{"gname":"University of Kansas","grp_id":"33","rels":[{"rel_title":"ICU admission and mortality in adult patients with influenza A\/H1N1-related pneumonia in Vietnam since the 2009 H1N1 pandemic: a 10-year cohort study","rel_doi":"10.64898\/2026.04.18.26351156","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.18.26351156","rel_abs":"The A(H1N1)pdm09 virus remains a major global health threat. This study examined the burden of ICU admission, mortality, and associated predictors among patients with A(H1N1)pdm09 pneumonia in a leading center for infectious diseases in Vietnam. Information on demographic, clinical, and laboratory characteristics, and outcomes was retrieved from medical records of adults admitted with influenza A(H1N1)pdm09 during 2009-2019. Among 729 cases, 21.7% (158\/729) developed pneumonia. Among 158 pneumonia cases, 36.7% (58\/158) developed moderate-to-severe acute respiratory distress syndrome (ARDS), and 15.2% (24\/158) received invasive ventilation. ICU admission and mortality rates were 48.7% (77\/158, 95%CI 41.1-56.5%) and 8.2% (13\/158, 95%CI 4.9-13.6%), respectively. Predictors of ICU admission included being >60 years old (adjusted OR [AOR] 13.864, 95%CI 2.185-87.956, P=0.005), comorbidities (AOR 6.527, 95%CI 1.710-24.915, P=0.006), AST (AOR 1.013, 95%CI 1.001-1.025, P=0.029), and moderate-to-severe ARDS (AOR 14.027, 95%CI 4.220-46.627, P<0.001). Predictors of mortality were invasive ventilation (AOR 55.355, 95%CI 1.486-2062.375, P=0.030) and double-dose oseltamivir or combination therapy (AOR 32.625, 95%CI 1.594-667.661, P=0.024). In conclusion, mortality is not rare in A(H1N1)pdm09 infection. Monitoring of older patients and those with comorbidities, liver enzyme elevation, or moderate-to-severe ARDS is essential for the timely detection of complications requiring intensive care.","rel_num_authors":13,"rel_authors":[{"author_name":"Minh  Quang Ho","author_inst":"HTD: Hospital for Tropical Diseases"},{"author_name":"Thuy  Bich Duong","author_inst":"FV Hospital: Franco Vietnamese Hospital"},{"author_name":"Tung  Le Nhu Nguyen","author_inst":"HTD: Hospital for Tropical Diseases"},{"author_name":"Nugraha Susilawati Tri","author_inst":"Sebelas Maret University: Universitas Sebelas Maret"},{"author_name":"Tam Bui","author_inst":"University Medical Center Ho Chi Minh City"},{"author_name":"Truc  Thanh Thai","author_inst":"University of Medicine and Pharmacy at Ho Chi Minh City"},{"author_name":"David  J. Muscatello","author_inst":"UNSW: University of New South Wales"},{"author_name":"Anthony  J. Sunjaya","author_inst":"UNSW: University of New South Wales"},{"author_name":"Siyu Chen","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Nguyen  Thanh Nguyen","author_inst":"Tam Anh general hospital Ho Chi Minh city"},{"author_name":"Thu  Minh Nguyen","author_inst":"HTD: Hospital for Tropical Diseases"},{"author_name":"Anh  Thi Kim Nguyen","author_inst":"OUCRU: Oxford University Clinical Research Unit"},{"author_name":"Cuong  Minh Duong","author_inst":"UNSW: University of New South Wales"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"ICU admission and mortality in adult patients with influenza A\/H1N1-related pneumonia in Vietnam since the 2009 H1N1 pandemic: a 10-year cohort study","rel_doi":"10.64898\/2026.04.18.26351156","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.18.26351156","rel_abs":"The A(H1N1)pdm09 virus remains a major global health threat. This study examined the burden of ICU admission, mortality, and associated predictors among patients with A(H1N1)pdm09 pneumonia in a leading center for infectious diseases in Vietnam. Information on demographic, clinical, and laboratory characteristics, and outcomes was retrieved from medical records of adults admitted with influenza A(H1N1)pdm09 during 2009-2019. Among 729 cases, 21.7% (158\/729) developed pneumonia. Among 158 pneumonia cases, 36.7% (58\/158) developed moderate-to-severe acute respiratory distress syndrome (ARDS), and 15.2% (24\/158) received invasive ventilation. ICU admission and mortality rates were 48.7% (77\/158, 95%CI 41.1-56.5%) and 8.2% (13\/158, 95%CI 4.9-13.6%), respectively. Predictors of ICU admission included being >60 years old (adjusted OR [AOR] 13.864, 95%CI 2.185-87.956, P=0.005), comorbidities (AOR 6.527, 95%CI 1.710-24.915, P=0.006), AST (AOR 1.013, 95%CI 1.001-1.025, P=0.029), and moderate-to-severe ARDS (AOR 14.027, 95%CI 4.220-46.627, P<0.001). Predictors of mortality were invasive ventilation (AOR 55.355, 95%CI 1.486-2062.375, P=0.030) and double-dose oseltamivir or combination therapy (AOR 32.625, 95%CI 1.594-667.661, P=0.024). In conclusion, mortality is not rare in A(H1N1)pdm09 infection. Monitoring of older patients and those with comorbidities, liver enzyme elevation, or moderate-to-severe ARDS is essential for the timely detection of complications requiring intensive care.","rel_num_authors":13,"rel_authors":[{"author_name":"Minh  Quang Ho","author_inst":"HTD: Hospital for Tropical Diseases"},{"author_name":"Thuy  Bich Duong","author_inst":"FV Hospital: Franco Vietnamese Hospital"},{"author_name":"Tung  Le Nhu Nguyen","author_inst":"HTD: Hospital for Tropical Diseases"},{"author_name":"Nugraha Susilawati Tri","author_inst":"Sebelas Maret University: Universitas Sebelas Maret"},{"author_name":"Tam Bui","author_inst":"University Medical Center Ho Chi Minh City"},{"author_name":"Truc  Thanh Thai","author_inst":"University of Medicine and Pharmacy at Ho Chi Minh City"},{"author_name":"David  J. Muscatello","author_inst":"UNSW: University of New South Wales"},{"author_name":"Anthony  J. Sunjaya","author_inst":"UNSW: University of New South Wales"},{"author_name":"Siyu Chen","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Nguyen  Thanh Nguyen","author_inst":"Tam Anh general hospital Ho Chi Minh city"},{"author_name":"Thu  Minh Nguyen","author_inst":"HTD: Hospital for Tropical Diseases"},{"author_name":"Anh  Thi Kim Nguyen","author_inst":"OUCRU: Oxford University Clinical Research Unit"},{"author_name":"Cuong  Minh Duong","author_inst":"UNSW: University of New South Wales"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Oral and plasma microbiome in the context of acute febrile illness","rel_doi":"10.64898\/2026.04.16.26351042","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351042","rel_abs":"Emerging infectious diseases and antimicrobial resistance (AMR) have surfaced as two major public health threats over the past two decades. Consequently, integrative surveillance systems capable of detecting both emerging pathogens and resistance-carrying bacteria are crucial. With advances in next-generation sequencing, simultaneous detection of pathogens and AMR is increasingly feasible. In this study, we used short-read metatranscriptomics complemented by total 16S rRNA metagenomic long-read sequencing to analyze paired oral and plasma samples from a cohort of febrile individuals at two locations in Senegal. Oral microbiomes differed in community composition between locations, and reduced diversity and richness were significantly associated with high fever. We identified at least one known pathogen in 15.33 % (23\/150) of samples, with Borrelia crocidurae as the most frequently detected pathogen. We detected both pathogenic and non-pathogenic viruses in oral (10\/72) and plasma (09\/78) samples. Finally, we observed a high frequency of genes associated with resistance and virulence: 10% of samples expressed at least one AMR gene (ARG), and 24% expressed virulence factor genes. Resistance to widely used beta-lactam antibiotics was the most prevalent. Our findings provide critical data on oral and plasma microbiomes in the context of acute febrile illness in Senegal while expanding understanding of circulating ARGs.","rel_num_authors":21,"rel_authors":[{"author_name":"Mouhamad Sy","author_inst":"Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.; International Research and Training Center for Applied Genomics and"},{"author_name":"Tolla Ndiaye","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal.; Department of Microbiology and Immuno"},{"author_name":"Ritika Thakur","author_inst":"Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA."},{"author_name":"Amy Gaye","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal."},{"author_name":"Zoe C. Levine","author_inst":"Harvard\/MIT MD-PhD Program, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, United States."},{"author_name":"Bassirou Ngom","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal."},{"author_name":"Karina L. Bellavia","author_inst":"Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA."},{"author_name":"David Firer","author_inst":"Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA."},{"author_name":"Mariama Toure","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal."},{"author_name":"Ibrahima M. Ndiaye","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal."},{"author_name":"Younouss Diedhiou","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal."},{"author_name":"Amadou M. Mbaye","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal."},{"author_name":"Jules F. Gomis","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal."},{"author_name":"Katherine C. DeRuff","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, United States."},{"author_name":"Awa B. Deme","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal."},{"author_name":"Mouhamadou Ndiaye","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal.; Department of Parasitology, Faculty o"},{"author_name":"Aida S. Badiane","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal.; Department of Parasitology, Faculty o"},{"author_name":"Marietou Faye Paye","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, United States."},{"author_name":"Pardis C. Sabeti","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, U"},{"author_name":"Daouda Ndiaye","author_inst":"International Research and Training Center for Applied Genomics and Health Surveillance (CIGASS) at UCAD, Dakar, Senegal.; Department of Parasitology, Faculty o"},{"author_name":"Katherine J. Siddle","author_inst":"Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA."}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Proteomic Age Acceleration in Multiple Sclerosis Precedes Symptom Onset and Associates with Severity","rel_doi":"10.64898\/2026.04.13.26350634","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.13.26350634","rel_abs":"Biological aging is accelerated in people with multiple sclerosis; however, whether such acceleration occurs during the pre-symptomatic phase or varies by organ system is understudied. We analyzed two independent proteomics datasets profiled using distinct platforms: the Johns Hopkins cohort profiled using the SomaScan platform (348 multiple sclerosis\/49 age-matched controls) and the Department of Defense cohort profiled using the Olink platform (134 multiple sclerosis\/79 age-matched controls), including 117 pre-symptomatic samples from people with multiple sclerosis (median lead time: 4.0 years), to estimate systemic and organ-specific proteomic age gaps using established clocks in pre-symptomatic and symptomatic phases, and assess their associations with severity. In the Johns Hopkins cohort, people with multiple sclerosis demonstrated acceleration of systemic ({beta}=2.2, 95% CI 1.2-3.2, P<0.001, FDR<0.001), brain ({beta}=1.7, 95% CI 0.6-2.7, P=0.003, FDR=0.01), muscle ({beta}=2.5, 95% CI 1.3-3.7, P<0.001, FDR<0.001), and immune age ({beta}=1.8, 95% CI 0.6-2.9, P=0.003, FDR=0.01), with findings reproduced in the Department of Defense cohort for systemic ({beta}=0.7, 95% CI 0.0-1.4, P=0.04, FDR=0.34) and brain age ({beta}=3.2, 95% CI 2.1-4.3, P<0.001, FDR<0.001). Proteomic age acceleration was evident prior to symptom onset [systemic: ({beta}=1.0, 95% CI 0.4-1.7, P=0.002, FDR=0.02); brain: ({beta}=2.4, 95% CI 1.2-3.7, P<0.001, FDR=0.002)], whereas no immune age acceleration was detected before or after onset. Higher systemic age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.14, 95% CI 0.05-0.24, P=0.005, FDR=0.03) and slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.006, FDR=0.04), while higher muscle age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.17, 95% CI 0.10-0.24, P<0.001, FDR<0.001), poorer manual dexterity ({beta}=0.28, 95% CI 0.04-0.52, P=0.03, FDR=0.30), slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.002, FDR=0.02), lower peripapillary retinal nerve fiber layer ({beta}= -0.26, 95% CI -0.41 to -0.10, P=0.001, FDR=0.02) and ganglion cell-inner plexiform layer thicknesses ({beta}= -0.35; 95% CI -0.65 to -0.05; P=0.02, FDR=0.30). Higher brain age gap was associated with several imaging measures, including lower whole-brain ({beta}= -0.002, 95% CI -0.003 to -0.001, P=0.002, FDR=0.02), and lower peripapillary retinal nerve fiber layer thickness ({beta}= -0.21, 95% CI -0.39 to -0.03, P=0.02, FDR=0.10). Proteomic age acceleration in multiple sclerosis is detectable years before symptom onset and distinct organ-specific aging signatures are associated with disease severity. Proteomic aging may provide a biologically informative marker of early disease processes and a clinically relevant readout of disease heterogeneity.","rel_num_authors":15,"rel_authors":[{"author_name":"Fatemeh Siavoshi","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Julian Candia","author_inst":"National Institute on Aging"},{"author_name":"Dimitrios C Ladakis","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Blake E Dewey","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Angeliki Filippatou","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Matthew D Smith","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Elias S Sotirchos","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Shiv Saidha","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jerry L Prince","author_inst":"Johns Hopkins University"},{"author_name":"Ahmed Abdelhak","author_inst":"University of California San Francisco (UCSF)"},{"author_name":"Ellen M Mowry","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Peter A Calabresi","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Keenan  A. Walker","author_inst":"National Institute on Aging"},{"author_name":"Kathryn C Fitzgerald","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Pavan Bhargava","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Proteomic Age Acceleration in Multiple Sclerosis Precedes Symptom Onset and Associates with Severity","rel_doi":"10.64898\/2026.04.13.26350634","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.13.26350634","rel_abs":"Biological aging is accelerated in people with multiple sclerosis; however, whether such acceleration occurs during the pre-symptomatic phase or varies by organ system is understudied. We analyzed two independent proteomics datasets profiled using distinct platforms: the Johns Hopkins cohort profiled using the SomaScan platform (348 multiple sclerosis\/49 age-matched controls) and the Department of Defense cohort profiled using the Olink platform (134 multiple sclerosis\/79 age-matched controls), including 117 pre-symptomatic samples from people with multiple sclerosis (median lead time: 4.0 years), to estimate systemic and organ-specific proteomic age gaps using established clocks in pre-symptomatic and symptomatic phases, and assess their associations with severity. In the Johns Hopkins cohort, people with multiple sclerosis demonstrated acceleration of systemic ({beta}=2.2, 95% CI 1.2-3.2, P<0.001, FDR<0.001), brain ({beta}=1.7, 95% CI 0.6-2.7, P=0.003, FDR=0.01), muscle ({beta}=2.5, 95% CI 1.3-3.7, P<0.001, FDR<0.001), and immune age ({beta}=1.8, 95% CI 0.6-2.9, P=0.003, FDR=0.01), with findings reproduced in the Department of Defense cohort for systemic ({beta}=0.7, 95% CI 0.0-1.4, P=0.04, FDR=0.34) and brain age ({beta}=3.2, 95% CI 2.1-4.3, P<0.001, FDR<0.001). Proteomic age acceleration was evident prior to symptom onset [systemic: ({beta}=1.0, 95% CI 0.4-1.7, P=0.002, FDR=0.02); brain: ({beta}=2.4, 95% CI 1.2-3.7, P<0.001, FDR=0.002)], whereas no immune age acceleration was detected before or after onset. Higher systemic age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.14, 95% CI 0.05-0.24, P=0.005, FDR=0.03) and slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.006, FDR=0.04), while higher muscle age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.17, 95% CI 0.10-0.24, P<0.001, FDR<0.001), poorer manual dexterity ({beta}=0.28, 95% CI 0.04-0.52, P=0.03, FDR=0.30), slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.002, FDR=0.02), lower peripapillary retinal nerve fiber layer ({beta}= -0.26, 95% CI -0.41 to -0.10, P=0.001, FDR=0.02) and ganglion cell-inner plexiform layer thicknesses ({beta}= -0.35; 95% CI -0.65 to -0.05; P=0.02, FDR=0.30). Higher brain age gap was associated with several imaging measures, including lower whole-brain ({beta}= -0.002, 95% CI -0.003 to -0.001, P=0.002, FDR=0.02), and lower peripapillary retinal nerve fiber layer thickness ({beta}= -0.21, 95% CI -0.39 to -0.03, P=0.02, FDR=0.10). Proteomic age acceleration in multiple sclerosis is detectable years before symptom onset and distinct organ-specific aging signatures are associated with disease severity. Proteomic aging may provide a biologically informative marker of early disease processes and a clinically relevant readout of disease heterogeneity.","rel_num_authors":15,"rel_authors":[{"author_name":"Fatemeh Siavoshi","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Julian Candia","author_inst":"National Institute on Aging"},{"author_name":"Dimitrios C Ladakis","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Blake E Dewey","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Angeliki Filippatou","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Matthew D Smith","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Elias S Sotirchos","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Shiv Saidha","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jerry L Prince","author_inst":"Johns Hopkins University"},{"author_name":"Ahmed Abdelhak","author_inst":"University of California San Francisco (UCSF)"},{"author_name":"Ellen M Mowry","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Peter A Calabresi","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Keenan  A. Walker","author_inst":"National Institute on Aging"},{"author_name":"Kathryn C Fitzgerald","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Pavan Bhargava","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Trial protocol: RadTARGET, a multicenter phase II randomized controlled trial evaluating focal radiotherapy boost with de-intensification of dose to non-suspicious prostate in patients with intermediate- or high-risk prostate cancer","rel_doi":"10.64898\/2026.04.18.26351182","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.18.26351182","rel_abs":"Definitive radiotherapy (RT) for prostate cancer (PC) with dose intensification and\/or focal boosting has excellent oncologic outcomes, but many patients experience adverse events. Dose escalation to the whole prostate improves outcomes at the expense of increased late adverse events. Intraprostatic recurrence after definitive RT typically occurs at the site of the primary tumor, suggesting that dose to the site of the dominant lesion is an important predictor of future failure. The efficacy and safety of tumor-focused RT compared to that of standard RT for definitive treatment of localized PC has not been assessed. RadTARGET (RAdiation Dose TAiloRing Guided by Enhanced Targeting) is a phase II randomized trial that aims to demonstrate superior safety of image-guided, tumor-focused RT compared to standard RT for acute genitourinary (GU) or gastrointestinal (GI) in the setting of definitive RT for intermediate- and high-risk PC. The study intervention is image-guided, tumor-focused RT with dose intensification of cancer visible on imaging and dose de-intensification to remaining prostate. Patients will be randomized to two arms: those who receive standard RT dose and those that receive tumor-focused RT. The study population will be patients with intermediate- or high-risk PC planning to undergo definitive RT with or without systemic therapy. The primary endpoint to compare between randomized arms is acute GU or GI grade [&ge;]2 adverse events. Participant and study duration are 5 years and 8 years, respectively. RadTARGET will compare the efficacy and safety of tumor-focused RT to that of standard RT for definitive treatment of localized PC. We hypothesize that the tumor-focused approach will substantially reduce adverse events after prostate RT while retaining high efficacy. If this hypothesis is confirmed, we will conclude that a phase III randomized control trial is warranted to formally establish oncologic non-inferiority compared to the current standard of whole-gland dose escalation.","rel_num_authors":20,"rel_authors":[{"author_name":"Anna Dornisch","author_inst":"UC San Diego"},{"author_name":"Mariluz Rojo Domingo","author_inst":"University of California San Diego"},{"author_name":"Roberta Vezza Alexander","author_inst":"UC San Diego"},{"author_name":"Christopher Charles Conlin","author_inst":"UC San Diego"},{"author_name":"Son Do","author_inst":"UC San Diego"},{"author_name":"Rana R McKay","author_inst":"UC San Diego"},{"author_name":"Vitali Moiseenko","author_inst":"UC San Diego"},{"author_name":"Michael A Liss","author_inst":"UC San Diego"},{"author_name":"Jasmine Liu","author_inst":"UC San Diego"},{"author_name":"Todd Pawlicki","author_inst":"UC San Diego"},{"author_name":"Samuel Pena","author_inst":"UC San Diego"},{"author_name":"Edmund M Qiao","author_inst":"UC San Diego"},{"author_name":"Brent S Rose","author_inst":"UC San Diego"},{"author_name":"Rhea Rupareliya","author_inst":"UC San Diego"},{"author_name":"Ajay P Sandhu","author_inst":"UC San Diego"},{"author_name":"Jessica Scholey","author_inst":"UC San Francisco"},{"author_name":"Steven N Seyedin","author_inst":"UC San Francisco"},{"author_name":"James J Urbanic","author_inst":"UC San Diego"},{"author_name":"Lee-Jen Wei","author_inst":"Harvard TH Chan School of Public Health"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Trial protocol: RadTARGET, a multicenter phase II randomized controlled trial evaluating focal radiotherapy boost with de-intensification of dose to non-suspicious prostate in patients with intermediate- or high-risk prostate cancer","rel_doi":"10.64898\/2026.04.18.26351182","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.18.26351182","rel_abs":"Definitive radiotherapy (RT) for prostate cancer (PC) with dose intensification and\/or focal boosting has excellent oncologic outcomes, but many patients experience adverse events. Dose escalation to the whole prostate improves outcomes at the expense of increased late adverse events. Intraprostatic recurrence after definitive RT typically occurs at the site of the primary tumor, suggesting that dose to the site of the dominant lesion is an important predictor of future failure. The efficacy and safety of tumor-focused RT compared to that of standard RT for definitive treatment of localized PC has not been assessed. RadTARGET (RAdiation Dose TAiloRing Guided by Enhanced Targeting) is a phase II randomized trial that aims to demonstrate superior safety of image-guided, tumor-focused RT compared to standard RT for acute genitourinary (GU) or gastrointestinal (GI) in the setting of definitive RT for intermediate- and high-risk PC. The study intervention is image-guided, tumor-focused RT with dose intensification of cancer visible on imaging and dose de-intensification to remaining prostate. Patients will be randomized to two arms: those who receive standard RT dose and those that receive tumor-focused RT. The study population will be patients with intermediate- or high-risk PC planning to undergo definitive RT with or without systemic therapy. The primary endpoint to compare between randomized arms is acute GU or GI grade [&ge;]2 adverse events. Participant and study duration are 5 years and 8 years, respectively. RadTARGET will compare the efficacy and safety of tumor-focused RT to that of standard RT for definitive treatment of localized PC. We hypothesize that the tumor-focused approach will substantially reduce adverse events after prostate RT while retaining high efficacy. If this hypothesis is confirmed, we will conclude that a phase III randomized control trial is warranted to formally establish oncologic non-inferiority compared to the current standard of whole-gland dose escalation.","rel_num_authors":20,"rel_authors":[{"author_name":"Anna Dornisch","author_inst":"UC San Diego"},{"author_name":"Mariluz Rojo Domingo","author_inst":"University of California San Diego"},{"author_name":"Roberta Vezza Alexander","author_inst":"UC San Diego"},{"author_name":"Christopher Charles Conlin","author_inst":"UC San Diego"},{"author_name":"Son Do","author_inst":"UC San Diego"},{"author_name":"Rana R McKay","author_inst":"UC San Diego"},{"author_name":"Vitali Moiseenko","author_inst":"UC San Diego"},{"author_name":"Michael A Liss","author_inst":"UC San Diego"},{"author_name":"Jasmine Liu","author_inst":"UC San Diego"},{"author_name":"Todd Pawlicki","author_inst":"UC San Diego"},{"author_name":"Samuel Pena","author_inst":"UC San Diego"},{"author_name":"Edmund M Qiao","author_inst":"UC San Diego"},{"author_name":"Brent S Rose","author_inst":"UC San Diego"},{"author_name":"Rhea Rupareliya","author_inst":"UC San Diego"},{"author_name":"Ajay P Sandhu","author_inst":"UC San Diego"},{"author_name":"Jessica Scholey","author_inst":"UC San Francisco"},{"author_name":"Steven N Seyedin","author_inst":"UC San Francisco"},{"author_name":"James J Urbanic","author_inst":"UC San Diego"},{"author_name":"Lee-Jen Wei","author_inst":"Harvard TH Chan School of Public Health"},{"author_name":"Tyler M Seibert","author_inst":"UC San Diego"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Machine Learning Prediction of Disease Trajectories for Children with Juvenile Idiopathic Arthritis","rel_doi":"10.64898\/2026.04.18.26351165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.18.26351165","rel_abs":"Background: Despite advances in therapy, optimal management of juvenile idiopathic arthritis (JIA) remains challenging. The ability to predict disease progression in JIA can improve personalized treatment decisions, but few reliable clinical predictors have been identified. We developed machine learning approaches to predict disease trajectories in children with JIA. Methods: Using data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry (years 2015-2024), we developed machine learning models to predict attainment of inactive disease in children with non-systemic JIA. We applied Dynamic Bayesian Networks (DBN) to model temporal dependencies and causal relationships, and Convolutional Neural Networks (CNN) to capture complex non-linear patterns. Model input included demographic factors, longitudinal clinical factors, and medication use in the preceding 12 months. Findings: A total of 8,093 participants were included. When tested on an independent test cohort, both DBN (AUC:0.76; precision:0.73; recall:0.83; F1-score:0.78; accuracy:0.71) and CNN (AUC:0.76; precision:0.71; recall:0.63; F1-score:0.67; accuracy:0.70) models achieved comparable performance in predicting inactive disease. Disease activity levels in the preceding 12 months, presence of enthesitis and uveitis were the strongest predictors. Causal relationships captured in the DBN model revealed suboptimal care patterns, likely shaped by insurance constraints and a predominantly reactive approach to JIA management. Interpretation: Our study demonstrates that machine learning approaches can predict disease trajectories in JIA with good discriminative performance. Unlike prior studies that predict outcomes at single timepoints, our models are the first to predict inactive disease longitudinally. However, suboptimal care patterns in retrospective data limit the capacity to learn treatment-outcome relationships, underscoring critical opportunities to improve JIA care and the need for prospective comparative studies to better inform prediction models.","rel_num_authors":9,"rel_authors":[{"author_name":"Seungwon Lee","author_inst":"Computational Health Informatics Program, Boston Children's Hospital"},{"author_name":"Marie Davidian","author_inst":"Department of Statistics, North Carolina State University, Raleigh, NC"},{"author_name":"Marc D Natter","author_inst":"Computational Health Informatics Program, Boston Children's Hospital"},{"author_name":"Bryce B Reeve","author_inst":"Center for Health Measurement, Department of Population Health Sciences, Duke University School of Medicine, Durham, NC"},{"author_name":"Laura E Schanberg","author_inst":"Duke Clinical Research Institute, Duke University Medical Center, Durham, NC"},{"author_name":"Eleanor Belkin","author_inst":"Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD"},{"author_name":"Min-Lee Chang","author_inst":"Computational Health Informatics Program, Boston Children's Hospital"},{"author_name":"Yukiko Kimura","author_inst":"Joseph M Sanzari Children's Hospital, Hackensack Meridian School of Medicine, Hackensack, NJ"},{"author_name":"Mei-Sing Ong","author_inst":"Computational Health Informatics Program, Boston Children's Hospital"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Machine Learning Prediction of Disease Trajectories for Children with Juvenile Idiopathic Arthritis","rel_doi":"10.64898\/2026.04.18.26351165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.18.26351165","rel_abs":"Background: Despite advances in therapy, optimal management of juvenile idiopathic arthritis (JIA) remains challenging. The ability to predict disease progression in JIA can improve personalized treatment decisions, but few reliable clinical predictors have been identified. We developed machine learning approaches to predict disease trajectories in children with JIA. Methods: Using data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry (years 2015-2024), we developed machine learning models to predict attainment of inactive disease in children with non-systemic JIA. We applied Dynamic Bayesian Networks (DBN) to model temporal dependencies and causal relationships, and Convolutional Neural Networks (CNN) to capture complex non-linear patterns. Model input included demographic factors, longitudinal clinical factors, and medication use in the preceding 12 months. Findings: A total of 8,093 participants were included. When tested on an independent test cohort, both DBN (AUC:0.76; precision:0.73; recall:0.83; F1-score:0.78; accuracy:0.71) and CNN (AUC:0.76; precision:0.71; recall:0.63; F1-score:0.67; accuracy:0.70) models achieved comparable performance in predicting inactive disease. Disease activity levels in the preceding 12 months, presence of enthesitis and uveitis were the strongest predictors. Causal relationships captured in the DBN model revealed suboptimal care patterns, likely shaped by insurance constraints and a predominantly reactive approach to JIA management. Interpretation: Our study demonstrates that machine learning approaches can predict disease trajectories in JIA with good discriminative performance. Unlike prior studies that predict outcomes at single timepoints, our models are the first to predict inactive disease longitudinally. However, suboptimal care patterns in retrospective data limit the capacity to learn treatment-outcome relationships, underscoring critical opportunities to improve JIA care and the need for prospective comparative studies to better inform prediction models.","rel_num_authors":9,"rel_authors":[{"author_name":"Seungwon Lee","author_inst":"Computational Health Informatics Program, Boston Children's Hospital"},{"author_name":"Marie Davidian","author_inst":"Department of Statistics, North Carolina State University, Raleigh, NC"},{"author_name":"Marc D Natter","author_inst":"Computational Health Informatics Program, Boston Children's Hospital"},{"author_name":"Bryce B Reeve","author_inst":"Center for Health Measurement, Department of Population Health Sciences, Duke University School of Medicine, Durham, NC"},{"author_name":"Laura E Schanberg","author_inst":"Duke Clinical Research Institute, Duke University Medical Center, Durham, NC"},{"author_name":"Eleanor Belkin","author_inst":"Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD"},{"author_name":"Min-Lee Chang","author_inst":"Computational Health Informatics Program, Boston Children's Hospital"},{"author_name":"Yukiko Kimura","author_inst":"Joseph M Sanzari Children's Hospital, Hackensack Meridian School of Medicine, Hackensack, NJ"},{"author_name":"Mei-Sing Ong","author_inst":"Computational Health Informatics Program, Boston Children's Hospital"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Human vs AI Clinical Assessment: Benchmarking a Multimodal Foundation Model Against Multi-Center Expert Judgment on the Mental Status Examination.","rel_doi":"10.64898\/2026.04.17.26351105","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.17.26351105","rel_abs":"The Mental Status Examination (MSE) is the cornerstone of the psychiatric evaluation, yet validating artificial intelligence (AI) against the inherent variance of clinical judgment remains a critical bottleneck. Here we introduce a multi-center framework to benchmark the open-weight multimodal foundation model Qwen3-Omni against independent expert panels at two sites, UTHealth and Yale. Evaluating 396 classifications across 10 MSE domains and three longitudinal timepoints of increasing symptom severity, we found that experts achieved substantial agreement (Gwet's AC1 = 0.87), whereas the model achieved only moderate alignment (AC1 = 0.70-0.72). Even as the model's overall pathology prediction rate approximated the experts', the aggregate equilibrium masked a profound \"clinical reasoning gap\". Specifically, the model systematically over-predicted observable signs (e.g., speech, affect) while notably failing in inferential domains requiring the interpretation of latent mental content (e.g., delusions, perceptions). A 4-bit quantization analysis of the model confirmed this mechanistically: reducing model capacity disproportionately degraded inferential reasoning while preserving perceptual feature extraction. Furthermore, model-to-expert agreement degraded linearly as clinical complexity intensified across longitudinal visits (Accuracy: T0 = 84.8-87%; T1 = 80-82%; T2 = 71-73%), whereas expert consensus remained robust. Notably, model errors increased 2.3-to-3.4 fold where human experts disagreed. These findings establish inter-expert variance as an essential measurable baseline for psychiatric AI, demonstrating that true clinical translation requires models to move beyond multimodal perceptual extraction to achieve higher-order diagnostic reasoning.","rel_num_authors":10,"rel_authors":[{"author_name":"Benson Mwangi","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"},{"author_name":"Hammza Jabbar Abdl Sattar Hamoudi","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"},{"author_name":"Marsal Sanches","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"},{"author_name":"Nurhak Dogan","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"},{"author_name":"Pooja Chaudhary","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"},{"author_name":"Mon-Ju Wu","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"},{"author_name":"Giovana B. Zunta-Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"},{"author_name":"Jair C. Soares","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"},{"author_name":"Andres Martin","author_inst":"Child Study Center, Yale School of Medicine, New Haven, CT, USA."