EBioMedicine最新文献

{"title":"A dietary pattern promoting gut sulfur metabolism is associated with increased mortality and altered circulating metabolites in low-income American adults.","authors":"Kui Deng, Lei Wang, Sang Minh Nguyen, Martha J Shrubsole, Qiuyin Cai, Loren Lipworth, Deepak K Gupta, Wei Zheng, Xiao-Ou Shu, Danxia Yu","doi":"10.1016/j.ebiom.2025.105690","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105690","url":null,"abstract":"<p><strong>Background: </strong>Excessive hydrogen sulfide in the gut, generated by sulfur-metabolising bacteria from foods, has been linked to intestinal inflammation and human diseases. We aim to investigate the interplay between diet and sulphur-metabolising bacteria in relation to mortality and circulating metabolites in understudied populations.</p><p><strong>Methods: </strong>In the Southern Community Cohort Study (SCCS), a prospective cohort of primarily low-income American adults, habitual diets were assessed using a food frequency questionnaire at baseline (2002-2009). A sulfur microbial diet score (SMDS) was developed among 514 Black/African American participants by linking habitual dietary intakes with the abundance of sulfur-metabolising bacteria profiled by faecal shotgun metagenomics. The SMDS was then constructed among all eligible SCCS participants (50,114 Black/African American and 23,923 non-Hispanic White adults), and its associations with mortality outcomes were examined by Cox proportional hazards model and Fine-Grey subdistribution hazard model. The association between SMDS and 1110 circulating metabolites was examined by linear regression among 1688 SCCS participants with untargeted metabolomic profiling of baseline plasma samples.</p><p><strong>Findings: </strong>Over an average 13.9-year follow-up, SMDS was associated with increased all-cause mortality (HR [95% CI] for the highest vs. lowest quartiles: 1.21 [1.15-1.27]) and cardiovascular disease (1.18 [1.08-1.29]), cancer (1.13 [1.02-1.25]), and gastrointestinal cancer-specific (1.22 [1.00-1.49]) mortality among Black/African American participants (all P-trend<0.05). The associations were largely consistent across participant subgroups. Similar results were observed among non-Hispanic White participants. The SMDS was associated with 112 circulating metabolites, which mediated 36.15% of the SMDS-mortality association (P = 0.002).</p><p><strong>Interpretation: </strong>A dietary pattern promoting sulfur-metabolising gut bacteria may contribute to increased total and disease mortality in low-income American adults.</p><p><strong>Funding: </strong>This study was funded by the National Institutes of Health, United States, to Vanderbilt University Medical Center, United States, and Anne Potter Wilson Chair endowment to Vanderbilt University, United States.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"115 ","pages":"105690"},"PeriodicalIF":9.7,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multi-omics profiling uncovers the immune heterogeneity in HIV-infected immunological non-responders.","authors":"Xiaosheng Liu, Leidan Zhang, Xiaodi Li, Ling Chen, Lianfeng Lu, Yang Yang, Yuanni Wu, Liyuan Zheng, Jia Tang, Fada Wang, Yang Han, Xiaojing Song, Wei Cao, Taisheng Li","doi":"10.1016/j.ebiom.2025.105667","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105667","url":null,"abstract":"<p><strong>Background: </strong>Immunological non-responders (INRs) are people living with HIV-1 who fail to achieve full immune reconstitution despite long-term effective antiretroviral therapy (ART). This incomplete recovery of CD4⁺ T cells increase the risk of opportunistic infections and non-AIDS-related morbidity and mortality. Understanding the mechanisms driving this immune dysfunction is critical for developing targeted therapies.</p><p><strong>Methods: </strong>We performed single-cell RNA sequencing (scRNA-seq) and single-cell VDJ sequencing (scVDJ-seq) on peripheral blood mononuclear cells (PBMCs) from INRs, immune responders (IRs), and healthy controls (HCs). We developed scGeneANOVA, a novel mixed model differential gene analysis tool, to detect differentially expressed genes and pathways. In addition, we developed the Viral Identification and Load Detection Analysis (VILDA) tool to quantify HIV-1 transcripts and investigate their relationship with interferon (IFN) pathway activation.</p><p><strong>Findings: </strong>Our analysis revealed that INRs exhibit a dysregulated IFN response, closely associated with CD4⁺ T cell exhaustion and immune recovery failure. The scGeneANOVA tool identified critical genes and pathways that were missed by traditional analysis methods, while VILDA showed higher levels of HIV-1 transcripts in INRs, which may drive the heightened IFN response. These findings support a potential contribution of IFN signalling in INR-related immune dysfunction.</p><p><strong>Interpretation: </strong>Our study provides new insights into the pathogenic mechanisms behind immune recovery failure in INRs, suggesting that IFN signalling might be involved in the development of CD4⁺ T cell exhaustion. The identification of key genes and pathways offers potential biomarkers and therapeutic targets for improving immune recovery in this vulnerable population.</p><p><strong>Funding: </strong>This study was supported by the grants from Special Research Fund for the Central High-level Hospitals of Peking Union Medical College Hospital (Grant No. 2022-PUMCH-D-008), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (Grant No. 2021-I2M-1-037), National Key Technologies R&D Program for the 13th Five-year Plan (Grant No. 2017ZX10202101-001). The funders played no role in the design, experiment conduction, data analysis and preparation of the manuscript of this work.