medRxiv : the preprint server for health sciences最新文献

{"title":"A multi-omics resource of B cell activation reveals genetic mechanisms for immune-mediated diseases.","authors":"Vitor R C Aguiar, Marcella E Franco, Nada Abdel Aziz, Daniela Fernandez-Salinas, Marcos Chiñas, Mariasilvia Colantuoni, Qian Xiao, Nicolaj Hackert, Yifei Liao, Rodrigo Cervantes-Diaz, Marc Todd, Brian Wauford, Alex Wactor, Vaishali Prahalad, Raquel Laza-Briviesca, Roxane Darbousset, Qiang Wang, Scott Jenks, Kevin S Cashman, Esther Zumaquero, Zhu Zhu, Junning Case, Paloma Cejas, Miguel Gomez, Hannah Ainsworth, Miranda Marion, Mehdi Benamar, Pui Lee, Lauren Henderson, Margaret Chang, Kevin Wei, Henry Long, Carl D Langefeld, Benjamin E Gewurz, Ignacio Sanz, Jeffrey A Sparks, Esra Meidan, Peter A Nigrovic, Maria Gutierrez-Arcelus","doi":"10.1101/2025.05.22.25328104","DOIUrl":"10.1101/2025.05.22.25328104","url":null,"abstract":"<p><p>Most genetic variants that confer risk of complex immune-mediated diseases (IMDs) affect gene regulation in specific cell types. Their target genes and focus cell types are often unknown, partially because some effects are hidden in untested cell states. B cells play central roles in IMDs, including autoimmune, allergic, infectious, and cancer-related diseases. Despite this established importance, B cell activation states are underrepresented in functional genomics studies. In this study, we obtained B cells from 26 healthy female donors and stimulated them <i>in vitro</i> with six activation conditions targeting key pathways: the B cell receptor (BCR), Toll-like receptor 7 (TLR7), TLR9, CD40, and a cocktail that promotes differentiation into double negative 2 (DN2) IgD^- CD27^- CD11c⁺ CD21^- B cells, a likely pathogenic subset implicated in autoimmunity and infection. We profiled up to 24 B cell activation states and up to 5 control conditions using RNA-seq, single-cell RNA-seq with surface protein markers (CITE-seq), and ATAC-seq. We characterize how IMD-associated genes respond to stimuli and group into distinct functional programs. High-depth RNA-seq data reveals widespread splicing effects during B cell activation. Using single-cell data, we describe stimulus-dependent B cell fates. Chromatin data reveal transcription factors likely involved in B cell activation, and activation-dependent open chromatin regions that are enriched in IMD genetic risk. We experimentally validate a lupus risk variant in a stimulus-specific open chromatin region that regulates <i>TNFSF4</i> expression, highlighting the relevance of studying B cell activation to elucidate disease association. These data are shared via an interactive browser that can be used to query the dynamics of gene regulation and B cell differentiation during activation by different stimuli, enhancing further investigation of B cells and their role in IMDs: https://mgalab.shinyapps.io/bcellactivation.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>CYP2B6*6</i> single nucleotide polymorphism among patients with uncomplicated malaria in Adjumani district, Uganda: implications on efficacy of artemether-lumefantrine.","authors":"Martin Kamilo Angwe, Norah Mwebaza, Sam Lubwama Nsobya, Ronald Kiguba, Patrick Vudriko, Savior Dralabu, Denis Omali, Maria Agnes Tumwebaze, Moses Ocan","doi":"10.1101/2025.06.13.25329585","DOIUrl":"10.1101/2025.06.13.25329585","url":null,"abstract":"<p><p>CYP2B6<i>,</i> one of the most polymorphic enzymes, plays a major role in the metabolism of artemisinin and its derivatives. Variation in the frequency of the most common yet functionally deficient <i>CYP2B6*6</i> allele may impact artemisinin exposure, potentially contributing to differences in treatment outcomes<i>.</i> This study assessed the prevalence of the <i>CYP2B6*6</i> genotype among patients with uncomplicated malaria treated with artemether-lumefantrine at Adjumani District Hospital in the West Nile region, Uganda. A total of 100 randomly selected patients with microscopically confirmed uncomplicated <i>P. falciparum</i> malaria receiving artemether-lumefantrine (AL) were included in the study. Blood samples, 2-3 mL each, were collected using EDTA tubes on days 0 and 3 after AL administration. DNA was extracted using Qiagen DNA Mini kit. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was used to determine the <i>CYP2B6*6</i> genotype of the participants. <i>P. falciparum</i> positivity was determined by microscopy and qPCR. For qPCR, parasite clearance was determined using comparative CT value. Data analysis was done using STATA <i>ver</i> 17.0 at a 95% significance level. Among the malaria patients genotyped, 65% were female, and 35% were male, with a mean age of 17±10 years. The <i>CYP2B6*6</i> variant allele frequency was 0.37, and the genotype frequency was 43% GG, 17% TT and 40% GT. <i>P. falciparum</i> day 3 microscopy positivity was 14% (6/43) among the GG, 37.5% (15/40) among the GT, and 17.64% (3/17) among the TT patients. PCR positivity rates were 58.1% (25/43) in the GG, 72.5% (29/40) in the GT, and 52.9% (9/17) in the TT patients. Heterozygous individuals (GT) had slow parasite clearance by a 10-fold difference compared to the homozygous (GG, TT) individuals (<i>U</i>=323.0; <i>Z</i>=-2.3442; <i>p</i>=0.019). Malaria patients in Adjumani district had a high frequency of the <i>CYP2B6*6</i> variant allele. Interindividual variability in <i>P. falciparum</i> clearance exists, with heterozygous patients demonstrating slow artemether-lumefantrine <i>P. falciparum</i> parasite clearance. There is a need to consider incorporating host genomic factors, such as metabolising enzyme genotype into routine Therapeutic Efficacy Studies (TES).</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Campus-based genomic surveillance uncovers early emergence of a future dominant A(H3N2) influenza clade.","authors":"Matthew Scotch, Temitope O C Faleye, Jillian M Wright, Sarah Finnerty, Rolf U Halden, Arvind Varsani","doi":"10.1101/2025.06.13.25329559","DOIUrl":"10.1101/2025.06.13.25329559","url":null,"abstract":"<p><p>We conducted genomic surveillance of seasonal influenza during the 2022-2023 northern hemisphere flu season on a large university setting in Southwest Arizona USA to understand the diversity, evolution, and spread within a local environment and how it relates to national data. Through high-throughput sequencing and bioinformatics, we identified 100 positive samples (19%) from 516 clinical swabs collected at the student health clinic. We observed a dominance of subtype A(H3N2) which was consistent nationally for the 2022-2023 season. However, we found stark differences when examining subtype-specific H3 clades, which included an early dominance of clade 2a.3a.1 variants contrasting from country-level data in which 2b variants were most abundant. These variants might have contributed to the early seasonal peak on campus which lagged national trends by one month. We used phylodynamics to understand the timing, source, and impact of clade-specific introductions on campus and observed introductions of 2b variants from North America, Europe, and Asia in early 2022 which possibly contributed to its later-season dominance on campus towards the end of 2022. We also observed the impact of 2b variants in our Bayesian epidemiological model, as its its emergence and rapid rise coincided with the peak of infection on campus. We found several highly prevalent H3 mutations in known epitope sites that have been observed in multiple 3c.2a clades. In particular, we note the presence of N96S (N=57, 63%) which is a defining mutation of 2a.3 and 2a.3a.1 variants and has been shown to create a new potential N-glycosylation site in the globular head. We estimated vaccine effectiveness via an H3 epitope model with a range of 0.13-0.48 which overlaps with estimates for that year. Taken together, the abundance of antigenic drift mutations, in addition to our identification of numerous sequons found within HA1 (globular head) with high glycosylation potential likely contributed to moderate vaccine effectiveness on campus for that season. As 2a.3a.1 variants became nearly the exclusive H3 clade nationally in 2023-2024 as well as 2024-2025, our identification of their dominance on campus highlights the importance of monitoring local settings as potential early examples for national and influenza trajectories. By using high-throughput sequencing and multiple bioinformatics methods, we show the importance of genomic epidemiology in semi-closed, highly-dense university settings and its potential for early insight of seasonal influenza diversity at a national scale.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 antibody immunity across three continents: the West Africa, West Indies, West London Consortium.","authors":"David Greenwood, Oliver Hague, Eliza Mari Kwesi-Maliepaard, Shanice A Redman, Flora Scott, Joshua J Anzinger, Gordon Awandare, David Lv Bauer, Yaw Bediako, Edward J Carr, Christine Vf Carrington, Adam Kucharski, Peter Quashie, Emma C Wall, Mary Y Wu","doi":"10.1101/2025.06.13.25329588","DOIUrl":"10.1101/2025.06.13.25329588","url":null,"abstract":"<p><strong>Background: </strong>The experience of the COVID-19 pandemic has differed across continents. We hypothesized that regional differences in SARS-CoV-2 immunity might explain this observation. We therefore established the WWW Consortium in Ghana, W Africa; Jamaica, W Indies; and W London. Here, we describe the extent to which antibody immunity differs between these geographic locations.