of benign truncations. Haploinsufficiency was further excluded by forced expression of full length ASXL3 in patient lines, which failed to rescue the disease-associated differential gene expression signature. By contrast, antisense oligonucleotides targeting ASXL3 largely normalized this signature, providing a mechanistic rationale for knockdown therapies in ASXL associated disease.","rel_num_authors":18,"rel_authors":[{"author_name":"Yuji Nakamura","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Toan Nguyen","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Nofar Mor","author_inst":"Cancer Research Center, Sheba Medical Center, Tel Hashomer 5262100, Israel"},{"author_name":"Dan Dominissini","author_inst":"Diagnostics and Laboratory Division, Sheba Medical Center, Tel Hashomer 5262100, Israel. Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel A"},{"author_name":"Isaac Tang","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Christopher Jay Torio","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Harikrishna Thulaseedharan","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Rachel Yibei Zhou","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Wenshu Zhang","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Konstantina Skourti-Stathaki","author_inst":"n-Lorem Foundation, Carlsbad, CA, 92931, USA"},{"author_name":"Julie Douville","author_inst":"n-Lorem Foundation, Carlsbad, CA, 92931, USA"},{"author_name":"Laurence Mignon","author_inst":"n-Lorem Foundation, Carlsbad, CA, 92931, USA"},{"author_name":"Ashley Dung","author_inst":"Ionis Pharmaceuticals, Carlsbad, CA, 92931, USA"},{"author_name":"Susan Freier","author_inst":"Ionis Pharmaceuticals, Carlsbad, CA, 92931, USA"},{"author_name":"Andrew Watt","author_inst":"Ionis Pharmaceuticals, Carlsbad, CA, 92931, USA"},{"author_name":"Sujatha Jagannathan","author_inst":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. RNA Bioscience Initiative, University "},{"author_name":"Stanley T. Crooke","author_inst":"n-Lorem Foundation, Carlsbad, CA, 92931, USA"},{"author_name":"Joseph G Gleeson","author_inst":"UCSD"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"ASXL3 truncating patient variants mediate transcriptional gain-of-function and are antisense oligonucleotide-responsive","rel_doi":"10.64898\/2026.07.20.26358515","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358515","rel_abs":"One Sentence SummaryASXL3 patient truncations cause BRS through GOF protein accumulation, not LOF, and ASO-mediated knockdown reverses disease transcriptional signatures.\n\nTruncating variants in the human Additional sex combs (asx) ASXL genes are frequent in clonal hematopoiesis and severe dominant neurodevelopmental syndromes, yet are assumed to represent loss-of-function (LOF) alleles. However, numerous LOF alleles are documented in healthy individuals. Here we show ASXL3 patient truncations in neurodevelopmental condition Bainbridge-Ropers syndrome (BRS), by virtue of their distinct location in the gene body, instead mediates gain-of-function (GOF) by escaping nonsense-mediated decay and Cullin 4-dependent degradation, resulting in aberrant protein accumulation, widespread transcriptional dysregulation, and altered chromatin accessibility. Patient-derived cell lines partnered with CRISPR knock-in of patient versus population truncations excluded simple haploinsufficiency, and instead support this  two-hit GOF mechanism. Deletion mapping identified a broad C-terminal destabilizing region, explaining the 3' clustering of benign truncations. Haploinsufficiency was further excluded by forced expression of full length ASXL3 in patient lines, which failed to rescue the disease-associated differential gene expression signature. By contrast, antisense oligonucleotides targeting ASXL3 largely normalized this signature, providing a mechanistic rationale for knockdown therapies in ASXL associated disease.","rel_num_authors":18,"rel_authors":[{"author_name":"Yuji Nakamura","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Toan Nguyen","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Nofar Mor","author_inst":"Cancer Research Center, Sheba Medical Center, Tel Hashomer 5262100, Israel"},{"author_name":"Dan Dominissini","author_inst":"Diagnostics and Laboratory Division, Sheba Medical Center, Tel Hashomer 5262100, Israel. Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel A"},{"author_name":"Isaac Tang","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Christopher Jay Torio","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Harikrishna Thulaseedharan","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Rachel Yibei Zhou","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Wenshu Zhang","author_inst":"Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Rady Childrens Institute for Genomic Medicine, Rady Childrens Hosp"},{"author_name":"Konstantina Skourti-Stathaki","author_inst":"n-Lorem Foundation, Carlsbad, CA, 92931, USA"},{"author_name":"Julie Douville","author_inst":"n-Lorem Foundation, Carlsbad, CA, 92931, USA"},{"author_name":"Laurence Mignon","author_inst":"n-Lorem Foundation, Carlsbad, CA, 92931, USA"},{"author_name":"Ashley Dung","author_inst":"Ionis Pharmaceuticals, Carlsbad, CA, 92931, USA"},{"author_name":"Susan Freier","author_inst":"Ionis Pharmaceuticals, Carlsbad, CA, 92931, USA"},{"author_name":"Andrew Watt","author_inst":"Ionis Pharmaceuticals, Carlsbad, CA, 92931, USA"},{"author_name":"Sujatha Jagannathan","author_inst":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. RNA Bioscience Initiative, University "},{"author_name":"Stanley T. Crooke","author_inst":"n-Lorem Foundation, Carlsbad, CA, 92931, USA"},{"author_name":"Joseph G Gleeson","author_inst":"UCSD"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Plasma Metabolite Associations with Incident Heart Failure with Reduced and Preserved Ejection Fraction","rel_doi":"10.64898\/2026.07.20.26358530","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358530","rel_abs":"Background: Prior studies on metabolite associations with incident heart failure (HF) used billing code-based definitions and lacked the data on left ventricular ejection fraction needed to determine associations with HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction. Objectives: Identify potentially causal plasma metabolite associations with HFrEF and HFpEF, ascertained using a validated machine learning- and natural language processing-based algorithm, in up to 38,000 individuals. Methods: We included MGB Biobank participants who had available metabolomics data and no history of HF at baseline. The primary exposures were plasma levels of 42 metabolites measured using a H1 nuclear magnetic resonance platform. The primary outcome was incident HF, ascertained by a validated machine learning- and natural language processing-based algorithm. Multivariable Cox proportional hazards regression to quantify the associations between a 1-SD difference in metabolite level and the time to incident HF. Mendelian randomization analysis was used test the potential causality of each metabolite-HF association. Results: The final analytical cohort included 38,628 individuals with a mean age of 63 years (56% women). Higher plasma levels of glutamine associated with a higher risk of incident HF (HR [95% CI]: 1.21 [1.07-1.35]) while higher levels of docosahexaenoic acid (an omega-3 fatty acid) (0.85 [0.75-0.95]), phosphatidylcholines (0.85 [0.75-0.97]), phosphoglycerides (0.86 [0.76-0.97]) and total cholines (0.85 [0.75-0.97]) associated with a lower HF risk. Docosahexaenoic acid and total omega-3 fatty acids associated with HFpEF. Associations with HFpEF tended to be stronger than with HFrEF for several fatty acids, including omega-3 fatty acids, in individuals with obesity, but not coronary artery disease or diabetes. Mendelian randomization analysis supported causal associations between higher levels of docosahexaenoic acid and omega-3 fatty acids with a higher risk of HF and greater left ventricular mass index. Conclusions: Dysregulated omega-3 fatty acid metabolism may be causally associated with a higher risk of incident HFpEF.","rel_num_authors":8,"rel_authors":[{"author_name":"Bhavya Chebrolu","author_inst":"Brigham and Women's Hospital"},{"author_name":"Priyam Choksi","author_inst":"Brigham and Women's Hospital"},{"author_name":"Salvatore Carbone","author_inst":"Old Dominion University"},{"author_name":"Brittany N. Weber","author_inst":"The University of Texas Southwestern Medical Center Cardiology Division"},{"author_name":"Jessica Lasky-Su","author_inst":"Brigham and Women's Hospital and Harvard Medical School"},{"author_name":"Elizabeth W. Karlson","author_inst":"Brigham and Women's Hospital Department of Medicine"},{"author_name":"Sheila M Hegde","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"Leo F Buckley","author_inst":"The University of Texas Southwestern Medical Center Cardiology Division"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Germline Variants in Centromere Binding Protein 126 Predispose to Glioblastoma","rel_doi":"10.64898\/2026.07.20.26358470","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358470","rel_abs":"Background Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. While only 5% of GBM cases arise in a familial context, the genetic basis of familial GBM remains unresolved in most affected clusters, suggesting that important susceptibility variants may reside outside recognized cancer-predisposition genes. Proband-based genomic studies of such families provide a rational path to discover rare inherited variants with large biological effects, prioritize candidate genes for functional validation, and define early mechanisms of gliomagenesis that may not be apparent from studies of sporadic tumors alone. Methods In this study, we investigated a family with GBM clustering spanning two generations. To investigate the possibility of shared germline susceptibility, we enrolled the proband and their two confirmed affected relatives in our study and performed whole-genome sequencing on available whole blood and tumor samples. Rare coding variants shared among the three study participants were identified and the genes harboring these variants were functionally interrogated with pooled loss-of-function CRISPR screens in human neural progenitor cells (NPCs) in vitro and in heterotopic xenograft models. Results Rare coding variants were identified in 139 candidate genes, and functional genetic screens of human NPCs in heterotopic xenograft models revealed Centrosomal Protein of 126 kDa (CEP126), as the top hit. Genetic disruption of CEP126 conferred a survival and tumorigenic advantage in neural progenitor cells. Conclusion Together, our results establish a functional framework for interrogating rare cancer germline variants and highlights CEP126 as a biologically tractable GBM predisposition gene for future mechanistic and genetic validation.","rel_num_authors":15,"rel_authors":[{"author_name":"Paul Renauer","author_inst":"Yale University"},{"author_name":"Bianca-Maria Marin","author_inst":"Yale University"},{"author_name":"Adrian Melo-Carrillo","author_inst":"Jackson Laboratory for Genomic Medicine"},{"author_name":"Mindy Carpenter","author_inst":"Jackson Laboratory for Genomic Medicine"},{"author_name":"Linbin Zhang","author_inst":"Yale University"},{"author_name":"MacLean Nasrallah","author_inst":"University of Pennsylvania"},{"author_name":"Jennifer Morrissette","author_inst":"University of Pennsylvania"},{"author_name":"Steven Brem","author_inst":"University of Pennsylvania"},{"author_name":"Yuan Rong","author_inst":"Temple University Hospital"},{"author_name":"Alex M. Miller","author_inst":"New York University Langone Medical Center"},{"author_name":"Daniel A. Orringer","author_inst":"New York University Langone Medical Center"},{"author_name":"Matthew Bainbridge","author_inst":"Rady Children's Institute for Genomic Medicine"},{"author_name":"Melissa Bondy","author_inst":"Stanford University"},{"author_name":"Sidi Chen","author_inst":"Yale University"},{"author_name":"Roel G.W. Verhaak","author_inst":"Yale University"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"A proteomic signature for prognostic stratification in amyotrophic lateral sclerosis","rel_doi":"10.64898\/2026.07.20.26358511","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358511","rel_abs":"In the pathologically and clinically heterogeneous neurodegenerative disorder amyotrophic lateral sclerosis (ALS), objective biochemical predictors of survival are essential to handle complexity in clinical trials, enrich clinical decision-making and interrogate the biology of disease progression. In this longitudinal study, we performed high-depth proximity extension assay proteomics using 1,095 samples of serum (N=851) and CSF (N=244) from 426 people with ALS, with orthogonal replication in an external cohort of 349 people with ALS. Age- and sex-adjusted Cox analysis identified 57 proteins in serum, including neurofilament light chain (NEFL) and peripherin, as well as five proteins in CSF, including tropomyosin 3 (TPM3) that were associated with survival (FDR-adjusted p<0.05). Penalised Cox regression identified a panel of 9 serum proteins - including NEFL, peripherin, TNF receptor superfamily member 27 (EDA2R) and calcitonin - that reflect the extent of disease as well as the progression rate, improving survival prediction compared with models using clinical parameters and NEFL. Joint modelling identified associations between the longitudinal trajectories of serum EDA2R and calcitonin with survival, highlighting their potential role in measuring disease progression. This work indicates the utility of multiple proteins reflecting diverse biological pathways in refining survival stratification and highlights systemic factors in ALS progression.","rel_num_authors":24,"rel_authors":[{"author_name":"David G Lester","author_inst":"University of Oxford"},{"author_name":"Paolo Piazza","author_inst":"University of Oxford"},{"author_name":"Elizabeth Dellar","author_inst":"University of Oxford"},{"author_name":"Prerak Desai","author_inst":"GSK plc"},{"author_name":"Hadar Klimovski","author_inst":"Weizmann Institute of Science"},{"author_name":"Christos Chalitsios","author_inst":"University of Oxford"},{"author_name":"Marcel Weinreich","author_inst":"University of Sheffield"},{"author_name":"Elham Alhathli","author_inst":"Taif University"},{"author_name":"Andrew Strange","author_inst":"University of Sheffield"},{"author_name":"Dganit Melamed-Kadosh","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Tamar Ziv","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Pamela Shaw","author_inst":"University of Sheffield"},{"author_name":"Arie Admon","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Vivian Drory","author_inst":"Tel-Aviv University"},{"author_name":"Andrea Malaspina","author_inst":"University College London"},{"author_name":"Johnathan Cooper-Knock","author_inst":"University of Sheffield"},{"author_name":"Iddo