},{"author_name":"Cesar A. Soutullo","author_inst":"Department of Psychiatry and Behavioral Sciences, School of Behavioral Health Sciences, The University of Texas Health Science Center at Houston, Houston,TX, US"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Common Electrophysiology Biomarkers Collected at Home Robustly Track Depression Recovery With Deep Brain Stimulation","rel_doi":"10.64898\/2026.04.13.26350107","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.13.26350107","rel_abs":"Subcallosal cingulate cortex (SCC) deep brain stimulation (DBS) can provide relief for individuals with Treatment Resistant Depression (TRD), but ongoing clinical management remains challenging due to nonspecific symptom fluctuations that can obscure core depression recovery on standard rating scales. Objective, stable biomarkers that selectively track the therapeutic effects of SCC DBS are therefore essential for developing principled decision support systems to guide stimulation adjustments. Recent bidirectional DBS systems enable chronic recording of local field potentials (LFPs) and prior work using the Activa PC+S device identified an electrophysiological signature of stable clinical recovery. However, translation to practical clinical deployment requires demonstrating that this biomarker is robustly generalizable, specific to the impact of the DBS therapy, and deployable in real-world recording contexts. To address this need, we developed an at-home SCC LFP data collection platform (built on the Medtronic Summit RC+S system) enabling at home data collection for a new cohort of ten SCC DBS participants with TRD (ClinicalTrials.gov identifier NCT04106466). Using longitudinal LFP recordings collected from this system, we report findings demonstrating that the previously reported biomarker of stable recovery generalizes across subject cohorts and devices, is robust to common potential confounds (including time of day and stimulation status), and shows symptom specificity, sensitivity and stability necessary to support clinical decision making. Across both cohorts, biomarker changes show relationships to pre-DBS white matter structure and network function measured using diffusion MRI and resting-state functional MRI (rsFMRI). These findings replicating and extending previous findings support the biomarker's utility as a foundation for scalable, electrophysiology-informed decision support in SCC DBS.","rel_num_authors":25,"rel_authors":[{"author_name":"Elif Ceren Fitoz","author_inst":"Georgia Institute of Technology"},{"author_name":"Sankaraleengam Alagapan","author_inst":"Georgia Institute of Technology"},{"author_name":"Jungho Cha","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ki Sueng Choi","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Martijn Figee","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Brian Kopell","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Mosadoluwa Obatusin","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Stephen Heisig","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Tanya Nauvel","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Aida Razavilar","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Parisa Sarikhani","author_inst":"Georgia Institute of Technology"},{"author_name":"Isha Trivedi","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jamie Gowatsky","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jessa Alexander","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Romain Guignon","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Maryam Khalid","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Gutemberg Bobby Forestal","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ha Neul Song","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Tim Dennison","author_inst":"University of Oxford"},{"author_name":"Shannon O'Neill","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Shreesh Karjagi","author_inst":"Georgia Institute of Technology"},{"author_name":"Allison C. Waters","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Patricio Riva-Posse","author_inst":"Emory University School of Medicine"},{"author_name":"Helen S. Mayberg","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Christopher J. Rozell","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Vital signs, demographics, and clinical events for low-birth-weight infants from four intensive care units","rel_doi":"10.64898\/2026.04.15.26350178","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350178","rel_abs":"Premature very low birth weight (VLBW) infants have high rates of mortality and morbidity from sepsis, necrotizing enterocolitis, and respiratory failure requiring intubation and mechanical ventilation. Earlier detection of cardiorespiratory deterioration using vital signs from continuous physiological monitoring may lead to more timely interventions and improved outcomes. To further this research area, we present PreMo, a publicly available dataset of continuous heart rate and oxygen saturation, demographics, clinical events, and outcomes for 3,829 VLBW patients from four Neonatal Intensive Care Units (NICUs) in the United States. The PreMo dataset consists of a collection of parquet files, ro-crate metadata, and sample usage code scripts hosted on the University of Virginia LibraData Dataverse website.","rel_num_authors":14,"rel_authors":[{"author_name":"Ian German Mesner","author_inst":"University of Virginia"},{"author_name":"Doug E. Lake","author_inst":"University of Virginia"},{"author_name":"Sherry L. Kausch","author_inst":"University of Virginia"},{"author_name":"Katy N Krahn","author_inst":"University of Virginia"},{"author_name":"Angela Gummadi","author_inst":"University of Virginia"},{"author_name":"Timothy W. Clark","author_inst":"University of Virginia"},{"author_name":"Justin C. Niestroy","author_inst":"University of Virginia"},{"author_name":"Rakesh Sahni","author_inst":"Columbia University"},{"author_name":"Zachary A. Vesoulis","author_inst":"Washington University"},{"author_name":"David B. Gootenberg","author_inst":"Washington University"},{"author_name":"N. Ambalavanan","author_inst":"University of Alabama at Birmingham"},{"author_name":"Colm P. Travers","author_inst":"University of Alabama at Birmingham"},{"author_name":"Karen D. Fairchild","author_inst":"University of Virginia"},{"author_name":"Brynne A. Sullivan","author_inst":"University of Virginia"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Vital signs, demographics, and clinical events for low-birth-weight infants from four intensive care units","rel_doi":"10.64898\/2026.04.15.26350178","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350178","rel_abs":"Premature very low birth weight (VLBW) infants have high rates of mortality and morbidity from sepsis, necrotizing enterocolitis, and respiratory failure requiring intubation and mechanical ventilation. Earlier detection of cardiorespiratory deterioration using vital signs from continuous physiological monitoring may lead to more timely interventions and improved outcomes. To further this research area, we present PreMo, a publicly available dataset of continuous heart rate and oxygen saturation, demographics, clinical events, and outcomes for 3,829 VLBW patients from four Neonatal Intensive Care Units (NICUs) in the United States. The PreMo dataset consists of a collection of parquet files, ro-crate metadata, and sample usage code scripts hosted on the University of Virginia LibraData Dataverse website.","rel_num_authors":14,"rel_authors":[{"author_name":"Ian German Mesner","author_inst":"University of Virginia"},{"author_name":"Doug E. Lake","author_inst":"University of Virginia"},{"author_name":"Sherry L. Kausch","author_inst":"University of Virginia"},{"author_name":"Katy N Krahn","author_inst":"University of Virginia"},{"author_name":"Angela Gummadi","author_inst":"University of Virginia"},{"author_name":"Timothy W. Clark","author_inst":"University of Virginia"},{"author_name":"Justin C. Niestroy","author_inst":"University of Virginia"},{"author_name":"Rakesh Sahni","author_inst":"Columbia University"},{"author_name":"Zachary A. Vesoulis","author_inst":"Washington University"},{"author_name":"David B. Gootenberg","author_inst":"Washington University"},{"author_name":"N. Ambalavanan","author_inst":"University of Alabama at Birmingham"},{"author_name":"Colm P. Travers","author_inst":"University of Alabama at Birmingham"},{"author_name":"Karen D. Fairchild","author_inst":"University of Virginia"},{"author_name":"Brynne A. Sullivan","author_inst":"University of Virginia"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"A loss of function variant in SLC30A8\/ZnT8 drives proteomic changes associated with lowered apoptosis in human stem cell-derived islets","rel_doi":"10.64898\/2026.04.17.26351108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.17.26351108","rel_abs":"(1) Aims and hypothesis Loss-of-function mutations in SLC30A8, encoding the zinc ion (Zn++) transporter ZnT8 in pancreatic beta cells, lower type 2 diabetes risk dose-dependently, but the underlying mechanisms remain unclear. Here, we combine proteomic, transcriptomic and functional approaches in human stem cell-derived islet-like clusters bearing common alleles or the inactivating variant R138X. We hypothesized that this variant protects against the deleterious effect of Zn2+ depletion on cell survival and function. (2) Methods Human embryonic stem cells INS(GFP\/w) (MEL1), and CRISPR\/Cas9-derived heterozygous or homozygous R138X lines were differentiated into stem cell-derived islet-like clusters. Intracellular Zn++ levels were reduced using the chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-1,2-ethanediamine (TPEN). Apoptosis was assessed by TUNEL staining and protein expression by immunofluorescence. Glucose-stimulated calcium (Ca++) dynamics were measured using the intracellular probe (Cal590) and insulin secretion by homogenous time-resolved fluorescence. Transcriptomic profiling was performed by bulk mRNA sequencing and proteomics by liquid chromatography-tandem mass spectrometry. (3) Results Intracellular Zn++ depletion increased apoptosis in wild-type islet-like clusters, whereas R138X clusters were protected. R138X heterozygous clusters showed a mild increase in GCG+ cells and R138X homozygous clusters exhibited increased NKX6.1+ cells, without affecting polyhormonal populations. These changes were reversed under Zn2+ depletion. Transcriptomic and proteomic analyses, assessing genotype effects while accounting for Zn2+ depletion, showed that R138X clusters (versus wild-type) exhibited upregulation of genes and proteins involved in vesicle trafficking, secretion, Ca++; signaling and mitochondrial metabolism, consistent with enhanced glucose-stimulated insulin secretion in homozygous clusters. Conversely, genes and proteins associated with extracellular matrix remodeling, metal-ion handling, apoptosis and cellular stress were downregulated. R138X clusters displayed altered Ca2+ signaling, with decreased area under the curve and oscillation amplitude, but increased frequency. These differences were reversed by TPEN, while Zn++ depletion impaired Ca2+ response in wild-type clusters. Despite lowered overall activity, R138X homozygous clusters showed enhanced overall cell-cell connectivity, reversed by TPEN treatment. The opposite effects were observed in R138X heterozygous clusters, showing improved connectivity and activity under Zn++ depletion. (4) Conclusion and interpretation Intracellular Zn++ depletion compromises islet-like cluster identity and function, while the R138X variant confers protection against these effects. Under Zn2+-depleted conditions, ZnT8 deficiency promotes a more mature and metabolically active state of the R138X clusters, with enhanced Ca2+ signaling and insulin secretion, supported by a structural remodeling and the downregulation of apoptosis and cellular stress. These findings highlight the therapeutic potential of targeting ZnT8 in type 2 diabetes and support its relevance for further improving cell-based therapies.","rel_num_authors":7,"rel_authors":[{"author_name":"Marie Gasser","author_inst":"Centre Hospitalier de l'Universite de Montreal (CHUM) Research Center and Department of Medicine, University of Montreal, Montreal, QC, Canada"},{"author_name":"Ines Cherkaoui","author_inst":"Centre Hospitalier de l'Universite de Montreal (CHUM) Research Center and Department of Medicine, University of Montreal, Montreal, QC, Canada"},{"author_name":"Giada Ostinelli","author_inst":"Centre Hospitalier de l'Universite de Montreal (CHUM) Research Center and Department of Medicine, University of Montreal, Montreal, QC, Canada"},{"author_name":"Mathieu Ferron","author_inst":"Institut de Recherche Clinique de Montreal and Department of Medicine, University of Montreal, Montreal, QC, Canada"},{"author_name":"Qian Du","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Dieter Egli","author_inst":"Columbia University, New York, NY, USA"},{"author_name":"Guy Rutter","author_inst":"Imperial College London"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Interventions to improve retention in HIV care: a systematic review and network meta-analysis of randomised controlled trials","rel_doi":"10.64898\/2026.04.18.26351146","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.18.26351146","rel_abs":"Background: Sustained retention in care supports continuous access to antiretroviral therapy, routine clinical monitoring, and long-term viral suppression. Objective: To compare the effectiveness of interventions for improving retention in care among people living with HIV (PLHIV). Design: Systematic review and network meta-analysis Data sources: PubMed, Embase, CINAHL, PsycINFO, Web of Science, and the Cochrane Library from 1995 to December 2024. Eligibility criteria: Randomised controlled trials (RCTs) evaluating interventions to improve retention in care, viral load suppression, or quality of life (QoL) among PLHIV, compared with standard of care (SoC) or other interventions. Data extraction and synthesis: Pairs of reviewers independently screened studies, extracted data, and assessed risk of bias using ROBUST-RCT. We conducted a fixed-effect frequentist network meta-analysis and rated interventions categories relative to SoC based on effect estimates effects and the certainty of evidence.. Dichotomous outcomes were summarized as odds ratios (ORs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with 95% CI. Results: Eighty-four trials enrolling 107137 PLHIV evaluated 13 intervention categories. For retention in care, five interventions supported by moderate or high certainty evidence proved superior to SoC: multi-month dispensing (OR 2.02, 95% CI 1.32 to 3.09), task shifting (OR 1.94, 95% CI 1.42 to 2.66), differentiated service delivery (OR 1.47, 95% CI 1.22 to 1.76), behavioural counselling (OR 1.36, 95% CI 1.21 to 1.54), and supportive interventions (OR 1.31, 95% CI 1.11 to 1.55). For viral load suppression, two interventions supported by moderate or high certainty evidence proved superior to SoC: task shifting (OR 2.07, 95% CI 1.25 to 3.43) and behavioural counselling (OR 1.34, 95% CI 1.11 to 1.67). Across outcomes, no intervention demonstrated convincing superiority over other active interventions. Conclusions: Among 13 intervention categories, only a subset provided moderate or high-certainty evidence of superiority to the standard of care, and no superiority to other interventions. Persistent evidence gaps for key populations, diverse settings, and long-term outcomes support the need for context-sensitive and patient-centred interventions.","rel_num_authors":15,"rel_authors":[{"author_name":"Nadia Rehman","author_inst":"Department of Health, Research, Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Gordon Guyatt","author_inst":"Department of Health, Research, Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Mou JinJin","author_inst":"Department of Pharmacy, Beijing United Family Hospital, Beijing, China"},{"author_name":"Lucas Kallas Silva","author_inst":"Department of Infectious Diseases, Federal University of Sao Paulo, Sao Paulo, Brazil"},{"author_name":"Jessica Gu","author_inst":"Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada"},{"author_name":"Mehnaz Munir","author_inst":"Mary Heersink School of Global Health and Social Medicine, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Raha Sadagari","author_inst":"Department of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran"},{"author_name":"Michelle Li","author_inst":"Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada"},{"author_name":"Daniel Xie","author_inst":"McMaster University"},{"author_name":"Sahith Rajkumar","author_inst":"Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Yan Lijiao","author_inst":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China"},{"author_name":"Elina Najmabadi","author_inst":"Department of Biological Sciences, University of Guelph, Guelph, Ontario, Canada"},{"author_name":"Varun Dhanam","author_inst":"Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada"},{"author_name":"Dominik Mertz","author_inst":"McMaster University Department of Health Research Methods Evidence and Impact"},{"author_name":"Aaron Jones","author_inst":"McMaster University"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Leveraging Predictive AI and LLM-Powered Trial Matching to Improve Clinical Trial Recruitment: A Usability Assessment of Trialshub","rel_doi":"10.64898\/2026.04.17.26351107","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.17.26351107","rel_abs":"Background: Recruitment remains a major barrier to timely clinical trial completion. Trialshub is an LLM-powered, chat-based platform intended to help users identify relevant trials and connect with coordinators to streamline recruitment workflows. Objective: To evaluate the perceived usability and operational value of Trialshub, and identify implementation considerations for real-world deployment. Methods: A usability test was conducted at Morehouse School of Medicine for the Trialshub application. Purposively selected participants included clinical research coordinators and individuals with and without clinical trial search experience. Participants completed a pre-test survey assessing demographics, digital health information behaviors, and familiarity with AI tools, followed by a moderated usability session using a Trialshub prototype. Users completed scenario-based tasks (locating a breast cancer trial, reviewing results, and initiating coordinator contact) using a think-aloud protocol. Task ratings, screen recordings, and transcribed feedback were analyzed descriptively and thematically, and reported. Results: Participants reported high comfort with using digital tools and moderate-to-high familiarity with AI. Trialshub's chat-first design, guided prompts, and checklist-style eligibility display were perceived as intuitive and reduced cognitive load. Fast access to trials and the coordinator-contact workflow were viewed positively. Key usability issues included uncertainty at step transitions, insufficient cues for selecting results and next actions, and inconsistent system reliability (loading delays, errors, and broken trial detail pages). Participants also noted redundant questioning due to limited conversational memory, requested improved filtering\/sorting, and clearer calls-to-action. All participants indicated that Trialshub has strong potential to meaningfully improve clinical trial processes. Conclusions: Trialshub shows promise for improving trial discovery and recruitment workflows, with identified design implications for real-world deployment.","rel_num_authors":10,"rel_authors":[{"author_name":"Paa-Kwesi Blankson","author_inst":"Morehouse School of Medicine"},{"author_name":"Shakira Hussien","author_inst":"Kennesaw State University"},{"author_name":"Ferdose Idris","author_inst":"Princeton University"},{"author_name":"Geannene Trevillion","author_inst":"Morehouse School of Medicine"},{"author_name":"Ali Aslam","author_inst":"Morehouse School of Medicine"},{"author_name":"Amir Afani","author_inst":"Morehouse School of Medicine"},{"author_name":"Phenesse Dunlap","author_inst":"Stanford University"},{"author_name":"Joyline Chepkorir","author_inst":"Johns Hopkins University School of Nursing"},{"author_name":"Paolo Melgarejo","author_inst":"McGill University, Desautels Faculty of Management"},{"author_name":"Muhammed Idris","author_inst":"Morehouse School of Medicine"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Uncertainty-Gated Glaucoma Screening: Combining Semi-Supervised Classification with Multi-Agent Large Language Model Deliberation","rel_doi":"10.64898\/2026.04.17.26351127","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.17.26351127","rel_abs":"Automated glaucoma screening from optical coherence tomography (OCT) faces two persistent challenges: scarcity of expert labeled data and unreliable model predictions on diagnostically ambiguous cases. We present a two tier diagnostic pipeline that addresses both. In the first tier, an EfficientNetV2S classifier trained under a semi supervised pseudo supervisor framework achieves 0.84 AUC on 150 held out test patients from the Harvard Glaucoma Detection and Progression dataset, using only 350 labeled training samples out of 700. In the second tier, 124 flagged cases are routed to a multi agent system built on MedGemma 4B, where three specialist agents deliberate over three rounds before rendering a final diagnosis. On these flagged cases, the agent system achieves 100% sensitivity detecting all 55 glaucoma cases with zero missed diagnoses and 89.5% overall accuracy (111\/124), compared to the classifiers 73.4% (91\/124). Uncertainty analysis confirms that the classifiers output probability reliably separates confident predictions (96.3% accuracy, n = 27) from uncertain ones (74.0%, n = 123), producing a 22-percentage-point gap that serves as a triage signal. The agents fix 32 cases the classifier misclassifies while introducing 12 new errors, yielding a net improvement of 20 cases. These results are from a single training run without variance estimates and should be interpreted as preliminary evidence that uncertainty gated routing to vision language model agents can meaningfully improve diagnostic accuracy on the cases where automated classifiers are least reliable.","rel_num_authors":3,"rel_authors":[{"author_name":"Sai Varun Garimella Narasimha","author_inst":"Northeastern University"},{"author_name":"Nicholas Brown","author_inst":"Northeastern University"},{"author_name":"Srinivas Sridhar","author_inst":"Northeastern University"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Generative AI-assisted Bayesian-frequentist Hybrid Inference in Single-cell RNA Sequencing Analysis for Genes Associated with Alzheimer's Disease","rel_doi":"10.64898\/2026.04.17.26351142","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.17.26351142","rel_abs":"Alzheimer's disease genomics and other high-dimensional omics studies demand powerful statistical methods, yet Bayesian inference remains underutilized despite its advantages in small-sample settings, owing to the prohibitive cost of eliciting reliable priors across thousands or millions of parameters. We propose an AI-assisted Bayesian-frequentist hybrid inference framework that couples large language model based prior elicitation with the hybrid inference theory of Yuan (2009). ChatGPT-4o is queried via a standardized prompt to assess the strength of evidence linking each gene to a disease of interest, and the response is mapped to an informative normal prior via a standardized effect-size calibration. Parameters for covariates of secondary interest are treated as frequentist parameters, preserving efficiency and avoiding sensitivity to mis-specified priors. We derive closed-form hybrid estimators under uniform and conjugate normal priors in linear models, establish their asymptotic equivalence to the frequentist and full Bayes estimators, and show in simulations that hybrid inference using unconditional variance estimation leads to high statistical power while accurately controlling the Type I error rate. Applied to single-cell RNA sequencing data from the ROSMAP cohort for Alzheimer's disease as an example, the framework identifies biologically coherent pathways (such as gamma-secretase pathways) previously undetected. The proposed framework offers a principled and computationally scalable approach to genome-wide Bayesian analysis, with potential for broad application across omics platforms and disease settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Gang Han","author_inst":"Texas A and M University"},{"author_name":"Ao Yuan","author_inst":"Georgetown University Medical Center"},{"author_name":"King David Oware","author_inst":"Texas A and M University"},{"author_name":"Fred Wright","author_inst":"Department of Statistics, North Carolina State University"},{"author_name":"Raymond J. Carroll","author_inst":"Department of Statistics, Texas A and M University"},{"author_name":"Matthew Smith","author_inst":"Department of Applied Health Science, School of Public Health, Indiana University"},{"author_name":"Marcia G. Ory","author_inst":"Department of Environmental and Occupational Health, Texas A and M University"},{"author_name":"Dongyan Yan","author_inst":"Eli Lilly and Company"},{"author_name":"Wenjie Wang","author_inst":"Eli Lilly and Company"},{"author_name":"Zhe Sun","author_inst":"Eli Lilly and Company"},{"author_name":"Qile Dai","author_inst":"Eli Lilly and Company"},{"author_name":"Carter Allen","author_inst":"Eli Lilly and Company"},{"author_name":"Andy Dang","author_inst":"Eli Lilly and Company"},{"author_name":"Yushi Liu","author_inst":"Eli Lilly and Company"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Synuclein and dopamine transporter biomarkers among phenoconverters to parkinsonian disorders","rel_doi":"10.64898\/2026.04.15.26350768","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350768","rel_abs":"Background: Phenoconversion to Parkinson's disease (PD) or dementia with Lewy bodies (DLB) currently relies on established clinical diagnostic criteria. Availability of in vivo biomarkers--CSF -synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter (DAT) imaging--offer the opportunity to investigate congruency between clinical phenoconversion and biologically defined disease. Methods: We analyzed Parkinson's Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA), Alzheimer's disease (AD) or other dementias from prodromal and non-manifesting genetic carrier (NMC) groups and controls. Site investigators determined phenoconversion based on established diagnostic criteria. All phenoconverters with [&ge;]1 annual follow-up visit, with available biomarkers and persistent clinically defined diagnosis at last observation were included. Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-SS) staging was applied. Results: Among 121 phenoconverters, 103 had evaluable CSFaSynSAA and DAT data and were included in analysis: 92 PD, 7 DLB, 2 MSA, 2 AD\/other dementias. Phenoconversion annual rates varied widely across groups: iRBD 7.9%, hyposmia 4.2%, GBA1 0.3%, LRRK2 1.3%, LRRK2+GBA1 0.9%, and controls 0.5%. Median time from baseline to phenoconversion ranged from 13-14 months in iRBD and hyposmia to 36-85 months in NMCs. The expected biomarker profile (CSFaSynSAA+\/DAT+) for clinically-diagnosed synucleinopathy occurred in 74 (71.8%) participants. Biological alignment (CSFaSynSAA+\/DAT+) was present in 87% hyposmics and 72% iRBD phenoconverters. CSFaSynSAA negativity was high among LRRK2 phenoconverters (67%), who also were more likely to have a preserved sense of smell (83%). Phenoconversion occurred later than onset of functional impairment: 15\/47 (31.9%) iRBDs and 7\/38 (18.4%) hyposmics were already NSD-ISS stage [&ge;]4 at time of phenoconversion. Conclusions: Clinical phenoconversion did not necessarily align with biological evidence of synucleinopathy or dopaminergic loss and can be delayed compared to onset of meaningful functional impairment. Longitudinal follow up on converters without biological evidence of PD is required to confirm conversion diagnosis and evaluate for a later occurrence of biomarker positivity.","rel_num_authors":17,"rel_authors":[{"author_name":"Cristina Simonet","author_inst":"Centre for Preventive Neurology, Wolfson Institute of Population Health; Queen Mary University of London, UK"},{"author_name":"Jie Yin","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Lana M Chahine","author_inst":"University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Daniel Weintraub","author_inst":"University of Pennsylvania, Philadelphia, PA"},{"author_name":"Krittika Chatterjee","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Chelsea Caspell-Garcia","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Alastair Noyce","author_inst":"Centre for Preventive Neurology, Wolfson Institute of Population Health; Queen Mary University of London, UK"},{"author_name":"Andrew Siderowf","author_inst":"University of Pennsylvania; Philadelphia, PA, USA"},{"author_name":"Carlie Tanner","author_inst":"University of California, San Francisco; San Francisco, CA, USA"},{"author_name":"Ethan Brown","author_inst":"University of California, San Francisco; San Francisco, CA, USA"},{"author_name":"Thomas F Tropea","author_inst":"The Institute for Neurodegenerative Disorders; New Haven, Connecticut, USA"},{"author_name":"Brit Mollenhauer","author_inst":"Paracelsus-Elena Klinik; Kassel, Germany"},{"author_name":"Roy N Alcalay","author_inst":"Tel Aviv Sourasky Medical Center; Tel Aviv, Israel and Columbia University Irving Medical Center, NY, USA"},{"author_name":"Kathleen Poston","author_inst":"Stanford University; Stanford, CA, USA"},{"author_name":"Kenneth Marek","author_inst":"The Institute for Neurodegenerative Disorders; New Haven, Connecticut, USA"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Synuclein and dopamine transporter biomarkers among phenoconverters to parkinsonian disorders","rel_doi":"10.64898\/2026.04.15.26350768","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350768","rel_abs":"Background: Phenoconversion to Parkinson's disease (PD) or dementia with Lewy bodies (DLB) currently relies on established clinical diagnostic criteria. Availability of in vivo biomarkers--CSF -synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter (DAT) imaging--offer the opportunity to investigate congruency between clinical phenoconversion and biologically defined disease. Methods: We analyzed Parkinson's Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA), Alzheimer's disease (AD) or other dementias from prodromal and non-manifesting genetic carrier (NMC) groups and controls. Site investigators determined phenoconversion based on established diagnostic criteria. All phenoconverters with [&ge;]1 annual follow-up visit, with available biomarkers and persistent clinically defined diagnosis at last observation were included. Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-SS) staging was applied. Results: Among 121 phenoconverters, 103 had evaluable CSFaSynSAA and DAT data and were included in analysis: 92 PD, 7 DLB, 2 MSA, 2 AD\/other dementias. Phenoconversion annual rates varied widely across groups: iRBD 7.9%, hyposmia 4.2%, GBA1 0.3%, LRRK2 1.3%, LRRK2+GBA1 0.9%, and controls 0.5%. Median time from baseline to phenoconversion ranged from 13-14 months in iRBD and hyposmia to 36-85 months in NMCs. The expected biomarker profile (CSFaSynSAA+\/DAT+) for clinically-diagnosed synucleinopathy occurred in 74 (71.8%) participants. Biological alignment (CSFaSynSAA+\/DAT+) was present in 87% hyposmics and 72% iRBD phenoconverters. CSFaSynSAA negativity was high among LRRK2 phenoconverters (67%), who also were more likely to have a preserved sense of smell (83%). Phenoconversion occurred later than onset of functional impairment: 15\/47 (31.9%) iRBDs and 7\/38 (18.4%) hyposmics were already NSD-ISS stage [&ge;]4 at time of phenoconversion. Conclusions: Clinical phenoconversion did not necessarily align with biological evidence of synucleinopathy or dopaminergic loss and can be delayed compared to onset of meaningful functional impairment. Longitudinal follow up on converters without biological evidence of PD is required to confirm conversion diagnosis and evaluate for a later occurrence of biomarker positivity.","rel_num_authors":17,"rel_authors":[{"author_name":"Cristina Simonet","author_inst":"Centre for Preventive Neurology, Wolfson Institute of Population Health; Queen Mary University of London, UK"},{"author_name":"Jie Yin","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Lana M Chahine","author_inst":"University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Daniel Weintraub","author_inst":"University of Pennsylvania, Philadelphia, PA"},{"author_name":"Krittika Chatterjee","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Chelsea Caspell-Garcia","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Alastair Noyce","author_inst":"Centre for Preventive Neurology, Wolfson Institute of Population Health; Queen Mary University of London, UK"},{"author_name":"Andrew Siderowf","author_inst":"University of Pennsylvania; Philadelphia, PA, USA"},{"author_name":"Carlie Tanner","author_inst":"University of California, San Francisco; San Francisco, CA, USA"},{"author_name":"Ethan Brown","author_inst":"University of California, San Francisco; San Francisco, CA, USA"},{"author_name":"Thomas F Tropea","author_inst":"The Institute for Neurodegenerative Disorders; New Haven, Connecticut, USA"},{"author_name":"Brit Mollenhauer","author_inst":"Paracelsus-Elena Klinik; Kassel, Germany"},{"author_name":"Roy N Alcalay","author_inst":"Tel Aviv Sourasky Medical Center; Tel Aviv, Israel and Columbia University Irving Medical Center, NY, USA"},{"author_name":"Kathleen Poston","author_inst":"Stanford University; Stanford, CA, USA"},{"author_name":"Kenneth Marek","author_inst":"The Institute for Neurodegenerative Disorders; New Haven, Connecticut, USA"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Synuclein and dopamine transporter biomarkers among phenoconverters to parkinsonian disorders","rel_doi":"10.64898\/2026.04.15.26350768","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350768","rel_abs":"Background: Phenoconversion to Parkinson's disease (PD) or dementia with Lewy bodies (DLB) currently relies on established clinical diagnostic criteria. Availability of in vivo biomarkers--CSF -synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter (DAT) imaging--offer the opportunity to investigate congruency between clinical phenoconversion and biologically defined disease. Methods: We analyzed Parkinson's Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA), Alzheimer's disease (AD) or other dementias from prodromal and non-manifesting genetic carrier (NMC) groups and controls. Site investigators determined phenoconversion based on established diagnostic criteria. All phenoconverters with [&ge;]1 annual follow-up visit, with available biomarkers and persistent clinically defined diagnosis at last observation were included. Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-SS) staging was applied. Results: Among 121 phenoconverters, 103 had evaluable CSFaSynSAA and DAT data and were included in analysis: 92 PD, 7 DLB, 2 MSA, 2 AD\/other dementias. Phenoconversion annual rates varied widely across groups: iRBD 7.9%, hyposmia 4.2%, GBA1 0.3%, LRRK2 1.3%, LRRK2+GBA1 0.9%, and controls 0.5%. Median time from baseline to phenoconversion ranged from 13-14 months in iRBD and hyposmia to 36-85 months in NMCs. The expected biomarker profile (CSFaSynSAA+\/DAT+) for clinically-diagnosed synucleinopathy occurred in 74 (71.8%) participants. Biological alignment (CSFaSynSAA+\/DAT+) was present in 87% hyposmics and 72% iRBD phenoconverters. CSFaSynSAA negativity was high among LRRK2 phenoconverters (67%), who also were more likely to have a preserved sense of smell (83%). Phenoconversion occurred later than onset of functional impairment: 15\/47 (31.9%) iRBDs and 7\/38 (18.4%) hyposmics were already NSD-ISS stage [&ge;]4 at time of phenoconversion. Conclusions: Clinical phenoconversion did not necessarily align with biological evidence of synucleinopathy or dopaminergic loss and can be delayed compared to onset of meaningful functional impairment. Longitudinal follow up on converters without biological evidence of PD is required to confirm conversion diagnosis and evaluate for a later occurrence of biomarker positivity.","rel_num_authors":17,"rel_authors":[{"author_name":"Cristina Simonet","author_inst":"Centre for Preventive Neurology, Wolfson Institute of Population Health; Queen Mary University of London, UK"},{"author_name":"Jie Yin","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Lana M Chahine","author_inst":"University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Daniel Weintraub","author_inst":"University of Pennsylvania, Philadelphia, PA"},{"author_name":"Krittika Chatterjee","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Chelsea Caspell-Garcia","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"David-Erick Lafontant","author_inst":"Department of Biostatistics, University of Iowa, Iowa City, IA"},{"author_name":"Alastair Noyce","author_inst":"Centre for Preventive Neurology, Wolfson Institute of Population Health; Queen Mary University of London, UK"},{"author_name":"Andrew Siderowf","author_inst":"University of Pennsylvania; Philadelphia, PA, USA"},{"author_name":"Carlie Tanner","author_inst":"University of California, San Francisco; San Francisco, CA, USA"},{"author_name":"Ethan Brown","author_inst":"University of California, San Francisco; San Francisco, CA, USA"},{"author_name":"Thomas F Tropea","author_inst":"The Institute for Neurodegenerative Disorders; New Haven, Connecticut, USA"},{"author_name":"Brit Mollenhauer","author_inst":"Paracelsus-Elena Klinik; Kassel, Germany"},{"author_name":"Roy N Alcalay","author_inst":"Tel Aviv Sourasky Medical Center; Tel Aviv, Israel and Columbia University Irving Medical Center, NY, USA"},{"author_name":"Kathleen Poston","author_inst":"Stanford University; Stanford, CA, USA"},{"author_name":"Kenneth Marek","author_inst":"The Institute for Neurodegenerative Disorders; New Haven, Connecticut, USA"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Prevalence and Risk Factors of Respiratory Tract Infections Following Medically-Attended-Diarrhea in Children Aged 6-35 Months: Enterics for Global Health (EFGH)-Shigella Surveillance Study, 2022-2024.","rel_doi":"10.64898\/2026.04.17.26351078","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.17.26351078","rel_abs":"Globally, respiratory tract infections (RTI) are the main cause of morbidity, and in Low-middle-income countries (LMICs) RTI including pneumonia are a leading cause of morbidity and mortality in children <5 years. Diarrheal illness increases RTI risk in young children through micronutrient depletion, and immune stress, yet data on post-diarrhea RTI burden in LMICs are limited. We determined the prevalence and risk factors of RTI within three months following medically-attended diarrhea (MAD) in children aged 6-35 months enrolled in seven EFGH country sites in Asia, Africa and South America. The EFGH study prospectively enrolled children aged 6-35 months with MAD in selected health facilities during a 24-month period from 2022 to 2024 and followed them for three months. RTI was defined as cough or difficulty breathing and the presence of one of the following symptoms at any scheduled or unscheduled visit during follow-up: stridor; fast-breathing; oxygen saturation <90%; or chest indrawing. The period prevalence and 95% confidence intervals of RTI were calculated, and correlates of RTI were assessed using modified-Poisson regression. From June 2022 to August 2024, 9,476 children aged 6-35 months presenting with MAD in the EFGH study sites were screened: 9,116 (96.2%) included in the current study. Nearly half were female (46.7%), and median age was 15 months. Overall, 48.5% received all age-appropriate vaccines, and 87.6% received the pneumococcal vaccine, with significant variation across countries. Nearly one-quarter of children were stunted, 17.2% wasted, and 21.9% underweight. RTI occurred in 3.8% of children during the three-month follow-up, mostly within the first month. Higher prevalence of RTI occurred among children aged 12-23 months (8.7%), those undernourished (16.1%), unvaccinated (4.0%) or living in poor sanitation settings (4.1%). While children who received all age-appropriate or pneumococcal vaccinations had a lower crude prevalence of RTI, these associations were not statistically significant after adjusting for age, sex and study site. RTI was infrequently observed in the three months following MAD presentation, with significant variability by site and with the highest prevalence in Malawi. RTI risk was highest in 12-23-month-olds and among children with undernutrition, and those living in poor sanitation conditions.","rel_num_authors":20,"rel_authors":[{"author_name":"Bakary Conteh","author_inst":"MRC Unit The Gambia at LSHTM: Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine"},{"author_name":"Sean  R. Galagan","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"Henry Badji","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine"},{"author_name":"Ousman Secka","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine"},{"author_name":"Beth  Tippett Bar","author_inst":"Nyanja Health Institute, Salima, Malawi"},{"author_name":"Sonia  I. Rao","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"Hannah Atlas","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"Richard Omore","author_inst":"Kenya Medical Research Institute"},{"author_name":"John  B. Ochieng","author_inst":"Kenya Medical Research Institute"},{"author_name":"Milagritos Tapia","author_inst":"Centre pour le Developpement des Vaccins Mali"},{"author_name":"Jen Cornick","author_inst":"Malawi-Liverpool-Wellcome Trust Clinical Research Programme"},{"author_name":"Nigel Cunliffe","author_inst":"Malawi-Liverpool-Wellcome Trust Clinical Research Programme"},{"author_name":"Loyda  Fiorella Zegarra Paredes","author_inst":"Asociacion Benefica Prisma"},{"author_name":"Josh Colston","author_inst":"University of Virginia School of Medicine"},{"author_name":"Md  Taufiqul Islam","author_inst":"International Centre for Diarrhoeal Disease Research Bangladesh"},{"author_name":"Md.  