</p><p><strong>Methods: </strong>The WWW Consortium harmonises across the HERITAGE (Accra, Ghana), WINDFall (Kingston, Jamaica) and Legacy (London, UK) studies, establishing sharing frameworks for samples, metadata, and data; related permissions and oversight; and associated physical and cloud infrastructure. With centralised testing, we performed serological assessments across all three locations at two snapshots in 2024 (April 1^st - August 18^th; August 19^th - December 31^st) using high-throughput live virus neutralization and anti-nucleocapsid IgG, including n=763 individuals.</p><p><strong>Findings: </strong>We found that across all sites most participants had detectable neutralising antibody titres against JN.1 and XEC - the predominant variants in 2024. There were site-related differences in immunity: vaccine-included SARS-CoV-2 strains were better neutralised by participants from the Legacy study - Ancestral, BA.5, XBB.1.5 initially, and JN.1 after a homologous booster in autumn 2024. For HERITAGE, neutralisation of both alpha- (HCoV-229E) and beta-coronaviruses (HCoV-OC43) was higher than WINDFall suggesting a cross-coronavirus serological response in West Africa. Finally, antigenic cartography identified two distinct antibody landscapes, with JN.1 and XEC antigenically distant in Legacy, but not in HERITAGE and WINDFall.</p><p><strong>Interpretation: </strong>There is international heterogeneity in SARS-CoV-2 antibody immunity. Global recommendations for vaccine strain selection should incorporate data from diverse populations to ensure accurate, equitable recommendations.</p><p><strong>Funding: </strong>The Wellcome Trust.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding <i>Plasmodium vivax</i> recurrent infections using an amplicon deep sequencing assay, PvAmpSeq, identity-by-descent and model-based classification.","authors":"Jason Rosado, Jiru Han, Thomas Obadia, Jacob Munro, Zeinabou Traore, Kael Schoffer, Jessica Brewster, Caitlin Bourke, Joseph M Vinetz, Michael White, Melanie Bahlo, Dionicia Gamboa, Ivo Mueller, Shazia Ruybal-Pesántez","doi":"10.1101/2025.05.26.25327775","DOIUrl":"10.1101/2025.05.26.25327775","url":null,"abstract":"<p><p><i>Plasmodium vivax</i> infections are characterised by recurrent bouts of blood-stage parasitaemia. Understanding the genetic relatedness of recurrences can distinguish whether these are caused by relapse, reinfection, or recrudescence, which is critical to understand treatment efficacy and transmission dynamics. We developed PvAmpseq, an amplicon sequencing assay targeting 11 SNP-rich regions of the <i>P. vivax</i> genome. PvAmpSeq was validated on field isolates from a clinical trial in the Solomon Islands and a longitudinal observational cohort in Peru, and statistical models were applied for genetic classification of infection pairs. In the Solomon Islands trial, where participants received antimalarials at baseline, half of the recurrent infections were caused by parasites with >50% relatedness to the baseline infection, with statistical models classifying 25% and 25% as probable relapses and recrudescences, respectively. In the Peruvian cohort, 26% of recurrences were likely relapses. PvAmpSeq provides high-resolution genotyping to characterise <i>P. vivax</i> recurrences, offering insights into transmission and treatment outcomes.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12148277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypertension Self-Management and Stroke Recovery Among Rural Adults in the Stroke Belt: A Mixed-Methods Study.","authors":"Mudasir Andrabi, Betty Key, Rn Chaitali Dagali, Kayla Glass, Stephine Hart, Susan Appel, Lin Chen, Karlene Ball","doi":"10.1101/2025.06.12.25329283","DOIUrl":"10.1101/2025.06.12.25329283","url":null,"abstract":"<p><p>Limited knowledge exist on HTN-related knowledge and health behaviors among African American adult stroke survivors with hypertension condition living in rural Alabama. To address this gap, we conducted a small pilot study with a mixed methods design for needs assessment of stroke survivors with a hypertension condition living in rural areas of Alabama. We followed the community engagement strategy approach to conduct our study. After the approval from the Institutional Review Board, participants were recruited (N=25) using convenience sampling. We conducted surveys, followed by sequential interviews of our participants. Our needs assessment focused on knowledge and actual behaviors related to hypertension management among this population. This paper presents findings from the quantitative and qualitative data collected for this needs assessment study. Data collection included: (i) HTN Knowledge-Level Scale test (HK-LS), (ii) HTN Self-Care Activity Level Effects (H-SCALE), and (iii) The Southampton Stroke Self-Management