Magen","author_inst":"Weizmann Institute of Science"},{"author_name":"Eran Hornstein","author_inst":"Weizmann Institute of Science"},{"author_name":"Armina Omole","author_inst":"GSK plc"},{"author_name":"Guhan Nagappan","author_inst":"GSK plc"},{"author_name":"Avigail Taylor","author_inst":"University of Oxford"},{"author_name":"Kevin Talbot","author_inst":"University of Oxford"},{"author_name":"Martin R Turner","author_inst":"University of Oxford"},{"author_name":"Alexander G Thompson","author_inst":"University of Oxford"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"A proteomic signature for prognostic stratification in amyotrophic lateral sclerosis","rel_doi":"10.64898\/2026.07.20.26358511","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358511","rel_abs":"In the pathologically and clinically heterogeneous neurodegenerative disorder amyotrophic lateral sclerosis (ALS), objective biochemical predictors of survival are essential to handle complexity in clinical trials, enrich clinical decision-making and interrogate the biology of disease progression. In this longitudinal study, we performed high-depth proximity extension assay proteomics using 1,095 samples of serum (N=851) and CSF (N=244) from 426 people with ALS, with orthogonal replication in an external cohort of 349 people with ALS. Age- and sex-adjusted Cox analysis identified 57 proteins in serum, including neurofilament light chain (NEFL) and peripherin, as well as five proteins in CSF, including tropomyosin 3 (TPM3) that were associated with survival (FDR-adjusted p<0.05). Penalised Cox regression identified a panel of 9 serum proteins - including NEFL, peripherin, TNF receptor superfamily member 27 (EDA2R) and calcitonin - that reflect the extent of disease as well as the progression rate, improving survival prediction compared with models using clinical parameters and NEFL. Joint modelling identified associations between the longitudinal trajectories of serum EDA2R and calcitonin with survival, highlighting their potential role in measuring disease progression. This work indicates the utility of multiple proteins reflecting diverse biological pathways in refining survival stratification and highlights systemic factors in ALS progression.","rel_num_authors":24,"rel_authors":[{"author_name":"David G Lester","author_inst":"University of Oxford"},{"author_name":"Paolo Piazza","author_inst":"University of Oxford"},{"author_name":"Elizabeth Dellar","author_inst":"University of Oxford"},{"author_name":"Prerak Desai","author_inst":"GSK plc"},{"author_name":"Hadar Klimovski","author_inst":"Weizmann Institute of Science"},{"author_name":"Christos Chalitsios","author_inst":"University of Oxford"},{"author_name":"Marcel Weinreich","author_inst":"University of Sheffield"},{"author_name":"Elham Alhathli","author_inst":"Taif University"},{"author_name":"Andrew Strange","author_inst":"University of Sheffield"},{"author_name":"Dganit Melamed-Kadosh","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Tamar Ziv","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Pamela Shaw","author_inst":"University of Sheffield"},{"author_name":"Arie Admon","author_inst":"Technion-Israel Institute of Technology"},{"author_name":"Vivian Drory","author_inst":"Tel-Aviv University"},{"author_name":"Andrea Malaspina","author_inst":"University College London"},{"author_name":"Johnathan Cooper-Knock","author_inst":"University of Sheffield"},{"author_name":"Iddo Magen","author_inst":"Weizmann Institute of Science"},{"author_name":"Eran Hornstein","author_inst":"Weizmann Institute of Science"},{"author_name":"Armina Omole","author_inst":"GSK plc"},{"author_name":"Guhan Nagappan","author_inst":"GSK plc"},{"author_name":"Avigail Taylor","author_inst":"University of Oxford"},{"author_name":"Kevin Talbot","author_inst":"University of Oxford"},{"author_name":"Martin R Turner","author_inst":"University of Oxford"},{"author_name":"Alexander G Thompson","author_inst":"University of Oxford"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"A Multimodal Multiomics Machine Learning (MMM) approach for biomarker discovery and acceleration of clinical trial readiness for childhood-onset neurological disorders","rel_doi":"10.64898\/2026.07.21.26358463","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.21.26358463","rel_abs":"BackgroundChildhood neurodegenerative disorders are usually rare, genetic, and life-limiting. Whilst targeted approaches present huge potential, significant hurdles include disease rarity, geographical dispersion of patients, funding, clinical trial design, and execution. Crucially, the paucity of robust biomarkers and objective measures of disease progression hampers evaluation of efficacy, drug development and regulatory approval. To address this paradigm, we developed a Multimodal Multiomics Machine Learning (MMM) framework, integrating large-scale, multi-source patient datasets to generate quantitative metrics for disease stratification and longitudinal tracking. We applied MMM to PLA2G6-associated neurodegeneration (PLAN), an ultra-rare condition currently lacking validated biomarkers, where precision gene therapy approaches are at an advanced preclinical stage.\n\nMethodsA large, single time-point international natural history study (n = 310) was conducted alongside development of a disease-specific rating scale (CoPLAN-DRS), prospective longitudinal neuroimaging, and multiomic biomarker discovery. Machine learning methods were applied to the integrated dataset.\n\nResultsKaplan-Meier analyses enabled estimates for survival and time to loss of ambulation. Multiple clinical, radiological, and biofluid biomarkers were identified, clearly correlating with disease progression. The CoPLAN-DRS and brain MRI Quantitative Susceptibility Mapping showed strong positive correlation with age (rho = 0.69, 0.96 respectively). Nicastrin, a critical structural component of the gamma-secretase complex in Amyloid Precursor Protein (APP) processing, was identified as a novel biomarker. Neurofilament light levels showed strong negative correlation with disease progression (rho = -0.74). The complex multi-dimensional dataset was distilled into a simplified, clinically intuitive Digital Disease Dashboard (DDD), enabling real-time visualisation of disease severity.\n\nConclusionsOur study highlights the clinical utility of MMM in integrating multi-dimensional data from rare disease cohorts, delivering an unbiased, data-driven, optimised biomarker set. Condensing this into the DDD provides a pragmatically useful tool for clinicians, facilitating longitudinal tracking of disease. The MMM and DDD have accelerated clinical-trial readiness for PLAN, and potentially applicable to a broad range of neurogenetic disorders.\n\nRESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSPLA2G6-associated neurodegeneration (PLAN) is a devastating rare, genetic neurodegenerative disorder. Young children affected by PLAN often appear to be developing normally initially before rapid motor and cognitive deterioration, losing any previously gained skills like walking, speaking, and feeding independently. This is a life-limiting disorder without any effective treatments at present, although gene therapy is in advanced stages of preclinical development. The lack of in-depth understanding of the disease spectrum and paucity of biomarkers could potentially hamper the clinical translation of gene therapy and other novel precision therapies.\n\nAdded value of this studyThis study describes a unique approach, harnessing technological advances and machine learning methodology to optimise big data generated from patients, even for relatively small datasets from rare disease cohorts. As proof-of-concept, a Multimodal Multiomics Machine Learning (MMM) strategy was applied to a patient cohort affected by PLAN, for which there are currently no established reliable biomarkers. A machine learning approach was used to distil the complex raw datasets into an accessible platform for applying to clinical practice.\n\nThe MMM approach has:\n\nO_LIidentified the best discriminatory biomarkers that differentiate PLAN patients from controls thereby aiding diagnosis\nC_LIO_LIidentified a range of robust biomarkers that reflect disease severity and progression, aiding longitudinal monitoring and prognostication\nC_LIO_LIobjectively assembled an array of the best data-driven optimised biomarkers as potential PLAN outcome measures for upcoming clinical trials\nC_LI\n\nWe have also developed the Digital Disease Dashboard (DDD), a new visual tool for clinical application that condenses large-scale multidimensional datasets into a single intuitive platform and estimates disease severity at a specific timepoint. The DDD therefore bridges the gap between complex bioinformatics and real-world clinical decision making, offering a powerful new way of communicating disease severity and trajectory, tracking individual patients longitudinally over time.\n\nImplications of all the available evidenceThis MMM toolkit is broadly applicable, not only to rare, neurological disorders like PLAN but also to other childhood-onset genetic disorders. This data-driven, translational approach to generate and utilise big data will rationalise biomarker discovery, providing better measures of disease progression, thereby accelerating clinical trial readiness and development of more effective therapies.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC=\"FIGDIR\/small\/26358463v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (42K):\norg.highwire.dtl.DTLVardef@5f1994org.highwire.dtl.DTLVardef@1885947org.highwire.dtl.DTLVardef@9d6a08org.highwire.dtl.DTLVardef@9c3ed1_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG","rel_num_authors":37,"rel_authors":[{"author_name":"Audrey Ker Shin Soo","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health and Great Ormond Street Hospital (London, UK)"},{"author_name":"Jenny H\u00e4llqvist","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Kiran Seunarine","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Robert Spaull","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London,  UK)"},{"author_name":"Ivan Doykov","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Sara Guttmann","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Kathleen Gorman","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Apostolos Papandreou","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Tian Luo","author_inst":"Children's Hospital of Fudan University (Shanghai, China)"},{"author_name":"Yi Wang","author_inst":"Children's Hospital of Fudan University (Shanghai, China)"},{"author_name":"Maya Thomas","author_inst":"Christian Medical College (Vellore, India)"},{"author_name":"Sangeetha Yoganathan","author_inst":"Christian Medical College (Vellore, India)"},{"author_name":"Evangeline Wassmer","author_inst":"Birmingham Children's Hospital (Birmingham, UK)"},{"author_name":"Bel\u00e9n P\u00e9rez-Due\u00f1as","author_inst":"Vall d'Hebron University Hospital and Biomedical Research Networking Centre on Rare Diseases (CIBERER) (Barcelona, Spain)"},{"author_name":"Alejandra Darling","author_inst":"Sant Joan de D\u00e9u Barcelona Children's Hospital (Barcelona, Spain)"},{"author_name":"Nardo Nardocci","author_inst":"The Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan, Italy)"},{"author_name":"Giovanna Zorzi","author_inst":"The Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan, Italy)"},{"author_name":"Boriana B\u00fcchner","author_inst":"Ludwig-Maximilians-Universit\u00e4t (LMU) Hospital (Munich, Germany)"},{"author_name":"Thomas Klopstock","author_inst":"Ludwig-Maximilians-Universit\u00e4t (LMU) Hospital, German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for Systems Neurology (SyNergy)  (Munich, "},{"author_name":"Amitav Parida","author_inst":"Birmingham Children's Hospital (Birmingham, UK)"},{"author_name":"Francesca Magrinelli","author_inst":"UCL Queen Square Institute of Neurology (London, UK)"},{"author_name":"Kailash P Bhatia","author_inst":"UCL Queen Square Institute of Neurology (London, UK)"},{"author_name":"Allison Gregory","author_inst":"Oregon Health and Science University (Oregon, USA)"},{"author_name":"Katrina Wakeman","author_inst":"Oregon Health and Science University (Oregon, USA)"},{"author_name":"Penelope Hogarth","author_inst":"Oregon Health and Science University (Oregon, USA)"},{"author_name":"Susan Hayflick","author_inst":"Oregon Health and Science University (Oregon, USA)"},{"author_name":"Amanda Heslegrave","author_inst":"UCL UK Dementia Research Institute and UCL Queen Square Institute of Neurology (London, UK)"},{"author_name":"Henrik Zetterberg","author_inst":"UCL and University of Gothenburg"},{"author_name":"Wendy E Heywood","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Asthik Biswas","author_inst":"Great Ormond Street Hospital (London, UK)"},{"author_name":"Ulrike L\u00f6bel","author_inst":"Great Ormond Street Hospital (London, UK)"},{"author_name":"Kshitij Mankad","author_inst":"Great Ormond Street Hospital (London, UK)"},{"author_name":"Jan Sedlacik","author_inst":"UCL and Imperial College London"},{"author_name":"Sniya Sudhakar","author_inst":"Great Ormond Street Hospital (London, UK)"},{"author_name":"Christopher Clark","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Kevin MIlls","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health (London, UK)"},{"author_name":"Manju A Kurian","author_inst":"University College London (UCL) Great Ormond Street Institute of Child Health and Great Ormond Street Hospital (London, UK)"}],"rel_date":"2026-07-22","rel_site":"medrxiv"},{"rel_title":"Deep interpretable learning of sample representations for characterizing disease states in single-cell transcriptomics","rel_doi":"10.64898\/2026.07.21.738207","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.738207","rel_abs":"Single-cell transcriptomics technology offers unprecedented insights into molecular heterogeneity. However, capturing sample-level representations that reflect both systemic and cellular states remains challenging, especially when disease annotations are mostly available as coarse sample-level labels. Here, we introduce Phenoverse, an interpretable deep learning framework that learns sample-level disease state representations through cell type-aware residual encoding, prototype learning, and Perceiver-based aggregation. Applied to independent single-cell transcriptomic cohorts of COVID-19, Alzheimer's disease, and systemic lupus erythematosus, totaling over 5 million cells, we demonstrate that learned sample representations enable disease state prediction and encode a continuous spectrum of disease severity on unseen data that correlate with multiple clinical and pathological measures, despite being trained solely on binary phenotype labels. Further, we demonstrate that trajectory-derived genes reveal cross-cohort molecular programs and show consistently higher reproducibility than traditional case-control comparisons. Finally, prototype