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"115 ","pages":"105667"},"PeriodicalIF":9.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Essentiality of the virulence plasmid-encoded factors in disease pathogenesis of the major lineage of hypervirulent Klebsiella pneumoniae varies in different infection niches.","authors":"Carey Lim, Chu-Yun Zhang, Guoxiang Cheam, Wilson H W Chu, Yahua Chen, Melvin Yong, Kai Yi E Lim, Margaret M C Lam, Teck Hui Teo, Yunn-Hwen Gan","doi":"10.1016/j.ebiom.2025.105683","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105683","url":null,"abstract":"<p><strong>Background: </strong>Hypervirulent Klebsiella pneumoniae (HvKp) can metastasise to extra-intestinal sites to cause disseminated disease such as pyogenic liver abscesses. HvKp harbours a large virulence plasmid (KpVP) that contributes to pathogenicity. We previously identified a crucial gene region that confers virulence in SGH10 (ST23, K1 capsule), spanning genes encoding the siderophores aerobactin and salmochelin, as well as the regulator of mucoidy phenotype A (iuc-rmp-iro).</p><p><strong>Methods: </strong>SGH10 isogenic mutants of aerobactin, rmpA, and salmochelin were generated and tested in vitro for their siderophore production, hypermucoviscosity and growth. We investigated the essentiality of these factors in different murine infection or colonisation models.</p><p><strong>Findings: </strong>In a lung pneumonia model, capsule modulation by rmpA was the primary driver of high bacterial burden in the lung. In a systemic infection setting, rmpA was still the primary driver, followed by a significant contribution by salmochelin, that conferred virulence. However, the role of aerobactin was more significant in hvKp persistence in the gut. We further examined a large collection of Kp genomes and observed that the iro loci is often co-inherited with iuc in KpVP-1, suggesting the evolutionary importance of expressing both siderophores in these lineages.</p><p><strong>Interpretation: </strong>HvKp typically colonises the intestinal niche, however, the acquisition of the KpVP plasmid has enabled it to thrive outside the gut and cause metastatic infections. While the iuc-rmp-iro region is pivotal in bestowing virulence, the encoded factors contribute differently to the success of the pathogen in various infection sites, where the microenvironment, nutrient availability and immune response can vary. Thus, our study demonstrates that possessing the iuc-rmp-iro gene region can be an evolutionary advantage by allowing for flexibility in modulating siderophore and capsule expression in order for K. pneumoniae to thrive in distinct host niches.</p><p><strong>Funding: </strong>This work is funded by the National Research FoundationMOH-000925-00 to YH Gan and OFYIRG22jul-0042 by the National Medical Research Council (NMRC) to THT.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"115 ","pages":"105683"},"PeriodicalIF":9.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-ancestry genome-wide association meta-analysis identifies novel associations and informs genetic risk prediction for Hirschsprung disease.","authors":"Yuanxin Zhong, Man-Ting So, Zuyi Ma, Detao Zhang, Yanbing Wang, Zewei Xiong, João Fadista, You-Qiang Song, Kathryn Song-Eng Cheah, Maria M Alves, Salud Borrego, Isabella Ceccherini, Mikko P Pakarinen, Bjarke Feenstra, Vincent Chi-Hang Lui, Maria-Merce Garcia-Barcelo, Pak Chung Sham, Paul Kwong-Hang Tam, Clara Sze-Man Tang","doi":"10.1016/j.ebiom.2025.105680","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105680","url":null,"abstract":"<p><strong>Background: </strong>Hirschsprung disease (HSCR) is a rare, congenital disease characterized by the absence of enteric ganglia in the hindgut. Common genetic variation contributes substantially to the heritability of the disease yet only three HSCR-associated loci were identified from genome-wide association studies (GWAS) thus far.</p><p><strong>Methods: </strong>We performed the largest multi-ancestry meta-analysis of GWAS to date, totalling 1250 HSCR cases and 7140 controls. Prioritized candidate genes were further characterized using single-cell transcriptomic data of developing human and mouse gut for their roles in development of enteric nervous system (ENS). Functional characterisation using human cells and zebrafish models was performed. Global and ancestry-matched polygenic risk score (PRS) models were derived and evaluated for predicting risk of HSCR.</p><p><strong>Findings: </strong>We identified four HSCR-susceptibility loci, with three loci (JAG1, HAND2 and ZNF25) reaching genome-wide significance and one putative locus (UNC5C) prioritized by functional relevance. Spatiotemporal analysis revealed hotspots of gene dysregulation during ENS development. Functional analyses further demonstrated that knockdown of the candidate genes impaired cell migration and zebrafish knockouts displayed abnormal ENS development. We also demonstrated comparable performance for a PRS model derived from multi-ancestry meta-analysis to those of ancestry-matched PRS models, supporting its potential clinical application in risk prediction of HSCR across populations.</p><p><strong>Interpretation: </strong>Overall, the meta-analysis implicated novel genes, pathways and spatiotemporal developmental hotspots in the genetic aetiology of HSCR. Development of a PRS universally applicable irrespective of ancestries may leverage its clinical utility in risk prediction.