Questionnaire. Interested participants ( n=14) were interviewed using a PI-developed semi-structured interview guide. Descriptive and inferential statistics were used to analyze the data collected from the surveys. The majority of participants (76%) had low level knowledge related to hypertension. Most participants also demonstrated limited adherence to hypertension behaviors including hypertension medication adherence (76%), DASH Diet (84%), physical activity ( 56%), and 72% had smoking habits. Our findings from qualitative interview data revealed the major themes of lack of knowledge related to hypertension management and post-stroke life management, lack of adherence to prescribe hypertension treatment, lack of continuity of care after discharge from hospital, and lack of social support. These results indicated poor adherence to prescribed hypertension management behaviors. These findings highlight the need for a larger-scale study to assess heart health knowledge further and to identify the specific needs and preferences of this underserved population, an essential step toward developing tailored, community-informed interventions.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of brain age using structural magnetic resonance imaging: A comparison of clinical validity of publicly available software packages.","authors":"Ruben P Dörfel, Brice Ozenne, Melanie Ganz, Jonas E Svensson, Pontus Plavén-Sigray","doi":"10.1101/2025.03.13.25323902","DOIUrl":"https://doi.org/10.1101/2025.03.13.25323902","url":null,"abstract":"<p><p>Brain age estimated from structural magnetic resonance images is commonly used as a biomarker of biological aging and brain health. Ideally, as a clinically valid biomarker, brain age should indicate the current state of health and be predictive of future disease onset and detrimental changes in brain biology. In this preregistered study, we evaluated and compared the clinical validity, i.e., diagnostic and prognostic performance, of six publicly available brain age prediction packages using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Baseline brain age differed significantly between groups consisting of individuals with normal cognitive function, mild cognitive impairment, and Alzheimer's disease for all packages, but with comparable performance to estimates of gray matter volume. Further, brain age estimates were not centered around zero for cognitively normal subjects and showed considerable variation between packages. Finally, brain age was only weakly correlated with disease onset, memory decline, and gray matter atrophy within four years from baseline in individuals without neurodegenerative disease. The systematic discrepancy between chronological age and brain age among healthy subjects, combined with the weak associations between brain age and longitudinal changes in memory performance or gray matter volume, suggests that the current brain age estimates have limited clinical validity as a biomarker for biological aging.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the Heterogeneity of Myasthenia Gravis Severity Scores for Digital Twin Development.","authors":"Marc Garbey, Quentin Lesport, Henry J Kaminski","doi":"10.1101/2025.06.13.25329566","DOIUrl":"https://doi.org/10.1101/2025.06.13.25329566","url":null,"abstract":"<p><p>Myasthenia gravis (MG) is a rare autoimmune neuromuscular disease. Clinical trials with rigorously collected data, especially for rare diseases, provide opportunities for mathematical modeling of patient outcomes over time; however, building a larger data set from multiple trials faces the challenge of harmonization of outcome measures. To accurately model MG and predict individual patient trajectories, one requires integrating three primary data types: (i) Laboratory and medication data, (ii) Electronic Health Record (EHR) data (e.g., age, sex, years since diagnosis, BMI), (iii) Disease severity scores. Among these, MG severity scores are crucial for measuring disease progression from the patient's and clinical evaluator's perspectives. However, clinical studies often employ various scoring systems (e.g., ADL, QMG, MG-CE, MGQOL-15), making it challenging to determine the most reliable measure. In this study, we investigate the relationships among clinical outcome measures across multiple clinical studies. Our objective is to develop a robust \"Myasthenia Gravis Portrait\" that can be applied across diverse clinical studies. This standardized portrait will facilitate the creation of a virtual population of digital twins, enabling the application of machine learning techniques to a larger patient population.