learning provides intrinsic model interpretability and enables the characterization of cell type-specific disease states. Taken together, Phenoverse offers an interpretable disease-phenotyping approach to dissecting sample heterogeneity, and our results highlight its utility in translating complex single-cell transcriptomic data into patient-level biological insights.","rel_num_authors":7,"rel_authors":[{"author_name":"Manoj M Wagle","author_inst":"The University of Sydney, MIT CSAIL"},{"author_name":"Yongheng Wang","author_inst":"MIT CSAIL, The Broad Institute of MIT and Harvard"},{"author_name":"Soham Samanta","author_inst":"MIT CSAIL"},{"author_name":"Zunpeng Liu","author_inst":"MIT CSAIL, The Broad Institute of MIT and Harvard"},{"author_name":"Ellis Patrick","author_inst":"The University of Sydney"},{"author_name":"Pengyi Yang","author_inst":"The University of Sydney"},{"author_name":"Manolis Kellis","author_inst":"MIT CSAIL, The Broad Institute of MIT and Harvard"}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"fastCDS: proteome-scale mapping of protein domains to genomic coordinates","rel_doi":"10.64898\/2026.07.18.739381","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.18.739381","rel_abs":"Abstract Summary: Mapping protein regions to genomic coordinates underpins the study of exon architecture and the interpretation of clinical variants in their exon context. Existing tools resolve individual queries accurately but scale poorly to proteome-wide analyses. We present fastCDS, a C++ toolkit with command line and Python interfaces for rapid protein-to-genome coordinate mapping from GTF annotations. It matches the accuracy of existing methods while running at least two to three orders of magnitude faster. Mapping all human Pfam domains in seconds, we used the resulting atlas to examine how exonic architecture varies with domain function. Availability and Implementation: fastCDS is freely available under the MIT license at {{https:\/\/github.com\/SotoLF\/fastCDS}} and can be installed with pip install fastCDS or mamba install -c bioconda fastCDS. Pre-built GTF genome indices are archived at Zenodo, DOI: https:\/\/zenodo.org\/records\/21436146.","rel_num_authors":3,"rel_authors":[{"author_name":"George Munoz-Esquivel","author_inst":"Universidad Nacional Mayor de San Marcos"},{"author_name":"Juan I Fuxman Bass","author_inst":"Boston University"},{"author_name":"Luis F Soto-Ugaldi","author_inst":"The Rockefeller University"}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"MagicLamp: a web server and software toolkit for targeted gene annotation of microbial functions","rel_doi":"10.64898\/2026.07.19.739457","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.19.739457","rel_abs":"Genome and metagenome annotation tools designed for large databases are ill-suited to the discovery of specialized, ecologically relevant microbial functions. MagicLamp (https:\/\/github.com\/Arkadiy-Garber\/MagicLamp) is a modular command-line software toolkit that performs targeted functional gene annotation searches using curated collections of hidden Markov models (HMMs), each representing discrete microbial metabolic processes. MagicLamp is also available as a web server: https:\/\/midauthorbio.com\/#magiclamp. This targeted approach enables sensitive and specific annotation of genes involved in defined microbial processes, allowing MagicLamp to serve as a dedicated repository for the annotation of specialized microbial functions currently overlooked in other databases and software. The server accepts unannotated genome assemblies or GenBank-formatted annotations to perform HMM-based searches against curated model sets with reproducible, model-specific bit-score thresholds. Automated results are returned as tabular summaries and interactive HTML reports containing cross-genome\/metagenome comparisons.","rel_num_authors":14,"rel_authors":[{"author_name":"Arkadiy Garber","author_inst":"Arizona State University"},{"author_name":"Isabella A Viney","author_inst":"University of Pennsylvania"},{"author_name":"Nancy Merino","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Gustavo Ramirez","author_inst":"California State University, Los Angeles"},{"author_name":"Michael J Pavia","author_inst":"Arizona State University"},{"author_name":"Sean M McAllister","author_inst":"University of Washington"},{"author_name":"Shiva Sadeghpour","author_inst":"California State University, Los Angeles"},{"author_name":"Abhijit Manna","author_inst":"University of Pennsylvania"},{"author_name":"Maya L Kreger","author_inst":"University of Pennsylvania"},{"author_name":"Brandon Wolk","author_inst":"University of Pennsylvania"},{"author_name":"Kim Eunwoo","author_inst":"University of Pennsylvania"},{"author_name":"June Qu","author_inst":"Carnegie Mellon University"},{"author_name":"Catherine R Armbruster","author_inst":"Carnegie Mellon University"},{"author_name":"Ileana Perez-Rodriguez","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"MGM2 as a Unified Foundation Model for Microbiome World Exploration","rel_doi":"10.64898\/2026.07.20.739063","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.20.739063","rel_abs":"Microbiomes are information-rich biological systems, yet most computational analyses still reduce communities to cohort-specific abundance tables. Here we introduce MGM2, a multimodal foundation model pretrained on 1,821,291 MicrobeAtlas samples and 225,067 OTUs clustered at 99% sequence similarity. MGM2 couples NTv3-derived microbial sequence embeddings with abundance conditioning and community-semantic alignment to learn transferable sample- and token-level representations. Frozen MGM2 representations outperformed DeepPhylo by 0.06 to 0.21 macro-AUROC across five temporally held-out MGnify hierarchy levels, with the largest gains for rare and fine-grained labels. In fecal microbiota transplantation, MGM2-XLarge achieved a response ROC AUC of 0.79 and reduced post-transplant Bray-Curtis distance by 15% relative to the recipient baseline. The same representation supported ASV-level trend forecasting across 24 wastewater treatment plants. Sparse autoencoder analysis resolved MGM2-XLarge token states into a 4,096-feature dictionary spanning taxonomic identity, abundance state, ecological context and technical variation. MGM2 therefore provides a sequence-aware and interpretable representation layer for microbiome classification, paired-community prediction, forecasting and feature discovery.","rel_num_authors":6,"rel_authors":[{"author_name":"Haohong Zhang","author_inst":"Huazhong University of Science and Technology"},{"author_name":"Yuli Zhang","author_inst":"Huazhong University of Science and Technology"},{"author_name":"Yuxuan Qi","author_inst":"Huazhong University of Science and Technology"},{"author_name":"Tianao Liu","author_inst":"The University of Sydney"},{"author_name":"Ronghua Yang","author_inst":"Dovetree synbio Ltd."},{"author_name":"Kang Ning","author_inst":"Huazhong University of Science and Technology"}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"Community diversity favors coexistence between bacteria and parasitic bacteriophages","rel_doi":"10.64898\/2026.07.21.739906","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739906","rel_abs":"Microbial communities often contain diverse bacteria and their specific viruses (bacteriophages). Lytic phages frequently select for host bacteria to evolve resistance, in-turn threatening phage extinction. However, in nature phage-bacteria interactions do not occur in isolation, but within complex communities containing other species. To test how community context can alter resistance evolution and phage persistence, we experimentally evolved Pseudomonas aeruginosa bacteria and a Pseudomonas-targeting phage with and without a community representing a cystic fibrosis disease pulmonary infection. Phages selected for rapid evolution of receptor-mediated resistance, regardless of community context. However, susceptible bacteria often persisted due to resistance-growth trade-offs. A diverse community favored increased frequencies of susceptibility, fueling higher phage densities and fewer phage extinctions. Our findings show that community complexity can constrain the evolution of phage resistance in bacteria, promoting host-parasite coexistence and fostering microbial diversity.","rel_num_authors":4,"rel_authors":[{"author_name":"Michael Blazanin","author_inst":"University of British Columbia"},{"author_name":"William An","author_inst":"Yale University"},{"author_name":"Abraham B. Tolkoff","author_inst":"Yale University"},{"author_name":"Paul E. Turner","author_inst":"Yale University"}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"Epistasis facilitates the long-term antigenic evolution of the influenza B virus hemagglutinin","rel_doi":"10.64898\/2026.07.22.739994","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.22.739994","rel_abs":"The antigenic drift of viral glycoproteins must be balanced by purifying selection pressure to maintain functionality. Understanding these evolutionary processes is key to predicting and combating viral evolution but is primarily based on influenza A(H3N2), which may limit generalisability. By characterising the influenza B virus haemagglutinin (HA) over 8 decades of circulation in humans, we found continuous genetic diversification, punctuated with antigenic changes that did not follow a linear path in antigenic space. Antigenic change is primarily underpinned by re-occurring mutations and deletions at positions 136, 150, 162-165, 197 and 203. These residues form complex epistatic networks that modulate the antigenic impact of mutation recycling. They also generate permissive backbones on which immune escape can emerge with limited replicative fitness cost. Our study identifies critical similarities and differences with A(H3N2) evolution and demonstrates the role of epistasis in balancing antigenic novelty with viral fitness. Our findings and genetic, antigenic and phenotypic datasets support the development of genotype-to-phenotype prediction tools, but such predictions need to capture the complex outcomes of epistasis.","rel_num_authors":18,"rel_authors":[{"author_name":"Lara S. U. Schwab","author_inst":"The University of Melbourne"},{"author_name":"RUOPENG XIE","author_inst":"University of Hong Kong"},{"author_name":"Ellie Reilly","author_inst":"The Peter Doherty Institute for Infection and Immunity"},{"author_name":"Malet Aban","author_inst":"WHO Collaborating Centre for Reference and Research on Influenza"},{"author_name":"Natalie Spirason","author_inst":"WHO Collaborating Centre for Reference and Research on Influenza"},{"author_name":"Yi-Mo Deng","author_inst":"WHO Collaborating Centre for Reference and Research on Influenza"},{"author_name":"Hu Shu","author_inst":"The University of Hong Kong"},{"author_name":"Randy Suryadinata","author_inst":"Royal Children's Hospital"},{"author_name":"Monica Galiano","author_inst":"Public Health England"},{"author_name":"Matthew Gartner","author_inst":"The Peter Doherty Institute"},{"author_name":"Kanta Subbarao","author_inst":"Laval University"},{"author_name":"Karen Laurie","author_inst":"Seqirus"},{"author_name":"Steve Rockman","author_inst":"University of Melbourne"},{"author_name":"Adam K Wheatley","author_inst":"University of Melbourne"},{"author_name":"Stephen J. Kent","author_inst":"University of Melbourne"},{"author_name":"Ian G Barr","author_inst":"WHO Collaborating Centre for Reference and Research Australia"},{"author_name":"Vijaykrishna Dhanasekaran","author_inst":"The University of Hong Kong"},{"author_name":"Marios Koutsakos","author_inst":"University of Melbourne"}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"Bacterial RNA polymerase exemplifies a general physical mechanism for accelerating protein-DNA association","rel_doi":"10.64898\/2026.07.21.739884","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739884","rel_abs":"Bacterial RNA polymerases (RNAPs) have two flexibly tethered  subunit C-terminal domains (-CTDs) that bind DNA. Interaction between -CTDs and some promoter DNA motifs is known to accelerate transcription initiation, but the physical mechanism by which it does so is unclear. We used single-molecule multiwavelength fluorescence microscopy to test how the diffusion-limited binding kinetics of core RNAP to non-promoter DNA differ from those of mutant RNAPs that lack one or both -CTDs. We find that even though -CTDs and their tethers are small compared to the complete RNAP molecule, the presence of two -CTDs accelerates DNA binding by ~10-fold and ~55-fold respectively relative to RNAP constructs in which one or both -CTDs are deleted. In contrast, the presence of -CTDs did not have a detectable effect on RNAP-DNA complex lifetimes in the absence of RNA synthesis. We explain how -CTDs achieve the dramatic acceleration of RNAP binding to DNA using a quantitative three-state kinetic model that includes a transient binding intermediate where only the -CTD(s) are bound to DNA, tethering the rest of the RNAP in the vicinity of DNA. The model and assumed parameters are validated using Brownian dynamics simulations of the DNA association reactions for two-, one-, or zero-CTD RNAP constructs. The combination of single-molecule experiments, mathematical theory, and simulations suggests that adding a flexible DNA-binding tether is a general physical mechanism which can accelerate the diffusion-limited binding of a large protein like RNAP to DNA and quantitatively defines the conditions under which this acceleration can occur.","rel_num_authors":10,"rel_authors":[{"author_name":"Francis Rivera","author_inst":"Brandeis Univ."},{"author_name":"Alex Turek","author_inst":"Brandeis Univ."},{"author_name":"Wencheng Ji","author_inst":"Weizmann Institute of Science"},{"author_name":"Matt Copeland","author_inst":"Brandeis Univ."},{"author_name":"Larry Friedman","author_inst":"Brandeis University"},{"author_name":"Fiona Stewart","author_inst":"Brandeis Univ."},{"author_name":"Johnson Chung","author_inst":"Brandeis Univ."},{"author_name":"Ariel Amir","author_inst":"Weizmann Institute of Science"},{"author_name":"Jane Kondev","author_inst":"Brandeis University"},{"author_name":"Jeff Gelles","author_inst":"Brandeis Univ."