Parvej Mosharraf","author_inst":"International Centre for Diarrhoeal Disease Research Bangladesh"},{"author_name":"Farah  Naz Qamar","author_inst":"Aga Khan University"},{"author_name":"Irum Fatima","author_inst":"Aga Khan University"},{"author_name":"Patricia  B. Pavlinac","author_inst":"University of Washington Seattle Campus: University of Washington"},{"author_name":"M.  Jahangir Hossain","author_inst":"Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine"}],"rel_date":"2026-04-20","rel_site":"medrxiv"},{"rel_title":"Small-Molecule Structure Determination and Anisotropic Displacement Analysis at Turkish Light Source","rel_doi":"10.64898\/2026.04.19.719451","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.19.719451","rel_abs":"Single-crystal X-ray diffraction remains one of the most direct and reliable techniques for clarifying the three-dimensional structures of small molecules; however, its wider use in developing research settings has historically been limited by access to advanced instrumentation. Here, we consider the performance of the in-house diffractometer, Turkish Light Source, for small-molecule structure determination using three rhodanine-derivative compounds. Diffraction data were collected, processed, and followed by full-matrix least-squares refinement as a user-friendly pipeline. The compounds were successfully resolved in the triclinic space group P-1 and refined to chemically reasonable models, although notable differences in data quality and refinement parameters were observed. Compounds 1 and 2 produced the most robust and internally coherent structure, whereas compound 3 displayed refinement tribulations. These might be attributed to the intrinsic structural disorder of c-5b, analogous to polymorphic perversity in higher Z' phase, likely due to the presence of dissymmetric molecules within the asymmetric unit (Z' = 2), rather than empirical limitations. Anisotropic displacement parameters were systematically computed by atom-resolved Ueq factors and anisotropy index. The combined analyses reveal that structural ambiguity of c-5b is largely governed by localized maxima in atomic displacement (up to 0.29 [A]2 in Ueq with 6.67 anisotropy) rather than by global disorder, caused by the fluorinated aryl moiety of c-5b. These findings indicate that the in-house SCXRD system, when coupled with our user-friendly downstream pipeline, can yield reliable structural data for small molecules. Brief video tutorials and detailed SOPs have been provided in the Tutorials folder, including CrysAlisPro and Olex2 tutorials, as well as are easily accessible for users.","rel_num_authors":2,"rel_authors":[{"author_name":"Esra AYAN","author_inst":"University of Health Sciences"},{"author_name":"Arif Mermer","author_inst":"University of Health Sciences"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Positional information and information flows in dynamic tissues","rel_doi":"10.64898\/2026.04.15.718553","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718553","rel_abs":"During development, embryos store, transmit, and transform information to generate spatial patterns. Positional information (PI) quantifies how precisely cells form patterns at a given time, but cell motion has limited its application to static tissues. We introduce a framework for PI in dynamic tissues by decomposing mutual information between cells' positions and properties over time into information flows contributing to PI preservation, loss and generation. These reveal information-theoretic signatures of ubiquitous developmental processes, including instruction, sorting and mixing, directly from data. Applying this framework to whole-embryo cell trajectories in Drosophila, mouse and zebrafish gastrulation, we provide local and global information-theoretic quantification of cell mixing and derive bounds on PI preservation imposed by tissue dynamics. Analyzing tissue flows as dynamical systems, we further show that morphogenesis structures mixing, preferentially preserving specific patterns. Finally, we derive inequality conditions for tracing generated PI to candidate information sources and distinguishing among alternative pattern-formation mechanisms, from programmed extracellular cues to self-organizing intercellular interactions.","rel_num_authors":2,"rel_authors":[{"author_name":"Alex M Plum","author_inst":"University of California San Diego"},{"author_name":"Mattia Serra","author_inst":"University of California San Diego"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Full-Atom MPNN Based Redesign of Plant Dehydrogenase Enables Thermostability Enhancement Without Loss of Stereoselectivity","rel_doi":"10.64898\/2026.04.20.719482","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.20.719482","rel_abs":"Protein stabilization is a \"Holy Grail\" of biocatalysis, and stability design is an area of intense research interest. While it is increasingly feasible to effectively increase enzyme thermostability, optimization without compromising activity or selectivity remains a significant challenge. Here, we use full-atom protein sequence design with sidechain conditioning (FAMPNN) to engineer thermostable variants of the borneol dehydrogenase from Salvia rosmarinus (SrBDH1), an enzyme from a family where unselective enzymes dominate, and selectivity is determined by dynamical considerations. By combining FAMPNN design with residue conservation analysis and avoiding active site residues, we were able to computationally design SrBDH1 variants with up to 10 {degrees}C enhanced thermostability and strongly increased half-life time at elevated temperature, while retaining selectivity towards (+)-borneol. This design framework, integrating de novo and physics-based protein design tools, demonstrates that stability can be enhanced without disrupting functionally relevant dynamics, providing a route to engineer robust and selective biocatalysts.","rel_num_authors":6,"rel_authors":[{"author_name":"Bruno Di Geronimo","author_inst":"Georgia Institute of Technology"},{"author_name":"Jasmin Zuson","author_inst":"Graz University of Technology"},{"author_name":"Ana Udzenija","author_inst":"Graz University of Technology"},{"author_name":"Andrea Chanique","author_inst":"Graz University of Technology"},{"author_name":"Robert Kourist","author_inst":"Graz University of Technology"},{"author_name":"Shina Caroline Lynn Kamerlin","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"The functional organization of retinal input to the mouse superior colliculus","rel_doi":"10.64898\/2026.04.15.718783","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718783","rel_abs":"The superior colliculus integrates retinal input to drive rapid, adaptive visual behavior, yet how the functional diversity of retinal ganglion cell types is represented in superior colliculus remains poorly understood. Using chronic two-photon calcium imaging of retinal ganglion cell axonal boutons in awake mice, we recorded over 200,000 boutons across superficial superior colliculus layers --- a scale that enabled systematic comparison with large-scale ex vivo retinal datasets. This revealed that the superior colliculus receives a near-complete sampling of retinal ganglion cell functional diversity. Functionally distinct response types were organized in systematic laminar gradients: not only response properties such as direction selectivity and contrast suppression, but retinal response types themselves varied systematically with depth. To probe how this organized input encodes natural scenes, we trained a ''digital twin'' deep network model on natural movie responses and validated its generalization to parametric stimuli, including cell type identification. Leveraging this model to generate predicted responses to looming stimuli, we identify a discrete subset of retinal response types tuned for collision detection at low angular thresholds --- a specialization embedded within a broader, non-specialized retinal population. The digital twin is made publicly available as a community resource. Together, these findings provide a comprehensive functional map of retinal drive to the superior colliculus and an in silico platform for linking retinal cell types to behaviorally relevant superior colliculus computations.","rel_num_authors":17,"rel_authors":[{"author_name":"Yongrong Qiu","author_inst":"Stanford University"},{"author_name":"Lisa Schmors","author_inst":"University of Tuebingen"},{"author_name":"Na Zhou","author_inst":"Baylor College of Medicine"},{"author_name":"Mels Akhmetali","author_inst":"University of Goettingen"},{"author_name":"Dominic Gonschorek","author_inst":"University of Tuebingen"},{"author_name":"Cameron Smith","author_inst":"Baylor College of Medicine"},{"author_name":"Anton Sumser","author_inst":"Ludwig-Maximilian-University Munich"},{"author_name":"Marie Vallens","author_inst":"Baylor College of Medicine"},{"author_name":"Cathryn R. Cadwell","author_inst":"UCSF"},{"author_name":"Fabrizio Gabbiani","author_inst":"Baylor College of Medicine"},{"author_name":"Maximilian Joesch","author_inst":"Institute of Science and Technology Austria"},{"author_name":"Andreas Tolias","author_inst":"Stanford University"},{"author_name":"Philipp Berens","author_inst":"University of Tuebingen"},{"author_name":"Thomas Euler","author_inst":"University of Tuebingen"},{"author_name":"Fabian Sinz","author_inst":"University of Goettingen"},{"author_name":"Jacob Reimer","author_inst":"Baylor College of Medicine"},{"author_name":"Katrin Franke","author_inst":"Stanford University"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Plectin promotes an aggressive phenotype and represses cytotoxic T cell activity in pancreatic cancer","rel_doi":"10.64898\/2026.04.16.718901","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718901","rel_abs":"Background: Pancreatic adenocarcinoma (PDAC) is an abysmal disease, with a poor clinical outcome, largely due to limited life-extending treatments for patients. Notoriously, PDAC displays a T cell-suppressive tumor microenvironment where underlying molecular mechanisms that lead to this phenotype remain poorly understood. To unravel specific mechanisms, we utilized bioinformatic analyses with functional studies and revealed the cytolinker protein plectin (PLEC) as a novel player in regulating the T cell-suppressive tumor microenvironment of PDAC. Methods: Utilizing the TCGA-PAAD dataset, tumor samples were separated by PLEC expression to evaluate patient survival, and pathway analyses associated with increased tumorigenesis. Evaluation of immune infiltration and subsequent immune deconvolution was performed using tidyestimate and CIBERSORTx R packages. Single-cell RNA-seq (scRNA-seq) analysis from 229 PDAC patients was analyzed to investigate signaling dynamics and immune cell infiltration in PLECHigh patients. Functional validation was provided using a monoclonal antibody (mAb) against cell surface plectin (CSP) in two murine PDAC models to examine changes in tumor growth and immune cell subset abundance. Results: Our studies revealed that high plectin expression results in an overall worse survival associated with activation of pro-tumorigenic pathways and decreased anti-tumor immune signature in PDAC patients. Analysis via GSEA indicates PLECHigh patients display an aggressive phenotype and suppressed pro-inflammatory signaling pathways. Immune ESTIMATE scores were significantly decreased in PLECHigh patients, and scRNA-seq analysis revealed that PLECHigh tumors display a decrease in anti-tumor CD8+ T cells. In vivo analyses using an anti-CSP mAb revealed a reduction in tumor growth kinetics compared to IgG control corresponding with a significant increase in proliferating and activated cytotoxic CD8+ T cells. Anti-CSP-mediated tumor suppression was inhibited when CD8+ T cells were depleted, indicating that anti-CSP treatment is contingent on cytotoxic T cell functionality. Conclusion: Our findings identify plectin as a biomarker of aggressive disease in PDAC, with high plectin expression associated with decreased T cell infiltration, and that treatment with anti-CSP mAb reinstates anti-tumor immunity and decreases tumor volume in vivo. These findings position plectin as a high-priority therapeutic target, with the potential to fundamentally reshape immune responses in PDAC and improve outcomes for patients with few remaining options.","rel_num_authors":10,"rel_authors":[{"author_name":"Cody L Wolf","author_inst":"Department of Biomedical Engineering, University of Virginia"},{"author_name":"Roxanne K. Ruiz","author_inst":"Department of Molecular Physiology and Biological Physics, University of Virginia"},{"author_name":"Sokchea Khou","author_inst":"Department of Cell, Developmental, & Cancer Biology, Oregon Health and Science University"},{"author_name":"Robert Cornelison","author_inst":"Department of Experimental Pathology, University of Virginia"},{"author_name":"Edward B. Stelow","author_inst":"Department of Experimental Pathology, University of Virginia"},{"author_name":"Karl M. Kowalewski","author_inst":"Department of Chemical Engineering, University of Virginia"},{"author_name":"Matthew J. Lazzara","author_inst":"Department of Chemical Engineering, University of Virginia"},{"author_name":"Amanda Poissonnier","author_inst":"Department of Cell, Developmental, & Cancer Biology, Oregon Health and Science University"},{"author_name":"Lisa M. Coussens","author_inst":"Department of Cell, Developmental, & Cancer Biology, Oregon Health and Science University"},{"author_name":"Kimberly A. Kelly","author_inst":"Department of Biomedical Engineering, University of Virginia School of Engineering, Charlottesville"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"The resource-rational dynamics of evidence accumulation","rel_doi":"10.64898\/2026.04.15.718716","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718716","rel_abs":"Evidence accumulation is a fundamental aspect of human decision-making. However, how the precise temporal structure of evidence shapes the accumulation process has not been systematically studied. As a result, current understanding of evidence accumulation remains largely limited to its time-averaged behavior. We tested human subjects in a visual estimation task in which they inferred the angular position of an unknown source from a noisy stimulus sequence. Introducing systematic temporal perturbations, i.e., breaks of different durations and at different positions in the otherwise regular evidence sequence, revealed that subjects actively compensated for the memory loss endured during the break by dynamically enhancing evidence integration and memory maintenance immediately after the break. We derived a new time-continuous Bayesian updating model that is dynamically constrained by optimal performance-effort trade-offs. With two free parameters determining the overall resource-efficiencies of encoding and memory maintenance, the model accurately predicts the rich dependencies of subjects' accumulation behavior on the evidence schedule, including subjects' individual tendencies to emphasize either early (primacy) or late (recency) samples in the evidence sequence. Our results suggest that evidence accumulation is a non-stationary, dynamically controlled process that optimally balances the information gained from incoming evidence against the cognitive effort required to acquire and maintain it. The proposed model is general and should apply broadly across many task domains.","rel_num_authors":4,"rel_authors":[{"author_name":"Mengting Fang","author_inst":"University of Pennsylvania"},{"author_name":"Jiang Mao","author_inst":"Columbia University"},{"author_name":"Tobias H Donner","author_inst":"University Medical Center Hamburg-Eppendorf"},{"author_name":"Alan A Stocker","author_inst":"University of Pennsylvania"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Early mitophagy defects and impaired mitochondrial energy metabolism drive target organ damage progression: lessons from the Fabry heart","rel_doi":"10.64898\/2026.04.15.718770","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718770","rel_abs":"Increased literature support the pathogenetic role of dysfunctional energetic metabolism in the setup and progression of organ damage and failure. Genetic diseases often offer the possibility to investigate pathogenetic mechanisms. In particular, excessive cardiac damage is the most frequent cause of mortality in Fabry disease (FD), a genetic condition caused by deficient -galactosidase A (GLA) activity, leading to globotriaosylceramide (Gb3) accumulation. Beyond Gb3 storage, metabolic alterations and mitochondrial dysfunction, supported by in vitro evidence or studies in other tissues, may contribute to FD cardiomyopathy. This study investigated, for the first time, the mechanisms of mitochondrial involvement in FD, its role in determining cardiac manifestations, and its potential as a therapeutic target. We used a humanized FD mouse model (R301Q-Tg\/GLA knockout), along with derived embryonic fibroblasts and neonatal and adult cardiomyocytes, to assess mitochondrial function across the lifespan. FD cells showed impaired mitophagy, reduced mitochondrial respiration, and increased reactive oxygen species production. Importantly, this mitochondrial dysfunction exacerbated the lysosomal deficit in FD cells, forming a vicious cycle. In cardiomyocytes, these alterations progressed with age, leading to the accumulation of dysfunctional mitochondria, energetic failure, and, in adult hearts, terminal mitochondrial damage and apoptosis. These events ultimately result in cardiac remodeling and dysfunction, including hypertrophy and diastolic impairment. Indeed, L-arginine supplementation, which promotes NO\/PGC-1-dependent mitochondrial rescue, prevented the development of cardiac abnormalities in FD mice. Our findings identify early mitochondrial dysfunction as a key driver of FD cardiomyopathy and support mitochondrial targeting, including L-arginine supplementation, as a promising adjuvant therapeutic strategy. The mechanistic link between lysosomal dysfunction, altered mitochondrial turnover, and energetic collapse emerges as a key targetable pathway in organ damage, extending beyond FD.","rel_num_authors":25,"rel_authors":[{"author_name":"Jessica GAMBARDELLA","author_inst":"Federico II University of Naples"},{"author_name":"Antonella Fiordelisi","author_inst":"Federico II University of Naples"},{"author_name":"Federica Andrea Cerasuolo","author_inst":"Federico II Unievrsity of Naples"},{"author_name":"Antonietta Buonaiuto","author_inst":"Federico II University of Naples"},{"author_name":"Roberta Avvisato","author_inst":"Federico II University of Naples"},{"author_name":"Alessandro Viti","author_inst":"Federico II Univesrity of Naples"},{"author_name":"Eduardo Sommella","author_inst":"University of Salerno"},{"author_name":"Pietro Campiglia","author_inst":"University of Salerno"},{"author_name":"Valeria D'Argenio","author_inst":"CEINGE- Advanced Biotechnologies, Naples, Italy."},{"author_name":"Nella Prevete","author_inst":"Federico II University of Naples"},{"author_name":"Antonio Pezone","author_inst":"University of Naples Federico II"},{"author_name":"Stefania D'Apice","author_inst":"Federico II University of Naples"},{"author_name":"Giovanna Giuseppina Altobelli","author_inst":"Federico II University of Naples"},{"author_name":"Fahimeh Varzideh","author_inst":"School of Medicine, City University of New York, Manhattan, NY, 10031, USA."},{"author_name":"Shivangi Pande","author_inst":"School of Medicine, City University of New York, Manhattan, NY, 10031, USA."},{"author_name":"Roberta Paolillo","author_inst":"Federico II University of Naples"},{"author_name":"Cinzia Perrino","author_inst":"Federico II University of Naples"},{"author_name":"Eleonora Riccio","author_inst":"Federico II University of Naples"},{"author_name":"Antonio Pisani","author_inst":"Federico II University of Naples"},{"author_name":"Antonio Bianco","author_inst":"Federico II University of Naples"},{"author_name":"Junichi Sadoshima","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Letizia Spinelli","author_inst":"Federico II University of Naples"},{"author_name":"Gaetano Santulli","author_inst":"Federico II University of Naples"},{"author_name":"Daniela Sorriento","author_inst":"Federico II University"},{"author_name":"Guido Iaccarino","author_inst":"Federico II University"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Early mitophagy defects and impaired mitochondrial energy metabolism drive target organ damage progression: lessons from the Fabry heart","rel_doi":"10.64898\/2026.04.15.718770","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718770","rel_abs":"Increased literature support the pathogenetic role of dysfunctional energetic metabolism in the setup and progression of organ damage and failure. Genetic diseases often offer the possibility to investigate pathogenetic mechanisms. In particular, excessive cardiac damage is the most frequent cause of mortality in Fabry disease (FD), a genetic condition caused by deficient -galactosidase A (GLA) activity, leading to globotriaosylceramide (Gb3) accumulation. Beyond Gb3 storage, metabolic alterations and mitochondrial dysfunction, supported by in vitro evidence or studies in other tissues, may contribute to FD cardiomyopathy. This study investigated, for the first time, the mechanisms of mitochondrial involvement in FD, its role in determining cardiac manifestations, and its potential as a therapeutic target. We used a humanized FD mouse model (R301Q-Tg\/GLA knockout), along with derived embryonic fibroblasts and neonatal and adult cardiomyocytes, to assess mitochondrial function across the lifespan. FD cells showed impaired mitophagy, reduced mitochondrial respiration, and increased reactive oxygen species production. Importantly, this mitochondrial dysfunction exacerbated the lysosomal deficit in FD cells, forming a vicious cycle. In cardiomyocytes, these alterations progressed with age, leading to the accumulation of dysfunctional mitochondria, energetic failure, and, in adult hearts, terminal mitochondrial damage and apoptosis. These events ultimately result in cardiac remodeling and dysfunction, including hypertrophy and diastolic impairment. Indeed, L-arginine supplementation, which promotes NO\/PGC-1-dependent mitochondrial rescue, prevented the development of cardiac abnormalities in FD mice. Our findings identify early mitochondrial dysfunction as a key driver of FD cardiomyopathy and support mitochondrial targeting, including L-arginine supplementation, as a promising adjuvant therapeutic strategy. The mechanistic link between lysosomal dysfunction, altered mitochondrial turnover, and energetic collapse emerges as a key targetable pathway in organ damage, extending beyond FD.","rel_num_authors":25,"rel_authors":[{"author_name":"Jessica GAMBARDELLA","author_inst":"Federico II University of Naples"},{"author_name":"Antonella Fiordelisi","author_inst":"Federico II University of Naples"},{"author_name":"Federica Andrea Cerasuolo","author_inst":"Federico II Unievrsity of Naples"},{"author_name":"Antonietta Buonaiuto","author_inst":"Federico II University of Naples"},{"author_name":"Roberta Avvisato","author_inst":"Federico II University of Naples"},{"author_name":"Alessandro Viti","author_inst":"Federico II Univesrity of Naples"},{"author_name":"Eduardo Sommella","author_inst":"University of Salerno"},{"author_name":"Pietro Campiglia","author_inst":"University of Salerno"},{"author_name":"Valeria D'Argenio","author_inst":"CEINGE- Advanced Biotechnologies, Naples, Italy."},{"author_name":"Nella Prevete","author_inst":"Federico II University of Naples"},{"author_name":"Antonio Pezone","author_inst":"University of Naples Federico II"},{"author_name":"Stefania D'Apice","author_inst":"Federico II University of Naples"},{"author_name":"Giovanna Giuseppina Altobelli","author_inst":"Federico II University of Naples"},{"author_name":"Fahimeh Varzideh","author_inst":"School of Medicine, City University of New York, Manhattan, NY, 10031, USA."},{"author_name":"Shivangi Pande","author_inst":"School of Medicine, City University of New York, Manhattan, NY, 10031, USA."},{"author_name":"Roberta Paolillo","author_inst":"Federico II University of Naples"},{"author_name":"Cinzia Perrino","author_inst":"Federico II University of Naples"},{"author_name":"Eleonora Riccio","author_inst":"Federico II University of Naples"},{"author_name":"Antonio Pisani","author_inst":"Federico II University of Naples"},{"author_name":"Antonio Bianco","author_inst":"Federico II University of Naples"},{"author_name":"Junichi Sadoshima","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Letizia Spinelli","author_inst":"Federico II University of Naples"},{"author_name":"Gaetano Santulli","author_inst":"Federico II University of Naples"},{"author_name":"Daniela Sorriento","author_inst":"Federico II University"},{"author_name":"Guido Iaccarino","author_inst":"Federico II University"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Inducible nitric oxide synthase (iNOS) regulates skin eschar lesions, bacterial persistence, and inflammatory resolution in mouse models of scrub typhus","rel_doi":"10.64898\/2026.04.15.718641","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718641","rel_abs":"Orientia tsutsugamushi (Ot) is an obligately intracellular bacterium that causes scrub typhus, a potentially severe infectious disease characterized by systemic inflammation and multiorgan dysfunction. We recently reported a protective role for IFN-{gamma} signaling in host defense against Ot infection; however, the underlying mechanisms remain obscure. Inducible nitric oxide synthase (iNOS, encoded by Nos2) is a key antimicrobial effector induced downstream of IFN-{gamma} signaling. Here, we used transgenic mouse models to further investigate the biological functions of iNOS. We first revealed the requirement of iNOS for the restriction of Ot growth in cultured bone marrow-derived macrophages. Using an intradermal mouse model, we found that while tissues of Nos2-\/- and wild-type mice exhibited comparable bacterial burdens during acute infection phases, Nos2-\/- mice developed eschar-like lesions similar to those observed in Ifngr1-\/- mice, indicating a critical role for the IFN-{gamma}\/iNOS axis in regulating skin pathology in scrub typhus. Notably, Nos2-\/- mice displayed impaired bacterial clearance during the recovery phase (day 42), with persistent bacterial burdens in multiple organs accompanied by sustained immune activation and elevated inflammatory responses. Histopathological and biochemical analyses further revealed increased tissue damage and dysregulated physiological homeostasis in the Nos2-\/- mice during recovery. Mechanistically, iNOS deficiency resulted in heightened myeloid cell activation and prolonged expression of proinflammatory mediators, suggesting a dual contribution of iNOS in both antimicrobial defense and inflammation resolution. Collectively, these findings provide new insight into IFN-{gamma}-mediated defense mechanisms and imply the distinct roles of iNOS during different stages of scrub typhus.","rel_num_authors":9,"rel_authors":[{"author_name":"Yixuan Zhou","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"Lihai Gao","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"Ryan H Cho","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"Judy Ly","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"Hui Wang","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"Hema Narra","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"Kun-Hsien Tsai","author_inst":"National Taiwan University"},{"author_name":"Lynn Soong","author_inst":"The University of Texas Medical Branch at Galveston"},{"author_name":"Yuejin Liang","author_inst":"The University of Texas Medical Branch at Galveston"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Not so cold after all: tumor infiltrating CD8+ T cells in EBV-positive Burkitt lymphoma are quiescent, not exhausted","rel_doi":"10.64898\/2026.04.15.718702","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718702","rel_abs":"Survival outcomes for pediatric Burkitt lymphoma (BL) substantially vary depending on geography (50-90%), which also serves as a proxy for the prevalence of Epstein-Barr virus (EBV) within the tumors. Although BL is considered an immunologically \"cold\" tumor with few tumor-infiltrating lymphocytes (TILs), their functional status has not been fully evaluated, especially for EBV-positive disease. Here, we characterize the exhaustion and activation profiles of T cells in the tumor microenvironment (TME) of EBV-positive BL using orthogonal methods, single-cell gene expression analysis, spectral flow cytometry, and immuno-histochemistry staining (IHC). We found that CD8+ TILs displayed a mosaic of immune inhibitory gene expression encoding, PD1, TIGIT, LAG3 and HAVCR2\/TIM3. IHC validated the expression of PD1 and TIGIT on CD8+ TILs, as well as their respective ligands, PDL-1, PVR, and Nectin-2 on malignant B cells. Despite exhaustion-associated signatures, CD8+ TILs retain cytotoxic potential, expressing granules (i.e. Granzyme A, Perforin) and cytokines (i.e. IFN{gamma}) and demonstrate an increased uptake of metabolites such as glucose, arginine, and methionine. In peripheral blood, pediatric BL patients exhibited a significantly higher abundance of PD1+TIGIT+ CD8+ T cells compared to healthy children. Notably, these circulating T cells from BL patients express significantly lower levels of TOX, suggesting they are not irreversibly dysfunctional. Together, our results indicate that CD8+ T cells both in the TME and in circulation of children with BL are not terminally exhausted but remain poised for functional re-invigoration. These findings support the potential integration of immune checkpoint inhibitors into combination chemotherapeutic regimens to improve outcomes for these children.","rel_num_authors":19,"rel_authors":[{"author_name":"Catherine S Forconi","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Cliff I Oduor","author_inst":"Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA"},{"author_name":"Priya L Saikumar","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Zachary J Racenet","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Gavin Fujimori","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Viriato M'Bana","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Angela Matta","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Jeni Melo","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Fabienne Laderach","author_inst":"Department of Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, Switzerland"},{"author_name":"Titus K Maina","author_inst":"Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA"},{"author_name":"Juliana A Otieno","author_inst":"Jaramogi Oginga Odinga Teaching and Referral Hospital, Kisumu, Kenya"},{"author_name":"Dan Chepsidor","author_inst":"Moi Teaching and Referral Hospital, Eldoret, Kenya"},{"author_name":"Kibet Kibor","author_inst":"Moi Teaching and Referral Hospital, Eldoret, Kenya"},{"author_name":"Festus Njuguna","author_inst":"Moi Teaching and Referral Hospital, Eldoret, Kenya"},{"author_name":"Terry Vik","author_inst":"Department of Pediatric Hematology\/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"author_name":"Ann W Kinyua","author_inst":"Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Christian Munz","author_inst":"Department of Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, Switzerland"},{"author_name":"Jeffrey A Bailey","author_inst":"Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA"},{"author_name":"Ann M Moormann","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Not so cold after all: tumor infiltrating CD8+ T cells in EBV-positive Burkitt lymphoma are quiescent, not exhausted","rel_doi":"10.64898\/2026.04.15.718702","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718702","rel_abs":"Survival outcomes for pediatric Burkitt lymphoma (BL) substantially vary depending on geography (50-90%), which also serves as a proxy for the prevalence of Epstein-Barr virus (EBV) within the tumors. Although BL is considered an immunologically \"cold\" tumor with few tumor-infiltrating lymphocytes (TILs), their functional status has not been fully evaluated, especially for EBV-positive disease. Here, we characterize the exhaustion and activation profiles of T cells in the tumor microenvironment (TME) of EBV-positive BL using orthogonal methods, single-cell gene expression analysis, spectral flow cytometry, and immuno-histochemistry staining (IHC). We found that CD8+ TILs displayed a mosaic of immune inhibitory gene expression encoding, PD1, TIGIT, LAG3 and HAVCR2\/TIM3. IHC validated the expression of PD1 and TIGIT on CD8+ TILs, as well as their respective ligands, PDL-1, PVR, and Nectin-2 on malignant B cells. Despite exhaustion-associated signatures, CD8+ TILs retain cytotoxic potential, expressing granules (i.e. Granzyme A, Perforin) and cytokines (i.e. IFN{gamma}) and demonstrate an increased uptake of metabolites such as glucose, arginine, and methionine. In peripheral blood, pediatric BL patients exhibited a significantly higher abundance of PD1+TIGIT+ CD8+ T cells compared to healthy children. Notably, these circulating T cells from BL patients express significantly lower levels of TOX, suggesting they are not irreversibly dysfunctional. Together, our results indicate that CD8+ T cells both in the TME and in circulation of children with BL are not terminally exhausted but remain poised for functional re-invigoration. These findings support the potential integration of immune checkpoint inhibitors into combination chemotherapeutic regimens to improve outcomes for these children.","rel_num_authors":19,"rel_authors":[{"author_name":"Catherine S Forconi","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Cliff I Oduor","author_inst":"Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA"},{"author_name":"Priya L Saikumar","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Zachary J Racenet","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Gavin Fujimori","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Viriato M'Bana","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Angela Matta","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Jeni Melo","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Fabienne Laderach","author_inst":"Department of Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, Switzerland"},{"author_name":"Titus K Maina","author_inst":"Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA"},{"author_name":"Juliana A Otieno","author_inst":"Jaramogi Oginga Odinga Teaching and Referral Hospital, Kisumu, Kenya"},{"author_name":"Dan Chepsidor","author_inst":"Moi Teaching and Referral Hospital, Eldoret, Kenya"},{"author_name":"Kibet Kibor","author_inst":"Moi Teaching and Referral Hospital, Eldoret, Kenya"},{"author_name":"Festus Njuguna","author_inst":"Moi Teaching and Referral Hospital, Eldoret, Kenya"},{"author_name":"Terry Vik","author_inst":"Department of Pediatric Hematology\/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"author_name":"Ann W Kinyua","author_inst":"Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Christian Munz","author_inst":"Department of Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, Switzerland"},{"author_name":"Jeffrey A Bailey","author_inst":"Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA"},{"author_name":"Ann M Moormann","author_inst":"Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases","rel_doi":"10.64898\/2026.04.15.718647","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718647","rel_abs":"Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, largely attributable to nonspecific spinal cord sampling. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.","rel_num_authors":13,"rel_authors":[{"author_name":"Leonie Sowoidnich","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Aaron L Norman","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Florian Gerstner","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Josiane K Siemund","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Jannik M Buettner","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"John G Pagiazitis","author_inst":"Center for Motor Neuron Biology and Disease, Columbia University"},{"author_name":"Vanessa Dreilich","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Konstantin Pilz","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Dajun Tian","author_inst":"Biogen"},{"author_name":"Charlotte J Sumner","author_inst":"Department of Neurology, Johns Hopkins University"},{"author_name":"Angela Paradis","author_inst":"Biogen"},{"author_name":"George Z Mentis","author_inst":"Center for Motor Neuron Biology and Disease, Columbia University"},{"author_name":"Christian M Simon","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases","rel_doi":"10.64898\/2026.04.15.718647","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718647","rel_abs":"Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, largely attributable to nonspecific spinal cord sampling. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.","rel_num_authors":13,"rel_authors":[{"author_name":"Leonie Sowoidnich","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Aaron L Norman","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Florian Gerstner","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Josiane K Siemund","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Jannik M Buettner","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"John G Pagiazitis","author_inst":"Center for Motor Neuron Biology and Disease, Columbia University"},{"author_name":"Vanessa Dreilich","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Konstantin Pilz","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"},{"author_name":"Dajun Tian","author_inst":"Biogen"},{"author_name":"Charlotte J Sumner","author_inst":"Department of Neurology, Johns Hopkins University"},{"author_name":"Angela Paradis","author_inst":"Biogen"},{"author_name":"George Z Mentis","author_inst":"Center for Motor Neuron Biology and Disease, Columbia University"},{"author_name":"Christian M Simon","author_inst":"Carl-Ludwig-Institute for Physiology, Leipzig University"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"HYPER-Net: Physics-Conditioned Self-Supervised Reconstruction for Fourier Light-Field Microscopy","rel_doi":"10.64898\/2026.04.14.718527","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718527","rel_abs":"The rapid convergence of optical innovation and machine intelligence is reshaping biological imaging by enabling platforms that jointly advance image formation and computational reconstruction for high-speed, high-resolution volumetric microscopy. However, broadly accessible three-dimensional imaging at high spatiotemporal resolution remains limited by the reliance of existing supervised methods on large modality-matched training datasets, the computational burden of conventional iterative reconstruction, and sensitivity to optical mismatch arising from small deviations in the spatial-angular point spread functions. Here, we introduce HYPER-Net, a physics-conditioned self-supervised framework for Fourier light-field microscopy that integrates scan-free volumetric acquisition with fast, robust three-dimensional reconstruction. HYPER-Net incorporates experiment-specific point-spread functions into the learning process in two complementary roles: as the forward operator that enforces measurement consistency and as a conditioning signal that adaptively modulates intermediate feature representations. This design reduces reliance on paired experimental ground-truth volumes, improves robustness to system variation, and enables generalizable reconstruction across diverse biological contexts. Using human colon organoids, embryonic Xenopus laevis hearts, hiPSC-derived cardiac spheroids, and freely moving Caenorhabditis elegans, we demonstrate high-fidelity volumetric imaging of tissue morphology, cardiac function, calcium-contraction coupling, and locomotion-associated neural and muscular dynamics. These results position HYPER-Net as a versatile framework for rapid volumetric imaging and quantitative analysis of dynamic biological systems across basic research and biomedical applications.","rel_num_authors":15,"rel_authors":[{"author_name":"Zhi Ling","author_inst":"Georgia Institute of Technology"},{"author_name":"Xuanwen Hua","author_inst":"Georgia Institute of Technology"},{"author_name":"Wenhao Liu","author_inst":"Georgia Institute of Technology"},{"author_name":"Hao Wu","author_inst":"Georgia Institute of Technology"},{"author_name":"Peng Chen","author_inst":"Georgia Institute of Technology"},{"author_name":"Lucinda Peng","author_inst":"Georgia Institute of Technology"},{"author_name":"Jessica Hou","author_inst":"Georgia Institute of Technology"},{"author_name":"Parvin Forghani","author_inst":"Emory University"},{"author_name":"Christopher Pierce","author_inst":"Georgia Institute of Technology"},{"author_name":"Ge-Ah Kim","author_inst":"Georgia Institute of Technology"},{"author_name":"Shuichi Takayama","author_inst":"Georgia Institute of Technology"},{"author_name":"Shuyi Nie","author_inst":"Georgia Institute of Technology"},{"author_name":"Chunhui Xu","author_inst":"Emory University"},{"author_name":"Hang Lu","author_inst":"Georgia Institute of Technology"},{"author_name":"Shu Jia","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Distinct contribution of autoreactive B cell Bruton's tyrosine kinase signaling to neuroinflammation","rel_doi":"10.64898\/2026.04.14.718534","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718534","rel_abs":"In multiple sclerosis (MS), autoreactive B cells play a central role in driving CD4 T cell-mediated inflammatory damage to myelin (1). Here we investigated how disrupting Bruton's tyrosine kinase (BTK) signaling exclusively in B cells shapes the course of experimental autoimmune encephalomyelitis (EAE), a model for MS, through alterations in B cell development and activity. B cell-specific BTK deletion significantly ameliorated both human MOG (hMOG) induced EAE (p = 0.0087) as well as spontaneous disease in 2D2+IgHMOG mice (p = 0.0004). Additionally, MOG-specific cells were found to be more sensitive to loss of BTK than tolerant clones (p = 0.0002) and production of anti-MOG immunoglobulins was also found to be diminished (p < 0.004) while overall IgG was unchanged (p = 0.44). B cells isolated from conditional knockout mice did not upregulate expression of co-stimulatory receptors or MHC II to the same extent as controls when cultured alongside MOG-specific CD4 T cells (p < 0.005) and were inferior at driving T cell proliferation (p < 0.0001) in vitro. Lastly, while BTK deletion diminished the proliferative and survival response of B cells following mitogen stimulation, B cell trafficking to the leptomeninges and organization into ectopic lymphoid tissues (ELTs) in 2D2+IgHMOG mice continued unabated. We identified that BTK signaling regulates several features adopted by autoreactive B cells that contribute to EAE pathogenesis. This study provides mechanistic insights into the therapeutic benefits of BTK inhibitors observed in clinical trials exploring BTK as a therapeutic target in the context of MS.","rel_num_authors":11,"rel_authors":[{"author_name":"Abraham T Ogbaslase","author_inst":"Washington University in St. Louis"},{"author_name":"Angela S Archambault","author_inst":"Washington University in St. Louis"},{"author_name":"Kia M Barclay","author_inst":"Washington University in St. Louis"},{"author_name":"Benedict E Ridore","author_inst":"Washington University in St. Louis"},{"author_name":"Joshua Amosu","author_inst":"Washington University in St. Louis"},{"author_name":"Kaitlyn Ying","author_inst":"Washington University in St. Louis"},{"author_name":"Sravanthi Bandla","author_inst":"Washington University in St. Louis"},{"author_name":"Alexandria J Sturtz","author_inst":"Washington University in St. Louis"},{"author_name":"Qingyun Li","author_inst":"Washington University in St. Louis"},{"author_name":"Peggy L Kendall","author_inst":"Washington University in St. Louis"},{"author_name":"Gregory F Wu","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"History of Traumatic Brain Injury with Loss of Consciousness and APOE \u03f54 Carriers Synergistically Increase Late-Life Amyloid PET Burden","rel_doi":"10.64898\/2026.04.14.717801","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.717801","rel_abs":"Background: Traumatic brain injury with loss of consciousness (TBI - LOC) is an established risk factor for dementia, yet the pathways linking remote TBI to Alzheimer disease (AD) biology remain incompletely defined. APOE {epsilon}4 is the strongest genetic risk factor for late - onset AD and is associated with greater amyloid accumulation; however, it remains unclear whether TBI - LOC amplifies APOE {epsilon}4 -- related vulnerability to amyloid deposition. This study assesses if a remote history of TBI - LOC synergistically interacts with APOE {epsilon}4 to increase late-life amyloid or tau burden. Methods: 429 participants completed the Ohio State University TBI screening tool and a PET amyloid scan quantified in centiloids. TBI history was classified by recency ( < 10 vs > 10 years) and severity (no TBI, dazing\/confusion [TBI - DZ], TBI - LOC) with analyses stratified by degree of clinical impairment as assessed by Clinical Dementia Rating (CDR {equiv} 0 vs CDR >0 ). Logistic and linear regression models examined associations between TBI and amyloid, adjusting for age, sex, education, and APOE {epsilon} 4, including an APOE*LOC interaction term, while Fisher exact tests evaluated TBI recency and biomarker positivity. Results: In CDR{equiv}0 participants ( n {equiv} 365), 119 reported a history of TBI, comprising 56 TBI - DZ and 63 TBI - LOC. TBI - LOC but not TBI - DZ, correlated with elevated PET amyloid levels (p < 0.001; [4.6 - 17]). Furthermore, an interaction between APOE {epsilon}4 and TBI - LOC indicated that TBI - LOC augmented the amyloid - related risk associated with the APOE {epsilon} 4 allele (p {equiv} 0.003; [4.3 - 21]). The interaction persisted when stratified by TBI recency with only remote TBI - LOC (occurring more than 10 years prior) associated with increased PET amyloid (p {equiv} 0.003 [5.2 - 25]). No association between TBI and tau was identified in a subset with tau PET, and no TBI - amyloid correlations were observed among symptomatic participants (CDR > 0; n {equiv} 64) suggesting a ceiling effect of pathology once clinical dementia is present. Conclusions: History of remote TBI - LOC is linked to elevated amyloid PET levels in later life, particularly among APOE {epsilon}4 carriers with a CDR {equiv} 0. The specificity for amyloid (as opposed to tau) and its attenuation in cases with a CDR > 0 underscore the value of incorporating TBI history when screening for preclinical AD.","rel_num_authors":15,"rel_authors":[{"author_name":"Jeremy Strain","author_inst":"Washington University in St. Louis"},{"author_name":"Nicolas R Barthelemy","author_inst":"Washington University School of Medicine"},{"author_name":"Ruchira jha","author_inst":"Barrow Neurological Institute"},{"author_name":"Owen Guo","author_inst":"Washington University School of Medicine"},{"author_name":"Madhur Parihar","author_inst":"Barrow Neurological Institute"},{"author_name":"Kyle Chan","author_inst":"Barrow Neurological Institute"},{"author_name":"Babatunde Adeyemo","author_inst":"Washington University School of Medicine"},{"author_name":"Peter R Millar","author_inst":"Washington University in St. Louis"},{"author_name":"Kyle Womack","author_inst":"Washington University School of Medicine"},{"author_name":"Brian A Gordon","author_inst":"Washington University School of Medicine"},{"author_name":"Suzanne E Schindler","author_inst":"Washington University in St. Louis"},{"author_name":"john Morris","author_inst":"Washington University School of Medicine"},{"author_name":"Tammie Lee Smith Benzinger","author_inst":"Washington University in Saint Louis"},{"author_name":"Beau Ances","author_inst":"Washington University in St. Louis"},{"author_name":"Chia-Ling Phuah","author_inst":"Barrow Neurological Institute"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Generation and long-term expansion of human pancreatic islet organoids in vitro","rel_doi":"10.64898\/2026.04.15.718643","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718643","rel_abs":"The scarcity of expandable, functional human islet cells remains a major barrier to diabetes therapy. Here, we identify PROCR+ cells within adult human islets and establish a defined culture system to generate pancreatic islet organoids. These organoids self-organize into -, {beta}-, {delta}-, and PP cells at near-native ratios, exhibit regulated insulin and glucagon secretion, and support exponential in vitro expansion. Single-cell transcriptomics reveals a unique progenitor-like cell population that is transcriptionally primed for endocrine differentiation but shares molecular features with fetal trunk cells and endocrine progenitors. When transplanted, the organoids rapidly ameliorate hyperglycemia in diabetic mice. Importantly, in a non-human primate model, intraportal transplantation of these organoids reduced exogenous insulin requirements, restored glucose-stimulated C-peptide secretion, and achieved sustained glycemic control-representing a critical step toward clinical translation. This study provides a strategy for expanding human islet organoids, offering a scalable platform for diabetes treatment, disease modeling, and regenerative medicine.","rel_num_authors":21,"rel_authors":[{"author_name":"Wenqian Song","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences; School of Life Science, Hangzhou Instit"},{"author_name":"Chunye Liu","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences"},{"author_name":"Shusen Wang","author_inst":"Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University"},{"author_name":"Daisong Wang","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences"},{"author_name":"Yishu Xu","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences"},{"author_name":"Shubo Yuan","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences"},{"author_name":"Jiali Chang","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences"},{"author_name":"Boya Zhang","author_inst":"Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University"},{"author_name":"Xu Han","author_inst":"Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University"},{"author_name":"Hongxing Fu","author_inst":"Department of Hepatobiliary and Pancreatic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine"},{"author_name":"Haili Bao","author_inst":"Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University"},{"author_name":"Aijing Shan","author_inst":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Center for Metabolic Diseases"},{"author_name":"Di Zheng","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences"},{"author_name":"Wenquan Wang","author_inst":"Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University"},{"author_name":"Yanan Cao","author_inst":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Center for Metabolic Diseases"},{"author_name":"Weiqiong Gu","author_inst":"Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Ji"},{"author_name":"Jiqiu Wang","author_inst":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseas"},{"author_name":"Liang Liu","author_inst":"Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University"},{"author_name":"Shaohua Song","author_inst":"Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University"},{"author_name":"Qing Cissy Yu","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences"},{"author_name":"Yi Arial Zeng","author_inst":"Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences; School of Life Science, Hangzhou Instit"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Gut-derived metabolic reprogramming drives immune aging and tissue degeneration","rel_doi":"10.64898\/2026.04.14.718497","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718497","rel_abs":"Aging is characterized by changes in gut microbiome, metabolic imbalance and chronic inflammation, yet how these processes integrate to drive tissue degeneration remains poorly defined. Using age-related macular degeneration (AMD) as a model of tissue aging, we identify a diet-induced metabolic-immune axis that promotes systemic and retinal degeneration. In mice, a high-fat, cholesterol-enriched (HFC) diet induced perturbations in the gut structural integrity and microbiome repertoire, as well as systemic metabolic aging signatures, prominently marked by reduced circulating histidine. Plasma histidine levels were similarly decreased in AMD patients and inversely correlated with body mass index (BMI) in control donors. These diet-induced gut microbiome changes and subsequent metabolic alterations promoted peripheral innate immune reprogramming, with expansion of inflammatory neutrophils and monocytes that infiltrated the outer retina in a mouse model. Mechanistically, the gut-derived IGF1R\/AKT2 signaling acts as a central regulator of global epigenetic remodeling and systemic immune aging under high-fat conditions in C. elegans. In a mouse model with an age-dependent dry AMD-like pathology, distinct retinal pigment epithelium (RPE) subpopulations exhibited downregulation of the histidine transporter SLC7A5, linking metabolic stress to activation of MIF\/CD74-dependent inflammatory signaling between RPE and infiltrating immune cells. Histidine supplementation or AKT2 phospho-state modulation attenuated systemic immune activation and rescued retinal degeneration. These findings identify histidine-axis dysregulation as a mechanistic bridge between diet-induced microbiome changes, metabolic stress, immune aging, and retinal degeneration.","rel_num_authors":25,"rel_authors":[{"author_name":"Sayan Ghosh","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Victoria Koontz","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Ying Xin","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Sridhar Bammidi","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Dominique Meyer","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Haochen Wang","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Vishnu Suresh Babu","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Puja Dutta","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Durgadas Cherukaraveedu","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Shreevadsaa A Mohanakrishnan","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Anupam K Mondal","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Jagnnath Das","author_inst":"University of Illinois"},{"author_name":"Jenny Nguyen","author_inst":"University of Alabama"},{"author_name":"Avinash Soundararajan","author_inst":"Indiana University School of Medicine"},{"author_name":"Idris A Adekale","author_inst":"Indiana University School of Medicine"},{"author_name":"Dulal Bhaumik","author_inst":"University of Illinois"},{"author_name":"Stacey Hose","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Sheldon Rowan","author_inst":"Tufts University School of Medicine"},{"author_name":"Padmanachan P Pattabiraman","author_inst":"Indiana University School of Medicine"},{"author_name":"Rangaramanujam M Kannan","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"James T Handa","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Ji Yi","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Srinivasa R Sripathi","author_inst":"Retina Foundation of the Southwest"},{"author_name":"Jiang Qian","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Debasish Sinha","author_inst":"The Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Gut-derived metabolic reprogramming drives immune aging and tissue degeneration","rel_doi":"10.64898\/2026.04.14.718497","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718497","rel_abs":"Aging is characterized by changes in gut microbiome, metabolic imbalance and chronic inflammation, yet how these processes integrate to drive tissue degeneration remains poorly defined. Using age-related macular degeneration (AMD) as a model of tissue aging, we identify a diet-induced metabolic-immune axis that promotes systemic and retinal degeneration. In mice, a high-fat, cholesterol-enriched (HFC) diet induced perturbations in the gut structural integrity and microbiome repertoire, as well as systemic metabolic aging signatures, prominently marked by reduced circulating histidine. Plasma histidine levels were similarly decreased in AMD patients and inversely correlated with body mass index (BMI) in control donors. These diet-induced gut microbiome changes and subsequent metabolic alterations promoted peripheral innate immune reprogramming, with expansion of inflammatory neutrophils and monocytes that infiltrated the outer retina in a mouse model. Mechanistically, the gut-derived IGF1R\/AKT2 signaling acts as a central regulator of global epigenetic remodeling and systemic immune aging under high-fat conditions in C. elegans. In a mouse model with an age-dependent dry AMD-like pathology, distinct retinal pigment epithelium (RPE) subpopulations exhibited downregulation of the histidine transporter SLC7A5, linking metabolic stress to activation of MIF\/CD74-dependent inflammatory signaling between RPE and infiltrating immune cells. Histidine supplementation or AKT2 phospho-state modulation attenuated systemic immune activation and rescued retinal degeneration. These findings identify histidine-axis dysregulation as a mechanistic bridge between diet-induced microbiome changes, metabolic stress, immune aging, and retinal degeneration.","rel_num_authors":25,"rel_authors":[{"author_name":"Sayan Ghosh","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Victoria Koontz","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Ying Xin","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Sridhar Bammidi","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Dominique Meyer","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Haochen Wang","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Vishnu Suresh Babu","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Puja Dutta","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Durgadas Cherukaraveedu","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Shreevadsaa A Mohanakrishnan","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Anupam K Mondal","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Jagnnath Das","author_inst":"University of Illinois"},{"author_name":"Jenny Nguyen","author_inst":"University of Alabama"},{"author_name":"Avinash Soundararajan","author_inst":"Indiana University School of Medicine"},{"author_name":"Idris A Adekale","author_inst":"Indiana University School of Medicine"},{"author_name":"Dulal Bhaumik","author_inst":"University of Illinois"},{"author_name":"Stacey Hose","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Sheldon Rowan","author_inst":"Tufts University School of Medicine"},{"author_name":"Padmanachan P Pattabiraman","author_inst":"Indiana University School of Medicine"},{"author_name":"Rangaramanujam M Kannan","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"James T Handa","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Ji Yi","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Srinivasa R Sripathi","author_inst":"Retina Foundation of the Southwest"},{"author_name":"Jiang Qian","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Debasish Sinha","author_inst":"The Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-20","rel_site":"biorxiv"},{"rel_title":"Physical Activity Levels and Associated Factors among Upper Primary School Children in Lusaka, Zambia: Implications for Health Interventions.","rel_doi":"10.64898\/2026.04.17.26351077","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.17.26351077","rel_abs":"Introduction: Physical inactivity and sedentary behaviour are significant risk factors for noncommunicable diseases. Engaging in regular physical activity (PA) during childhood is crucial for preventing long-term health burdens. This study examined PA levels and associated factors among upper primary school children in Lusaka, Zambia. Methodology: A cross-sectional survey was conducted from August to October 2022 among 638 children aged 9-18 years from six public and six private schools. Data were collected using the Physical Activity Questionnaire for Children (PAQ-C), Youth Risk Behaviour Survey (YRBS), Model of Youth Physical Activity Questionnaire (MYPA), and 3-Day Physical Activity Recall Questionnaire (3DPAR). Analyses included descriptive statistics, Chi-square, Fishers exact tests and multivariable binary logistic regression at a 0.05 significance level and 95% confidence interval. Results: Most participants (82%) were insufficiently active, with only 18% achieving sufficient PA. Reported barriers included lack of playgrounds or parks near home (p=0.012), neighbourhood safety concerns (p=0.041), and limited parental supervision (p=0.006). Watching television reduced the odds of PA by 69% (aOR=0.31; 95% CI: 0.13-0.75). Conversely, peer support increased activity by 15% (aOR=1.15, 95% CI: 0.67-1.97), while not being concerned about showering or fixing hair after PA increased activity by 94% (aOR=1.94; 95% CI: 1.21-3.11). Conclusion: The majority of school children in this study did not meet recommended PA levels. Barriers to activity included personal, parental, and environmental factors. Interventions should prioritise safe play spaces, increased parental and peer support, and reduced screen time to curb future non-communicable disease risks.","rel_num_authors":9,"rel_authors":[{"author_name":"Simon Himalowa","author_inst":"UNZA: University of Zambia"},{"author_name":"John Zulu","author_inst":"Lusaka Apex Medical University"},{"author_name":"Titus Haakonde","author_inst":"University of Zambia"},{"author_name":"Joseph Lupenga","author_inst":"University of Zambia"},{"author_name":"Richard Kunda","author_inst":"Levy Mwanawasa Medical University School of Health Sciences"},{"author_name":"Yvonne Colgrove","author_inst":"The University of Kansas Medical Center"},{"author_name":"Jose' Frantz","author_inst":"University of the Western Cape Faculty of Community and Health Sciences"},{"author_name":"Margaret  M Mweshi","author_inst":"University of Zambia"},{"author_name":"Martha Banda","author_inst":"University of Zambia"}],"rel_date":"2026-04-19","rel_site":"medrxiv"},{"rel_title":"The LARP1 RRM functions as a ribosome responsive regulator of TOP mRNAs","rel_doi":"10.64898\/2026.04.18.719249","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.18.719249","rel_abs":"The synthesis of ribosomes in metazoans is an essential process that is dysregulated in disease. Previous studies implicate La-related protein 1 (LARP1) in binding inactive ribosomes and in repressing Terminal OligoPyrimidine motif mRNAs (TOPs), which encode ribosomal proteins. While the molecular details of LARP1 binding to the ribosome and to TOP mRNAs are deciphered, the mechanistic link between these two activities is not understood. Here, we show that ribosome binding is an essential step in LARP1-mediated TOP repression. The LARP1 ribosome binding region is part of a previously unrecognized RNA recognition motif (RRM) domain, which in turn directly interacts with its TOP-binding HEAT repeat domain. Remarkably, ribosome binding is both sufficient in vitro and required in cells for LARP1 to bind, repress, and stabilize TOPs via unfolding and remodeling of the RRM domain. Disrupting the coordinated architecture of these domains by mutating the RRM constitutively represses TOPs and compromises cell fitness. Together, these data reveal a general ribosome-sensing function of LARP1, orchestrated through the unique coordinating role of its RRM, which tunes the synthesis of ribosomal proteins to cellular demand for ribosomes.","rel_num_authors":5,"rel_authors":[{"author_name":"James A Saba","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Phoebe E White","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"A. Maxwell Burroughs","author_inst":"National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health"},{"author_name":"L. Aravind","author_inst":"National Center of Biotechnology Information"},{"author_name":"Rachel Green","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"An N-degron proteolytic pathway modulates recipient susceptibility to T6SS DNase effectors","rel_doi":"10.64898\/2026.04.17.719174","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.17.719174","rel_abs":"The type VI secretion system (T6SS) is a contractile nanoweapon widely employed by Gram-negative bacteria to gain competitive advantages by injecting effector proteins into recipient cells. Although the biochemical activities of T6SS effectors have been well characterized, how recipient factors modulate effector toxicity remains poorly understood. Using Agrobacterium C58 as a model, previous work identified the Escherichia coli ClpAP protease as a recipient susceptibility (RS) factor that enhances T6SS-mediated interbacterial competition. Agrobacterium C58 deploys two DNase effectors, Tde1 and Tde2, as the major antibacterial weapon. Here, we demonstrate that the recipient ClpAP protease and its adaptor ClpS enhanced C58-mediated interbacterial competition in a Tde2-dependent manner in both intra- and interspecies competition. Ectopic expression of Tde2 in E. coli caused growth inhibition and DNA cleavage in the presence of a functional ClpAPS protease complex, but not in any of the clpP, clpA or clpS mutants. Notably, Tde2 accumulated in these mutants but not in wild-type cells, whereas a catalytic variant accumulated regardless of ClpAPS status, suggesting that Tde2 is not directly degraded by ClpAPS. Instead, Tde2 depends on ClpAPS for full toxicity, likely through degradation of inhibitory N-degron substrate(s). Affinity purification of His-tagged Tde2 in a clpP mutant background, followed by mass spectrometry, identified eight N-degron substrate candidates. Tde2-mediated interbacterial competition was significantly reduced by overexpression of three candidates. Among them, the Tde2 DNase domain directly associated with guanosine 5'-monophosphate reductase GuaC, supporting a model in which Tde2 toxicity is blocked by binding of GuaC. Collectively, our findings reveal an unanticipated layer of recipient-mediated regulation in T6SS competition and highlight proteolytic control of inhibitory substrates as a determinant of bacterial susceptibility during interbacterial conflict.","rel_num_authors":5,"rel_authors":[{"author_name":"Yung-Hui Victoria Wen","author_inst":"Academia Sinica"},{"author_name":"Hsiao-Han Lin","author_inst":"Academia Sinica"},{"author_name":"Xing-Tai Zheng","author_inst":"Academia Sinica"},{"author_name":"Hau-Hsuan Hwang","author_inst":"National Chung Hsing University"},{"author_name":"Erh-Min Lai","author_inst":"Academia Sinica"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"Loss of Vpr-driven TRAIL-R2 expression protects HIV-infected cells from non-canonical NK cell TRAIL attack","rel_doi":"10.64898\/2026.04.15.718741","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718741","rel_abs":"HIV escapes sterilizing immunity through a variety of mechanisms, including the downregulation of MHC-I expression by HIV Nef and Vpu to counteract CD8+ T cell responses. While reduced MHC-I expression would be expected to support targeting by NK cells, a subpopulation of infected CD4+ T cells consistently resists multiple rounds of NK cell natural and antibody-dependent cytotoxicity. Studies further reveal that the HIV accessory protein Vpr induces expression of TNFRSF10B (TRAIL-R2) in CD4+ T cells, with survivors of NK cell targeting exhibiting relatively higher MHC-I and weaker expression of TRAIL-R2. In fact, reverse TRAIL signaling in NK cells leads to the release of perforin and granzymes, a pathway limited when TRAIL-R2 expression is diminished. Thus, independent of canonical death receptor signaling, TRAIL-R2 serves as an activating ligand that augments NK cell killing. These observations demonstrate that through Vpr, HIV can regulate the TRAIL\/TRAIL-R2 axis to control NK cell functionality.","rel_num_authors":18,"rel_authors":[{"author_name":"Paula E Grasberger","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Abigail R Sondrini","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Nicole Glidden","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Amanda Modica","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Natalie Pushlar","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Seden Bedir","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Tara Bromfield","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Sheldon Gentling","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Komal Cheema","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Alper Kucukural","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Milena Ozdemir","author_inst":"VIA Scientific"},{"author_name":"Maria Zapp","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Alberto Bosque","author_inst":"George Washington University"},{"author_name":"Louise Leyre","author_inst":"Weill Cornell Medicine"},{"author_name":"Aaron Shulkin","author_inst":"Ragon Institute of MGH, MIT, and Harvard"},{"author_name":"Alicja Piechocka-Trocha","author_inst":"Ragon Institute of MGH, MIT, and Harvard"},{"author_name":"R. Brad Jones","author_inst":"Cornell University Joan and Sanford I Weill Medical College"},{"author_name":"Kiera L Clayton","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"Acute exposure to cell-free mitochondrial DNA induces pregnancy-specific aortic endothelial dysfunction and organ-selective inflammation in rats","rel_doi":"10.64898\/2026.04.15.718761","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718761","rel_abs":"Pregnancy complications such as preeclampsia are associated with circulating cell-free mitochondrial DNA (mtDNA), a damage-associated molecular pattern capable of activating Toll-like receptor 9 (TLR9). We hypothesized that acute mtDNA exposure induces maternal inflammation and endothelial dysfunction during pregnancy via TLR9 activation. Non-pregnant and pregnant rats (gestational days 14-15) were treated intravenously with saline or purified mtDNA and euthanized 4 h after treatment. mtDNA increased cytokine mRNA expression in lung and liver of non-pregnant and pregnant rats, with magnitude varying by pregnancy status and organ. Aortas from pregnant, but not non-pregnant, rats exhibited reduced acetylcholine (ACh)-induced relaxation following mtDNA treatment (Emax, saline: 90.1 {+\/-} 3.9 % vs. mtDNA: 62.1 {+\/-} 20.7 % KClmax, p<0.05), while uterine artery function was preserved, indicating vascular bed-specific effects. Ex vivo incubation of aortic rings with mtDNA {+\/-} white blood cells did not replicate in vivo findings, implicating systemic rather than direct vascular mechanisms. Nuclear DNA did not affect ACh-induced relaxation (p>0.05), confirming that the vascular effects were mtDNA-specific. Pharmacological antagonism of TLR9 with ODN2088 partially attenuated mtDNA-induced maternal endothelial dysfunction. Although overt vascular ROS increases were not detected, aortas from pregnant rats had reduced sod-1 expression (p<0.05) and increased eNOS protein abundance (p<0.05). Acute mtDNA exposure during pregnancy induces maternal organ inflammation and impairs endothelium-dependent vasodilation, with partial TLR9 involvement. In conclusion, aortic transcriptional changes in antioxidant pathways and increased eNOS abundance were also observed, though their functional significance remains to be determined.","rel_num_authors":14,"rel_authors":[{"author_name":"Nataliia Hula","author_inst":"Loma Linda University"},{"author_name":"Ren\u00e9e De Nazare Oliveira Da Silva","author_inst":"Rutgers University"},{"author_name":"Desirae Escalera","author_inst":"Loma Linda University"},{"author_name":"Leslie Lopez","author_inst":"Loma Linda University"},{"author_name":"Gabrielle Kelly","author_inst":"Loma LInda University"},{"author_name":"Isabelle K Gorham","author_inst":"University of North Texas Health Science Center"},{"author_name":"Megan Rowe","author_inst":"University of North Texas Health Science Center"},{"author_name":"Taiming Liu","author_inst":"Loma Linda University"},{"author_name":"Arlin B Blood","author_inst":"Loma Linda University"},{"author_name":"Eugenia Mata-Greenwood","author_inst":"Loma Linda University"},{"author_name":"Xiang-Qun Hu","author_inst":"Loma Linda University"},{"author_name":"Lubo Zhang","author_inst":"Loma Linda University School of Medicine"},{"author_name":"Nicole R Phillips","author_inst":"University of North Texas Health Science Center"},{"author_name":"Styliani Goulopoulou","author_inst":"Loma Linda University"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"CXCL-CXCR2 signaling drives cancer-endothelium interactions in SCLC metastatic seeding","rel_doi":"10.64898\/2026.04.15.716394","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.716394","rel_abs":"Small cell lung cancer (SCLC) is a highly metastatic malignancy with tropism to the liver, yet the signals that enable organ-specific metastatic colonization remain largely undefined. During metastasis, disseminated cancer cells first encounter endothelial cells (ECs) at the vascular-tissue interface, positioning cancer-endothelium crosstalk as a key determinant of metastatic success. Defining the signaling pathways underlying this reciprocal communication may uncover actionable vulnerabilities for preventing and treating this lethal disease. Here, we uncover an EC-derived CXCL chemokine program that activates cancer-intrinsic CXCR2-RAC1 signaling as a critical mediator of SCLC liver metastasis. By integrating in vitro and in vivo models, we show that SCLC cells induce robust CXCL chemokine expression from liver ECs, which in turn enhances SCLC migration and reinforces cancer cell-EC interactions. We applied highly quantitative metastatic colony barcode sequencing coupled with individual gene inactivation to demonstrate that CXCR2 is essential for SCLC migration and liver metastatic seeding. Mechanistically, CXCL-CXCR2 signaling activates RAC1-dependent F-actin assembling to drive SCLC motility during CXCL-induced metastatic seeding. Pharmacologic inhibition of CXCR2 or RAC1 suppresses SCLC migration and prevents SCLC liver metastasis. Together, our research defined a chemokine-driven signaling circuit that governs cancer-endothelium communication during the metastatic cascade and nominate the CXCL-CXCR2-RAC1 axis as a promising therapeutic vulnerability for preventing and treating metastatic SCLC.","rel_num_authors":17,"rel_authors":[{"author_name":"Zhang Yang","author_inst":"Washington University School of Medicine"},{"author_name":"Andy Xu","author_inst":"Washington University School of Medicine"},{"author_name":"Nicholas Hughes","author_inst":"Stanford University"},{"author_name":"Chien-Wei Peng","author_inst":"Washington University School of Medicine"},{"author_name":"Adrienne Visani","author_inst":"Washington University School of Medicine"},{"author_name":"Susrutha Puthanmadhom Narayanan","author_inst":"Washington University School of Medicine"},{"author_name":"Xue Wen Ng","author_inst":"Washington University School of Medicine"},{"author_name":"Isabella Guppy","author_inst":"Washington University School of Medicine"},{"author_name":"Chris Roberts","author_inst":"Washington University School of Medicine"},{"author_name":"Yaoxuan You","author_inst":"Washington University School of Medicine"},{"author_name":"Monte M. Winslow","author_inst":"Stanford University"},{"author_name":"David W. Piston","author_inst":"Washington University School of Medicine"},{"author_name":"Jon Park","author_inst":"Stanford University"},{"author_name":"Zhonglin Lyu","author_inst":"Stanford University"},{"author_name":"Feng Chen","author_inst":"Washington University School of Medicine"},{"author_name":"Li Ding","author_inst":"Washington University School of Medicine"},{"author_name":"Rui Tang","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"Membrane-Free Alveolus-on-a-Chip via Biodegradable Scaffold Recapitulates Interstitial Mechanics, Immune Trafficking, and Aerosolized mRNA Delivery","rel_doi":"10.64898\/2026.04.17.719302","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.17.719302","rel_abs":"The pulmonary alveolus is a highly specialized microenvironment where epithelial, interstitial, and immune components interact to maintain gas exchange and tissue homeostasis. In vivo, the air-blood barrier consists of an epithelial layer and a capillary endothelium separated by an ultrathin interstitium composed of extracellular matrix (ECM) and lung fibroblasts. However, most existing lung-on-a-chip platforms rely on permanent synthetic membranes, which fail to recapitulate the dynamic biological and mechanical properties of the native interstitium. Here, we present a membrane-free human alveoli-on-a-chip enabled by a biodegradable poly(lactic-co-glycolic acid) (PLGA) scaffold that is progressively replaced by fibroblast-derived ECM. This process reconstructs a biologically formed interstitial layer while