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling temporal dynamics of the post-mortem transcriptome in amyotrophic lateral sclerosis.","authors":"Ting Shen, Barbara E Spencer, Pavel P Kuksa, Vivianna M Van Deerlin, Hemali Phatnani, Edward B Lee, Corey T McMillan","doi":"10.1101/2025.06.10.25329061","DOIUrl":"https://doi.org/10.1101/2025.06.10.25329061","url":null,"abstract":"<p><p>Human tissue transcriptomics are crucial for understanding neurodegeneration but limited by cross-sectional post-mortem sampling, which represents end-stage disease. Subtype and Stage Inference (SuStaIn) modeling addresses these limitations by inferring temporal gene expression dynamics while also identifying potential transcriptomic subtypes. Applied to bulk RNA-seq data from post-mortem lumbar spinal cord in amyotrophic lateral sclerosis (ALS), SuStaIn unraveled that more advanced transcriptomic stages were associated with higher microglia and reduced neuron proportions, which mapped onto two ALS subtypes: Immune/Apoptosis/Proteostasis subtype with early immune/apoptotic/proteostatic dysregulation, worse prognosis and higher microglia proportions; Synapse/RNA-Metabolism subtype with early synaptic/RNA-processing deficits, lower male prevalence and neuron loss. Lumbar patterns demonstrated high concordance with cervical patterns and a strong correlation in staging across regional tissues. These findings revealed subtype-specific mechanisms underlying ALS heterogeneities, prioritized key genes driving subtyping/staging as potential therapeutic targets. More broadly, we established a framework to decode temporal dynamics from traditionally constrained post-mortem transcriptomic studies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Funding distributions, trends, gaps, and policy implications for spinal cord injury research: A systematic analysis of US federal funds.","authors":"Tucker Gillespie, Andrew Buxton, Bethany R Kondiles, Miranda Leal-Garcia, Mia R Pacheco, Ashley V Tran, Katie Vo, Lucy Abu, James Barr, Tanya A Barretto, Jason Biundo, Sam Duenwald, Abigail Evans, Timothy N Friedman, Isabella Gadaleta, Saahas Ganesh, Bryson Gottschall, Peyton Green, Grant Lee, Lilian Liu, Raza N Malik, Elizabeth J Nava, Chiara Sorani, Vansh Tandon, Hannah Thomas, Kyndal Thomas, Chris Barr, Ian Burkhart, Dylan A McCreedy, Peter Nowell, Heath Blackmon, Alexander G Rabchevsky, Matthew Rodreick, Abel Torres-Espín, Jennifer N Dulin","doi":"10.1101/2025.06.01.25328764","DOIUrl":"10.1101/2025.06.01.25328764","url":null,"abstract":"<p><p>Federal agencies including the National Institutes of Health (NIH), Department of Defense (DoD) Congressionally Directed Medical Research Program (CDMRP) Spinal Cord Injury Research Program (SCIRP), and Department of Veterans Affairs (VA) provide the majority of funding for spinal cord injury (SCI) research in the United States. However, systematic evaluation of how funding is distributed across research areas, therapeutic approaches, and translational stages has been limited. To understand the distribution of funds, we curated and classified 1,589 federally funded SCI research awards from the NIH (2008-2023), the CDMRP SCIRP (2009-2023), and the VA (2017-2025). Each award was annotated based on the biological system or problem studied, the therapeutic intervention or approach utilized, and its placement along the translational continuum. Our analysis revealed that the NIH predominantly supports basic and early stage translational research, especially in areas of SCI pathology, regeneration, and motor functional recovery. In contrast, the CDMRP funding is more concentrated on applied and clinical research, particularly in the areas of pain, bladder function, and neuromodulatory device development. The VA predominantly invests in rehabilitation-focused studies and interventions aimed at improving musculoskeletal and functional health outcomes. While the complementary missions of these agencies collectively support a diverse SCI research ecosystem, we identified critical gaps in funding for high-priority areas such as bowel/gastrointestinal health, cardiovascular function, and mental health. Furthermore, the recent discontinuation of the CDMRP SCIRP and proposed NIH budget reductions are projected to lead to an approximate 50% decline in federal SCI research funding by 2026-posing a substantial risk to the field's progress and threatening the stability of this ecosystem. These findings underscore the urgent need for coordinated, data-driven funding strategies that align more closely with the needs and priorities of the SCI community. To that end, we propose the development of a publicly accessible \"living dashboard\" to enhance transparency, foster interdisciplinary collaboration, and guide strategic investment in SCI research moving forward.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12154993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}