}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"Haplotype and diversity signatures of ultra-soft selective sweeps in HIV-1","rel_doi":"10.64898\/2026.07.21.739925","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.21.739925","rel_abs":"Many urgent medical and agricultural challenges are driven by resistance evolution via soft selective sweeps of multiple simultaneous mutations. Standard approaches to detect these mutations involve genome scans for regions with reduced diversity and increased haplotype lengths. However, it is unknown the extent to which those signatures persist as the number of mutations driving resistance grows. Here, we analyzed longitudinal linkage-resolved data from 10 intra-host HIV populations treated with broadly neutralizing antibody 10-1074. We found that HIV escapes 10-1074 with minimal perturbations to diversity and haplotype homozygosity in the region surrounding the sweep in the majority (8\/10) of treated individuals. We matched these in vivo escape trajectories to forward simulations and found that adaptive mutations conferring escape must have been present on 20 or more genetic backgrounds to generate these signatures. These \"ultra-soft\" sweep signatures more closely resemble genetic patterns in a treatment non-responder without an adaptive response to 10-1074 than those of two other trial participants where adaptation occurred via harder selective sweeps. Our results demonstrate that HIV can adapt to a broadly neutralizing antibody treatment while retaining nearly all of its standing genetic diversity and that selection scans dependent on regional diversity and haplotype homozygosity signatures fail in this \"ultra-soft\" regime.","rel_num_authors":4,"rel_authors":[{"author_name":"Elena Violeta Romero","author_inst":"University of Washington"},{"author_name":"Dylan A Clark","author_inst":"University of Washington"},{"author_name":"Lillian B Cohn","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Alison F Feder","author_inst":"University of Washington"}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"Motor Learning and Transfer Are Symmetric Across Hands","rel_doi":"10.64898\/2026.07.17.739258","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.17.739258","rel_abs":"Functional asymmetry between the cerebral hemispheres is a defining feature of the sensorimotor system, with the dominant hemisphere playing a central role in motor control. Whether motor learning is similarly lateralized, however, remains unresolved. To tackle this question, we combined a comprehensive meta-analysis (114 datasets) with a series of well-powered, preregistered experiments (N = 526) to test two core behavioral predictions of hemispheric lateralization in sensorimotor adaptation, a canonical form of motor learning: (1) adaptation is preferentially expressed in the dominant hand and (2) transfers asymmetrically between limbs. Across both approaches, we found that adaptation and interlimb transfer were strikingly symmetric. Together, these findings support a fundamental dissociation in the neural organization of skilled behavior: whereas motor control is lateralized to the dominant hemisphere, motor learning is supported by a neural architecture that functions symmetrically.","rel_num_authors":7,"rel_authors":[{"author_name":"Indranil Nyamsuren","author_inst":"Carnegie Mellon University"},{"author_name":"Ashley Statham","author_inst":"Carnegie Mellon University"},{"author_name":"Elise Mitchell","author_inst":"Carnegie Mellon University"},{"author_name":"Brayden Kohler","author_inst":"Carnegie Mellon University"},{"author_name":"Phoebe Lam","author_inst":"Carnegie Mellon University"},{"author_name":"Roberta L. Klatzky","author_inst":"Carnegie Mellon University"},{"author_name":"Jonathan S Tsay","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-07-22","rel_site":"biorxiv"},{"rel_title":"Social Adversity, Systemic Inflammation, and the Ticking of the Biological Aging Clocks in Men and Women","rel_doi":"10.64898\/2026.07.20.26358488","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358488","rel_abs":"ObjectivesWe tested how multi-level socioeconomic disadvantage relates to biological aging and systemic inflammation in women and men from the population-based Canadian Longitudinal Study on Aging (CLSA).\n\nMethodsWe examined cross-sectional data from 8,516 CLSA participants with baseline measures on systemic inflammatory biomarkers (C-reactive protein, interleukin-6, and tumoral necrosis factor-) and biological aging (metabolomic and six DNA methylation [DNAm] age estimates). Plasma samples underwent metabolomic profiling by Metabolon, Inc. Metabolomic age was estimated separately in males and females using sex-stratified models based on age-correlated metabolite levels. DNAm data generated using the Illumina Infinium MethylationEPIC v1.0 array were used to estimate DNAm age across six established models, including Horvath, Hannum, PhenoAge, GrimAge, GrimAge2, and DunedinPACE. We used log-transformed metabolite levels to calculate metabolomic age by sex. We linked education, income, material and social deprivation to biomarkers of systemic inflammation and biological aging stratified by sex using generalized linear models. Multivariable models were adjusted by age, major behavioral risk factors, and chronic conditions.\n\nResultsParticipants were aged on average of 62.6 years of age, and approximately 50% were females. In multivariable linear adjusted models, we found that in comparison to those earning [&ge;]$100K a year, women earning less <$20K were on average 1.14 (95%CI: 0.46, 1.82) year older with respect to metabolomic age; those earning [&ge;]$20K & <$50K were on average 0.90 (95%CI: 0.26, 1.53) years older; and those earning [&ge;]$50K & <$100K were on average 0.70 (95%CI: 0.05, 1.34) years older. We did not observe this dose response among men. A similar dose-response association was observed for interleukin-6 in both men and women.\n\nDiscussionThese findings suggest that socioeconomic adversity influences not only inflammatory pathways but also distinct biological aging processes, including metabolomic aging.","rel_num_authors":5,"rel_authors":[{"author_name":"Cesar Higgins Tejera","author_inst":"Johns Hopkins University"},{"author_name":"Rose Noroozi","author_inst":"Johns Hopkins University"},{"author_name":"Keenan  A. Walker","author_inst":"National Institute on Aging"},{"author_name":"Leah H. Rubin","author_inst":"Johns Hopkins University"},{"author_name":"Kathryn C Fitzgerald","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Acute associations between ambient air pollution and risks of preterm and early-term births: results from 8 states in the United States","rel_doi":"10.64898\/2026.07.19.26358434","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.19.26358434","rel_abs":"Ambient air pollution during pregnancy has been linked to adverse pregnancy outcomes, but evidence of acute exposure and shorter gestation length remains inconsistent. We examined the association between ambient air pollution and preterm (28-36 weeks) or early-term (37-38 weeks) births. Daily concentrations of 12 bias-corrected model-derived pollutants were linked to vital records of 1,085,162 preterm and 3,901,185 early-term singleton live births (2005-2017) across eight U.S. states. Under a time-stratified case-crossover design, odds ratios (OR) were estimated, adjusting for risks among ongoing pregnancies, meteorology, time trends and federal holidays. We estimated cumulative associations up to a 6-day lag using distributed lag models. Risk estimates per interquartile range increase were pooled across states using inverse-variance weighting. We observed positive associations between 0-2 day cumulative exposure to several air pollutants and early-term births, including NO2 (OR: 1.0023, 95% CI:1.0010, 1.0037 per 7.1 g\/m3), PM2.5 (OR=1.0022, 95% CI: 1.0006, 1.0038 per 4.6 g\/m3), PM2.5 organic carbon (OR= 1.0026, 95% CI: 1.0013, 1.0039 per 1.7 g\/m3) and PM2.5 elemental carbon (OR=1.0025, 95% CI: 1.0014, 1.0035 per 0.26 g\/m3). Associations with preterm birth were mostly null. Our findings suggest positive associations between short-term air pollution exposure, including PM and major PM2.5 components, and risks of early-term birth.","rel_num_authors":8,"rel_authors":[{"author_name":"Xiaping Zheng","author_inst":"Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University"},{"author_name":"Amy Fitch","author_inst":"School of Public Health, University of Nevada, Reno, Reno NV, USA"},{"author_name":"Joshua L. Warren","author_inst":"Department of Biostatistics, School of Public Health, Yale University"},{"author_name":"Hua Hao","author_inst":"Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University"},{"author_name":"Matthew J. Strickland","author_inst":"School of Public Health, University of Nevada Reno"},{"author_name":"Andrew J. Newman","author_inst":"NSF National Center for Atmospheric Research, Boulder CO, USA"},{"author_name":"Lyndsey A. Darrow","author_inst":"School of Public Health, University of Nevada, Reno"},{"author_name":"Howard H. Chang","author_inst":"Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Povidone-iodine ear wash and oral cotrimoxazole for chronic suppurative otitis media in Australian Aboriginal children: a randomised controlled 2x2 factorial design trial","rel_doi":"10.64898\/2026.07.20.26358454","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358454","rel_abs":"ObjectivesTo compare the effectiveness of povidone-iodine ear wash compared to no ear wash and oral cotrimoxazole compared to placebo given in addition to standard topical antibiotic treatment (ciprofloxacin drops) for chronic suppurative otitis media (CSOM) in Australian Aboriginal children.\n\nMethodsA randomised, parallel, 2 x 2 factorial design, assessor-blinded clinical trial in the remote Northern Territory of Australia. Aboriginal children with confirmed CSOM were eligible to be randomised into four treatment groups, allowing two primary treatment comparisons in a 2-in-1 trial approach. Participants received standard treatment (twice daily cleaning and topical ciprofloxacin drops) plus: i) either 16 weeks of pre-treatment povidone-iodine ear wash or no povidone-iodine ear wash; and ii) either 16 weeks of oral cotrimoxazole or placebo. Central randomisation with allocation concealment and triple-blinding of the oral antibiotic treatment arms was used. The relative risk (RR) and risk difference (RD) were estimated after adjustment for age, community, and the other intervention.\n\nThe primary outcome was the proportion of children with any otorrhoea (clinical failure) after 16 weeks of treatment. Secondary outcomes included size of tympanic membrane (TM) perforation and amount of discharge, time to cessation of discharge, proportion of children with respiratory and other pathogens in ear discharge (at baseline and 16 weeks) and hearing levels (at 12 months).\n\nFindings280 children with CSOM were randomised and 270 had their primary outcome assessed. Clinical failure (presence of any ear discharge) after 16 weeks of treatment was 66\/134 (49%) in the povidone-iodine group versus 69\/136 (51%) in the no povidone-iodine group (RD= -1% (-12,11), p= 0{middle dot}93) and 56\/134 (42%) in the cotrimoxazole group versus 79\/136 (58%) in the placebo group (RD= -16% (-28,-4), p=0{middle dot}007). The amount of discharge, TM perforation size, the level of hearing impairment, and serious adverse events were not significantly different in both treatment comparisons. Anaerobic growth (24%), Pseudomonas aeruginosa (21%) and Haemophilus influenzae (17%) were the most common pathogens found in the ear discharge before treatment. Fungi or yeast (24%), Staphylococcus aureus (15%), and anaerobic growth (10%) were the common pathogens after 16 weeks of treatment, with no significant differences between groups. At 12 months post-randomisation, 55-60% of children had at least one discharging ear and there was no difference between treatment groups.\n\nInterpretationPovidone-iodine ear washes did not contribute to better ear outcomes in this study. Cotrimoxazole for 16 weeks resulted in more children with clinical improvement to dry ears. Oral cotrimoxazole may play a role in reducing the burden of CSOM in populations with high rates of persistent disease.\n\nFundingThis study is funded by the National Health and Medical Research Council (NHMRC) grant number: 1060764.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSThere are three clinical trials relevant to the chronic suppurative otitis media (CSOM) treatments used in this study, two using povidone-iodine, and one of oral cotrimoxazole. Neither of the povidone-iodine trials showed impact from treatment. The trial of 6-12 weeks oral cotrimoxazole demonstrated benefit (15% increased clinical cure). The beneficial effect was not sustained, and the study was not placebo controlled.\n\nAdded value of this studyThis placebo-controlled factorial randomised controlled trial tests the efficacy of oral cotrimoxazole and povidone-iodine in a group of high-risk children. It combines clinical, hearing, and microbiological outcomes. We demonstrate the efficacy of oral cotrimoxazole for up to 16 weeks for children with CSOM.\n\nImplications of all the available evidenceThe best available evidence supports the use of cotrimoxazole as an adjunct therapy. A course longer than 12 weeks may be required to support clinical cure. The beneficial effect of cotrimoxazole did not persist to the 12 month follow up. The use of topical povidone-iodine as an adjunct therapy for CSOM is not supported.","rel_num_authors":16,"rel_authors":[{"author_name":"Jemima Beissbarth","author_inst":"Menzies School of Health Research, Charles Darwin University"},{"author_name":"Christine Wigger","author_inst":"Menzies School of Health Research, Charles Darwin University"},{"author_name":"Victor  M Oguoma","author_inst":"Menzies School of Health Research: Charles Darwin University"},{"author_name":"Amanda Jane Leach","author_inst":"Charles Darwin University - Casuarina Campus: Charles Darwin University"},{"author_name":"Ruth Lennox","author_inst":"Nil"},{"author_name":"Sandra Nelson","author_inst":"Northern Territory Department of Health"},{"author_name":"Hemanshu Patel","author_inst":"Northern Territory Department of Health"},{"author_name":"Mark D Chatfield","author_inst":"The University of Queensland"},{"author_name":"Katherine Currie","author_inst":"Central Australian Aboriginal Congress"},{"author_name":"Harvey Coates","author_inst":"Nil"},{"author_name":"Keith Edwards","author_inst":"Nil"},{"author_name":"Heidi C Smith-Vaughan","author_inst":"Menzies School of Health Research: Charles Darwin University"},{"author_name":"Kim M Hare","author_inst":"Nil"},{"author_name":"Paul John Torzillo","author_inst":"The University of Sydney"},{"author_name":"Steven Y.C Tong","author_inst":"Doherty Institute"},{"author_name":"Peter S Morris","author_inst":"Menzies School of Health Research, Charles Darwin University"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Complement drives PNH red cell hemolysis independently of inflammasome activation","rel_doi":"10.64898\/2026.07.20.26358486","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358486","rel_abs":"Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterized by hemolysis due to the loss of GPI-anchored complement regulators. While terminal complement inhibitors improve survival, the precise intracellular mechanisms driving the destruction of PNH erythrocytes remain controversial. A recently proposed model suggests PNH cells undergo an inflammatory programmed cell death (\"spectosis\") driven by an NLRP3-Caspase-8 signaling cascade. Here, we use a whole packed cell lysis approach to map the cytoskeletal degradation of primary erythrocytes across a 22-patient PNH cohort. Our data show that membrane attack complex (MAC) pore formation drives targeted {beta}-spectrin fragmentation, which correlates with rapid intracellular potassium (K+) efflux. Notably, when probing these primary patient samples, we detected a complete absence of the NLRP3 protein and found no functional evidence of Caspase-8 activation during MAC pore formation. Furthermore, caspase inhibition did not alter cytoskeletal degradation or K+ efflux. Instead, our data demonstrate that MAC-induced membrane perforation permits a rapid influx of calcium, which activates calpain, the dominant calcium-dependent protease in erythrocytes. Rather than an inflammatory cascade, this calcium-dependent calpain activity executes the degradation of {beta}-spectrin. These findings challenge current models of PNH hemolysis. We show that the destruction of PNH erythrocytes is a consequence of the MAC-calcium-calpain axis, rather than an inflammatory programmed cell death event. Consequently, therapeutic strategies aimed at targeting the inflammasome or caspase signaling will likely offer no clinical benefit for PNH patients.