preserving an alveolus-like dome architecture. The resulting system supports multicellular organization under air-liquid interface conditions, enabling epithelial barrier formation and surfactant-related phenotypes. Additionally, direct epithelial-fibroblast interactions enhanced surfactant-related phenotypes, as evidenced by increased SPC and LAMP3 expression. Importantly, we demonstrate that conventional rigid substrates promote fibroblast-to-myofibroblast differentiation, leading to elevated reactive oxygen species (ROS) production, increased epithelial cell death, and compromised barrier integrity. In contrast, the membrane-free PLGA system mitigates stiffness-driven myofibroblast activation, preserving epithelial viability and maintaining barrier function. These findings highlight the critical role of interstitial mechanics in regulating alveolar homeostasis and reveal limitations of conventional membrane-based platforms. The platform further enables chemokine-driven monocyte migration across the alveolar barrier, recapitulating key immune trafficking processes observed in vivo. In addition, aerosolized metal organic framework (MOF) nanoparticles efficiently mediated mRNA delivery to epithelial and interstitial cells with minimal cytotoxicity and modest inflammatory responses. Together, this membrane-free alveoli-on-a-chip reconstructs essential structural, mechanical, and functional features of the human alveolar microenvironment and provides a physiologically relevant platform for studying pulmonary biology, fibrosis-related mechanisms, immune cell trafficking, and inhaled nanomedicine delivery.","rel_num_authors":5,"rel_authors":[{"author_name":"Jae-Won Choi","author_inst":"Carnegie Mellon University"},{"author_name":"Huy Hoang Nguyen","author_inst":"Carnegie Mellon University"},{"author_name":"Abbas Jalili","author_inst":"Carnegie Mellon University"},{"author_name":"Matthew Andersen","author_inst":"Carnegie Mellon University"},{"author_name":"Si-Yang Zheng","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"Structural Mechanism of Electron Shuttling in Inducible Nitric Oxide Synthase","rel_doi":"10.64898\/2026.04.17.719136","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.17.719136","rel_abs":"Nitric oxide (NO) signaling is pivotal in numerous physiological processes and is implicated in a spectrum of human diseases. Nitric oxide synthases (NOS) initiate NO signaling and govern its magnitude and duration, making them key drug targets. Despite decades of investigation, the structural mechanism by which NOS enzymes transfer electrons from NADPH to haem remains incompletely understood. Here, we report cryo electron microscopy studies of the inducible NOS (iNOS) homodimer in complex with calmodulin captured under the catalytic turnover condition, resolving two important functional states: the electron input state and output state. In the input state, the FMN binding subdomain (FMND) docks onto the FAD\/NADPH-binding subdomain (FNR), positioning the FMN cofactor to accept electrons from FAD. The FMND then undergoes a large rotational movement to engage the oxygenase domain of the other protomer, adopting the output state, which enables electron transfer from FMN to the haem center via W366. This dynamic movement of the FMND shuttles electrons from the reductase domain to the oxygenase active site in iNOS. A point mutation (S594E) that disrupts the FMND oxygenase interface markedly reduces catalytic activity of iNOS and traps the enzyme in a non-productive intermediate conformation. Together, these findings elucidate the structural mechanism of FMND mediated electron transfer in the iNOS catalytic cycle.","rel_num_authors":3,"rel_authors":[{"author_name":"Yiting Shi","author_inst":"Peking University"},{"author_name":"Xiaoyu Liu","author_inst":"Peking University"},{"author_name":"Lei Chen","author_inst":"Peking University"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"Astrocytes mediate the pro-cognitive value of \u03b17nAChRs and of \u03b17nAChR-targeting therapeutics","rel_doi":"10.64898\/2026.04.16.719027","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.719027","rel_abs":"The 7nicotinic acetylcholine receptor (7nAChR) has driven extensive research over the past three decades for its pro-cognitive potential. It is the leading druggable target for the cognitive deficits associated with schizophrenia and has motivated major pharmaceutical and clinical efforts to ameliorate similar impairments in other neurological disorders, such as Alzheimer's disease (AD). Yet, a systematic evaluation of the role played by 7nAChR in cognition, and its mechanistic underpinnings, is still lacking. Here we report that 7nAChRs on principal and inhibitory forebrain neurons are largely inconsequential to mouse behavior, including in domains that are most sensitive to schizophrenia-related cognitive impairments. By contrast, loss of 7nAChR from astrocytes produces profound behavioral alterations that are cognitive domain-specific, are time-of-day dependent, coincide with reduced levels of the N-methyl D-aspartate receptor (NMDAR) co-agonist D-serine, and are fully restored by D-serine supplementation. Further, an 7nAChR partial agonist previously evaluated in Phase III trials for cognitive enhancement in schizophrenia and AD fails to augment behavior in mice lacking astrocytic 7nAChRs. Together, these findings identify astrocytes and D-serine\/NMDAR signaling as a central mechanism through which 7nAChR, a major drug target, promotes cognitive behavior","rel_num_authors":10,"rel_authors":[{"author_name":"Yifan Wu","author_inst":"Washington University in St. Louis"},{"author_name":"Michaela Tolman","author_inst":"Neuroscience Department, Tufts University School of Medicine"},{"author_name":"Yanchao Dai","author_inst":"Washington University in St. Louis"},{"author_name":"Sarah Walsh","author_inst":"Department of Neuroscience, Washington University in St Louis, School of Medicine"},{"author_name":"Humza Agha","author_inst":"Department of Neuroscience, Washington University in St Louis, School of Medicine"},{"author_name":"Katheryn B Lefton","author_inst":"Department of Neuroscience, Washington University in St Louis, School of Medicine"},{"author_name":"Hannah An","author_inst":"Department of Neuroscience, Washington University in St Louis, School of Medicine"},{"author_name":"Rachel Manno","author_inst":"Department of Neuroscience, Washington University in St Louis, School of Medicine"},{"author_name":"Philip G Haydon","author_inst":"Neuroscience Department, Tufts University, School of Medicine"},{"author_name":"Thomas Papouin","author_inst":"Washington University in St Louis, Department of Neuroscience"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"Highly replicable multisite patterns of adolescent white matter maturation","rel_doi":"10.64898\/2026.04.18.719321","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.18.719321","rel_abs":"The Adolescent Brain Cognitive Development (ABCD) Study is the largest U.S.-based neuroimaging initiative of adolescent brain maturation. Diffusion MRI (dMRI) provides unique insights into white matter organization, yet applying advanced processing pipelines and managing technical variability across scanning environments remains challenging at scale. To address these issues, we present ABCD-BIDS Community Collection (ABCC) release 3.1.0, including a curated resource of more than 24,000 fully processed ABCD dMRI datasets. ABCC provides fully processed images, nuanced image quality metrics, advanced microstructural measures, and person-specific bundle tractography. Evaluating these rich data revealed that measures of diffusion restriction and non-Gaussianity--in particular the intracellular volume fraction from NODDI and return-to-origin probability from MAP-MRI--were highly sensitive to neurodevelopment and robust to variation in image quality. Additionally, harmonization of microstructural features markedly improved the cross-vendor generalizability of developmental effects. Together, ABCC accelerates reproducible, rigorous research on adolescent white matter development.","rel_num_authors":50,"rel_authors":[{"author_name":"Steven L. Meisler","author_inst":"University of Pennsylvania"},{"author_name":"Matthew Cieslak","author_inst":"University of Pennsylvania"},{"author_name":"Jo\u00eblle Bagautdinova","author_inst":"University of Pennsylvania"},{"author_name":"Timothy J. Hendrickson","author_inst":"University of Minnesota"},{"author_name":"Tanya Pandhi","author_inst":"University of Minnesota"},{"author_name":"Andrew A. Chen","author_inst":"Medical University of South Carolina"},{"author_name":"Noah Hillman","author_inst":"University of Pennsylvania"},{"author_name":"Hamsanandini Radhakrishnan","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Salo","author_inst":"University of Pennsylvania"},{"author_name":"Eric Feczko","author_inst":"University of Minnesota"},{"author_name":"Kimberly B. Weldon","author_inst":"University of Minnesota"},{"author_name":"rae McCollum","author_inst":"University of Minnesota"},{"author_name":"Begim Fayzullobekova","author_inst":"University of Minnesota"},{"author_name":"Lucille A. Moore","author_inst":"University of Minnesota"},{"author_name":"Lucinda Sisk","author_inst":"University of Pennsylvania"},{"author_name":"Christos Davatzikos","author_inst":"University of Pennsylvania"},{"author_name":"Hao Huang","author_inst":"University of Pennsylvania"},{"author_name":"B\u00e1rbara Avelar-Pereira","author_inst":"Karolinska Institute"},{"author_name":"Sendy Caffarra","author_inst":"University of Modena and Reggio Emilia"},{"author_name":"Kelly Chang","author_inst":"University of Washington"},{"author_name":"Philip A. Cook","author_inst":"University of Pennsylvania"},{"author_name":"Elizabeth A. Flook","author_inst":"University of Pennsylvania"},{"author_name":"Teresa Gomez","author_inst":"University of Washington"},{"author_name":"Mareike Grotheer","author_inst":"Phillips-Universit\u00e4t Marburg"},{"author_name":"McKenzie P. Hagen","author_inst":"University of Washington"},{"author_name":"Zeeshan M. Huque","author_inst":"Temple University"},{"author_name":"Iliana I. Karipidis","author_inst":"University of Zurich"},{"author_name":"Arielle S. Keller","author_inst":"University of Connecticut"},{"author_name":"John Kruper","author_inst":"University of Washington"},{"author_name":"Audrey C. Luo","author_inst":"University of Pennsylvania"},{"author_name":"Briana Macedo","author_inst":"University of Pennsylvania"},{"author_name":"Kahini Mehta","author_inst":"Columbia University"},{"author_name":"Jamie L. Mitchell","author_inst":"Stanford University"},{"author_name":"Adam R. Pines","author_inst":"Stanford University"},{"author_name":"Laura Pritschet","author_inst":"University of Pennsylvania"},{"author_name":"Amelie Rauland","author_inst":"Forschungszentrum J\u00fclich"},{"author_name":"Ethan Roy","author_inst":"Stanford University"},{"author_name":"Brooke L. Sevchik","author_inst":"University of Pennsylvania"},{"author_name":"Golia Shafiei","author_inst":"University of Pennsylvania"},{"author_name":"S. Parker Singleton","author_inst":"University of Pennsylvania"},{"author_name":"Hannah L. Stone","author_inst":"University of California, Santa Barbara"},{"author_name":"Kevin Y. Sun","author_inst":"University of Pennsylvania"},{"author_name":"Valerie J. Sydnor","author_inst":"University of Pittsburgh Medical Center"},{"author_name":"Tien T. Tong","author_inst":"University of Pennsylvania"},{"author_name":"Maya Yablonski","author_inst":"Stanford University"},{"author_name":"Jason D. Yeatman","author_inst":"Stanford University"},{"author_name":"Ariel Rokem","author_inst":"University of Washington"},{"author_name":"Russell T. Shinohara","author_inst":"University of Pennsylvania"},{"author_name":"Damien A. Fair","author_inst":"University of Minnesota"},{"author_name":"Theodore D. Satterthwaite","author_inst":"University of Pennsylvania"}],"rel_date":"2026-04-19","rel_site":"biorxiv"},{"rel_title":"Factors Associated with Diet Quality in Middle-Aged and Older Adults with HIV: Insights from the PROSPER-HIV study","rel_doi":"10.64898\/2026.04.16.26351056","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351056","rel_abs":"Objective: Improved diet quality is increasingly important for comorbidities management and healthy aging in people with HIV (PWH). Yet, limited data exist on dietary patterns and their correlates in this population. This study aimed to (1) characterize dietary patterns among adult PWH and (2) identify demographic, clinical, and HIV related factors associated with diet quality. Methods: We conducted a cross sectional analysis of PWH enrolled in the PROSPER HIV study across four U.S. academic medical centers. Dietary intake was assessed using three 24 hour dietary recalls and scored using the Healthy Eating Index 2015 (HEI2015). Participants were categorized into tertiles based on total HEI2015 scores. Between group comparisons were performed using Kruskal Wallis and chi square tests. Factors independently associated with HEI2015 scores were identified using multivariable linear regression. Results: A total of 491 PWH were included with a median age of 54 years; 76.4% were male. Overall diet quality was low with inadequate intake of dietary protein, fiber, and micronutrients. When classified by tertiles of HEI 2015 score, higher diet quality was characterized by greater intake of fiber, protein, and key micronutrients. Older age was independently associated with higher HEI 2015 scores, while Black race was associated with lower scores. Full time employment and absence of current pain were marginally associated with better diet quality. Conclusions: Diet quality among PWH varies substantially and is influenced by age, race, and social determinants. Tailored nutritional strategies are needed to support healthy aging and reduce disparities in this population.","rel_num_authors":16,"rel_authors":[{"author_name":"Mari Katundu","author_inst":"University of Alabama at Birmingham"},{"author_name":"Allison R Webel","author_inst":"University of Washington"},{"author_name":"Andre Pereira dos Santos","author_inst":"University of Washington"},{"author_name":"John D Cleveland","author_inst":"University of Alabama at Birmingham"},{"author_name":"Dustin M Long","author_inst":"Wake Forest University"},{"author_name":"Vitor Oliveira","author_inst":"University of Washington School of Nursing"},{"author_name":"Christine Horvat Davey","author_inst":"Case Western Reserve University"},{"author_name":"Heidi M Crane","author_inst":"University of Washington"},{"author_name":"Stephanie A Ruderman","author_inst":"University of Washington"},{"author_name":"Thomas W Buford","author_inst":"University of Alabama at Birmingham"},{"author_name":"Julia Fleming","author_inst":"Fenway Health"},{"author_name":"Kenneth  H Mayer","author_inst":"Harvard Medical School"},{"author_name":"Greer Burkholder","author_inst":"University of Alabama at Birmingham"},{"author_name":"Barbara Gripshover","author_inst":"Case Western Reserve University"},{"author_name":"Michael S Saag","author_inst":"University of Alabama at Birmingham"},{"author_name":"Amanda L Willig","author_inst":"TW Education"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Predicting Musculoskeletal Adverse Events During Moderate- to High-Intensity Walking Training in Chronic Stroke","rel_doi":"10.64898\/2026.04.16.26351040","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351040","rel_abs":"Background: Moderate- to high-intensity walking training (M-HIT) is an established intervention for improving walking capacity in chronic stroke. Musculoskeletal (MSK) adverse events commonly occur during M-HIT, yet tools to identify individuals at higher risk are limited. Baseline clinical characteristics may provide insight into susceptibility to training-related MSK adverse events during M-HIT. Thus, this study aimed to develop and internally validate a model for predicting MSK adverse events during a 12-week M-HIT program in chronic stroke using baseline clinical characteristics. Methods: Participants (n=100) from HIT-Stroke Trials 1 and 2 were included. Baseline clinical characteristics included measures of orthopedic history, pre-existing pain, motor function, recent exercise history, demographics and health characteristics, stroke chronicity, and psychological health. Logistic regression models evaluated all possible combinations of baseline characteristics with up to three predictors. Leave-one-out cross-validation was used for internal validation to mitigate overfitting. Predictive performance was quantified using the C-statistic, and the candidate model with the highest cross-validated C-statistic was selected as the final model. Results: MSK adverse events occurred in 32.0% of participants. The optimal three-variable model included prior orthopedic condition (Odds ratio [OR] 3.02 [95% CI 1.14-8.64]), Fugl-Meyer lower extremity motor score (OR 1.14 [95% CI 1.02-1.28]), and self-reported participation in regular walking exercise (OR 0.17 [95% CI 0.05-0.49]) at baseline. This model demonstrated moderate discrimination (cross-validated C-statistic = 0.74; apparent C-statistic = 0.78). Conclusions: Participants reporting at least one pre-existing lower extremity or lumbar spine orthopedic condition and those with better lower-extremity motor function exhibited greater odds of experiencing MSK adverse events during M-HIT, while participants reporting participation in regular walking exercise had lower odds. These findings suggest that baseline clinical characteristics may help identify individuals at elevated risk for MSK adverse events during M-HIT who may warrant closer monitoring or risk-reduction strategies. Future studies are needed for external validation. Clinical Trial Registration: https:\/\/ClinicalTrials.gov; Unique identifiers: NCT03760016, NCT06268041","rel_num_authors":8,"rel_authors":[{"author_name":"Daria Pressler","author_inst":"University of Cincinnati"},{"author_name":"Sarah M. Schwab-Farrell","author_inst":"University of Cincinnati"},{"author_name":"Oluwole O. Awosika","author_inst":"University of Cincinnati"},{"author_name":"Darcy S. Reisman","author_inst":"University of Delaware"},{"author_name":"Sandra A. Billinger","author_inst":"University of Kansas Medical Center"},{"author_name":"Michael A. Riley","author_inst":"University of Cincinnati"},{"author_name":"Pierce Boyne","author_inst":"University of Cincinnati"},{"author_name":"- On behalf of the HIT-Stroke Trial investigators","author_inst":""}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Sex moderates apolipoprotein E \u03b54 effects on sleep expression and memory retention","rel_doi":"10.64898\/2026.04.16.26351049","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351049","rel_abs":"Introduction: Sleep-dependent memory consolidation differs by sex and maybe disrupted by Alzheimer disease (AD) risk. Whether sex moderates associations between apolipoprotein E {varepsilon}4(APOE {varepsilon}4) status, non-rapid eye movement (NREM) sleep, and memory remains unclear. Methods: Eighty cognitively unimpaired older adults completed a word-pair memory task with encoding and immediate testing occurring prior to overnight polysomnography with high-density electroencephalography (hdEEG) and delayed recall occurring after sleep. Sleep-memory associations were examined as a function of sex and APOE {varepsilon}4 status. Results: In this sample, a sex by APOE {varepsilon}4 interaction was associated with overnight memory retention, with female carriers exhibiting less overnight forgetting than female non-carriers and male {varepsilon}4 carriers. NREM sleep differed by sex and APOE {varepsilon}4 status and was associated with memory retention in {varepsilon}4 carriers. Discussion: These findings indicate sex-specific, sleep-dependent memory mechanisms associated with genetic AD risk, highlighting sleep as a potential early target for intervention, pending replication in larger samples. This study was not a clinical trial.","rel_num_authors":12,"rel_authors":[{"author_name":"Negin Sattari Barabadi","author_inst":"UC Irvine"},{"author_name":"Abhishek Dave","author_inst":"UC Irvine"},{"author_name":"Ivy Y. Chen","author_inst":"UC Irvine"},{"author_name":"Kitty K Kui","author_inst":"San Diego State University"},{"author_name":"Miranda G Chappel-Farley","author_inst":"University of Pittsburgh"},{"author_name":"Destiny E Berisha","author_inst":"UC Irvine"},{"author_name":"Kate E Sprecher","author_inst":"University of Wisconsin-Madison"},{"author_name":"brady A Riedner","author_inst":"University of Wisconsin-Madison"},{"author_name":"Stephanie Jones","author_inst":"riedner@wisc.edu"},{"author_name":"Barbara B Bendlin","author_inst":"University of Wisconsin-Madison"},{"author_name":"Bryce A Mander","author_inst":"UC Irvine"},{"author_name":"Ruth M Benca","author_inst":"Wake Forest University"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"A Randomized Pilot Trial of Medically Tailored Meals and Lifestyle Support for Gestational Diabetes: Feasibility, Acceptability, and Implementation Challenges","rel_doi":"10.64898\/2026.04.16.26351041","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351041","rel_abs":"Background: Lifestyle interventions incorporating medically-tailored meal delivery may support rapid behavior change among pregnant individuals with gestational diabetes (GDM). Purpose: To examine the feasibility and acceptability of a multicomponent lifestyle intervention for pregnant individuals with GDM. Primary outcomes included recruitment, retention, intervention receipt, and acceptability. Methods: We conducted a pilot randomized feasibility trial among pregnant individuals with GDM recruited from maternal fetal medicine clinics in the Hartford, Connecticut area. Participants were randomized to usual GDM care or the Meals4Moms intervention plus usual care. The intervention included medically-tailored meal delivery, personalized physical activity support, and multimodal education with digital tools. Participants completed a survey and three 24-hour dietary recalls at baseline and post-intervention. Meals4Moms participants also completed a semi-structured interview at follow-up. Intervention receipt was tracked by study staff. Results: Of 30 individuals approached, we screened 80% (n=24), of whom 75% (n=18\/24) were eligible; we randomized 8 participants. Seventy-five percent (n=6\/8) completed at least one component of the follow-up assessment (100%, n=4\/4 Meals4Moms, 50%, n=2\/4 Usual Care). One participant spent [&ge;]80% of her total food budget (n=1\/4, 25%), and no participants completed [&ge;]80% of prescribed exercise sessions (range: 0-50%). All (n=4) Meals4Moms participants reported they would be very likely to participate in the program if they had GDM again, and 100% (n=4) would be very likely to recommend the program to a friend with GDM. Conclusions: While the Meals4Moms intervention was highly acceptable to participants, procedural refinements are needed prior to conducting a full-scale efficacy trial.","rel_num_authors":9,"rel_authors":[{"author_name":"Andrea D. Shields","author_inst":"University of Connecticut Health"},{"author_name":"Molly E. Waring","author_inst":"University of Connecticut"},{"author_name":"Makayla Murphy","author_inst":"University of Connecticut Health"},{"author_name":"Linda S. Pescatello","author_inst":"University of Connecticut"},{"author_name":"Ock K. Chun","author_inst":"University of Connecticut"},{"author_name":"Helen Wu","author_inst":"University of Connecticut Health"},{"author_name":"Vanessa Sena","author_inst":"My Local Chefs"},{"author_name":"Christiana M. Field","author_inst":"University of Connecticut"},{"author_name":"Annie D. Kearns","author_inst":"University of Connecticut Health"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Multi-Ancestry Epigenome-Wide Meta-Analysis Identifies Novel Bulk and Cell-Type-Specific Epigenetic Markers of Asthma with Severe Exacerbations","rel_doi":"10.64898\/2026.04.16.26350345","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26350345","rel_abs":"Background: Extreme-phenotype comparisons allowed the discovery of novel asthma genetic risk loci. However, this approach remains unexplored in epigenome-wide association studies (EWAS). We aimed to identify bulk and cell-specific methylation markers of asthma with severe exacerbations across diverse ancestry groups. Methods: We conducted a meta-EWAS of 739,543 CpGs in whole blood among 1,192 African American and Latino pediatric populations, comparing non-asthmatics and asthma exacerbators. Genome-wide CpGs were followed up for replication in a meta-analysis across 1,516 ethnically diverse participants and in a cross-tissue evaluation of 393 nasal samples. We conducted differentially methylated region (DMRs), cell-type-deconvoluted, and quantitative trait loci analyses (whole-genome sequencing n=1,668; RNA-seq n=1,209). We examined enrichment in traits, pathways, and druggable genes, and analyzed DNAm predictors of plasma proteins and aging. Results: DNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (p<9x10-8, {lambda}=1.05). We replicated 25 CpGs in blood cells, cross-validated 7 in nasal samples, and detected 42 cell-specific DNAm markers mainly driven by T cells. DNAm at 134 CpGs was associated with gene expression in whole blood, including 118 associations with T-cell receptor genes, and 446 CpGs were regulated by [&ge;]1 genetic variant. We found enrichment for previous associations with environmental exposures, immune disorders, immune and inflammatory pathways, and druggable genes by developmental drugs. 21 methylation-predicted plasma proteins, involved in host defense, and one lung aging clock were associated with asthma exacerbations. Conclusions: The first meta-EWAS of extreme asthma phenotypes identified hundreds of novel DNAm markers, suggesting novel methylation biomarkers and candidate drugs for asthma and supporting the role of T cells.","rel_num_authors":28,"rel_authors":[{"author_name":"Javier Perez-Garcia","author_inst":"Universidad de La Laguna and Stanford University"},{"author_name":"Elena Martin-Gonzalez","author_inst":"Universidad de La Laguna"},{"author_name":"Zeyuan Johnson Chen","author_inst":"University of California, Los Angeles"},{"author_name":"Mario Martin-Almeida","author_inst":"Universidad de La Laguna"},{"author_name":"Jonathan Witonsky","author_inst":"University of California, San Francisco"},{"author_name":"Aditya Gorla","author_inst":"University of California, Los Angeles"},{"author_name":"Celeste Eng","author_inst":"University of California, San Francisco"},{"author_name":"Fabian Lorenzo-Diaz","author_inst":"Universidad de La Laguna"},{"author_name":"Anne K Bozack","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Jennifer Elhawary","author_inst":"University of California, San Francisco"},{"author_name":"Donglei Hu","author_inst":"University of California, San Francisco"},{"author_name":"Scott Huntsman","author_inst":"University of California, San Francisco"},{"author_name":"Ruperto Gonzalez-Perez","author_inst":"Hospital Universitario de Canarias"},{"author_name":"Jose M Hernandez-Perez","author_inst":"Hospital Universitario La Candelaria"},{"author_name":"Paloma Poza-Guedes","author_inst":"Hospital Universitario de Canarias"},{"author_name":"Elena Mederos-Luis","author_inst":"Hospital Universitario de Canarias"},{"author_name":"Inmaculada Sanchez-Machin","author_inst":"Hospital Universitario de Canarias"},{"author_name":"Jose Rodriguez-Santana","author_inst":"Centro de Neumologia Pediatrica, Puerto Rico"},{"author_name":"Jesus Villar","author_inst":"Hospital Universitario Dr Negrin and CIBERES, ISCIII"},{"author_name":"Shreyl L Rifas-Shiman","author_inst":"Harvard Medical School and Harvard Pilgrim Health Care Institute"},{"author_name":"Marie-France Hivert","author_inst":"Harvard Medical School"},{"author_name":"Emily Oken","author_inst":"Harvard Medical School and Harvard Pilgrim Health Care Institute"},{"author_name":"Diane R Gold","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Elad Ziv","author_inst":"University of California, San Francisco"},{"author_name":"Elior Rahmani","author_inst":"Stanford University"},{"author_name":"Esteban Gonzalez Burchard","author_inst":"University of California, San Francisco"},{"author_name":"Andres Cardenas","author_inst":"Stanford University"},{"author_name":"Maria Pino-Yanes","author_inst":"Universidad de La Laguna"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Herpes simplex virus type 1 DNA is less prevalent in persons with Alzheimers disease and genetic factors modify the effect","rel_doi":"10.64898\/2026.04.16.26351043","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351043","rel_abs":"INTRODUCTION: Herpes simplex virus-1 (HSV-1) has been implicated in Alzheimers disease (AD). METHODS: Reads from Alzheimers Disease Sequencing Project whole-genome sequencing data collected from brain (2,203 AD; 616 controls) and blood (8,908 AD; 15,768 controls) were aligned to viral genomes. Generalized linear mixed-models tested for the effect of HSV-1 DNA on AD, and we performed GWAS on HSV-1 presence and SNPxHSV-1 interaction effects on AD, adjusting for age, sex, tissue, library preparation, relatedness, and ancestry principal components. RESULTS: Across ancestry groups, HSV-1 DNA was consistently less frequent in AD cases; reads predominantly mapped to regions containing the latency-associated transcript region. DNA prevalence was lower in APOE-{epsilon}4 carriers; HSV-1 was associated with reduced AD risk in {epsilon}4 non-carriers but increased risk in carriers. GWAS identified host genetic influences on HSV-1 detection and interaction loci affecting AD risk. DISCUSSION: HSV-1 DNA showed an inverse association with AD and is affected by genetics.","rel_num_authors":13,"rel_authors":[{"author_name":"Marlene Tejeda","author_inst":"Department of Medicine Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"John Farrell","author_inst":"Department of Medicine Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Congcong Zhu","author_inst":"Department of Medicine Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Lee Wetzler","author_inst":"Department of Medicine Boston University Chobanian & Avedisian School of Medicine Chobanian & Avedisian School of Medicine"},{"author_name":"Kathryn L. Lunetta","author_inst":"Department of Biostatistics Boston University School of Public Health"},{"author_name":"William S. Bush","author_inst":"Department of Population & Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine"},{"author_name":"Eden R. Martin","author_inst":"John P. Hussman Institute for Human Genomics and Dr. John T. MacDonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami"},{"author_name":"Li-San Wang","author_inst":"Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine"},{"author_name":"Gerard D. Schellenberg","author_inst":"Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine"},{"author_name":"Margaret A. Pericak-Vance","author_inst":"John P. Hussman Institute for Human Genomics and Dr. John T. MacDonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami"},{"author_name":"Jonathan L. Haines","author_inst":"Department of Population & Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine"},{"author_name":"Lindsay A. Farrer","author_inst":"Department of Medicine Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Richard Sherva","author_inst":"Department of Medicine Boston University Chobanian & Avedisian School of Medicine"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Evaluating Individual Level Performance of Polygenic Risk Scores Using Early Onset High Genetic Risk Coronary Artery Disease as a Benchmark","rel_doi":"10.64898\/2026.04.16.26350801","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26350801","rel_abs":"Polygenic risk scores (PRSs) are typically validated using population-level metrics, masking variability in individual-level risk prediction and hindering clinical translation. To address this, we introduced a novel framework using a \"benchmark\" cohort (N=1184) of \"unexpected coronary artery disease (CAD)\": early-onset patients (<55 years) with a clinical profile of low 10-year risk, no diabetes or severe hypercholesterolemia that excludes therapy indications. The occurrence of early CAD in these clinically low-risk individuals establishes a \"ground truth\" for high genetic risk. We evaluated 58 published CAD PRSs and demonstrated a disconnection between population-level performance and individual-level accuracy (proportion of benchmark patients captured). The proportion captured by 58 PRSs varied from 10.8% to 33.1%, and the top-performing score was 2-fold more effective at identifying the benchmark group than established non-genetic biomarkers, such as lipoprotein(a). Furthermore, benchmark patients never captured by any score exhibited significantly healthier lipid profiles. Our framework provides an essential method for validating clinical readiness of PRSs.","rel_num_authors":15,"rel_authors":[{"author_name":"Shengxin Liang","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Min Seo Kim","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Yang Sui","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Youxin Tan","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Linke Li","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"So Mi Cho","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Satoshi Koyama","author_inst":"Broad Institute of MIT And Harvard"},{"author_name":"Yixuan Liu","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Kaavya Paruchuri","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Andrew Chan","author_inst":"Massachusetts General Hospital"},{"author_name":"Michael Honigberg","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Pradeep Natarajan","author_inst":"Massachusetts General Hospital"},{"author_name":"Nilanjan Chatterjee","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Akl C. Fahed","author_inst":"Massachussets General Hospital"},{"author_name":"Zhi Yu","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Phenome-derived polygenic scores and social determinants jointly shape context-dependent disease risk","rel_doi":"10.64898\/2026.04.16.26351039","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351039","rel_abs":"Polygenic scores (PGS) are typically derived from single-trait genome-wide association studies (GWAS), yet many complex diseases arise from shared genetic liability distributed across correlated clinical dimensions. Accordingly, disease risk depends not only on how genetic liability is represented but also on the social context in which that liability is expressed. Whether phenome-derived latent factors improve prediction, and how social determinants of health (SDoH) modify the realized utility of PGS, remains unclear. Here we constructed PGS for 35 orthogonal latent phenomic factors derived from 2,772 phenotypes in 361,114 UK Biobank (UKB) participants and evaluated their phenomic specificity, cross-dataset portability and predictive performance relative to conventional disease-specific PGS across the UKB holdout, Mass General Brigham Biobank and the All of Us (AoU) Research Program. Factor-based PGS showed widespread, biologically coherent phenome-wide associations that were reproducible across biobanks and ancestries. Their predictive utility, however, was strongly disease dependent. For asthma, a respiratory factor PGS outperformed an internally derived disease-specific PGS and showed superior cross-ancestry portability, retaining 41.5% of European-ancestry predictive accuracy in African-ancestry individuals, compared with 22.9% for an asthma PGS derived from the largest available multi-ancestry GWAS. By contrast, disease-specific PGS remained superior for coronary artery disease (CAD) and type 2 diabetes (T2D). These findings suggest that phenome-derived aggregation is most beneficial when disease-specific GWAS incompletely capture underlying liability, including settings of biological heterogeneity or imprecise phenotyping. We then evaluated SDoH in AoU as a complementary axis shaping prevalent disease prediction beyond genetic susceptibility. Across all three diseases, SDoH contributed substantial and largely independent predictive information beyond the disease-optimal genetic model. SDoH also modified how genetic liability translated into observed disease prevalence: for asthma and CAD, genetic stratification attenuated with increasing social burden, whereas this attenuation was substantially weaker for T2D. As a result, the same genetic percentile corresponded to different standardized predicted prevalences across social strata, reflecting disease-specific shifts in baseline prevalence, genetic gradients and calibration. Together, these findings indicate that disease risk is shaped by both genetic liability and the social context in which that liability is realized. Phenome-derived PGS improve prediction under specific architectural conditions, whereas social context independently modifies the performance, calibration and interpretation of genetic risk across populations.","rel_num_authors":19,"rel_authors":[{"author_name":"Ying Wang","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"},{"author_name":"Buu Truong","author_inst":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Heart and Vascular Institute, Massachusetts General Br"},{"author_name":"Wenhan Lu","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"},{"author_name":"Chaimaa Fadil","author_inst":"Division of Medical Sciences, Harvard University, Boston, MA 02115, USA"},{"author_name":"Yixuan He","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Human Genetics Center, The University of Texas Health Science C"},{"author_name":"Weijun Luo","author_inst":"College of Computing, The Georgia Institute of Technology, Atlanta, GA 30332, USA"},{"author_name":"Satoshi Koyama","author_inst":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Heart and Vascular Institute, Massachusetts General Br"},{"author_name":"Kristin Tsuo","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"},{"author_name":"Kaavya Paruchuri","author_inst":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Heart and Vascular Institute, Massachusetts General Br"},{"author_name":"Zhi Yu","author_inst":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Heart and Vascular Institute, Massachusetts General Br"},{"author_name":"Leland E. Hull","author_inst":"Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, "},{"author_name":"Zhili Zheng","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"},{"author_name":"Caitlin E. Carey","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"},{"author_name":"Raymond K. Walters","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"},{"author_name":"Benjamin M. Neale","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"},{"author_name":"Elise B. Robinson","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"},{"author_name":"Peter Kraft","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA"},{"author_name":"Pradeep Natarajan","author_inst":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Heart and Vascular Institute, Massachusetts General Br"},{"author_name":"Alicia R. Martin","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Polygenic risk scores enhance the identification of carriers of monogenic forms of idiopathic pulmonary fibrosis","rel_doi":"10.64898\/2026.04.16.26350967","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26350967","rel_abs":"Background: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performance was evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Results: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Conclusions: Incorporating IPF-PRS into a model based on the patient clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.","rel_num_authors":24,"rel_authors":[{"author_name":"Aitana Alonso-Gonzalez","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"David Jaspez","author_inst":"Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain"},{"author_name":"Jose M. Lorenzo-Salazar","author_inst":"Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain"},{"author_name":"Andrea Delgado","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"Ariadna Quintero-Bacallado","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Josyf Mychaleckyj","author_inst":"Center for Public Health Genomics; University of Virginia, Charlottesville, VA, USA"},{"author_name":"John S. Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL USA"},{"author_name":"Justin M. Oldham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Toby M. Maher","author_inst":"National Heart and Lung Institute, Imperial National Institute of Health and Care Research, Biomedical Research Centre, Imperial College London, London, UK"},{"author_name":"Beatriz Guillen-Guio","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Louise V. Wain","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Richard J. Allen","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Gauri Saini","author_inst":"Royal Papworth University Hospital NHS Foundation Trust and University of Nottingham, UK;"},{"author_name":"R. Gisli Jenkins","author_inst":"National Heart and Lung Institute, Imperial National Institute of Health and Care Research, Biomedical Research Centre, Imperial College London, London, UK"},{"author_name":"Maria Molina-Molina","author_inst":"Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain"},{"author_name":"David Zhang","author_inst":"Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Christine Kim Garcia","author_inst":"Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Fernando J. Martinez","author_inst":"Weill Cornell Medical Center, New York, NY USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Carlos Flores","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Polygenic risk scores enhance the identification of carriers of monogenic forms of idiopathic pulmonary fibrosis","rel_doi":"10.64898\/2026.04.16.26350967","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26350967","rel_abs":"Background: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performance was evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Results: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Conclusions: Incorporating IPF-PRS into a model based on the patient clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.","rel_num_authors":24,"rel_authors":[{"author_name":"Aitana Alonso-Gonzalez","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"David Jaspez","author_inst":"Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain"},{"author_name":"Jose M. Lorenzo-Salazar","author_inst":"Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain"},{"author_name":"Andrea Delgado","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"Ariadna Quintero-Bacallado","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Josyf Mychaleckyj","author_inst":"Center for Public Health Genomics; University of Virginia, Charlottesville, VA, USA"},{"author_name":"John S. Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL USA"},{"author_name":"Justin M. Oldham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Toby M. Maher","author_inst":"National Heart and Lung Institute, Imperial National Institute of Health and Care Research, Biomedical Research Centre, Imperial College London, London, UK"},{"author_name":"Beatriz Guillen-Guio","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Louise V. Wain","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Richard J. Allen","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Gauri Saini","author_inst":"Royal Papworth University Hospital NHS Foundation Trust and University of Nottingham, UK;"},{"author_name":"R. Gisli Jenkins","author_inst":"National Heart and Lung Institute, Imperial National Institute of Health and Care Research, Biomedical Research Centre, Imperial College London, London, UK"},{"author_name":"Maria Molina-Molina","author_inst":"Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain"},{"author_name":"David Zhang","author_inst":"Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Christine Kim Garcia","author_inst":"Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Fernando J. Martinez","author_inst":"Weill Cornell Medical Center, New York, NY USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Carlos Flores","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Polygenic risk scores enhance the identification of carriers of monogenic forms of idiopathic pulmonary fibrosis","rel_doi":"10.64898\/2026.04.16.26350967","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26350967","rel_abs":"Background: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performance was evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Results: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Conclusions: Incorporating IPF-PRS into a model based on the patient clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.","rel_num_authors":24,"rel_authors":[{"author_name":"Aitana Alonso-Gonzalez","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"David Jaspez","author_inst":"Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain"},{"author_name":"Jose M. Lorenzo-Salazar","author_inst":"Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain"},{"author_name":"Andrea Delgado","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"Ariadna Quintero-Bacallado","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"},{"author_name":"Shwu-Fan Ma","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Emma Strickland","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Josyf Mychaleckyj","author_inst":"Center for Public Health Genomics; University of Virginia, Charlottesville, VA, USA"},{"author_name":"John S. Kim","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Yong Huang","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Ayodeji Adegunsoye","author_inst":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL USA"},{"author_name":"Justin M. Oldham","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI USA"},{"author_name":"Toby M. Maher","author_inst":"National Heart and Lung Institute, Imperial National Institute of Health and Care Research, Biomedical Research Centre, Imperial College London, London, UK"},{"author_name":"Beatriz Guillen-Guio","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Louise V. Wain","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Richard J. Allen","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Gauri Saini","author_inst":"Royal Papworth University Hospital NHS Foundation Trust and University of Nottingham, UK;"},{"author_name":"R. Gisli Jenkins","author_inst":"National Heart and Lung Institute, Imperial National Institute of Health and Care Research, Biomedical Research Centre, Imperial College London, London, UK"},{"author_name":"Maria Molina-Molina","author_inst":"Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain"},{"author_name":"David Zhang","author_inst":"Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Christine Kim Garcia","author_inst":"Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA"},{"author_name":"Fernando J. Martinez","author_inst":"Weill Cornell Medical Center, New York, NY USA"},{"author_name":"Imre Noth","author_inst":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA USA"},{"author_name":"Carlos Flores","author_inst":"Research Unit, Hospital Universitario Nuestra Senora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Validation of methods for forecasting the frequency of non-vaccine serotypes after introduction or switch of a pneumococcal conjugate vaccine","rel_doi":"10.64898\/2026.04.16.26351051","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351051","rel_abs":"Background To anticipate the impact of new pneumococcal vaccines and guide future updates, accurate forecasts of changes in non-vaccine serotypes (NVTs) are needed. We developed and evaluated three models that incorporated different assumptions about the way in which NVTs will increase and generated ensemble predictions for the frequency of NVTs in different post- pneumococcal conjugate vaccines (PCV) periods. Methods We analyzed age- and serotype-specific invasive pneumococcal disease (IPD) cases from the United States CDCs Active Bacterial Core surveillance during the pre-PCV (1998-1999), early post-PCV7 (2000-2004), late post-PCV7\/pre-PCV13 (2005-2009), early post-PCV13 (2010-2014), and late post-PCV13 (2015-2019) periods. These data were augmented with IPD cases from several countries and combined with serotype-specific invasiveness to infer serotype-specific carriage prevalence. Three models (Ranking, Proportionate, NFDS-lite) generated independent predictions of post-PCV IPD frequencies, which were integrated using an accuracy-weighted ensemble. Model performance was evaluated using the normalized root mean square error (NRMSE). Results A total of 23,959 non-PCV7 and 15,580 non-PCV13 cases were analyzed. NVT cases increased from the pre-PCV7 to the late post-PCV7 and post-PCV13 periods. The accuracy of predictions across age groups and models was consistent and high during the post-PCV13 periods but varied during the post-PCV7 periods. The Proportionate model (NRMSE=0.70-3.95) outperformed the NFDS-lite (NRMSE=0.93-8.91) and Ranking (NRMSE=1.51-5.37) models during the early-post-PCV7 period, whereas the NFDS-lite model (NRMSE=1.55-9.82) was superior to the Proportionate (NRMSE=1.45-10.22) and Ranking (NRMSE=1.86-11.35) models during the late post-PCV7 period. The Ensemble model improved on these individual models. Conclusions The Ensemble model offers a tool for forecasting serotype patterns to inform pneumococcal vaccines impact and future pneumococcal vaccine formulation.","rel_num_authors":2,"rel_authors":[{"author_name":"Deus Thindwa","author_inst":"Department of Epidemiology of Microbial Diseases and the Public Health Modeling Unit, Yale School of Public Health, New Haven, CT, 06511, United States"},{"author_name":"Daniel M Weinberger","author_inst":"Department of Epidemiology of Microbial Diseases and the Public Health Modeling Unit, Yale School of Public Health, New Haven, CT, 06511, United States"}],"rel_date":"2026-04-18","rel_site":"medrxiv"},{"rel_title":"Mechanism of HIV-1 Capsid Rupture and Uncoating by Reverse Transcription","rel_doi":"10.64898\/2026.04.17.719300","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.17.719300","rel_abs":"One of the key events in the HIV-1 life cycle is reverse transcription, during which single-stranded viral RNA (ssRNA) is converted into double-stranded DNA (dsDNA). This process occurs inside the mature virus capsid and, once it reaches a critical threshold, drives capsid rupture. This uncoating is essential for infection because it releases viral genetic material into the host cell nucleus. Despite its importance, many mechanistic details of this process remain poorly understood. To address this gap, we develop a multiscale computational method for simulating reverse transcription inside the capsid, termed Coarse-Grained Kinetic Monte Carlo (CG-KMC). CG-KMC stochastically adds deoxynucleotide triphosphates (dNTPs) to the coarse-grained RNA model, enabling stepwise growth of DNA inside the HIV-1 capsid. We implement this method within an integrative coarse-grained framework that combines a \"bottom-up\" capsid model with a \"top-down\" representation of the viral RNA\/DNA genome. Our simulations phenomenologically capture and predict diverse capsid rupture pathways during reverse transcription. The resulting ruptured structures closely match previously identified cryo-ET images. We further perform an extensive analysis of the rupture process, examining its mechanistic and kinetic aspects as well as the role of capsid-DNA interactions. Our findings illuminate how different capsid-DNA conditions give rise to distinct rupture pathways, which differ from ruptures due to simple outward pressure expansion models from within the capsid.","rel_num_authors":3,"rel_authors":[{"author_name":"Kuntal Ghosh","author_inst":"The University of Chicago"},{"author_name":"Manish Gupta","author_inst":"The University of Chicago"},{"author_name":"Gregory A Voth","author_inst":"University of Chicago"}],"rel_date":"2026-04-18","rel_site":"biorxiv"},{"rel_title":"Mechanism of HIV-1 Capsid Rupture and Uncoating by Reverse Transcription","rel_doi":"10.64898\/2026.04.17.719300","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.17.719300","rel_abs":"One of the key events in the HIV-1 life cycle is reverse transcription, during which single-stranded viral RNA (ssRNA) is converted into double-stranded DNA (dsDNA). This process occurs inside the mature virus capsid and, once it reaches a critical threshold, drives capsid rupture. This uncoating is essential for infection because it releases viral genetic material into the host cell nucleus. Despite its importance, many mechanistic details of this process remain poorly understood. To address this gap, we develop a multiscale computational method for simulating reverse transcription inside the capsid, termed Coarse-Grained Kinetic Monte Carlo (CG-KMC). CG-KMC stochastically adds deoxynucleotide triphosphates (dNTPs) to the coarse-grained RNA model, enabling stepwise growth of DNA inside the HIV-1 capsid. We implement this method within an integrative coarse-grained framework that combines a \"bottom-up\" capsid model with a \"top-down\" representation of the viral RNA\/DNA genome. Our simulations phenomenologically capture and predict diverse capsid rupture pathways during reverse transcription. The resulting ruptured structures closely match previously identified cryo-ET images. We further perform an extensive analysis of the rupture process, examining its mechanistic and kinetic aspects as well as the role of capsid-DNA interactions. Our findings illuminate how different capsid-DNA conditions give rise to distinct rupture pathways, which differ from ruptures due to simple outward pressure expansion models from within the capsid.","rel_num_authors":3,"rel_authors":[{"author_name":"Kuntal Ghosh","author_inst":"The University of Chicago"},{"author_name":"Manish Gupta","author_inst":"The University of Chicago"},{"author_name":"Gregory A Voth","author_inst":"University of Chicago"}],"rel_date":"2026-04-18","rel_site":"biorxiv"},{"rel_title":"16S rRNA k-mer composition encodes microbial functional potential","rel_doi":"10.64898\/2026.04.16.718937","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718937","rel_abs":"16S rRNA amplicon sequencing is widely used to profile microbiome taxonomic composition and functional potential. Most 16S rRNA-based analysis methods depend on comparing sequenced reads against reference marker genes from previously characterized organisms. Thus, method accuracy declines in environments dominated by uncharacterized microbes. We uncovered a direct link between 16S rRNA and genome-encoded functions. Using fully sequenced bacterial genomes, we show that (i) whole-genome k-mer composition is predictive of functions encoded in the genome and (ii) 16S rRNA k-mer profiles reflect their source genome k-mer compositions. Leveraging these relationships, we developed embeRNA, a neural network-based framework that predicts functions directly from 16S rRNA k-mer embeddings, without taxonomy assignment or phylogenetic placement. Furthermore, by producing per-function probability scores rather than categorical assignments, embeRNA allows users to adapt decision thresholds to match study goals and sample characteristics, e.g. balancing precision vs. recall or accounting for community novelty. We trained embeRNA on a large collection of bacterial function-omes and evaluated it using a stringent novel microbes benchmark, where all test 16S rRNA sequences were dissimilar to those seen in training (all <97% identical). On this test set of phylogenetically novel organisms, embeRNA outperformed reference-based methods overall and achieved significantly better performance for the hard to label set of functions. In testing on soil metagenomes with paired 16S rRNA amplicon and whole metagenome shotgun (WMS) sequencing data, embeRNA recovered most WMS-inferred functions and yielded abundance profiles strongly correlated with WMS results. Together, our results indicate that 16S rRNA k-mer composition carries substantial functional signal and that 16S amplicon data can be used to complement WMS -based inference to broaden functional characterization of microbiomes, particularly in understudied environments.","rel_num_authors":3,"rel_authors":[{"author_name":"Jia Liu","author_inst":"Emory University"},{"author_name":"M. Clara De Paolis Kaluza","author_inst":"Northeastern University"},{"author_name":"Yana Bromberg","author_inst":"Emory University"}],"rel_date":"2026-04-18","rel_site":"biorxiv"},{"rel_title":"Systematic comparisons between long-read and short-read based amplicon sequencing to characterize mixed microalgal communities.","rel_doi":"10.64898\/2026.04.17.719029","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.17.719029","rel_abs":"The 18S rRNA gene has emerged as the primary molecular marker for amplicon-based characterization of microalgal communities, including in wastewater treatment systems, yet trade-offs between short- and long-read approaches remain poorly defined. We systematically compared V8V9 short-read sequencing (Illumina MiSeq), full-length long-read sequencing with ss5ss3 primers (PacBio Sequel II), and computationally extracted V8V9 regions from long-read data. Both in silico and in vitro analyses confirmed V8V9 captured broader taxonomic coverage than ss5ss3, though partial reference sequences and taxonomic misannotations biased in silico assessments. Long reads taxonomic advantage was database-dependent, constrained by SILVA databases genus-level curation but fully realized when paired with the species-level-curated and eukaryotes-focused PR2 (Protist Ribosomal Reference) database. Long-read sequencing uniquely identified amplicon sequence variants (ASVs) assigned to key phosphorus assimilators (Scenedesmus obliquus, Desmodesmus sp., and Acutodesmus sp.) at the species level during successful phosphorus removal in a full-scale microalgal cultivation system, while V8V9 short-read sequencing revealed ASVs assigned to algal-predatory (Leptophryidae) and bacterivorous (Choanoflagellata and Rhogostoma-lineage) protists when performance declined, suggesting grazing pressure on the phosphorus-removing community. Although both approaches performed comparably for operational monitoring, these complementary strengths support short-read sequencing for routine community profiling and long-read sequencing for detailed functional investigations of Chlorophyta.","rel_num_authors":9,"rel_authors":[{"author_name":"Zihan Dai","author_inst":"School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, GA, United States"},{"author_name":"Md Mahbubul Alam","author_inst":"Department of Civil, Structural and Environmental Engineering, University at Buffalo, The State University of New York, Buffalo, New York, United States"},{"author_name":"Benjamin Gincley","author_inst":"School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, GA, United States"},{"author_name":"Farhan Khan","author_inst":"School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, GA, United States"},{"author_name":"Ga-Yeong Kim","author_inst":"The Grainger College of Engineering, Civil & Environmental Engineering, University of Illinois Urbana-Champaign, Urbana, IL, United State"},{"author_name":"Hannah Molitor","author_inst":"The Grainger College of Engineering, Civil & Environmental Engineering, University of Illinois Urbana-Champaign, Urbana, IL, United State"},{"author_name":"Jeremy S Guest","author_inst":"The Grainger College of Engineering, Civil & Environmental Engineering, University of Illinois Urbana-Champaign, Urbana, IL, United State"},{"author_name":"Ian Bradley","author_inst":"Department of Civil, Structural and Environmental Engineering, University at Buffalo, The State University of New York, Buffalo, New York, United States"},{"author_name":"Ameet J Pinto","author_inst":"School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, GA, United States"}],"rel_date":"2026-04-18","rel_site":"biorxiv"},{"rel_title":"Calibration of in-frame indel variant effect predictors for clinical variant classification","rel_doi":"10.64898\/2026.04.15.718599","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718599","rel_abs":"Insertions and deletions (indels) represent a substantial source of genetic variation in humans and are associated with a diverse array of functional consequences. Despite their prevalence and clinical importance, indels, particularly short in-frame indels, remain critically understudied compared to single nucleotide variants and are challenging to interpret clinically. While many computational predictors for missense variants have been rigorously evaluated and calibrated for clinical use, the clinical utility of tools for in-frame indels remains uncertain. To address this gap, we have calibrated in-frame indel prediction tools for clinical variant classification. We constructed a high-confidence dataset of in-frame indel variants ([&le;] 50bp) from clinical and population databases and estimated the prior probability of pathogenicity of a rare in-frame indel observed in a disease-associated gene, and of an insertion and deletion separately. Using a previously developed statistical framework based on local posterior probabilities, we then established score thresholds for eight computational tools, corresponding to distinct evidence levels for pathogenic and benign classification according to ACMG\/AMP guidelines. All in-frame indel predictors evaluated here reached multiple evidence levels of pathogenicity and\/or benignity, demonstrating measurable clinical value. However, these models consistently exhibited lower performance levels compared to missense predictors, highlighting the need for improved computational approaches for indel classification.","rel_num_authors":10,"rel_authors":[{"author_name":"Haneen Abderrazzaq","author_inst":"Northeastern University"},{"author_name":"Mugdha Singh","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Larry Babb","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Timothy Bergquist","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Steven E Brenner","author_inst":"University of California, Berkeley"},{"author_name":"Vikas Pejaver","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Anne O'Donnell-Luria","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Predrag Radivojac","author_inst":"Northeastern University"},{"author_name":"- ClinGen Computational Working Group","author_inst":"-"},{"author_name":"- ClinGen Variant Classification Working Group","author_inst":"-"}],"rel_date":"2026-04-18","rel_site":"biorxiv"},{"rel_title":"Calibration of in-frame indel variant effect predictors for clinical variant classification","rel_doi":"10.64898\/2026.04.15.718599","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718599","rel_abs":"Insertions and deletions (indels) represent a substantial source of genetic variation in humans and are associated with a diverse array of functional consequences. Despite their prevalence and clinical importance, indels, particularly short in-frame indels, remain critically understudied compared to single nucleotide variants and are challenging to interpret clinically. While many computational predictors for missense variants have been rigorously evaluated and calibrated for clinical use, the clinical utility of tools for in-frame indels remains uncertain. To address this gap, we have calibrated in-frame indel prediction tools for clinical variant classification. We constructed a high-confidence dataset of in-frame indel variants ([&le;] 50bp) from clinical and population databases and estimated the prior probability of pathogenicity of a rare in-frame indel observed in a disease-associated gene, and of an insertion and deletion separately. Using a previously developed statistical framework based on local posterior probabilities, we then established score thresholds for eight computational tools, corresponding to distinct evidence levels for pathogenic and benign classification according to ACMG\/AMP guidelines. All in-frame indel predictors evaluated here reached multiple evidence levels of pathogenicity and\/or benignity, demonstrating measurable clinical value. However, these models consistently exhibited lower performance levels compared to missense predictors, highlighting the need for improved computational approaches for indel classification.","rel_num_authors":10,"rel_authors":[{"author_name":"Haneen Abderrazzaq","author_inst":"Northeastern University"},{"author_name":"Mugdha Singh","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Larry Babb","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Timothy Bergquist","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Steven E Brenner","author_inst":"University of California, Berkeley"},{"author_name":"Vikas Pejaver","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Anne O'Donnell-Luria","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Predrag Radivojac","author_inst":"Northeastern University"},{"author_name":"- ClinGen Computational Working Group","author_inst":"-"},{"author_name":"- ClinGen Variant Classification Working Group","author_inst":"-"}],"rel_date":"2026-04-18","rel_site":"biorxiv"},{"rel_title":"LagCI Enables Inference of Temporal Causal Relationships from Dense Multi-Omic Time Series","rel_doi":"10.64898\/2026.04.15.718654","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.15.718654","rel_abs":"Inferring causal relationships from time-series data is critical for uncovering the dynamics of biological regulation. However, in multi-omics studies, this task is often hampered by sparse temporal sampling and the limitations of existing methods. To address this, we developed Lagged-Correlation Based Causal Inference (lagCI), a computational framework designed to identify time-lagged associations by combining comprehensive lag-correlation profiling with a robust statistical filtering scheme. Rather than relying on simple cross-correlation, lagCI analyzes the entire correlation profile and applies a quality-scoring system to filter out spurious associations that often plague high-dimensional datasets. We first tested lagCI on wearable physiological data, where it successfully captured the well-known causal link between physical activity and heart rate, even accounting for variations in lag times between individuals. Moving to high-frequency human multi-omics, we used lagCI to build a directed network of 1,624 molecules connected by over 157,000 predicted interactions. This network didn't just mirror established biology (such as cytokine-hormone crosstalk); it also pointed to specific molecular hubs that seem to orchestrate the timing of metabolic and immune responses. Overall, lagCI provides a data-driven way to extract temporal insights from dense longitudinal omics. We've made the tool available as an R package with multiple interfaces to ensure it's accessible for both bioinformaticians and clinicians.","rel_num_authors":6,"rel_authors":[{"author_name":"Yifei Ge","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore"},{"author_name":"Shunpeng Bai","author_inst":"College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China"},{"author_name":"Zirui Qiang","author_inst":"College of Computer Science and Technology, Harbin Institute of Technology, Shenzhen, Guangdong 518055, China"},{"author_name":"Yijiang Liu","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore"},{"author_name":"Yitong Wu","author_inst":"School of Biological Sciences, The University of Hong Kong, Hong Kong, China"},{"author_name":"Xiaotao Shen","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore"}],"rel_date":"2026-04-18","rel_site":"biorxiv"},{"rel_title":"Supporting Underrepresented Undergraduate Entry into Aging and Neurosciences Research and Clinical Careers: Student-rated Mentor Behaviors, Relationship Quality and Research Training Satisfaction","rel_doi":"10.64898\/2026.04.15.26350982","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350982","rel_abs":"Improving diversity in U.S. Alzheimers disease (AD) research is a pressing need. By 2050, Hispanic and Latino Americans will comprise 30% of the population. Hispanics are 1.5 times more likely and Blacks are twice as likely to develop AD compared to Whites, yet both remain vastly underrepresented in clinical trials research. Aging and AD research mentorship of underrepresented STEM undergraduates is designed to promote entry into related professions by students committed to decreasing disparities in AD research participation and clinical care. The NIA-funded MADURA program recruited 93 students from backgrounds historically underrepresented in STEM majors and\/or from NIH-defined disadvantaged backgrounds. Trainees were placed in aging\/AD research labs and received weekly training and mentorship from faculty research PIs and other types of supervisors (postdoctoral researchers, graduate students, research assistant staff...) Our study examined student ratings of the program and mentor behaviors, using a program-specific survey and the Mentoring Competency Assessment-21 (MCA-21). Trainees were highly satisfied with both mentoring relationships and the overall program. Student rated MCA-21 competency areas were quite high for both P.I.s and other types of research mentors. However, there were striking differences in associations between competencies and relationship and program satisfaction, by mentor type. For PI mentors, no MCA-21 competencies were associated with relationship satisfaction, but five of six competencies were associated with relationship satisfaction for other mentor types. Similarly, no PI mentor competencies were significantly correlated with overall placement satisfaction, but all six competencies were correlated with overall placement satisfaction for other mentor types. The authors discuss the likelihood of differing student expectations of faculty PI versus other types of research mentors, recommendations for assessing role-specific student expectations (including functions primarily possible only for senior faculty PIs), and utilizing nearer-peer plus PI faculty mentors to comprehensively address the gamut of mentee needs.","rel_num_authors":6,"rel_authors":[{"author_name":"Sharon Thompson","author_inst":"UC San Diego: University of California San Diego"},{"author_name":"Lawrence Ong","author_inst":"University of California San Diego"},{"author_name":"Becky Marquez","author_inst":"University of California San Diego"},{"author_name":"Anthony  J.A. Molina","author_inst":"University of California San Diego"},{"author_name":"Dennis  R. Trinidad","author_inst":"University of California San Diego"},{"author_name":"Steven  D. Edland","author_inst":"University of California San Diego"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Detection and Measurement of Hypopyon on Slit Lamp Examination Versus Anterior Segment Optical Coherence Tomography","rel_doi":"10.64898\/2026.04.15.26350185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350185","rel_abs":"PurposeTo compare hypopyon detection using anterior segment optical coherence tomography (ASOCT) versus slit lamp examination (SLE) in microbial keratitis, and to evaluate intra- and inter-grader agreement for ASOCT hypopyon measurement.\n\nMethodsTwo masked graders independently evaluated ASOCT images for hypopyon presence or absence in eyes with microbial keratitis, with disagreements resolved by consensus. A subset of hypopyon eyes underwent triplicate height measurement using two methods (endothelial length, vertical height). Cohens kappa, intraclass correlation coefficients (ICC), sensitivity, and specificity were calculated comparing diagnostic performance of ASOCT versus SLE.\n\nResultsInter-grader agreement for hypopyon detection on ASOCT was excellent ({kappa}=0.94; 95% CI 0.84-1.00) and intra-grader agreement was excellent ({kappa}=0.89-1.00). ASOCT detected hypopyon in 67.1% of eyes versus 57.0% by SLE (sensitivity 83.0%, specificity 96.2% using ASOCT as reference). Intra-grader reproducibility was excellent for both endothelial length and vertical height measurements (ICC 0.977-0.996). Inter-grader agreement was good for endothelial length (ICC 0.831) and vertical height (ICC 0.827), though a statistically significant inter-grader bias was identified for vertical height only (Wilcoxon p=0.008).\n\nConclusionsASOCT detected hypopyon with greater sensitivity than SLE and demonstrated excellent intra-grader and good inter-grader measurement reproducibility. Endothelial length showed slightly superior inter-grader concordance to vertical height measurement.","rel_num_authors":8,"rel_authors":[{"author_name":"Kamini Narendra Reddy","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine"},{"author_name":"Folahan Ibukun","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine"},{"author_name":"Kaiyang Huang","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine; Whiting School of Engineering, Johns Hopkins University"},{"author_name":"Ji Yi","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine; Whiting School of Engineering, Johns Hopkins University"},{"author_name":"Elesh Jain","author_inst":"SNC Chitrakoot"},{"author_name":"Subeesh Kuyyadiyil","author_inst":"SNC Chitrakoot"},{"author_name":"Gautam S Parmar","author_inst":"SNC Chitrakoot"},{"author_name":"Nakul S Shekhawat","author_inst":"Wilmer Eye Institute, Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Motor-tasks fMRI BOLD activations in chronic stroke with residual hemiparesis in the upper extremity: a pre-neurofeedback baseline characterization","rel_doi":"10.64898\/2026.04.15.26350962","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350962","rel_abs":"Stroke is the third leading cause of death and disability combined worldwide and often results in hemiparesis. Functional magnetic resonance imaging (fMRI) is a non-invasive technique used to investigate changes in brain activations during tasks aimed at restoring the lost motor function. Participants with chronic stroke and residual hemiparesis in the upper extremity were recruited for a clinical intervention that included neurofeedback training and fMRI sessions with motor-execution and motor-imagery tasks. The present study provides a baseline characterization of brain activations prior to neurofeedback training. Since lesion site and volume varied across participants, two fMRI preprocessing pipelines were applied. The first one was used for twelve participants with lesions restricted to a single hemisphere and for one participant with small secondary lesions in the contralesional hemisphere, whereas the second one was used for two participants with large bilateral lesions. These were followed by quality control measures and statistical analysis. First-level (i.e., single-participant) analysis returned the strongest and most extensive activation across participants during motor-execution tasks, with clusters identified in the ipsilesional parietal lobe, bilateral occipital lobes, and cerebellum after Family-Wise Error correction. Second-level (i.e., group-level) analysis involving participants who underwent the first fMRI preprocessing pipeline revealed a significant cluster in the cerebellum after False Discovery Rate correction. These results are consistent with previous studies involving participants with chronic stroke performing motor-tasks. Cerebellar recruitment observed consistently across participants could reflect compensatory mechanisms supporting motor control after stroke.","rel_num_authors":5,"rel_authors":[{"author_name":"Gabriele Varisco","author_inst":"Malardalen University"},{"author_name":"Jeanette Plantin","author_inst":"Danderyd Hospital Division of Rehabilitation Medicine, Karolinska Institutet"},{"author_name":"Rita Almeida","author_inst":"Stockholm University Brain Imaging Centre, Stockholm University"},{"author_name":"Susanne Palmcrantz","author_inst":"Danderyd Hospital Division of Rehabilitation Medicine, Karolinska Institutet"},{"author_name":"Elaine Astrand","author_inst":"Malardalen University"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Transmission dynamics of the COVID-19 pandemic across the emerging variants in mainland China: a hypergraph-based spatiotemporal modeling study","rel_doi":"10.64898\/2026.04.16.26351004","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.16.26351004","rel_abs":"Mainland China experienced multiple waves of COVID-19 pandemic during 2020-2022, driven by emerging variants and changes in public health and social measures (PHSMs). We developed a hypergraph-based Susceptible-Vaccinated-Exposed-Infectious-Recovered-Susceptible (SVEIRS) model to reconstruct epidemic dynamics across 31 provinces, capturing transmission heterogeneity associated with clustered contacts. We assessed key characteristics of transmission at national and provincial levels during four outbreak periods: initial, localized pre-delta, Delta, and widespread Omicron, which accounted for 96.7% of all infections. We found significant diversity in transmission contributions across cluster sizes, with a small fraction of larger clusters responsible for a disproportionate share of infections. Counterfactual analyses showed that reducing cluster-size heterogeneity, while holding overall exposure constant, could have lowered national infections by 11.70-30.79%, with the largest effects during Omicron period. Ascertainment rates increased over time but remained spatially heterogeneous with a range: (14.40, 71.93)%. Population susceptibility declined following mass vaccination (to 42.49% in Aug 2021, nationally) and rebounded (to 89.89% in Nov 2022) due to waning immunity with variations across the provinces. Effective reproduction numbers displayed marked temporal and spatial variability, with higher estimates during Omicron. Overall, these results highlight critical role of group contact heterogeneity in shaping epidemic dynamics.","rel_num_authors":7,"rel_authors":[{"author_name":"Yi Wang","author_inst":"School of Science, Harbin Institute of Technology, Shenzhen, China"},{"author_name":"DONG WANG","author_inst":"University of Hong Kong"},{"author_name":"Yiu Chung Lau","author_inst":"WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong,"},{"author_name":"Zhanwei Du","author_inst":"1 WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kon"},{"author_name":"Benjamin J Cowling","author_inst":"The University of Hong Kong"},{"author_name":"Yi Zhao","author_inst":"School of Science, Harbin Institute of Technology, Shenzhen, China"},{"author_name":"Sheikh Taslim Ali","author_inst":"School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Cardiovascular Health at Midlife and Alzheimer Disease Biomarkers","rel_doi":"10.64898\/2026.04.15.26350968","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350968","rel_abs":"BackgroundCardiovascular health factors are associated with cognitive decline and risk of dementia, including Alzheimer disease (AD); however, this has been mostly studied in late life. We investigated whether vascular and lifestyle factors are associated with AD plasma and imaging biomarkers in midlife.