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC=\"FIGDIR\/small\/26358486v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (39K):\norg.highwire.dtl.DTLVardef@1852a95org.highwire.dtl.DTLVardef@1aead64org.highwire.dtl.DTLVardef@f997aaorg.highwire.dtl.DTLVardef@542de3_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":6,"rel_authors":[{"author_name":"Nikhil Ranjan","author_inst":"Johns Hopkins University"},{"author_name":"Michael Arthur Cole","author_inst":"Johns Hopkins University"},{"author_name":"Gloria Gerber","author_inst":"Johns Hopkins University"},{"author_name":"Daniel Flores-Guerrero","author_inst":"Johns Hopkins University"},{"author_name":"Shruti Chaturvedi","author_inst":"Johns Hopkins University"},{"author_name":"Robert Brodsky","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Genetic Counselor Utilization Across Non-Genetics Departments for Neurodevelopmental Disorders","rel_doi":"10.64898\/2026.07.20.26358492","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358492","rel_abs":"IMPORTANCEMost United States children with neurodevelopmental disorders have not received genetic testing aligned with current guidelines. Integration of genetic counselors into non-genetics departments is a potential strategy to improve uptake, but prevalence and details of integrated care models are unknown.\n\nOBJECTIVETo characterize availability, utilization, and perceived need for genetic counselors across non-genetics departments caring for patients with neurodevelopmental disorders\n\nDESIGNCross-sectional observational department-level survey\n\nSETTINGChild neurology, adult neurology, developmental pediatrics, child psychiatry, and adult psychiatry departments at Intellectual and Developmental Disabilities Research Centers\n\nPARTICIPANTSThe survey was distributed to 67 departments across 15 institutions. The departmental response rate was 52% (35\/67), with at least one response from 87% (13\/15) of institutions.\n\nEXPOSUREPresence\/absence of dedicated genetic counselor(s), where \"dedicated\" was defined as hired by the department\n\nMAIN OUTCOME(S) AND MEASURE(S)This was a descriptive study only, with no comparative statistical analyses due to the exploratory nature.\n\nRESULTSOne third of departments (34%; 12\/35) reported having dedicated clinical genetic counselors. Prevalence was highest in child neurology (67%; 8\/12), followed by adult neurology (40%; 2\/5) and developmental pediatrics (22%; 2\/9), with none in child psychiatry (0\/7) or adult psychiatry (0\/2). In almost all departments with genetic counselors (92%; 11\/12), they directly billed for their services, which universally included pre-test counseling\/consent and post-test counseling. In departments without genetic counselors, only 39% (9\/23) reported providers ordered their own genetic testing. Among all departments, over half (57%) were interested in adding\/increasing genetic counseling support, while 26% were unsure and 17% uninterested. Insufficient funding was the most cited barrier; only one department reported insufficient need.\n\nCONCLUSIONS AND RELEVANCEThough currently implemented in only one third of departments, our findings suggest those with dedicated genetic counselors directly pursue genetic testing (without referring to genetics) more than those without genetic counselors. Interest in increasing or adding genetic counseling support was high, and though funding was a reported barrier, feasible funding models were described. In the context of limited medical geneticists and expanding precision therapies, alternate delivery models for neurodevelopmental genetic testing including genetic counselor integration in non-genetics departments may help to scale and sustain uptake.\n\nKey PointsO_ST_ABSQUESTIONC_ST_ABSWhat is the availability, utilization, and perceived need for genetic counselors in non-genetics departments caring for individuals with neurodevelopmental disorders?\n\nFINDINGSIn this cross-sectional study of 35 neurology, psychiatry, and developmental pediatrics departments, one third reported having dedicated genetic counselors for clinical care. Most were interested in increasing or adding genetic counselor support; insufficient funding was the most reported barrier and only one department reported insufficient need.\n\nMEANINGMany non-genetics departments caring for individuals with neurodevelopmental disorders continue to rely on the traditional referral model to genetics departments for testing\/counseling despite substantial interest and support for integrating genetic counselors.","rel_num_authors":5,"rel_authors":[{"author_name":"Jordan Janae Cole","author_inst":"University of Colorado Anschutz"},{"author_name":"Julie S. Cohen","author_inst":"Kennedy Krieger Institute"},{"author_name":"Mustafa Sahin","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Siddharth Srivastava","author_inst":"Boston Children's Hospital, Harvard Medical School"},{"author_name":"Colleen A. Campbell","author_inst":"University of Iowa"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"LocusBlend: Flexible multi-index regional visualization of genomic association signals","rel_doi":"10.64898\/2026.07.15.26358129","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.15.26358129","rel_abs":"SummaryIt has become standard practice to visualize regional signals from genome-wide association studies (GWAS) using LocusZoom plots. Similarly, GWAS signals are compared to regionally matched quantitative trait loci (QTLs), i.e. variant-to-gene regulation data, using LocusCompare plots to aid assessment of candidate trait-related genes. Despite broad usage, these tools annotate variants by linkage disequilibrium (LD) to a single lead or index variant. This single-index representation has limitations for visualizing complex loci that contain multiple independent signals. We present LocusBlend, an interactive web application for multi-index LD-blended visualization of genomic loci. LocusBlend supports one or two genomic association summary-statistic datasets and one to three index variants, multi-index LocusZoom color-blended plots, and matching LocusCompare visualizations. Applications to Alzheimers disease GWAS and QTL signals illustrate LocusBlend enables visualization and separation of independent signals despite shared LD and high genomic complexity. Overall, LocusBlend is aimed at supporting researchers handle the continuously expanding complexity of human genomics findings.\n\nAvailability and ImplementationLocusBlend is freely available at https:\/\/locusblend.wustl.edu. Publication ready plots are generated in <1min. Source code, documentation, example datasets, input templates, and reproducibility instructions are available at https:\/\/github.com\/Belloy-Lab\/LocusBlend. LocusBlend is implemented in Python using Streamlit, Plotly, and PLINK.\n\nSupplementary InformationSupplementary data are available at Bioinformatics online.","rel_num_authors":7,"rel_authors":[{"author_name":"chenyu yang","author_inst":"washington university in st louis"},{"author_name":"Noah Cook","author_inst":"Washington University in St. Louis"},{"author_name":"Youjie Zeng","author_inst":"Washington University in Saint Louis"},{"author_name":"Tianyi Fu","author_inst":"Washington University in St Louis"},{"author_name":"John budde","author_inst":"Washington University in St Louis"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University St. Louis"},{"author_name":"Michael E Belloy","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Quantifying the global burden of lead exposure from dietary lead intake","rel_doi":"10.64898\/2026.07.20.26358457","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358457","rel_abs":"BackgroundLead exposure is estimated to cause approximately 3.5 million premature deaths a year, yet the key ongoing sources of lead exposure are unclear.\n\nMethodsWe estimated the contribution of dietary lead intake to global blood lead levels (BLLs) for 7-year-old children and 22-year-old adults by applying the All-Ages Lead Model (AALM) to calculate blood lead levels (BLLs) based on 25 total diet studies (TDS) that quantify dietary lead intake across 46 countries.\n\nResultsFor children, the population-weighted average dietary lead intake in low- and middle-income countries (LMICs) (32.0 g\/day) was found to be more than three times higher than in high-income countries (HICs) (9.3 g\/day), and more than 10 times higher than the FDAs reference level for children (2.2 g\/day). The average impact on BLLs for children is estimated to be near 29 g\/L in LMICs and near 12 g\/L in HICs. Averaged across the TDS data, vegetables (27%) and cereals (24%) were found to contribute the most to dietary lead.\n\nConclusionsWhile there are limitations associated with biokinetic modelling and the TDS data from LMICs, these results suggest that the contribution of dietary lead intake to global lead exposure is in the region of 40 to 50%, suggesting, in turn, that dietary lead intake is likely a major global driver of lead poisoning. Lead absorbed from the environment into food crops is expected to be the key driver of dietary lead. Current regulatory levels for maximum lead concentrations in foods (0.05-0.3 mg\/kg) are out-of-date and may imply a dietary lead intake of 200 g\/day, far higher than the FDA reference level (2.2 g\/day). Collecting representative TDS data in high lead burden countries should be a priority. Further research is also recommended on upstream lead sources and pathways of lead uptake in plants, driving global food contamination.\n\nThis manuscript is a preprint and has not undergone peer review. It may be revised following review.\n\nHighlights- Dietary lead intake is likely a major driver of global lead exposure\n- Food contamination is largely driven by environmental pollution\n- International reference levels for lead levels in food are out-of-date\n- Levels in HICs show interventions to reduce dietary lead intake are possible\n- Research is needed to aid interventions to reduce lead contamination in food crops","rel_num_authors":3,"rel_authors":[{"author_name":"Christopher Kinally","author_inst":"Pure Earth"},{"author_name":"Howard Hu","author_inst":"University of Southern California"},{"author_name":"Richard Fuller","author_inst":"Columbia University, New York, NY, United States"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"EASing Oxytocin in Early Labour - OUTcomes for Mothers and Babies (EASE-OUT): a feasibility randomised controlled trial","rel_doi":"10.64898\/2026.07.18.26358404","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.18.26358404","rel_abs":"ObjectiveTo assess the feasibility of a definitive randomised controlled trial comparing halved versus routine-concentration oxytocin infusion during active phase of the first stage of labour in women undergoing induction of labour.\n\nDesignMulticentre, double-blind, randomised feasibility trial with 1:1 allocation.\n\nParticipantsWomen & birthing people aged 18 years or older undergoing planned induction of labour in two public maternity hospitals in Sydney, Australia, between September 2023 and September 2025 were eligible. Key exclusions included previous caesarean delivery, pre-existing diabetes, major fetal anomaly, abnormal fetal cardiotocography, malpresentation, suspected cephalopelvic disproportion, suspected chorioamnionitis, intrapartum pyrexia, and other predefined maternal or fetal safety concerns.\n\nInterventionsAll participants commenced induction with standard oxytocin during the latent phase (10 IU in 1 L crystalloid). At established active labour, participants were randomised to receive either halved-concentration oxytocin (5 IU in 1 L crystalloid) or routine-concentration oxytocin (10 IU in 1 L normal saline), titrated according to the New South Wales (NSW) Health oxytocin protocol between one and 40 mIUmin-1.\n\nMain outcome measuresFeasibility outcomes were recruitment, consent, randomisation, retention, protocol adherence, unblinding, and treatment separation, assessed by total oxytocin dose and infusion rates. Secondary outcomes included maternal, neonatal, and participant-reported outcomes.\n\nResultsOf 771 women assessed for eligibility in two centres, 572 were approached and 293 (51%) consented to participate, of whom 101 (34%) were randomised. During active recruitment, randomised participants represented 9.2% of all births. Baseline characteristics were similar between groups. No between-group differences were observed in maternal, neonatal, or participant-reported outcomes, although the trial was not powered to assess clinical effectiveness. Satisfaction outcomes were ascertained for 69% (70\/101) participants. There was 100% ascertainment for short-term clinical outcomes and for readmissions to the hospital of delivery. Twenty-nine participants were interested in providing feedback and in being involved in developing a larger study across multiple hospitals.\n\nConclusionsA blinded randomised controlled trial of oxytocin dose reduction in active labour is feasible in a real-world labour ward.\n\nTrial registrationThis trial was registered on the ANZCTR (ACTRN12622001342707)\n\nFundingThis trial was supported through seed funding from the Sydney Institute for Women, Children and their Families, Sydney Local Health District and the NHMRC Clinical Trials Centre, University of Sydney.","rel_num_authors":11,"rel_authors":[{"author_name":"Alanna Krisanaleela","author_inst":"Royal Prince Alfred Women's and Babies Unit, Sydney Local Health District, Camperdown Australia"},{"author_name":"Belinda R Bruce","author_inst":"The University of Sydney Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, Camperdown, Australia"},{"author_name":"Hala Phipps","author_inst":"Sydney Institute for Women, Children and their Families, RPA Women and Babies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia"},{"author_name":"Rachael Morton","author_inst":"National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Australia"},{"author_name":"Jon A Hyett","author_inst":"Western Sydney University"},{"author_name":"William Tarnow-Mordi","author_inst":"National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Australia"},{"author_name":"Adrienne Gordon","author_inst":"Sydney Institute for Women, Children and their Families, RPA Women and Babies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown, Australia"},{"author_name":"Shideh Pakzadian","author_inst":"Royal Prince Alfred Women's and Babies Unit, Sydney Local Health District, Camperdown Australia"},{"author_name":"Karen Lawrence","author_inst":"Royal Prince Alfred Women's and Babies Unit, Sydney Local Health District, Camperdown Australia"},{"author_name":"Melissa Wang","author_inst":"Royal Prince Alfred Women's and Babies Unit, Sydney Local Health District, Camperdown Australia"},{"author_name":"Bradley S de Vries","author_inst":"Sydney Institute for Women, Children and their Families"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Quantitative Prognostic Modeling in Aneurysmal Subarachnoid Hemorrhage: Multicenter Validation of the eSAH Score","rel_doi":"10.64898\/2026.07.18.26358390","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.18.26358390","rel_abs":"Backgroundaneurysmal subarachnoid hemorrhage (aSAH) is neurological emergency associated with substantial mortality and disability. Current grading systems such as the modified Fisher Scale (mFS) and World Federation of Neurological Societies (WFNS) score, rely on semiquantitative and examination based assessments. Hence, they demonstrate limited predictive precision. The enhanced subarachnoid hemorrhage (eSAH) score is a simplified quantitative model integrating age, Glasgow Coma Scale (GCS), and cisternal subarachnoid hemorrhage volume (SAHV) to predict clinical outcomes after aSAH.\n\nMethodsWe performed a retrospective multicenter cohort study that included 1088 patients across three tertiary-care centers the United States. Predictive performance for unfavorable functional outcome, in-hospital mortality and delayed cerebral ischemia (DCI) was evaluated using receiver operating characteristic (ROC) analysis and area under the curve (AUC). Comparative analyses were performed and compared to the WFNS and mFS grading systems.\n\nResultsthe eSAH score demonstrated excellent discrimination for unfavorable functional outcome at discharge ( AUC 0.89 ) and in-hospital mortality (AUC 0.87). The DCI subscore demonstrated good discriminatory performance for predicting DCI (AUC 0.77). Compared with conventional grading systems, this was superior to both the WFNS (AUC 0.75) and the mFS ( AUC 0.70). increasing eSAH scores were additionally associated with progressively higher rates of mortality and unfavorable functional outcomes.\n\nConclusionthe eSAH score demonstrates strong external validity, reproducibility and superior predictive performance compared with conventional grading systems in a large multicenter cohort. These findings support the clinical utility of quantitative hemorrhage burden integration for early risk stratification in patients with aSAH.","rel_num_authors":21,"rel_authors":[{"author_name":"Saif Salman","author_inst":"Departments of Neurological surgery Neurology and Critical Care, Mayo Clinic, Jacksonville, Florida, USA"},{"author_name":"Constantin Graf von Moy","author_inst":"Departments of Neurologic Surgery, Neurology, and Critical Care, Mayo Clinic, Jacksonville, Florida, USA"},{"author_name":"Flora Haidenberger","author_inst":"Departments of Neurologic Surgery, Neurology, and Critical Care, Mayo Clinic, Jacksonville, Florida, USA"},{"author_name":"Mahlika Ahmed","author_inst":"Departments of Neurologic Surgery, Neurology, and Critical Care, Mayo Clinic, Jacksonville, Florida, USA"},{"author_name":"Fabian Foettinger","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria and Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University"},{"author_name":"Rohan Sharma","author_inst":"Neurology, Creighton University, Omaha, Nebraska, USA"},{"author_name":"Salvador Gutierrez-Aguirre","author_inst":"Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA"},{"author_name":"Otavio de Toledo","author_inst":"Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA"},{"author_name":"Vishal Patel","author_inst":"Department of Radiology, Mayo Clinic, Jacksonville, Florida, USA"},{"author_name":"David Yujia-Wei","author_inst":"Department of Radiology, Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA"},{"author_name":"Behnam Rezai Jahromi","author_inst":"Department of Neurosurgery, University of Helsinki, Helsinki, Finland"},{"author_name":"Nicholas Brandmeir","author_inst":"Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, West Virginia"},{"author_name":"Kausik Lakkaraju","author_inst":"Departments of Neurologic Surgery, Neurology, and Critical Care, Mayo Clinic, Jacksonville, Florida, USA"},{"author_name":"Mutaz Ombada","author_inst":"Charleston Area Medical Center Institute for Academic Medicine\/WVU School of Medicine Charleston campus, Charleston, South Carolina, USA"},{"author_name":"Pedro Aguilar-Salinas","author_inst":"Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA"},{"author_name":"David Miller","author_inst":"Departments of Neurologic Surgery, Neurology, and Critical Care, Mayo Clinic, Jacksonville, Florida, USA"},{"author_name":"Bradley Erickson","author_inst":"Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA"},{"author_name":"Ricardo Hanel","author_inst":"Endowed Chair of Stroke and Cerebrovascular Surgery, Baptist Health, Jacksonville, Florida, USA"},{"author_name":"Rabih Tawk","author_inst":"Departments of Neurologic Surgery, Neurology, and Critical Care, Mayo Clinic, Jacksonville, Florida, USA"},{"author_name":"Richard Byrne","author_inst":"Chair, Department of Neurologic Surgery, Mayo Clinic, Jacksonville, Florida, USA and Chair, Specialty Neurosurgery Council, Mayo Clinic, Jacksonville, Florida, "},{"author_name":"William David Freeman","author_inst":"Departments of Neurologic Surgery, Neurology, and Critical Care, Mayo Clinic, Jacksonville, Florida, USA"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Radiomics of the Airway (RadAr): Multi-Scale Airway Phenotyping for Disease Characterization on Routine CT Imaging","rel_doi":"10.64898\/2026.07.19.26358441","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.19.26358441","rel_abs":"PurposeAirway remodeling is a convergent feature across respiratory diseases, yet current CT tools provide limited characterization of the airway tree. We present Radiomics of the Airway (RadAr), an automated framework for multi-scale airway phenotyping from routine chest CT.\n\nMethodsRadAr extracts multi-scale, interpretable airway measurements capturing luminal dimensions, tapering, architectural distortion, and global morphology and provides an interactive web portal for analysis and visualization. It was evaluated across four settings: 63-week mortality prediction in fibrotic interstitial lung disease (fILD; N=147), COVID-19 severity prediction (N=1164), structure-function association in progressive pulmonary fibrosis (PPF; N=9) and structure-inflammation markers in pediatric cystic fibrosis (CF; N=11). Unsupervised clustering identified airway phenotypes across the fILD and COVID-19 cohorts.\n\nResultsIn fILD, lower-lobe architectural distortion was associated with mortality (balanced accuracy 0.654). In COVID-19, severe disease was independently associated with luminal dilation (AUC 0.719, odds ratio 2.32, p=0.017). In PPF, airway phenotypes correlated with forced vital capacity ({rho}=0.83), mid-expiratory flow ({rho}=0.87), and {superscript 1}{superscript 2}Xe MRI alveolar gas exchange impairment ({rho}=0.70). In pediatric CF, reduced tapering and increased cylindricity were associated with prior exacerbations and bronchoalveolar lavage neutrophilia ({rho}=-0.64 to -0.78). Five phenotypes were identified from extensive, tapered airway trees to sparse, dilated, thick-walled, tortuous trees, with increasing COVID-19 severity and fILD mortality across this spectrum.\n\nConclusionsRadAr identified interpretable, disease-specific airway signatures associated with function and outcomes across restrictive, obstructive, and mixed lung diseases in adult and pediatric settings. It provides a scalable framework that may support diagnosis, risk stratification, and longitudinal monitoring across pulmonary diseases.","rel_num_authors":11,"rel_authors":[{"author_name":"Pushkar Mutha","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology"},{"author_name":"Juyoung Lee","author_inst":"Emory University"},{"author_name":"George L. Silva","author_inst":"Emory University School of Medicine"},{"author_name":"Bastiaan Driehuys","author_inst":"Duke University"},{"author_name":"Zachary Healy","author_inst":"Duke University"},{"author_name":"David Mummy","author_inst":"Duke University"},{"author_name":"Bhavika Kaul","author_inst":"Veterans Affairs Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center"},{"author_name":"Sundaresh Ram","author_inst":"Emory University & Georgia Institute of Technology"},{"author_name":"Rabindra Tirouvanziam","author_inst":"Emory University School of Medicine"},{"author_name":"Lokesh Guglani","author_inst":"Emory University School of Medicine"},{"author_name":"Anant Madabhushi","author_inst":"Emory University"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Development and Validation of Machine Learning Models for Predicting 13 or More Sections in Mohs Micrographic Surgery","rel_doi":"10.64898\/2026.07.20.26358484","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.20.26358484","rel_abs":"BackgroundCases requiring 13 or more tissue sections in Mohs micrographic surgery (MMS) demand extended operative time, additional resources, and often specialised closure techniques. Pre-operative identification of such cases would improve surgical scheduling, resource allocation, and patient counselling. We aimed to develop and validate a machine learning prediction tool using pre-operative clinical features to identify cases likely to require [&ge;]13 sections.\n\nObjectivesTo develop and validate machine learning models for predicting which Mohs procedures will require [&ge;]13 sections, using pre-operative clinical features, and to identify key predictive factors.\n\nMethodsWe analysed 408 consecutive Mohs procedures with 16 pre-operative clinical variables. Thirty machine learning algorithms were evaluated, including ensemble methods (Stacking, Voting), gradient boosting (XGBoost, LightGBM, CatBoost), neural networks (3-7 layers), support vector machines, and traditional classifiers. Model performance was assessed using 5-fold stratified cross-validation and independent test set evaluation. Feature importance was determined using SHAP (SHapley Additive exPlanations) analysis.\n\nResultsThe stacking ensemble achieved the highest cross-validation AUC of 0.891 (95% CI: 0.849-0.934) and test AUC of 0.884. Tumour area (cm{superscript 2}), calculated using the ellipse formula to approximate clinical tumour morphology, emerged as the strongest predictor (SHAP importance: 0.141), followed by tumour size dimensions (0.086 and 0.068), aggressive histopathology (0.046), and recurrence status (0.035). Wide neural network architectures (5-layer) outperformed deeper configurations (7-layer). The model demonstrated 70.7% high-confidence predictions with uncertainty <15%.\n\nConclusionsMachine learning models using pre-operative clinical features can accurately predict which Mohs procedures will require 13 or more sections. The stacking ensemble approach provides robust predictions suitable for clinical decision support. External validation in multi-centre cohorts with diverse patient populations and practice patterns is warranted to assess model generalisability.","rel_num_authors":3,"rel_authors":[{"author_name":"Yagiz Alp Aksoy","author_inst":"University of Sydney"},{"author_name":"Simon Lee","author_inst":"Skin Hospital"},{"author_name":"Gilberto Moreno-Bonilla","author_inst":"Skin Hospital"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Renal Outcomes of Staged Versus Concomitant Percutaneous Coronary Intervention and Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis","rel_doi":"10.64898\/2026.07.19.26353414","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.19.26353414","rel_abs":"BackgroundThe optimal timing of percutaneous coronary intervention (PCI) in patients undergoing transcatheter aortic valve replacement (TAVR) remains unclear, particularly regarding its impact on renal outcomes.\n\nMethodsWe conducted systematic review and meta-analysis of studies comparing staged versus concomitant PCI in patients with aortic stenosis and coronary artery disease undergoing TAVR. We searched MEDLINE, Embase, and Cochrane databases comprehensively. Using a random-effects model, we calculated odds ratios (OR) with 95% confidence intervals (CI) to assess the incidence of contrast-induced acute coronary injury (CI-AKI) across different stages.\n\nResultsThe analysis included 11 studies encompassing 7,119 patients. Overall, staged PCI did not significantly differ from concomitant PCI in reducing CI-AKI (OR 1.02; 95% CI 0.53 to 1.98; p = 0.959; Figure 1A). Subgroup analysis revealed no significant differences in stage 1 (OR 1.99; 95% CI 0.38 to 10.47; p = 0.417; Figure 1B) or stage 2 CI-AKI (OR 1.01; 95% CI 0.39 to 2.64; p = 0.978; Figure 1C). However, a statistically significant difference emerged for stage 3\/4 CI-AKI, favoring the staged approach (OR 0.48; 95% CI 0.24 to 0.99; p = 0.046; Figure 1D).\n\nO_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC=\"FIGDIR\/small\/26353414v1_fig1.gif\" ALT=\"Figure 1\">\nO_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC=\"FIGDIR\/small\/26353414v1_fig1a.gif\" ALT=\"Figure 1\">\nView larger version (69K):\norg.highwire.dtl.DTLVardef@d89588org.highwire.dtl.DTLVardef@1414c92org.highwire.dtl.DTLVardef@a2cddorg.highwire.dtl.DTLVardef@79fc3_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 1.C_FLOATNO Primary Endpoints for CI-AKI\n\nLegend: Compared to concomitant procedures, PCI and TAVI in a staged approach significantly reduced the odds of stages 3 or 4 CI-AKI in patients with CAD and SAS.