\n\nMethodsWe investigated 1,406 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study with information on vascular and lifestyle factors framed from the American Heart Association (AHA) \"lifes essential 8\" (LE8) guidelines for cardiovascular health at early midlife (mean age 45.0 {+\/-} SD 3.6) and AD biomarkers in late midlife (mean age 60 {+\/-} SD 3.5). LE8 was calculated and categorized into poor (0-49), intermediate (50-79), and ideal (80-100) cardiovascular health, based on 8 components including smoking, diet, body mass index (BMI), sleep, fasting glucose, blood pressure, cholesterol, and physical activity. We assessed the AD plasma biomarkers phosphorylated tau 217 (ptau-217) and amyloid beta 42\/40 ratio (A{beta}42\/40) and the Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD), an algorithm that characterizes AD-like brain atrophy on brain MRI. We used linear regression to examine the association between LE8 and log transformed and standardized AD biomarker measures adjusting for age, sex, race, education, and kidney function.\n\nResultsCompared to ideal LE8, intermediate (67.9% of participants) and poor (12.6%) LE8 was associated with lower A{beta}42\/40 (adjusted mean difference: -2.37, 95% CI: -2.38 to -2.36 and -2.38, 95% CI: -2.40 to -2.36, respectively). There was no association between the LE8 group and ptau-217 level. Moreover, compared to ideal LE8 participants, those with poor LE8 had higher SPARE-AD atrophy pattern (adjusted mean difference: -0.71, 95% CI: -0.81 to -0.62).\n\nConclusionThese findings indicate that poor cardiovascular health in midlife, as defined by the AHA LE8, is linked to less favorable early AD biomarker profiles, particularly reflecting greater amyloid burden and structural brain changes.","rel_num_authors":5,"rel_authors":[{"author_name":"Christina Dintica","author_inst":"University of California, San Francisco"},{"author_name":"Xiaqing Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Leslie M Shaw","author_inst":"University of Pennsylvania"},{"author_name":"R. Nick Bryan","author_inst":"University of Pennsylvania"},{"author_name":"Kristine Yaffe","author_inst":"University of California San Francisco"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Diastolic Age: A Cardiac Biological Clock Derived from Echocardiography and the PREVENT Heart Failure Risk Score","rel_doi":"10.64898\/2026.04.15.26350995","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350995","rel_abs":"BackgroundAmong cardiac measures, diastolic parameters demonstrate the earliest and most consistent age-related changes. This can be leveraged to develop a continuous left ventricular (LV) Diastolic Age from routine echocardiographic parameters. Analogous to how epigenetic clocks weight molecular markers against mortality risk, we calibrated Diastolic Age by weighting echocardiographic features against the validated PREVENT-Heart Failure (HF) risk score.\n\nMethodsWe analyzed 1,952 participants from the Project Baseline Health Study (median age 50 [36-64] years, 54% female). The measure was derived using partial least-squares regression anchored on PREVENT-HF and calibrated within a healthy reference subgroup. External validation was performed in the WASE (n=1,708) and Stanford Cardiovascular Aging (n=313) cohorts. Associations with ASE-defined LV diastolic dysfunction (LVDD), epigenetic clocks, and major adverse cardiovascular events (MACE) were examined.\n\nResultsDiastolic Age correlated strongly with chronological age (r=0.78) with robust external validation (WASE r=0.76; Stanford r=0.82; calibration slopes {approx}1.0). It increased progressively across grades of diastolic dysfunction and discriminated LVDD with an AUC of 0.89 (95% CI 0.87-0.92), and was independently associated with hypertension, diabetes, and elevated C-reactive protein. While correlated with the Levine (r=0.76) and Horvath (r=0.41) epigenetic clocks, residual analyses indicated that Diastolic Age captures a distinct cardiac-specific dimension of biological aging. Over median follow-up of 4.2 years, it independently predicted MACE (HR 2.30, 95% CI 1.70-3.18), with accelerated diastolic aging across all age groups among those with events. Discrimination was comparable to ASE-defined LVDD (C-index 0.83 vs. 0.82).\n\nConclusionsDiastolic Age provides a continuous, echocardiography-derived measure of cardiac biological aging that complements categorical diastolic grading and epigenetic aging clocks, and independently predicts cardiovascular outcomes.","rel_num_authors":20,"rel_authors":[{"author_name":"Gracia Fahed","author_inst":"Stanford University Division of Cardiovascular Medicine"},{"author_name":"Nicholas Cauwenberghs","author_inst":"KU Leuven - University of Leuven"},{"author_name":"Everton Jose Santana","author_inst":"Katholieke Universiteit Leuven"},{"author_name":"Rongrong Chen","author_inst":"Stanford University; Zhangzhou Affiliated Hospital of Fujian Medical University"},{"author_name":"Bettia Edith Celestin","author_inst":"Stanford University"},{"author_name":"Bruna Filipa Gomes Botelho Quintas","author_inst":"Stanford University"},{"author_name":"Sarah Short","author_inst":"Verily"},{"author_name":"Megan Carroll","author_inst":"Verily Life Sciences"},{"author_name":"Tatsuya Miyoshi","author_inst":"MedStar Health Research Institute"},{"author_name":"Kevin Michael Alexander","author_inst":"Stanford University"},{"author_name":"Svati H. Shah","author_inst":"Duke Clinical Research Institute and Duke University Medical Center"},{"author_name":"Shai Shen Orr","author_inst":"Israel Institute of Technology Technion"},{"author_name":"Attila Kovacs","author_inst":"Gottsegen National Cardiovascular Center, Budapest, Hungary"},{"author_name":"Melissa A Daubert","author_inst":"Duke University Medical Center, Duke Clinical Research Institute"},{"author_name":"Tatiana Kuznetsova","author_inst":"University of Leuven"},{"author_name":"Karima Addetia","author_inst":"University of Chicago"},{"author_name":"Federico M. Asch","author_inst":"MedStar Health Research Institute"},{"author_name":"Kenneth W. Mahaffey","author_inst":"Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine"},{"author_name":"Pamela S. Douglas","author_inst":"Duke Clinical Research Institute, Duke University, Durham, NC"},{"author_name":"Francois Haddad","author_inst":"Stanford University"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Uncertainty Aware Decision Support with Computationally Expensive Simulation Models: A Case Study of HIV Intervention Scenarios","rel_doi":"10.64898\/2026.04.15.26350970","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350970","rel_abs":"Detailed agent-based simulations are increasingly used to support policy decisions, but their computational cost and complex uncertainty structure make systematic scenario analysis challenging. We present a data-driven, uncertainty-aware decision support (DDUADS) workflow for using stochastic simulation models as decision-support tools under limited computational budgets. The approach combines several established techniques--sensitivity screening, Bayesian calibration using simulation-based inference, and multi-surrogate model integration for translational efficiency--into a coherent pipeline that enables uncertainty-aware policy analysis. Rather than producing a single baseline, the calibration stage yields a posterior distribution over plausible model parameterizations, allowing flexible, uncertainty-aware forward projections. We demonstrate the DDUADS workflow on the INFORM-HIV agent-based model of HIV transmission in Chicago to evaluate potential disruptions in antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) use. While the specific application is HIV modeling, the challenges and techniques described here arise in other simulation studies and can be applied to decision support in other domains.","rel_num_authors":10,"rel_authors":[{"author_name":"arindam fadikar","author_inst":"Argonne National Laboratory"},{"author_name":"Anna Hotton","author_inst":"University of Chicago"},{"author_name":"Pedro Nascimento de Lima","author_inst":"Rand"},{"author_name":"Raffaele Vardavas","author_inst":"CausalPaths Analytics LLC"},{"author_name":"Nicholson Collier","author_inst":"Argonne National Laboratory"},{"author_name":"Kara Jia","author_inst":"Rand"},{"author_name":"Sara Rimer","author_inst":"Argonne National Laboratory"},{"author_name":"Aditya Khanna","author_inst":"Brown University"},{"author_name":"John Schneider","author_inst":"University of Chicago"},{"author_name":"Jonathan Ozik","author_inst":"Argonne National Laboratory"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Uncertainty Aware Decision Support with Computationally Expensive Simulation Models: A Case Study of HIV Intervention Scenarios","rel_doi":"10.64898\/2026.04.15.26350970","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350970","rel_abs":"Detailed agent-based simulations are increasingly used to support policy decisions, but their computational cost and complex uncertainty structure make systematic scenario analysis challenging. We present a data-driven, uncertainty-aware decision support (DDUADS) workflow for using stochastic simulation models as decision-support tools under limited computational budgets. The approach combines several established techniques--sensitivity screening, Bayesian calibration using simulation-based inference, and multi-surrogate model integration for translational efficiency--into a coherent pipeline that enables uncertainty-aware policy analysis. Rather than producing a single baseline, the calibration stage yields a posterior distribution over plausible model parameterizations, allowing flexible, uncertainty-aware forward projections. We demonstrate the DDUADS workflow on the INFORM-HIV agent-based model of HIV transmission in Chicago to evaluate potential disruptions in antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) use. While the specific application is HIV modeling, the challenges and techniques described here arise in other simulation studies and can be applied to decision support in other domains.","rel_num_authors":10,"rel_authors":[{"author_name":"arindam fadikar","author_inst":"Argonne National Laboratory"},{"author_name":"Anna Hotton","author_inst":"University of Chicago"},{"author_name":"Pedro Nascimento de Lima","author_inst":"Rand"},{"author_name":"Raffaele Vardavas","author_inst":"CausalPaths Analytics LLC"},{"author_name":"Nicholson Collier","author_inst":"Argonne National Laboratory"},{"author_name":"Kara Jia","author_inst":"Rand"},{"author_name":"Sara Rimer","author_inst":"Argonne National Laboratory"},{"author_name":"Aditya Khanna","author_inst":"Brown University"},{"author_name":"John Schneider","author_inst":"University of Chicago"},{"author_name":"Jonathan Ozik","author_inst":"Argonne National Laboratory"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Analysis Of Augmentation Techniques for Spine X-Ray Images","rel_doi":"10.64898\/2026.04.15.26350121","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.15.26350121","rel_abs":"Computer vision and deep learning techniques, including convolutional neural networks (CNNs) and transformers, have increased the performance of medical image classification systems. However, training deep learning models using medical images is a challenging task that necessitates a substantial amount of annotated data. In this paper, we implement data augmentation strategies to tackle dataset imbalance in the VinDr-SpineXR dataset, which has a lower number of spine abnormality X-ray images compared to normal spine X-ray images. Geometric transformations and synthetic image generation using Generative Adversarial Networks are explored and applied to the abnormal classes of the dataset, and classifier performance is validated using VGG-16 and InceptionNet to identify the most effective augmentation technique. Additionally, we introduce a hybrid augmentation technique that addresses class imbalance, reduces computational overhead relative to a GAN-only approach, and achieves [~]99% validation accuracy with both classifiers across all three case studies.","rel_num_authors":2,"rel_authors":[{"author_name":"Elakiya Sivakumar","author_inst":"Independent"},{"author_name":"Anjana Anand","author_inst":"Independent"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Association of coronary artery bypass with cognitive impairment in coronary artery disease across APO (\u03b5) genotypes in AllofUS","rel_doi":"10.64898\/2026.04.12.26350734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.12.26350734","rel_abs":"STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary artery bypass graft (CABG) is a widely performed procedure for coronary artery disease (CAD), yet its association with Impaired Cognition (IC), i.e., mild-cognitive impairment or all-cause dementia, while accounting for APO ({varepsilon}) genotype, remains unclear.\n\nMETHODSWe analyzed AllofUS participants with CAD (Age[&ge;]60 yrs) from 2017-2023. We defined CAD as a history of angina\/myocardial infarction\/chronic ischemic heart disease or having percutaneous coronary intervention\/CABG, and IC as mild cognitive impairment or all-cause dementia using ICD\/SNOMED codes. We performed logistic regression analyses to assess the association between CABG and IC, adjusting for clinical factors (age, sex, hypertension, diabetes, hyperlipidemia, depression, stroke, smoking, alcohol use, statin\/antihypertensive\/antidiabetic use), social determinants (self-reported race\/ethnicity, income, employment), and APO ({varepsilon}) genotypes. We further performed stratified analyses across APO ({varepsilon}) genotypes ({varepsilon}2\/{varepsilon}2, {varepsilon}2\/{varepsilon}3 {varepsilon}3\/{varepsilon}3, {varepsilon}2\/{varepsilon}4, {varepsilon}3\/{varepsilon}4, {varepsilon}4\/{varepsilon}4). We defined significance at p [&le;] 0.05.\n\nRESULTSWe included 22,349 with CAD and identified 908 with IC after CAD till 2023. 40% were females, 70% were White, 12% were Black, and 9% were Hispanic. The proportion of IC was higher (5.1% vs 3.5%, p=1e-08) in CABG (n=8,135) vs non-CABG (n=14,214). After adjusting for clinical factors, social determinants, and APO ({varepsilon}) genotypes, CABG (1.23;1.06-1.41, p = 0.005) was associated with IC. In APO ({varepsilon}) stratified analysis, the association of CABG with IC was strongest in the APO {varepsilon}2\/{varepsilon}3 group (1.91;1.21-3.02, p = 0.005).\n\nCONCLUSIONIn the AllofUS cohort, we observed an association between CABG and IC in CAD participants, with the strongest association in the APO {varepsilon}2\/{varepsilon}3 group.\n\nKey MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment and all-cause dementia, share genetic, sociodemographic, and clinical factors, including cardiovascular conditions like coronary artery bypass grafting (CABG) procedure.\n\nWhat this study addsWe observed an association between CABG and IC in CAD participants after adjusting for sociodemographic, clinical factors, and APO ({varepsilon}) effects. Further, when CAD participants were stratified across APO ({varepsilon}) groups, CABG was significantly associated with IC in the APO {varepsilon}2\/{varepsilon}3 group.\n\nHow this study might affect research, practice or policyOur observations highlight the role of APO ({varepsilon}) genotype evaluation in CAD patients for IC risk assessment.","rel_num_authors":7,"rel_authors":[{"author_name":"Praveen Hariharan","author_inst":"Brown university"},{"author_name":"Minoo Bagheri","author_inst":"Vanderbilt University"},{"author_name":"Emeliah Asamoah","author_inst":"Morgan State University School of Community Health and Policy"},{"author_name":"Ioana Voiculescu","author_inst":"City College of New York"},{"author_name":"Purnima Singh","author_inst":"University of Tennessee, Memphis"},{"author_name":"Tafadzwa Machipisa","author_inst":"University of Pennsylvania"},{"author_name":"Tess D Pottinger","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Association of coronary artery bypass with cognitive impairment in coronary artery disease across APO (\u03b5) genotypes in AllofUS","rel_doi":"10.64898\/2026.04.12.26350734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.12.26350734","rel_abs":"STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary artery bypass graft (CABG) is a widely performed procedure for coronary artery disease (CAD), yet its association with Impaired Cognition (IC), i.e., mild-cognitive impairment or all-cause dementia, while accounting for APO ({varepsilon}) genotype, remains unclear.\n\nMETHODSWe analyzed AllofUS participants with CAD (Age[&ge;]60 yrs) from 2017-2023. We defined CAD as a history of angina\/myocardial infarction\/chronic ischemic heart disease or having percutaneous coronary intervention\/CABG, and IC as mild cognitive impairment or all-cause dementia using ICD\/SNOMED codes. We performed logistic regression analyses to assess the association between CABG and IC, adjusting for clinical factors (age, sex, hypertension, diabetes, hyperlipidemia, depression, stroke, smoking, alcohol use, statin\/antihypertensive\/antidiabetic use), social determinants (self-reported race\/ethnicity, income, employment), and APO ({varepsilon}) genotypes. We further performed stratified analyses across APO ({varepsilon}) genotypes ({varepsilon}2\/{varepsilon}2, {varepsilon}2\/{varepsilon}3 {varepsilon}3\/{varepsilon}3, {varepsilon}2\/{varepsilon}4, {varepsilon}3\/{varepsilon}4, {varepsilon}4\/{varepsilon}4). We defined significance at p [&le;] 0.05.\n\nRESULTSWe included 22,349 with CAD and identified 908 with IC after CAD till 2023. 40% were females, 70% were White, 12% were Black, and 9% were Hispanic. The proportion of IC was higher (5.1% vs 3.5%, p=1e-08) in CABG (n=8,135) vs non-CABG (n=14,214). After adjusting for clinical factors, social determinants, and APO ({varepsilon}) genotypes, CABG (1.23;1.06-1.41, p = 0.005) was associated with IC. In APO ({varepsilon}) stratified analysis, the association of CABG with IC was strongest in the APO {varepsilon}2\/{varepsilon}3 group (1.91;1.21-3.02, p = 0.005).\n\nCONCLUSIONIn the AllofUS cohort, we observed an association between CABG and IC in CAD participants, with the strongest association in the APO {varepsilon}2\/{varepsilon}3 group.\n\nKey MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment and all-cause dementia, share genetic, sociodemographic, and clinical factors, including cardiovascular conditions like coronary artery bypass grafting (CABG) procedure.\n\nWhat this study addsWe observed an association between CABG and IC in CAD participants after adjusting for sociodemographic, clinical factors, and APO ({varepsilon}) effects. Further, when CAD participants were stratified across APO ({varepsilon}) groups, CABG was significantly associated with IC in the APO {varepsilon}2\/{varepsilon}3 group.\n\nHow this study might affect research, practice or policyOur observations highlight the role of APO ({varepsilon}) genotype evaluation in CAD patients for IC risk assessment.","rel_num_authors":7,"rel_authors":[{"author_name":"Praveen Hariharan","author_inst":"Brown university"},{"author_name":"Minoo Bagheri","author_inst":"Vanderbilt University"},{"author_name":"Emeliah Asamoah","author_inst":"Morgan State University School of Community Health and Policy"},{"author_name":"Ioana Voiculescu","author_inst":"City College of New York"},{"author_name":"Purnima Singh","author_inst":"University of Tennessee, Memphis"},{"author_name":"Tafadzwa Machipisa","author_inst":"University of Pennsylvania"},{"author_name":"Tess D Pottinger","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Association of coronary artery bypass with cognitive impairment in coronary artery disease across APO (\u03b5) genotypes in AllofUS","rel_doi":"10.64898\/2026.04.12.26350734","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.12.26350734","rel_abs":"STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary artery bypass graft (CABG) is a widely performed procedure for coronary artery disease (CAD), yet its association with Impaired Cognition (IC), i.e., mild-cognitive impairment or all-cause dementia, while accounting for APO ({varepsilon}) genotype, remains unclear.\n\nMETHODSWe analyzed AllofUS participants with CAD (Age[&ge;]60 yrs) from 2017-2023. We defined CAD as a history of angina\/myocardial infarction\/chronic ischemic heart disease or having percutaneous coronary intervention\/CABG, and IC as mild cognitive impairment or all-cause dementia using ICD\/SNOMED codes. We performed logistic regression analyses to assess the association between CABG and IC, adjusting for clinical factors (age, sex, hypertension, diabetes, hyperlipidemia, depression, stroke, smoking, alcohol use, statin\/antihypertensive\/antidiabetic use), social determinants (self-reported race\/ethnicity, income, employment), and APO ({varepsilon}) genotypes. We further performed stratified analyses across APO ({varepsilon}) genotypes ({varepsilon}2\/{varepsilon}2, {varepsilon}2\/{varepsilon}3 {varepsilon}3\/{varepsilon}3, {varepsilon}2\/{varepsilon}4, {varepsilon}3\/{varepsilon}4, {varepsilon}4\/{varepsilon}4). We defined significance at p [&le;] 0.05.\n\nRESULTSWe included 22,349 with CAD and identified 908 with IC after CAD till 2023. 40% were females, 70% were White, 12% were Black, and 9% were Hispanic. The proportion of IC was higher (5.1% vs 3.5%, p=1e-08) in CABG (n=8,135) vs non-CABG (n=14,214). After adjusting for clinical factors, social determinants, and APO ({varepsilon}) genotypes, CABG (1.23;1.06-1.41, p = 0.005) was associated with IC. In APO ({varepsilon}) stratified analysis, the association of CABG with IC was strongest in the APO {varepsilon}2\/{varepsilon}3 group (1.91;1.21-3.02, p = 0.005).\n\nCONCLUSIONIn the AllofUS cohort, we observed an association between CABG and IC in CAD participants, with the strongest association in the APO {varepsilon}2\/{varepsilon}3 group.\n\nKey MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment and all-cause dementia, share genetic, sociodemographic, and clinical factors, including cardiovascular conditions like coronary artery bypass grafting (CABG) procedure.\n\nWhat this study addsWe observed an association between CABG and IC in CAD participants after adjusting for sociodemographic, clinical factors, and APO ({varepsilon}) effects. Further, when CAD participants were stratified across APO ({varepsilon}) groups, CABG was significantly associated with IC in the APO {varepsilon}2\/{varepsilon}3 group.\n\nHow this study might affect research, practice or policyOur observations highlight the role of APO ({varepsilon}) genotype evaluation in CAD patients for IC risk assessment.","rel_num_authors":7,"rel_authors":[{"author_name":"Praveen Hariharan","author_inst":"Brown university"},{"author_name":"Minoo Bagheri","author_inst":"Vanderbilt University"},{"author_name":"Emeliah Asamoah","author_inst":"Morgan State University School of Community Health and Policy"},{"author_name":"Ioana Voiculescu","author_inst":"City College of New York"},{"author_name":"Purnima Singh","author_inst":"University of Tennessee, Memphis"},{"author_name":"Tafadzwa Machipisa","author_inst":"University of Pennsylvania"},{"author_name":"Tess D Pottinger","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"Leveraging State-of-the-Art LLMs for the De-identification of Sensitive Health Information in Clinical Speech","rel_doi":"10.64898\/2026.04.13.26349911","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.13.26349911","rel_abs":"Accurate recognition and deidentification of sensitive health information (SHI) in spoken dialogues requires multimodal algorithms that can understand medical language and contextual nuance. However, the recognition and deidentification risks expose sensitive health information (SHI). Additionally, the variability and complexity of medical terminology, along with the inherent biases in medical datasets, further complicate this task. This study introduces the SREDH\/AI-Cup 2025 Medical Speech Sensitive Information Recognition Challenge, which focuses on two tasks: Task-1: Speech transcription systems must accurately transcribe speech into text; and Task-2: Medical speech de-identification to detect and appropriately classify mentions of SHI. The competition attracted 246 teams; top-performing systems achieved a mixed error rate (MER) of 0.1147 and a macro F1-score of 0.7103, with average MER and macro F1-score of 0.3539 and 0.2696, respectively. Results were presented at the IW-DMRN workshop in 2025. Notably, the results reveal that LLMs were prevalent across both tasks: 97.5% of teams adopted LLMs for Task 1 and 100% for Task 2. Highlighting their growing role in healthcare. Furthermore, we finetuned six models, demonstrating strong precision ([~]0.885-0.889) with slightly lower recall ([~]0.830-0.847), resulting in F1-scores of 0.857-0.867.","rel_num_authors":14,"rel_authors":[{"author_name":"Hong-Jie Dai","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Tatheer Hussain Mir","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Liang-Chun Fang","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Ching-Tai Chen","author_inst":"Machine Learning and Bioinformatics Lab, Department of Computer Science, University of Taipei, Taipei, Taiwan"},{"author_name":"Hui-Hsien Feng","author_inst":"Department of English, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan"},{"author_name":"Jiunn-Ru Lai","author_inst":"Wireless Networking and Mobile Computing Research Lab, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Ka"},{"author_name":"Hsieh-Chih Hsu","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Pratham Nandy","author_inst":"CGD Health Pvt. Ltd. Mumbai, India"},{"author_name":"Omkar Panchal","author_inst":"CGD Health Pvt. Ltd. Mumbai, India"},{"author_name":"Wei-Hsiang Liao","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"You-Zhen Tien","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Pin-Zhen Chen","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Yun-Ru Lin","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Jitendra Jonnagaddala","author_inst":"UNSW Sydney"}],"rel_date":"2026-04-17","rel_site":"medrxiv"},{"rel_title":"In silico structural analysis of EthA substitutions for ranking priority mutations leading to ethionamide resistance in Mycobacterium tuberculosis","rel_doi":"10.64898\/2026.04.16.718980","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.718980","rel_abs":"Background: Tuberculosis (TB) is the second-leading cause of deaths from infectious agents and remains a global health threat. Ethionamide (ETH) is a prodrug used in regimens for multidrug-resistant TB, and, partly due to side effects that can lead to low treatment adhesion, resistance arises. Changes in EthA, the monooxygenase that activates ETH, are the main mechanism of resistance. Yet, of hundreds of EthA substitutions found in resistant isolates, only a handful have been annotated as resistance determinants. Results: An in silico analysis was carried out on a previously described panel of Mycobacterium tuberculosis clinical isolates for which genomes and ETH susceptibility testing results were available. EthA substitutions were mapped, revealing the existence of hotspots in its sequence. Visualization of the hotspots in the EthA structural model shows that they cluster in three regions, including ligand binding pockets. Models were built of twenty-three variants found in resistant isolates and changes in local configuration was mapped to identify investigate impact on ETH activation. Information from these models contributed to establishing five criteria for scoring whether substitutions are most likely to lead to resistance. Using these criteria, EthA D58G was selected and its expression is shown to increase growth in high ETH concentrations. Conclusion: Functionally relevant regions of EthA are revealed and point out priority substitutions for functional studies, enhancing identification and detection of substitutions not been previously associated with resistance.","rel_num_authors":7,"rel_authors":[{"author_name":"Rodrigo Fernandes Machado","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Sophia Lincoln Cardoso","author_inst":"Universidade de Sao Paulo"},{"author_name":"Isabela Cordeiro Pinheiro","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Jesus Paes Ramos","author_inst":"ENSP-Fiocruz"},{"author_name":"Caetano Antunes","author_inst":"The University of Kansas"},{"author_name":"Priscila Capriles","author_inst":"Universidade Federal de Juiz de Fora"},{"author_name":"Teca C Galvao","author_inst":"Instituto Oswaldo Cruz"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Functional Genomics Reveals TNT Bioremediation Strategies in Pantoea sp. MT58 and Pseudomonas putida KT2440","rel_doi":"10.64898\/2026.04.16.711451","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.711451","rel_abs":"2,4,6-Trinitrotoluene (TNT) is a recalcitrant and pervasive environmental pollutant. Although different environmental microbes have demonstrated their ability to degrade or transform TNT, the underlying genetic basis and cellular machinery remain unclear. In this study, we investigated bacterial strategies in response to TNT exposure in Pantoea sp. MT58 and P. putida KT2440 using proteomics and random barcode transposon-site sequencing (RB-TnSeq). Pantoea sp. MT58 was found to utilize TNT as a sole nitrogen source, whereas P. putida KT2440 exhibited only stress tolerance without assimilation. Pantoea sp. MT58 encodes multiple putative nitroreductases that were upregulated, yet deletion of these genes did not affect growth on TNT, revealing pathway redundancy. Furthermore, fitness profiling provided no evidence for genes involved in the canonical Meisenheimer-complex pathway associated with nitrite release. Instead, the data are most consistent with a sequential nitro-group reduction route in which nitrogen is ultimately recovered as ammonium, with nitrogen routed through the GS-GOGAT pathway with purine and urea pools as the candidate buffering architecture for TNT mineralization. Conversely, P. putida KT2440 relied on Ttg\/RND efflux pumps and toluene tolerance proteins for survival without nitrogen assimilation from TNT. This work distinguishes routes for productive nitrogen assimilation from those involved in nitroaromatic tolerance, expanding the mechanistic understanding of anthropogenic compound metabolism to inform future bioremediation efforts.","rel_num_authors":11,"rel_authors":[{"author_name":"Li-Wen (Audrey) Wang","author_inst":"University of California, Berkeley"},{"author_name":"Thomas Eng","author_inst":"Lawrence Berkeley National Lab"},{"author_name":"Alex Rivier","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Saad Naseem","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Alex Codik","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Yan Chen","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Aparajitha Srinivasan","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Christopher J Petzold","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Kara L Nelson","author_inst":"University of California, Berkeley"},{"author_name":"Adam M. Deutschbauer","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Aindrila Mukhopadhyay","author_inst":"Lawrence Berkeley National Laboratory"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Redox-Triggered Coupling Network Mediates Long-Range Energy Trans-duction in Respiratory Complex I","rel_doi":"10.64898\/2026.04.14.716442","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.716442","rel_abs":"Complex I is a gigantic redox-driven proton pump that powers oxidative phosphorylation by a unique long-range (>200 [A]) proton-coupled electron transfer process. To elucidate the molecular principles underlying this intricate action-at-a-distance effect, we combine here multiscale quantum\/classical (QM\/MM) simulations with site-directed mutagenesis, proteoliposome experiments, and cryo-electron microscopy (cryo-EM). We find that quinol binding at a distinct site within a local membrane cavity, triggers a long-range protonation cascade over water-mediated proton wires along a conserved carboxylate pathway (E-channel). We identify a central mechanical switch point, comprising the conserved Tyr156H, the mutation of which impedes conformational changes along conserved loops, but not the proton transfer reaction itself. Using our integrative multi-disciplinary approach, we reveal central coupling sites along the redox-driven proton transport process mediating energy conversion in Complex I, and illustrate the power of theory-guided experiments.","rel_num_authors":9,"rel_authors":[{"author_name":"Niklas Hoja","author_inst":"Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden."},{"author_name":"Jonas Hentschel","author_inst":"Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Germany"},{"author_name":"Hyunho Kim","author_inst":"Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden."},{"author_name":"Thilo Seifermann","author_inst":"Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Germany"},{"author_name":"Adel Beghiah","author_inst":"Department of Biochemistry and Biophysics, Stockholm University, 10691, Stockholm, Sweden."