\n\nC_FIG\n\nConclusionWhile staged PCI does not consistently reduce CI-AKI in patients undergoing TAVR, it may offer potential benefits for more severe kidney injury (stages 3\/4). Given the observed heterogeneity, large-scale randomized controlled trials are essential to establish the relationship between procedural timing and renal outcomes.","rel_num_authors":4,"rel_authors":[{"author_name":"Veda Chanda","author_inst":"Johns Hopkins University"},{"author_name":"Vinicius Bittar","author_inst":"Centro Universitario das Faculdades Associadas de Ensino"},{"author_name":"Pedro Carvalho","author_inst":"Federal University of Minas Gerais"},{"author_name":"Philippe Garot","author_inst":"Institut Cardiovasculaire Paris Sud, Massy, France"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Implementing the National Alzheimer's Coordinating Center Uniform Data Set (v3) within the Diabetes Prevention Program Outcomes Study","rel_doi":"10.64898\/2026.07.17.26357765","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.17.26357765","rel_abs":"INTRODUCTIONThe Diabetes Prevention Program (DPP) was a randomized clinical trial designed to prevent type 2 diabetes (T2D) in adults with prediabetes. The DPP Outcomes Study (DPPOS) is the 30-year follow-up of this cohort, focusing on T2D, prediabetes, and related complications. Cognitive assessments began in 2009 and expanded in 2022 to examine cognitive impairment, including Alzheimers disease (AD) and AD related dementias (ADRD), in the surviving cohort. To support these aims, the National Alzheimers Coordinating Center Uniform Data Set version 3 (NACC-UDSv3), the standardized framework used by Alzheimers Disease Research Centers, was implemented in DPPOS in 2022 to enable data sharing with NACC. These forms were complemented by cognitive tests administered in DPPOS. We aimed to integrate the NACC-UDSv3 into the existing longitudinal DPPOS framework while maintaining fidelity to its structure and developing automated reports to streamline cognitive outcomes adjudication.\n\nMETHODSItems from the 16 NACC-UDSv3 data forms were compared with those already collected within DPPOS to integrate overlapping similar items, add missing NACC-UDSv3 items, and create a dataset harmonized with NACC-UDSv3. Forms were adapted for electronic data capture (EDC) using the MIDAS (Multimodal Integrated Data Acquisition System, George Washington University). Automated reports integrated current and prior neuropsychological scores to support adjudications. In the first wave of the DPPOS-AD\/ADRD study, 1561 cognitive adjudications were successfully completed using the harmonized DPPOS and NACC-UDSv3 data implemented into MIDAS.\n\nDISCUSSIONThe DPPOS-AD\/ADRD project demonstrated that NACC-UDSv3 can be successfully integrated into a long-standing longitudinal cohort not originally designed for AD\/ADRD research. The harmonization, electronic capture, and automated adjudication processes may provide a practical framework for other cohorts seeking to incorporate NACC-UDSv3 to align with national AD\/ADRD research standards.","rel_num_authors":15,"rel_authors":[{"author_name":"Lindsay Doherty","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute of Public Health, George Washington University, Bethesda, MD"},{"author_name":"Isabella Dechiario","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Hanna Sherif","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute of Public Health, George Washington University, Bethesda, MD"},{"author_name":"Anna Bowers","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute of Public Health, George Washington University, Bethesda, MD"},{"author_name":"Dianilka Martinez","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Danurys L Sanchez","author_inst":"Department of Neurology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Gerardo J Febres","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Owen Carmichael","author_inst":"Pennington Biomedical Research Center, Baton Rouge, LA"},{"author_name":"Vallabh Shah","author_inst":"Department of Internal Medicine, University of New Mexico HSC, Albuquerque, NM"},{"author_name":"Neelesh K Nadkarni","author_inst":"Department of Medicine (Division of Geriatric Medicine), and Neurology, University of Pittsburgh, Pittsburgh PA"},{"author_name":"Terry E Goldberg","author_inst":"Department of Psychiatry, Columbia University Irving Medical Center, New York, NY"},{"author_name":"James M Noble","author_inst":"Department of Neurology, Columbia University Irving Medical Center, New York, NY andTaub Institute for Research on Alzheimer Disease and the Aging Brain, and G."},{"author_name":"JA A Luchsinger","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY"},{"author_name":"Marinella Temprosa","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute of Public Health, George Washington University, Bethesda, MD"},{"author_name":"DPP Research Group","author_inst":"-"}],"rel_date":"2026-07-21","rel_site":"medrxiv"},{"rel_title":"Diffusion MRI Profiles Map onto Distinct Inflammatory States After Adolescent Concussion: A CARE4Kids Study","rel_doi":"10.64898\/2026.07.17.26358354","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.17.26358354","rel_abs":"ImportanceNeuroinflammation is a key component of the response to injury after concussion, but direct links between diffusion MRI metrics and specific plasma inflammatory pathways in human concussion have not been established.\n\nObjectiveTo examine associations between diffusion MRI metrics and pathway-level inflammatory proteomic signatures in adolescents during the subacute period after concussion.\n\nDesign, Setting, and ParticipantsCross-sectional analysis of data from the CARE4Kids Consortium, a six-site prospective study. Participants were English-speaking adolescents ages 11-17.99 with concussion and symptoms at 7-35 days post-injury. Data were collected between 2022-2024. Of 370 enrolled participants, 122 had both diffusion MRI and plasma proteomics available for analysis.\n\nExposureAdvanced diffusion MRI metrics were converted to z-scores and participants were grouped by the spatial extent of outlier values (potholes and peaks) across 15 white matter regions of interest. Nine non-redundant groupings were selected for primary analysis.\n\nMain Outcomes and MeasuresPathway-level inflammatory profiles derived from gene set enrichment analysis (GSEA) of [~]5,400 plasma proteins measured by Olink proximity extension assay, targeting nine hallmark inflammatory pathways spanning initiation through resolution. Persistent symptoms were assessed 64-115 days post-injury.\n\nResultsDiffusion metrics reflecting tissue disorganization were associated with upregulation of the coagulation pathway, consistent with hemostatic-inflammatory signaling. Metrics reflecting reduced tissue complexity and neurite density were associated with upregulation of interferon- and interferon-{gamma} response pathways, consistent with microstructural remodeling driven by cellular immune activation. Elevated free water content was associated with downregulation of most inflammatory pathways and trend-level transforming growth factor - {beta} upregulation, reflecting inflammatory resolution. Time since injury did not differ between groups based on free water (Kolmogorov-Smirnov p = 0.97), suggesting these differences reflect individual variability in recovery pace. Exploratory analyses showed a trend toward lower odds of persistent symptoms in the group with elevated free water content (odds ratio = 0.51, p = 0.18).\n\nConclusions and RelevanceMultiple diffusion MRI metrics are differentially sensitive to distinct neuroinflammatory states in the subacute period after adolescent concussion. These findings suggest that diffusion imaging could serve as a non-invasive tool for inflammatory phenotyping, with potential implications for identifying patients who may benefit from targeted immunomodulatory intervention.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSAre specific diffusion MRI metrics sensitive to distinct inflammatory pathway signatures in adolescents during the subacute period after concussion?\n\nFindingsIn this cross-sectional study of 122 adolescents with concussion, multimodal diffusion MRI metrics were associated with mechanistically distinct proteomic signatures rather than a uniform inflammatory response. Metrics reflecting tissue disorganization were associated with hemostatic-inflammatory pathway upregulation, metrics reflecting reduced tissue complexity and neurite density were associated with interferon signaling and coagulation suppression, and elevated free water content was associated with inflammatory pathway downregulation and trend-level resolution-phase signaling.\n\nMeaningDifferent diffusion MRI metrics are sensitive to qualitatively different neuroinflammatory processes, suggesting that multimodal diffusion imaging may enable non-invasive profiling of the post-injury inflammatory state and inform targeted therapeutic strategies.","rel_num_authors":14,"rel_authors":[{"author_name":"Arum Lim","author_inst":"Johns Hopkins University"},{"author_name":"Jessica M Gill","author_inst":"Johns Hopkins University"},{"author_name":"Kevin C Bickart","author_inst":"University of California, Los Angeles"},{"author_name":"Adrian I Onicas","author_inst":"University of Utah"},{"author_name":"Jeffrey K Bazarian","author_inst":"University of Rochester"},{"author_name":"John Alice","author_inst":"Johns Hopkins University"},{"author_name":"Christine L Mac Donald","author_inst":"University of Washington"},{"author_name":"Anne Brown","author_inst":"University of California, Los Angeles"},{"author_name":"Lawrence Cook","author_inst":"University of Utah"},{"author_name":"Frederick P Rivara","author_inst":"University of Washington"},{"author_name":"Gerald A Gioia","author_inst":"Children's National Hospital"},{"author_name":"Christopher C Giza","author_inst":"University of California, Los Angeles"},{"author_name":"Emily L Dennis","author_inst":"University of Utah"},{"author_name":"- Concussion Assessment, Research, and Education for Kids (CARE4Kids) Consortium","author_inst":"-"}],"rel_date":"2026-07-20","rel_site":"medrxiv"},{"rel_title":"Early identification of suboptimal responders to metformin in type 2 diabetes using long-term real-world HbA1c trajectories","rel_doi":"10.64898\/2026.07.17.26357984","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.17.26357984","rel_abs":"AimsMetformin remains the primary treatment for type 2 diabetes, yet over 40% of patients fail to maintain glycaemic control. We aimed to identify patients unlikely to respond to metformin prior to treatment initiation and to evaluate whether on-treatment management can improve glycaemic outcomes in suboptimal responders, informing early treatment decisions.\n\nMaterials and MethodsWe analyzed 59,881 longitudinal HbA1c measurements from 7,105 patients with type 2 diabetes receiving metformin monotherapy using real-world electronic health records from Kaiser Permanente Northern California with up to six years of follow-up. We integrated demographic, clinical, genetic, and pharmacological factors to characterize metformin responder phenotypes and quantify the impact of adherence and weight control on time to glycaemic failure.\n\nResultsThree distinct trajectory-based phenotypes were identified: good (63.6%), poor (8.9%), and non-responders (27.5%). Poor responders initially achieved glycaemic targets but lost control within 2.5 years, while non-responders showed minimal HbA1c reduction and failed within 1 year. Five baseline factors--HbA1c, age at diagnosis, body mass index, sex, and estimated glomerular filtration rate--classified phenotypes with good discrimination (area under the receiver operating characteristic curve = 0.84). Incorporating on-treatment HbA1c further enhanced identification of non-responders. Among suboptimal responders, weight control and improved adherence delayed glycaemic failure by approximately 7 months; however, eventual glycaemic failure remained likely.\n\nConclusionsWe characterized three clinically relevant metformin responder phenotypes and showed that suboptimal responders can be identified early using baseline features. Poor and non-responders are unlikely to achieve durable glycaemic control with metformin alone and may require alternative treatment strategies.","rel_num_authors":9,"rel_authors":[{"author_name":"Eunsol Yang","author_inst":"University of California, San Francisco"},{"author_name":"Andrew Riselli","author_inst":"University of California, San Francisco"},{"author_name":"Fei Xu","author_inst":"Kaiser Permanente Northern California"},{"author_name":"Sneha B Sridhar","author_inst":"Kaiser Permanente Northern California"},{"author_name":"Mark Kvale","author_inst":"University of California, San Francisco"},{"author_name":"Kathleen M Giacomini","author_inst":"University of California, San Francisco"},{"author_name":"Monique M Hedderson","author_inst":"Kaiser Permanente Northern California"},{"author_name":"Sook Wah Yee","author_inst":"University of California, San Francisco"},{"author_name":"Rada M Savic","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-20","rel_site":"medrxiv"},{"rel_title":"Human inherited RORgammaT deficiency encompasses genetic heterogeneity, T cell deficiency, and clinical homogeneity","rel_doi":"10.64898\/2026.07.18.26358075","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.18.26358075","rel_abs":"We previously reported inherited ROR{gamma}T deficiency in seven patients from three ancestries (Chilean, Palestinian, Saudi Arabian) with mycobacterial disease and chronic mucocutaneous candidiasis (CMC). We report here five additional patients from different ancestries (Afghan, Indian, Iranian, Japanese, Sri Lankan), each homozygous for a new loss-of-function RORC variant. All but one patient -- the exception receiving early prophylaxis -- developed mycobacterial disease due to a near-complete depletion of innate-like adaptive T cells, including MAIT and iNKT cells, low counts of adaptive TH1* and CD8+ T cells, and impaired Mycobacterium-induced IFN-{gamma} production by the remaining cells of these subsets, NK cells, conventional CD4+ T, V{delta}1, and V{delta}2 {gamma}{delta}T cells. Most patients also displayed CMC due to their low counts of TH17 and TH1* cells. One patient died from disseminated Bacille Calmette-Guerin (BCG) vaccine infection, but, unexpectedly, all the other patients are still alive and clinically stable. ROR{gamma}T is essential for protective immunity against mycobacteria and Candida in humans.","rel_num_authors":48,"rel_authors":[{"author_name":"Iris Fagniez","author_inst":"Rockefeller University"},{"author_name":"Miyuki Tsumura","author_inst":"Hiroshima University"},{"author_name":"Antoine Guerin","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Hassan Abolhassani","author_inst":"Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences"},{"author_name":"Samin Sharafian","author_inst":"Shahid Beheshti University"},{"author_name":"Mehrnaz Mesdaghi","author_inst":"Shahid Beheshti University"},{"author_name":"Toyoki Nishimura","author_inst":"University of Miyazaki"},{"author_name":"Harsha Prasada","author_inst":"Kasturba Medical College, Mangalore"},{"author_name":"Sadashiva Rao","author_inst":"Kasturba Medical College Hospital"},{"author_name":"Stephanie Richards","author_inst":"Royal Children's Hospital"},{"author_name":"Ji Eun Han","author_inst":"Rockefeller University"},{"author_name":"Ottavia M. Delmonte","author_inst":"National Institutes of Health"},{"author_name":"Camille Kergaravat","author_inst":"Institut de recherche Saint-Louis"},{"author_name":"Janet G. Markle","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Masato Ogishi","author_inst":"Stanford Medicine"},{"author_name":"Jing Han","author_inst":"Rockefeller University"},{"author_name":"Jessica Peel","author_inst":"Rockefeller University"},{"author_name":"Joseph Vellutini","author_inst":"Rockefeller University"},{"author_name":"Yi Feng","author_inst":"Rockefeller University"},{"author_name":"Camille Soudee","author_inst":"Imagine Institute for Genetic Diseases"},{"author_name":"Melanie Migaud","author_inst":"Human Genetic of Infectious Diseases"},{"author_name":"Boaz Palterer","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Katherine J.L. Jackson","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Shiho Nishimura","author_inst":"Hiroshima University"},{"author_name":"Sonoko Sakata","author_inst":"Hiroshima University"},{"author_name":"Keishiro Kinoshita","author_inst":"Kyushu University"},{"author_name":"Ayako Yamamoto","author_inst":"University of Miyazaki"},{"author_name":"Hiroshi Moritake","author_inst":"University of Miyazaki"},{"author_name":"Mohammed Alzahrani","author_inst":"Security Forces Hospital"},{"author_name":"Francisco Vallejos","author_inst":"Hospital Dr. Gustavo Fricke"},{"author_name":"Theresa Cole","author_inst":"Royal Children's Hospital"},{"author_name":"Joanne Smart","author_inst":"Royal Children's Hospital"},{"author_name":"Sharon Choo","author_inst":"Royal Children's Hospital"},{"author_name":"Zahra Chavoshzadeh","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Shahnaz Arman","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Antoine Toubert","author_inst":"Institut de recherche Saint-Louis"},{"author_name":"Peng Zhang","author_inst":"Rockefeller University"},{"author_name":"Jeremie Rosain","author_inst":"Human Genetic of Infectious Diseases"},{"author_name":"Luigi D. Notarangelo","author_inst":"National Institutes of Health"},{"author_name":"Qiang Pan-Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Stuart G. Tangye","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Jean-Laurent Casanova","author_inst":"Rockefeller University"},{"author_name":"Cindy S. Ma","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Anne Puel","author_inst":"Human Genetic of Infectious Diseases"},{"author_name":"Jacinta Bustamante","author_inst":"Human Genetic of Infectious Diseases"},{"author_name":"Satoshi Okada","author_inst":"Hiroshima University"},{"author_name":"Stephanie Boisson-Dupuis","author_inst":"Rockefeller University"},{"author_name":"Rui Yang","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-07-20","rel_site":"medrxiv"},{"rel_title":"Human inherited RORgammaT deficiency encompasses genetic heterogeneity, T cell deficiency, and clinical homogeneity","rel_doi":"10.64898\/2026.07.18.26358075","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.18.26358075","rel_abs":"We previously reported inherited ROR{gamma}T deficiency in seven patients from three ancestries (Chilean, Palestinian, Saudi Arabian) with mycobacterial disease and chronic mucocutaneous candidiasis (CMC). We report here five additional patients from different ancestries (Afghan, Indian, Iranian, Japanese, Sri Lankan), each homozygous for a new loss-of-function RORC variant. All but one patient -- the exception receiving early prophylaxis -- developed mycobacterial disease due to a near-complete depletion of innate-like adaptive T cells, including MAIT and iNKT cells, low counts of adaptive TH1* and CD8+ T cells, and impaired Mycobacterium-induced IFN-{gamma} production by the remaining cells of these subsets, NK cells, conventional CD4+ T, V{delta}1, and V{delta}2 {gamma}{delta}T cells. Most patients also displayed CMC due to their low counts of TH17 and TH1* cells. One patient died from disseminated Bacille Calmette-Guerin (BCG) vaccine infection, but, unexpectedly, all the other patients are still alive and clinically stable. ROR{gamma}T is essential for protective immunity against mycobacteria and Candida in humans.","rel_num_authors":48,"rel_authors":[{"author_name":"Iris Fagniez","author_inst":"Rockefeller University"},{"author_name":"Miyuki Tsumura","author_inst":"Hiroshima University"},{"author_name":"Antoine Guerin","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Hassan Abolhassani","author_inst":"Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences"},{"author_name":"Samin Sharafian","author_inst":"Shahid Beheshti University"},{"author_name":"Mehrnaz Mesdaghi","author_inst":"Shahid Beheshti University"},{"author_name":"Toyoki Nishimura","author_inst":"University of Miyazaki"},{"author_name":"Harsha Prasada","author_inst":"Kasturba Medical College, Mangalore"},{"author_name":"Sadashiva Rao","author_inst":"Kasturba Medical College Hospital"},{"author_name":"Stephanie Richards","author_inst":"Royal Children's Hospital"},{"author_name":"Ji Eun Han","author_inst":"Rockefeller University"},{"author_name":"Ottavia M. Delmonte","author_inst":"National Institutes of Health"},{"author_name":"Camille Kergaravat","author_inst":"Institut de recherche Saint-Louis"},{"author_name":"Janet G. Markle","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Masato Ogishi","author_inst":"Stanford Medicine"},{"author_name":"Jing Han","author_inst":"Rockefeller University"},{"author_name":"Jessica Peel","author_inst":"Rockefeller University"},{"author_name":"Joseph Vellutini","author_inst":"Rockefeller University"},{"author_name":"Yi Feng","author_inst":"Rockefeller University"},{"author_name":"Camille Soudee","author_inst":"Imagine Institute for Genetic Diseases"},{"author_name":"Melanie Migaud","author_inst":"Human Genetic of Infectious Diseases"},{"author_name":"Boaz Palterer","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Katherine J.L. Jackson","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Shiho Nishimura","author_inst":"Hiroshima University"},{"author_name":"Sonoko Sakata","author_inst":"Hiroshima University"},{"author_name":"Keishiro Kinoshita","author_inst":"Kyushu University"},{"author_name":"Ayako Yamamoto","author_inst":"University of Miyazaki"},{"author_name":"Hiroshi Moritake","author_inst":"University of Miyazaki"},{"author_name":"Mohammed Alzahrani","author_inst":"Security Forces Hospital"},{"author_name":"Francisco Vallejos","author_inst":"Hospital Dr. Gustavo Fricke"},{"author_name":"Theresa Cole","author_inst":"Royal Children's Hospital"},{"author_name":"Joanne Smart","author_inst":"Royal Children's Hospital"},{"author_name":"Sharon Choo","author_inst":"Royal Children's Hospital"},{"author_name":"Zahra Chavoshzadeh","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Shahnaz Arman","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Antoine Toubert","author_inst":"Institut de recherche Saint-Louis"},{"author_name":"Peng Zhang","author_inst":"Rockefeller University"},{"author_name":"Jeremie Rosain","author_inst":"Human Genetic of Infectious Diseases"},{"author_name":"Luigi D. Notarangelo","author_inst":"National Institutes of Health"},{"author_name":"Qiang Pan-Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Stuart G. Tangye","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Jean-Laurent Casanova","author_inst":"Rockefeller University"},{"author_name":"Cindy S. Ma","author_inst":"Garvan Institute of Medical Research"},{"author_name":"Anne Puel","author_inst":"Human Genetic of Infectious Diseases"},{"author_name":"Jacinta Bustamante","author_inst":"Human Genetic of Infectious Diseases"},{"author_name":"Satoshi Okada","author_inst":"Hiroshima University"},{"author_name":"Stephanie Boisson-Dupuis","author_inst":"Rockefeller University"},{"author_name":"Rui Yang","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-07-20","rel_site":"medrxiv"},{"rel_title":"Validation of the SPiRO score for the prediction of ICU admission in patients presenting with leptospirosis in tropical Australia","rel_doi":"10.64898\/2026.07.17.26358361","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.17.26358361","rel_abs":"ObjectivesIn some resource-limited settings the case-fatality rate of severe leptospirosis can exceed 50%. Early recognition of severe disease can expedite transfer to referral centres for advanced supportive care. The entirely clinical, 3-point SPiRO score can be calculated rapidly at presentation to predict a patients subsequent clinical course. In its derivation study, a SPiRO score of 0 had a negative predictive value (NPV) for intensive care unit (ICU) admission of 98% (95% confidence interval (CI): 96-99). In this validation cohort we sought to confirm the clinical utility of the SPiRO score and to compare its prognostic utility with other leptospirosis-specific and general disease severity scores.\n\nMethodsWe examined consecutive adults presenting to high-caseload hospitals in tropical Australia with laboratory-confirmed leptospirosis between June 2016 and April 2026. The SPiRO scores ability to predict requirement for ICU admission before hospital discharge was compared with that of the leptospirosis-specific QuickLepto score and commonly used disease severity scores, namely the SOFA, qSOFA, qSOFA-lactate, NEWS-2, qNEWS, UVA and the SIRS scores.\n\nResultsICU admission was required in 62\/309 (20%) episodes of leptospirosis. The SPiRO score performed as well as - or better than - all the other scores in predicting ICU admission. The Area Under the Receiver Operating Characteristic curve for the SPiRO score was 0.83 (95% CI: 0.77-0.89); only the SOFA score had a higher value: 0.84 (0.79-0.90), although the difference was not statistically significant (p=0.08). The SPiRO score had the highest NPV for ICU admission of any of the scores: 95 (95% CI: 91-97)%.\n\nConclusionsThe SPiRO score can be calculated easily at the bedside at presentation to expedite the recognition of patients with leptospirosis who are most likely to deteriorate. In resource-limited settings this entirely clinical score can also help reduce unnecessary escalation of care, optimising the use of finite health resources.","rel_num_authors":11,"rel_authors":[{"author_name":"Patrick Rosengren","author_inst":"School of Medicine and Dentistry, James Cook University, Cairns, Queensland, Australia"},{"author_name":"Simon Smith","author_inst":"Department of Medicine, Cairns Hospital, Cairns, Queensland, Australia"},{"author_name":"Liam Johnston","author_inst":"School of Medicine and Dentistry, James Cook University, Cairns, Queensland, Australia"},{"author_name":"Thomas Coombs","author_inst":"Innisfail Hospital, Innisfail, Queensland, Australia"},{"author_name":"Alfred Song","author_inst":"Tully Hospital, Tully, Queensland, Australia"},{"author_name":"Nicholas Cairns","author_inst":"Atherton Hospital, Atherton, Queensland, Australia"},{"author_name":"Megan Staples","author_inst":"Leptospirosis Reference Laboratory, Coronial and Public Health Sciences, Brisbane, Queensland, Australia"},{"author_name":"Anna Brischetto","author_inst":"Leptospirosis Reference Laboratory, Coronial and Public Health Sciences, Brisbane, Queensland, Australia"},{"author_name":"Ibrahim Ishmail","author_inst":"Department of Medicine, Cairns Hospital, Cairns, Queensland, Australia"},{"author_name":"Hayley Stratton","author_inst":"Department of Medicine, Cairns Hospital, Cairns, Queensland, Australia"},{"author_name":"Josh Hanson","author_inst":"Kirby Institute, University of New South Wales"}],"rel_date":"2026-07-20","rel_site":"medrxiv"},{"rel_title":"Mechanism of response to FHD-286 and decitabine combination in patients with advanced myeloid malignancies","rel_doi":"10.64898\/2026.07.17.26358055","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.17.26358055","rel_abs":"Impaired cellular differentiation is a defining characteristic of myeloid malignancies and remains a major therapeutic challenge. The BRG1\/Brahma-associated factor (BAF) chromatin remodeling complex, through the ATPases SMARCA4 and SMARCA2, maintains the stemness of leukemic blasts and thus represents a promising target for novel differentiation-based therapies. In a phase 1 study in advanced myeloid malignancies, the first-in-class dual SMARCA4\/2 inhibitor FHD-286 combined with decitabine (DAC) was tolerated and produced an objective response rate of 12.8% (6\/47) compared with no responses with FHD-286 monotherapy. To understand the basis of this activity, we integrated high-dimensional flow cytometry and single-cell genomic analyses of longitudinal bone marrow samples from responders and nonresponders. While FHD-286 monotherapy was predominantly associated with myeloid differentiation, responders to FHD-286+DAC combination therapy exhibited a range of myeloid and erythroid differentiation trajectories. FHD-286 potentiated the transcriptional impact of DAC, driving tumor clones to fully differentiate out of the immunophenotypically and transcriptionally defined blast compartment. Responders had a baseline transcriptional profile similar to that of CEBPA-mutant acute myeloid leukemia and showed further downregulation of CEBPA upon treatment. These findings reinforce tumor cell differentiation as a mechanism of response to pharmacologic SMARCA4\/2 inhibition and support further evaluation of FHD-286+DAC in molecularly defined patient subsets.\n\nONE SENTENCE SUMMARYIn a phase 1 R\/R AML study, FHD-286 potentiated the effects of decitabine to promote responses via tumor cell differentiation and CEBPA perturbation.","rel_num_authors":20,"rel_authors":[{"author_name":"Michael P Collins","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"David L Lahr","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"Salih Topal","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"Alexis Khalil","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"Denice Hickman","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"Nicholas Spidale","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"Nikhil Pandit","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"Sarah Reilly","author_inst":"Akebia Therapeutics, Inc."},{"author_name":"Kelly Lyons","author_inst":"Agios Pharmaceuticals, Inc."},{"author_name":"Kim Horrigan","author_inst":"Syndax Pharmaceuticals"},{"author_name":"Tina Zhao","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"Joelle Batonga","author_inst":"Certara Integrated Drug Development"},{"author_name":"Mia Bosinger","author_inst":"Diamond Age Data Science, LLC"},{"author_name":"Katie D'Aco","author_inst":"Diamond Age Data Science, LLC"},{"author_name":"Brian Ball","author_inst":"Duarte Cancer Center, City of Hope"},{"author_name":"Ashwin Kishtagari","author_inst":"Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center"},{"author_name":"Courtney D DiNardo","author_inst":"Department of Leukemia, The University of Texas MD Anderson Cancer Center"},{"author_name":"Eytan M Stein","author_inst":"Leukemia Service, Memorial Sloan Kettering Cancer Center"},{"author_name":"Alfonso Quint\u00e1s-Cardama","author_inst":"Foghorn Therapeutics Inc."},{"author_name":"Gromoslaw A Smolen","author_inst":"Foghorn Therapeutics Inc."}],"rel_date":"2026-07-20","rel_site":"medrxiv"}]}