},{"author_name":"Tim Schlosser","author_inst":"Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Germany"},{"author_name":"Patricia Saura","author_inst":"Stockholm University"},{"author_name":"Thorsten Friedrich","author_inst":"Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Germany"},{"author_name":"Ville R. I. Kaila","author_inst":"Stockholm University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Host background shapes the portability of a non-canonical translation initiation system across Escherichia coli strains","rel_doi":"10.64898\/2026.04.16.719103","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.16.719103","rel_abs":"Translation initiation has become an attractive target for engineering orthogonal translation systems, yet the extent to which these systems retain functionality across distinct host backgrounds remains poorly defined. In bacteria, start codon recognition depends on pairing between the initiator tRNA anticodon and a suitable start codon within the appropriate distance from the Shine-Dalgarno sequence. These sequence-specific interactions enable translation initiation to be reprogrammed through anticodon engineering. What is currently missing is an understanding of how anticodon mutants of initiator tRNAs function across different bacterial strains. Here, we systematically evaluated the portability of a library of twelve i-tRNA anticodon mutants paired with their complementary non-canonical start codons. Most i-tRNA-start codon pairs supported detectable translation initiation across multiple strains, demonstrating broad functional portability. However, initiation efficiency, absolute system output, and fitness effects varied substantially between strains. Comparative genomic analyses revealed host-specific gene differences broadly, and endogenous tRNA gene sequence and copy number specifically, was associated with this variability. While most i-tRNA variants were well tolerated, a subset produced strain-dependent growth defects that primarily affected growth rate rather than final culture density. Together, these findings show that translation initiation efficacy of engineered i-tRNAs is partially strain-dependent and that host background must be considered a key design variable when deploying these translation systems. Looking forward, this study provides a framework for host-aware selection of microbial chassis for orthogonal translation applications in synthetic biology.","rel_num_authors":3,"rel_authors":[{"author_name":"Dominic Scopelliti","author_inst":"Washington University in St. Louis"},{"author_name":"Andras Hutvagner","author_inst":"Macquarie University"},{"author_name":"Paul R Jaschke","author_inst":"Macquarie University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Robust MR-AIV: A Systematic Study of Robustness Improvement and Sensitivity Analysis of MR-AIV","rel_doi":"10.64898\/2026.04.14.718498","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718498","rel_abs":"AO_SCPLOWBSTRACTC_SCPLOWCerebrospinal and interstitial fluid transport play a central role in brain metabolic waste clearance, yet non-invasive quantification of deep-brain flow dynamics remains challenging. Magnetic Resonance Artificial Intelligence Velocimetry (MR-AIV) is a physics-informed neural network framework that infers three-dimensional velocity, pressure, and permeability fields from dynamic contrastenhanced MRI by embedding porous-media flow physics into the learning process. Here, we present a methodological refinement and systematic evaluation of MR-AIV. We introduce a universal, anatomically informed, region-of-interest-based permeability initialization that improves anatomical alignment and physical consistency across subjects. We quantify the sensitivity of inferred fields to key modelling choices, including initialization strategies, permeability bounds, diffusivity assumptions, signal-concentration relationships, and measurement noise. Across these conditions, MR-AIV yields stable velocity and permeability estimates with preserved spatial structure. Together, these results establish practical guidelines and identify stable operating regimes for reliable deployment of MR-AIV. By improving robustness and reproducibility, this work strengthens MR-AIV as a minimally invasive approach for mapping brain-wide porous fluid transport and supports its application to studies of neurological health and disease.","rel_num_authors":7,"rel_authors":[{"author_name":"Mohammad Vaezi","author_inst":"Department of Mechanical Engineering, University of Rochester, Rochester, 14627, NY, USA"},{"author_name":"Juan Diego Toscano","author_inst":"Division of Applied Mathematics, Brown University, Providence, 02912, RI, USA"},{"author_name":"Yisen Guo","author_inst":"Department of Mechanical Engineering, University of Rochester, Rochester, 14627, NY, USA"},{"author_name":"Ryszard Stefan Gomolka","author_inst":"Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen N, Denmark"},{"author_name":"George Em. Karniadakis","author_inst":"Division of Applied Mathematics, Brown University, Providence, 02912, RI, USA"},{"author_name":"Douglas H. Kelley","author_inst":"Department of Mechanical Engineering, University of Rochester, Rochester, 14627, NY, USA"},{"author_name":"Kimberly A. S. Boster","author_inst":"Department of Mechanical Engineering, University of Rochester, Rochester, 14627, NY, USA"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Reduced flexibility in predictive tuning and contextual adaptation in autism: an EEG and behavioral study.","rel_doi":"10.64898\/2026.04.14.718519","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718519","rel_abs":"The brain generates predictions to prepare for upcoming events. Because the environment is not perfectly predictable, the brain also estimates the certainty of these predictions and adjusts preparatory processes accordingly. Given that autistic individuals often resist even small changes to everyday routines, we hypothesized altered tuning of prediction certainty in autism. To test this, EEG was recorded from adolescents and young autistic adults (n = 20) and from age- and IQ-matched non-autistic adults (n = 19) during a probabilistic cued target identification task during which cue validity was systematically varied across four levels: 100%, 84%, 67%, and 33%. Participants were not informed of the cue-target validity nor when it changed. We focused on two neural signatures of anticipatory readiness, contingent negative variation (CNV) and alpha-band event-related desynchronization (-ERD), and one of cognitive updating: the P3 to targets and to invalid (e.g., a non-target in place of the target) stimuli. Across groups, preparatory activity increased as contextual certainty decreased, with larger CNV amplitudes and stronger -ERD preceding targets in lower-probability contexts, suggesting enhanced preparatory engagement under greater uncertainty. Furthermore, larger CNV amplitudes predicted faster reaction times, indicating functionally significant anticipatory dynamics. However, modulation of both neural preparation and response times as a function of cue-target probability was significantly reduced in the autistic group. In addition, autistic participants showed diminished probability-dependent modulation of the P3b to both targets and invalid stimuli, and coupling between anticipatory activity (CNV) and subsequent updating (P3b) was observed in non-autistic participants whereas it was absent in autism. Together, these findings suggest that while predictive mechanisms are present in autism, anticipatory processes are less flexibly tuned to contextual uncertainty and less effectively linked to subsequent cognitive updating. This reduced adaptability may reflect difficulty adjusting internal predictive models to changing environmental contingencies, potentially contributing to core features of autism such as resistance to change and insistence on sameness.","rel_num_authors":5,"rel_authors":[{"author_name":"Theo Vanneau","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Seydanur Reisli","author_inst":"Bristol Myers Squibb"},{"author_name":"Chloe Brittenham","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Michael J Crosse","author_inst":"SEGOTIA"},{"author_name":"Sophie Molholm","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"An Endocytic Checkpoint Controls Macrophage PD-1 Function and Immunotherapy Fate","rel_doi":"10.64898\/2026.04.14.718292","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718292","rel_abs":"Responses to PD1 blockade span durable tumor control to hyperprogressive disease (HPD), yet innate immune mechanisms governing these extremes remain undefined. Here we integrate a macrophage systems atlas (>12,500 transcriptomes) with single-cell profiles from >1,000 anti PD1 treated patients, to identify CCDC88A (GIV) as a macrophage-intrinsic determinant of durable response versus HPD. GIV loss increases PD1 surface retention, suppresses phagocytosis, and accelerates tumor growth across murine models, human macrophages, and patient-derived organoids. Myeloid-specific GIV deletion converts PD1 blockade from tumor-restraining to tumor-accelerating by reprogramming macrophages toward HPD-like states. Mechanistically, GIV engages a conserved TIR-like [TILL] motif within the PD1 cytoplasmic tail to drive dynamin-dependent endocytosis, coupling innate immune signaling logic to checkpoint receptor trafficking. Pharmacologic disruption of this axis phenocopies GIV loss, revealing an endocytic vulnerability that undermines checkpoint efficacy and triggers accelerated growth at relapse. These findings define PD1 routing, rather than ligand-binding, as a macrophage-encoded checkpoint governing antitumor immunity.","rel_num_authors":13,"rel_authors":[{"author_name":"Madhubanti Mullick","author_inst":"University of California, San Diego"},{"author_name":"Ella McLaren","author_inst":"University of California, San Diego"},{"author_name":"Suchismita Roy","author_inst":"University of California, San Diego"},{"author_name":"Brandon Biagas","author_inst":"University of California, San Diego"},{"author_name":"Mahitha Shree Anandachar","author_inst":"University of California, San Diego"},{"author_name":"Vanessa Castillo","author_inst":"University of California, San Diego"},{"author_name":"Samuel Williams","author_inst":"University of California, San Diego"},{"author_name":"Celia R. Espinoza","author_inst":"University of California, San Diego"},{"author_name":"Courtney Tindle","author_inst":"University of California, San Diego"},{"author_name":"Gajanan D. Katkar","author_inst":"University of California, San Diego"},{"author_name":"Patricia A. Thistlethwaite","author_inst":"University of California, San Diego"},{"author_name":"Saptarshi Sinha","author_inst":"University of California, San Diego"},{"author_name":"Pradipta Ghosh","author_inst":"University of California, San Diego"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Multiomic screening platform uncovers the impact of histone mutations on chromatin and cell fate","rel_doi":"10.64898\/2026.04.14.718582","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718582","rel_abs":"Somatic missense mutations in histone genes, often referred to as  oncohistones, have been identified in diverse types of human cancers. The functional and mechanistic impact of most oncohistones remains unknown. To address this gap, we developed CHANCLA, a modular platform for high-throughput functional screening of oncohistones using multiomic phenotypic readouts. We used CHANCLA to systematically measure the impact of 303 human oncohistones on cellular proliferation, differentiation, histone-specific post-translational modifications, and chromatin accessibility. Integrative multiomic analyses revealed discrete oncohistone molecular classes that promote proliferation, block lineage-specific differentiation, and physically remodel the chromatin landscape by altering specific histone modifications and reducing nucleosome stability. Structural mapping and computational modeling studies uncovered that functionally convergent mutations are clustered at key nucleosome interfaces, particularly H2B-H4, and that chromatin accessibility-promoting mutations are linked to mono-nucleosome destabilization. Leveraging this multiomic resource, we discovered that the H3.3-Q5H mutant histone is a bona fide human oncohistone that accelerates lung adenocarcinoma growth in vivo. Mechanistically, we found that H3.3-Q5H expression leads to suppression of promoter-associated H3K4me3 and expansion of repressive H3K27me3 domains, resulting in increased KRAS signaling and gene expression programs associated with epithelial-to-mesenchymal transition. Together, this work provides a multiomic functional atlas of cancer-associated histone mutations, identifies structural and mechanistic principles governing chromatin reprogramming by oncohistones, and establishes CHANCLA as a modular platform for systematic discovery of mechanisms and vulnerabilities associated with these genetic lesions.","rel_num_authors":14,"rel_authors":[{"author_name":"Ziyang Ye","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Alireza Khademi","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Ren\u00e9e L. Barbosa","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Foster Birnbaum","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Margaret R. Brown","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Colin E. Fowler","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Arianna Arroyo-Ortega","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Daniel Lee","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Lijuan Feng","author_inst":"WashU Medicine"},{"author_name":"Leah A. Gates","author_inst":"Case Western Reserve University"},{"author_name":"Agata L. Patriotis","author_inst":"Massachussets Institute of Technology"},{"author_name":"Amy E. Keating","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Francisco J. S\u00e1nchez-Rivera","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Yadira M. Soto-Feliciano","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Multiomic screening platform uncovers the impact of histone mutations on chromatin and cell fate","rel_doi":"10.64898\/2026.04.14.718582","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718582","rel_abs":"Somatic missense mutations in histone genes, often referred to as  oncohistones, have been identified in diverse types of human cancers. The functional and mechanistic impact of most oncohistones remains unknown. To address this gap, we developed CHANCLA, a modular platform for high-throughput functional screening of oncohistones using multiomic phenotypic readouts. We used CHANCLA to systematically measure the impact of 303 human oncohistones on cellular proliferation, differentiation, histone-specific post-translational modifications, and chromatin accessibility. Integrative multiomic analyses revealed discrete oncohistone molecular classes that promote proliferation, block lineage-specific differentiation, and physically remodel the chromatin landscape by altering specific histone modifications and reducing nucleosome stability. Structural mapping and computational modeling studies uncovered that functionally convergent mutations are clustered at key nucleosome interfaces, particularly H2B-H4, and that chromatin accessibility-promoting mutations are linked to mono-nucleosome destabilization. Leveraging this multiomic resource, we discovered that the H3.3-Q5H mutant histone is a bona fide human oncohistone that accelerates lung adenocarcinoma growth in vivo. Mechanistically, we found that H3.3-Q5H expression leads to suppression of promoter-associated H3K4me3 and expansion of repressive H3K27me3 domains, resulting in increased KRAS signaling and gene expression programs associated with epithelial-to-mesenchymal transition. Together, this work provides a multiomic functional atlas of cancer-associated histone mutations, identifies structural and mechanistic principles governing chromatin reprogramming by oncohistones, and establishes CHANCLA as a modular platform for systematic discovery of mechanisms and vulnerabilities associated with these genetic lesions.","rel_num_authors":14,"rel_authors":[{"author_name":"Ziyang Ye","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Alireza Khademi","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Ren\u00e9e L. Barbosa","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Foster Birnbaum","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Margaret R. Brown","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Colin E. Fowler","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Arianna Arroyo-Ortega","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Daniel Lee","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Lijuan Feng","author_inst":"WashU Medicine"},{"author_name":"Leah A. Gates","author_inst":"Case Western Reserve University"},{"author_name":"Agata L. Patriotis","author_inst":"Massachussets Institute of Technology"},{"author_name":"Amy E. Keating","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Francisco J. S\u00e1nchez-Rivera","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Yadira M. Soto-Feliciano","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Metabolic Salvage and Acyl-chain Remodeling Support Glycosphingolipid Synthesis with the PDAC Tumor Microenvironment","rel_doi":"10.64898\/2026.04.14.718544","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718544","rel_abs":"Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy where metabolic homeostasis is maintained by tumor and stromal cells within the tumor microenvironment (TME). To better assess pathways supporting macromolecule biosynthesis in PDAC tumors, we apply 13C metabolic flux analysis (MFA) to slice cultures of treatment-naive human tumors and mouse models that retain the native TME. Glycans, lipid headgroups, and very long-chain fatty acids are the most dynamic metabolic pools, while long chain fatty acids, purines, and pyrimidines are predominantly salvaged locally in situ. We use targeted pharmacological modulators to highlight the importance of recycling pathways and metabolic redundancies which mitigate changes in lipid abundances. Finally, we leverage targeted lipid fluxomics and the distinct ganglioside and globoside profiles of tumor and stromal cells, respectively, to demonstrate the role of the lipid kinase PIKfyve in supporting ganglioside homeostasis via sialic acid and ceramide salvage. These data establish application of MFA to slice cultures of PDAC tumors as an effective approach for assessing metabolic mechanisms and therapeutic responses within an intact TME.","rel_num_authors":14,"rel_authors":[{"author_name":"Anna S Trimble","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Casie S Kubota","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Elaine Zhao","author_inst":"University of California San Diego"},{"author_name":"Maureen L Ruchhoeft","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Jonathan R Weitz","author_inst":"Moores Cancer Center, UC San Diego"},{"author_name":"Woncheol Jung","author_inst":"Stephenson Cancer Center, University of Oklahoma Health"},{"author_name":"Kristina L Peck","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Satoshi Ogawa","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Ethan L Ashley","author_inst":"University of California San Diego"},{"author_name":"Herv\u00e9 Tiriac","author_inst":"Moores Cancer Center, UCSD"},{"author_name":"Tae Gyu Oh","author_inst":"Stephenson Cancer Center, University of Oklahoma Health"},{"author_name":"Andrew M Lowy","author_inst":"Moores Cancer Center, UCSD"},{"author_name":"Dannielle D Engle","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Christian M Metallo","author_inst":"The Salk Institute for Biological Studies"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Virtual multiplex staining of the pancreatic islets across type 1 diabetes progression using a Schroedinger bridge","rel_doi":"10.64898\/2026.04.14.718559","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718559","rel_abs":"Classical hematoxylin and eosin (H&E) staining enables review of tissue morphology but lacks information regarding the molecular state of cells. Immunohistochemical (IHC) techniques label specific proteins in tissue, allowing differentiation of relevant structures that may go undetectable in H&E. However, the IHC process is complex, expensive, and time-consuming, especially for multiplex IHC (mIHC) limiting its use in large cohorts. Stain conversion of H&E to IHC using generative artificial intelligence models such as generative adversarial networks (GANs) represent one solution to this problem. However, GANs are unstable during out of distribution sampling and are prone to hallucinations or mode collapse, limiting their accuracy in challenging image conversion tasks. To address this, the field has recently turned to diffusion models. Here, we introduce Schrodinger-bridge for Multiplex ImmunoLabel Estimation (SMILE). Unlike conventional diffusion models that map from source to target through an intermediate Gaussian noise, Schrodinger-bridge diffusion models skip this step and have been shown to better preserve structures during image translation.\n\nTo test the performance of SMILE, we generated a large cohort of high-fidelity H&E-mIHC image pairs from pancreatic organ donors, targeting insulin, glucagon, and CD3. Our dataset well-sampled across type-1 diabetes status, pancreas anatomical location, age, and sex. Using this cohort, we demonstrate the superiority of SMILE compared to GANs via a comprehensive evaluation framework incorporating texture, distribution, and antibody-specific metrics, as well as blinded pathologist reviews. We further confirmed the ability of SMILE to generate accurate mIHC images from H&Es generated at an external site, to perform whole slide image conversion, and to generate realistic three-dimensional maps of the pancreatic islets in non-diabetic, auto-antibody positive, and type-1 diabetic donor tissue. Finally, we performed stain conversion of paired H&E to HER2 and Ki67 images in breast cancer, confirming the superiority of SMILE in diverse stain conversion applications. Collectively, this framework provides a scalable pipeline for high-throughput proteomic inference from archival H&Es, providing transformative potential for pancreatic research and digital pathology.","rel_num_authors":22,"rel_authors":[{"author_name":"Yu Shen","author_inst":"Johns Hopkins University"},{"author_name":"Won June Cho","author_inst":"Johns Hopkins University"},{"author_name":"Saurabh Joshi","author_inst":"Johns Hopkins University"},{"author_name":"Benjamin Wen","author_inst":"Johns Hopkins University"},{"author_name":"Swarnagouri Naganathanhalli","author_inst":"Johns Hopkins University"},{"author_name":"Maria Beery","author_inst":"University of Florida"},{"author_name":"Casey R Grubel","author_inst":"University of Florida"},{"author_name":"Arrun Sivasubramanian","author_inst":"Johns Hopkins University"},{"author_name":"Andr\u00e9 Forjaz","author_inst":"Johns Hopkins University"},{"author_name":"Mia P Grahn","author_inst":"Johns Hopkins University"},{"author_name":"Lucie Dequiedt","author_inst":"Johns Hopkins University"},{"author_name":"Yichen Huang","author_inst":"Johns Hopkins University"},{"author_name":"Kyu Sang Han","author_inst":"Johns Hopkins University"},{"author_name":"Fan Wu","author_inst":"Johns Hopkins University"},{"author_name":"Brian A Pedro","author_inst":"Johns Hopkins University"},{"author_name":"Laura D Wood","author_inst":"Johns Hopkins University"},{"author_name":"Tiane Chen","author_inst":"Johns Hopkins University"},{"author_name":"Ralph H Hruban","author_inst":"Johns Hopkins University"},{"author_name":"Irina Kusmartseva","author_inst":"University of Florida"},{"author_name":"Mark A Atkinson","author_inst":"University of Florida"},{"author_name":"Denis Wirtz","author_inst":"Johns Hopkins University"},{"author_name":"Ashley L Kiemen","author_inst":"Johns Hopkins University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Coordinate-Based fMRI Meta-Analyses of Episodic Memory Encoding and Retrieval in Depression","rel_doi":"10.64898\/2026.04.14.718401","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.718401","rel_abs":"Background: Depression is a mood disorder frequently associated with episodic memory impairment. However, it remains unclear whether functional brain activity differs between depressed and non-depressed individuals during encoding or retrieval of autobiographical or non-autobiographical memories. Clarifying these differences is important for refining theoretical models of memory impairment in depression and, potentially, for developing targeted interventions. Methods: We conducted three coordinate-based meta-analyses examining encoding and retrieval of autobiographical and non-autobiographical memory in control participants and individuals with current, remitted, or subthreshold depression, or those at risk for depression. Studies were identified via database searches and analysed using Seed-based d Mapping. Results: We included coordinates from 21 fMRI studies. During encoding, depression was associated with reduced activity in the thalamus, the caudate, the salience network, the frontoparietal executive control network, and motor-related areas (ten studies, N = 506). During non-autobiographical retrieval, depression was associated with higher activity in the right inferior frontal gyrus (six studies, N = 332). During autobiographical retrieval, depression was associated with reduced activity in the right insula and fusiform gyrus, alongside increased activity in the left anterior cingulate cortex and the left middle frontal gyrus (ten studies, N = 423). Between-study heterogeneity was low and no evidence for publication bias was found. Discussion: Our results indicate that depression may be associated with impaired salience integration during encoding and autobiographical retrieval. In contrast, during non-autobiographical retrieval, increased frontal activity suggests a more vigilant or self-monitoring retrieval mode. Functional brain activity changes in depression therefore appear stage- and content-specific.","rel_num_authors":7,"rel_authors":[{"author_name":"Raphaela Sch\u00f6pfer","author_inst":"University of Bern"},{"author_name":"Reut Zabag","author_inst":"Yale University"},{"author_name":"Florian W\u00fcthrich","author_inst":"University of Bern"},{"author_name":"Romy Lorenz","author_inst":"Max Planck Institut for Biological Cybernetics"},{"author_name":"Jutta Joormann","author_inst":"Yale University"},{"author_name":"Sina Straub","author_inst":"University of Bern"},{"author_name":"Jessica Peter","author_inst":"University of Bern"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Dynamic-Structure Redesign of Calmodulin Reveals Mechanistic Constraints on Ryr2 Regulation","rel_doi":"10.64898\/2026.04.14.717973","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.14.717973","rel_abs":"2.Calmodulin (CaM) is a highly conserved Ca2+ sensor that regulates hundreds of cellular targets through Ca2+ -dependent conformational dynamics. Despite its central role in Ca2+ signaling and disease, its evolutionary conservation and structural flexibility have suggested that CaM is resistant to rational redesign. Here, using the cardiac Ca2+ release channel Ryanodine receptor 2 (RyR2) as a model system, we tested whether incorporating conformational dynamics into computational protein design enables functional reengineering of CaM. We first applied a static structure-based redesign to increase CaM-RyR2 affinity. Although the resulting variant bound more tightly to both the RyR2 peptide and the intact channel in vitro, it distorted peptide geometry and worsened Ca2+ leak in cardiomyocytes ex vivo. Guided by molecular dynamics simulations, we then developed a dynamic-structure redesign strategy that preserves conformational integrity while strengthening binding. The resulting CaM variant exhibited increased RyR2 affinity and reduced pathological Ca2+ leak in a disease-relevant model. These findings show that improved binding affinity alone is insufficient to enhance physiological regulation and that successful CaM redesign requires preservation of conformational dynamics. More broadly, they demonstrate that integrating conformational dynamics into protein redesign can enable functionally predictive engineering of flexible regulatory protein-protein interactions.","rel_num_authors":15,"rel_authors":[{"author_name":"Vladimir Bogdanov","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"},{"author_name":"Svetlana Tikunova","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"},{"author_name":"Nicolas Fadell","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"},{"author_name":"Robyn T. Rebbeck","author_inst":"Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minnesota, Minneapolis, 55455"},{"author_name":"Melanie L. Aprahamian","author_inst":"Department of Chemistry and Biochemistry, Ohio State University, Columbus, Ohio 43210, United States"},{"author_name":"Md Nure Alam Afsar","author_inst":"Department of Chemistry, Mississippi State University, Starkville, Mississippi, 39759"},{"author_name":"Aleksei Chekodanov","author_inst":"Independent Software Developer, Moscow, Russia, 119049."},{"author_name":"Daniel J Blackwell","author_inst":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, 37212"},{"author_name":"Bjorn C Knollmann","author_inst":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, 37212"},{"author_name":"Razvan L. Cornea","author_inst":"Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minnesota, Minneapolis, 55455"},{"author_name":"Pete M Kekenes-Huskey","author_inst":"Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, 60153"},{"author_name":"Steffen Lindert","author_inst":"Department of Chemistry and Biochemistry, The University of California, Los Angeles, California, 90095"},{"author_name":"Christopher N. Johnson","author_inst":"Department of Chemistry, Mississippi State University, Starkville, Mississippi, 39759"},{"author_name":"Sandor Gyorke","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"},{"author_name":"Jonathan P Davis","author_inst":"The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohi"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Modeling Synthetic Audience Reactions to Social-Cognitive Narratives: A Generative GSR Model to Predict Real-World Autonomic Alignment during Film Viewing","rel_doi":"10.64898\/2026.04.13.716763","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.13.716763","rel_abs":"While media consumption can be a solitary act, it produces a shared, socially coordinated experience where audiences bodies align in response to shared narrative events that are often social-affective in nature. Despite this recognition, traditional descriptive models of Galvanic skin response (GSR) have existed for decades, yet the socially coordinated aspect remains to be fully reflected in physiological models with the field of communication often treating the underlying generators of autonomic activity as a black box. To bridge this gap, we introduce a computational framework that models the underlying neural driver and its convolution to sweat gland physiology to explain how narrative events translate into measurable conductance. By leveraging multimodal AI models to \"interpret\" the social-cognitive content of a film, we generated a predictor timeline for a synthetic audience comprised of digital agents (i.e. artificial body systems responding to the film events with GSR responses). We then test this computational audience model by comparing its predictions against an empirical dataset collected as audience members (N = 96) processed the same stimulus, finding that AI-identified social triggers, like moments of comedic violence or shared emotional shifts, significantly predict the GSR time-course of audience engagement. In sum, this paper moves beyond simple and often retrospective labels like \"arousal\" to offer a computational account of how shared social narratives grip the human nervous system. We provide a scalable and expandable framework and a set of tools to predict media impact and understanding the psychophysiological basis of media.","rel_num_authors":4,"rel_authors":[{"author_name":"Ben A Bartling","author_inst":"Michigan State University"},{"author_name":"Ralf Schmaelzle","author_inst":"Michigan State University"},{"author_name":"Hee Jung Cho","author_inst":"Michigan State University"},{"author_name":"Yuetong Du","author_inst":"Michigan State University"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Multi-omic profiling of human antibody-secreting cells reveals diverse subsets sustain durable humoral immunity","rel_doi":"10.64898\/2026.04.13.717827","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.13.717827","rel_abs":"Antibody-secreting cells (ASCs) provide humoral immunity that can mediate lifelong protection against pathogens. Current classifications cannot delineate the heterogenous functionalities, tissue residencies, and lifespans of human ASC subsets, impeding clinical translation. We applied multi-omic sequencing, spatial proteomics, and functional assays to discover and characterize human bone marrow (BM) ASC subsets. We identified two peripheral subsets (ASCp) also present in blood and three BM-resident subsets (ASCr), comprising a maturation continuum associated with increased mitochondrial networking, diminished antibody secretion, differential transcription factor motif accessibility, and preferential co-localization in homotypic niches. CD19+9+ASCr and CD19-ASCr exhibited poor recovery years after BM transplantation, indicating a strong dependence on supportive niches. Childhood vaccine antigens were recognized by long-lived ASCr subsets in adults and by immature HLA-DR+ASCp, implying ASCs can differentiate without recent antigen exposure. Our results provide new insights into ASC identity, maturation, and longevity and a generalizable framework for study and manipulation of human ASCs.","rel_num_authors":43,"rel_authors":[{"author_name":"David R. Glass","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Elisabeth M. Dornisch","author_inst":"Allen Institute for Immunology"},{"author_name":"Hang Yin","author_inst":"Allen Institute for Immunology"},{"author_name":"Susan A Ludmann","author_inst":"Allen Institute for Immunology"},{"author_name":"Ashwin Samudre","author_inst":"Allen Institute for Cell Science"},{"author_name":"Sydney Kuhl","author_inst":"Allen Institute for Immunology"},{"author_name":"Jocelin Malone","author_inst":"Allen Institute for Immunology"},{"author_name":"Aishwarya Chander","author_inst":"Allen Institute for Immunology"},{"author_name":"Saransh N. Kaul","author_inst":"Allen Institute for Immunology"},{"author_name":"Cole G. Phalen","author_inst":"Allen Institute for Immunology"},{"author_name":"Vaishnavi Parthasarathy","author_inst":"Allen Institute for Immunology"},{"author_name":"Mebdh A. Dillon","author_inst":"Allen Institute for Immunology"},{"author_name":"Palak C. Genge","author_inst":"Allen Institute for Immunology"},{"author_name":"Tyanna J. Stuckey","author_inst":"Allen Institute for Immunology"},{"author_name":"Stephanie D. Anover-Sombke","author_inst":"Allen Institute for Immunology"},{"author_name":"Peter J. Wittig","author_inst":"Allen Institute for Immunology"},{"author_name":"Mark-Phillip Pebworth","author_inst":"Allen Institute for Immunology"},{"author_name":"Ziyuan He","author_inst":"Allen Institute for Immunology"},{"author_name":"Katherine E. Henderson","author_inst":"Allen Institute for Immunology"},{"author_name":"Priya Ravisankar","author_inst":"Allen Institute for Immunology"},{"author_name":"Veronica Hernandez","author_inst":"Allen Institute for Immunology"},{"author_name":"Blessing Musgrove","author_inst":"Allen Institute for Immunology"},{"author_name":"Suraj Mishra","author_inst":"Allen Institute for  Cell Science"},{"author_name":"Upaasana Krishnan","author_inst":"Allen Institute for Immunology"},{"author_name":"Zachary J. Thomson","author_inst":"Allen Institute for Immunology"},{"author_name":"Morgan Weiss","author_inst":"Allen Institute for Immunology"},{"author_name":"Nina Estep","author_inst":"Allen Institute for Immunology"},{"author_name":"Lucas T. Graybuck","author_inst":"Allen Institute for Immunology"},{"author_name":"Melinda L. Angus-Hill","author_inst":"Allen Institute for Immunology"},{"author_name":"Claire E. Gustafson","author_inst":"Allen Institute for Immunology"},{"author_name":"Mackenzie S. Kopp","author_inst":"Allen Institute for Immunology"},{"author_name":"Julian Reading","author_inst":"Allen Institute for Immunology"},{"author_name":"Xiao-jun Li","author_inst":"Allen Institute for Immunology"},{"author_name":"Matheus P. Viana","author_inst":"Allen Institute for  Cell Science"},{"author_name":"Thomas F. Bumol","author_inst":"Allen Institute for Immunology"},{"author_name":"Ananda W. Goldrath","author_inst":"Allen Institute for Immunology"},{"author_name":"Mikael Sigvardsson","author_inst":"Allen Institute for Immunology"},{"author_name":"Sean C. Bendall","author_inst":"Stanford University"},{"author_name":"Peter J. Skene","author_inst":"Allen Institute for Immunology"},{"author_name":"Damian J. Green","author_inst":"Sylvester Comprehensive Cancer Center"},{"author_name":"Evan W. Newell","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Troy R. Torgerson","author_inst":"Allen Institute for Immunology"},{"author_name":"Marla C. Glass","author_inst":"Allen Institute for Immunology"}],"rel_date":"2026-04-17","rel_site":"biorxiv"},{"rel_title":"Cooperative molecular mimicry drives prolonged autoinflammation in multisystem inflammatory syndrome in children","rel_doi":"10.64898\/2026.04.03.26350001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350001","rel_abs":"Multisystem inflammatory syndrome in children (MIS-C) is a pediatric hyperinflammatory disease manifesting 4-6 weeks after SARS-CoV-2 infection. While the immunological hallmarks of MIS-C have been defined, few details regarding the underlying disease pathology have been resolved. To address this, we used a multiomics approach to profile the plasma and peripheral immune cells of 13 acute MIS-C patients, 18 recovered MIS-C follow-ups resampled over multiple time points (1-18 months), and 15 healthy pediatric controls. Despite rapid clinical disease resolution, circulating pro-inflammatory (IL-8, IL-6, IL-1, IL-1{beta}, TNF-{beta}) and TH2-type cytokines (IL-4, IL-5, IL-13) remained elevated up to three months post-MIS-C onset, revealing a subclinical inflammatory state that endures in recovered children. Surprisingly, the majority of patient-expanded TCRs recognizing SARS-CoV-2 epitopes were cross-reactive (75%, 12\/16 SARS-CoV-2 TCRs) for autoantigens related to prostaglandin biology and insulin metabolism, suggesting a breakdown of self-tolerance via SARS-CoV-2 molecular mimicry. Indeed, autoantibody screening confirmed that 13 gene targets with self-antigen peptides also exhibited elevated autoantibodies in MIS-C patients. Further, autoreactive TCR expansions lasted over time and correlated with cytokines involved in allergic inflammation. Together, our findings point to a mechanism of sustained autoimmunity wherein promiscuous TCRs recognize both viral and self-antigens that are activated during primary SARS-CoV-2 infection in children who develop MIS-C. Upon onset, these circulating cross-reactive T cells drive clinically apparent sterile autoinflammation that persists subclinically into convalescence.","rel_num_authors":9,"rel_authors":[{"author_name":"Haley E Randolph","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Ashley Richardson","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sofija Buta","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Julie Samuels","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Nina N Brodsky","author_inst":"Yale University School of Medicine"},{"author_name":"Seunghee Kim-Schulze","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Carrie L Lucas","author_inst":"Yale University School of Medicine"},{"author_name":"Rebecca Trachtman","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Dusan Bogunovic","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-08","rel_site":"medrxiv"},{"rel_title":"Cooperative molecular mimicry drives prolonged autoinflammation in multisystem inflammatory syndrome in children","rel_doi":"10.64898\/2026.04.03.26350001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350001","rel_abs":"Multisystem inflammatory syndrome in children (MIS-C) is a pediatric hyperinflammatory disease manifesting 4-6 weeks after SARS-CoV-2 infection. While the immunological hallmarks of MIS-C have been defined, few details regarding the underlying disease pathology have been resolved. To address this, we used a multiomics approach to profile the plasma and peripheral immune cells of 13 acute MIS-C patients, 18 recovered MIS-C follow-ups resampled over multiple time points (1-18 months), and 15 healthy pediatric controls. Despite rapid clinical disease resolution, circulating pro-inflammatory (IL-8, IL-6, IL-1, IL-1{beta}, TNF-{beta}) and TH2-type cytokines (IL-4, IL-5, IL-13) remained elevated up to three months post-MIS-C onset, revealing a subclinical inflammatory state that endures in recovered children. Surprisingly, the majority of patient-expanded TCRs recognizing SARS-CoV-2 epitopes were cross-reactive (75%, 12\/16 SARS-CoV-2 TCRs) for autoantigens related to prostaglandin biology and insulin metabolism, suggesting a breakdown of self-tolerance via SARS-CoV-2 molecular mimicry. Indeed, autoantibody screening confirmed that 13 gene targets with self-antigen peptides also exhibited elevated autoantibodies in MIS-C patients. Further, autoreactive TCR expansions lasted over time and correlated with cytokines involved in allergic inflammation. Together, our findings point to a mechanism of sustained autoimmunity wherein promiscuous TCRs recognize both viral and self-antigens that are activated during primary SARS-CoV-2 infection in children who develop MIS-C. Upon onset, these circulating cross-reactive T cells drive clinically apparent sterile autoinflammation that persists subclinically into convalescence.","rel_num_authors":9,"rel_authors":[{"author_name":"Haley E Randolph","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Ashley Richardson","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sofija Buta","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Julie Samuels","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Nina N Brodsky","author_inst":"Yale University School of Medicine"},{"author_name":"Seunghee Kim-Schulze","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Carrie L Lucas","author_inst":"Yale University School of Medicine"},{"author_name":"Rebecca Trachtman","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Dusan Bogunovic","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-08","rel_site":"medrxiv"}]}