</p><p><strong>Funding: </strong>The full list of funding bodies can be found in the Acknowledgements section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"115 ","pages":"105680"},"PeriodicalIF":9.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A custom-made mouthguard reduces head acceleration during soccer heading and prevents acute electrophysiological and cognitive changes in amateur male players.","authors":"Claire Pitteu, Philippine Lepère, Philippe Poisson, Etienne Guillaud, Emilie Doat, Bertrand Glize, Patrick Dehail, Hélène Cassoudesalle","doi":"10.1016/j.ebiom.2025.105674","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105674","url":null,"abstract":"<p><strong>Background: </strong>Repetitive head impacts related to soccer heading might lead to long-term risk of neurodegenerative diseases. Helping to stabilise the head-neck-torso complex could be a preventive strategy. This study aims to investigate head acceleration and heading-related acute electrophysiological and cognitive changes in soccer players, with a custom-made mouthguard (CM-MG) and without.</p><p><strong>Methods: </strong>In this crossover study, 18 amateur male soccer players (age 22 ± 3 y) performed ten consecutive headers from machine-projected balls, with and without a CM-MG. Head accelerations during heading were recorded. Peak force of neck muscles were assessed. Before and immediately after heading, cognitive function was assessed, and the cortical silent period (cSP) was measured from the motor-evoked potentials recorded using Transcranial Magnetic Stimulation.</p><p><strong>Findings: </strong>A decrease of 6·40 g (95% CI [-11·74; 39·09]) of mean peak linear head acceleration was found with the CM-MG (26·43 g) compared to without (34·15 g, p = 0·01). The peak force of the head flexor muscles was higher with the CM-MG (172 N) than without (146·7 N), with a mean difference of 19·33 N (95% CI [13·39; 25·27]) (p < 0·001). The difference in mean cSP between pre- and post-heading decreased statistically significantly with the CM-MG (-9·17 ms) compared to without (20·03 ms; p = 0·0016), with a median difference of -22·87 ms (95% CI [-45·85; -4·02]). There was also a decrease in the changes to memory performance with the CM-MG versus without.</p><p><strong>Interpretation: </strong>A CM-MG may have the potential to protect the brain during soccer heading. More studies are still needed to confirm its benefits in all playing conditions on the field.</p><p><strong>Funding: </strong>This research received two grants from LabEx BRAIN- Bordeaux University and France Traumatisme Cranien (public sector).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"115 ","pages":"105674"},"PeriodicalIF":9.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of lithium on circadian activity level and flexibility in patients with bipolar disorder: results from the Oxford Lithium Trial.","authors":"Ni Xu, Yan Yan, Kate E A Saunders, John R Geddes, Michael Browning","doi":"10.1016/j.ebiom.2025.105676","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105676","url":null,"abstract":"<p><strong>Background: </strong>Disruption of circadian rest-activity is prevalent in patients with bipolar disorder (BD). Lithium's impact on circadian rhythms has been documented in cell lines, animal models, and pharmacogenomics studies in patients with BD. However, the causal relationship between such disruption and BD remains unclear.</p><p><strong>Methods: </strong>We investigated the early effects of lithium on circadian rest-activity in an exploratory analysis of a randomised, placebo-controlled, double-blind six-week study on patients with BD. Participants were assigned to receive either lithium or a placebo in a 1:1 ratio. Circadian activity was monitored using actigraphy, and daily affect was assessed through ecological momentary assessment. A computational model was used to quantify different types of activity variability, and the impact of lithium on activity level, activity onset time and their variability were analysed using linear mixed models.</p><p><strong>Findings: </strong>Of the thirty-five participants who began treatment, 19 received lithium and 16 received a placebo. Lithium significantly altered circadian rest-activity patterns, including reducing daytime activity levels (after 4 weeks, below as well: Cohen's d = -0.19, p = 0.002, linear mixed model, ibid.), advancing the onset of daytime activity (Cohen's d = -0.14, p = 0.018), and increasing the volatility of both daytime activity level (Cohen's d = 0.10, p = 0.002) and its onset time (Cohen's d = 0.13, p < 0.001), independent of affective symptoms changes.</p><p><strong>Interpretation: </strong>This study establishes a causal link between lithium treatment and reduced circadian activity with advanced circadian phase, potentially via temporarily increasing their volatility (flexibility). Significant circadian changes were detected within one week of starting lithium, highlighting their potential as an early biomarker for treatment response.</p><p><strong>Funding: </strong>This research was supported by the Wellcome Trust Strategic Award (CONBRIO: Collaborative Oxford Network for Bipolar Research to Improve Outcomes, reference No. 102,616/Z), NIHR Oxford Health Biomedical Research Centre and the NIHR Oxford cognitive health Clinical Research Facility.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"115 ","pages":"105676"},"PeriodicalIF":9.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The severity of SLC1A2-associated neurodevelopmental disorders correlates with transporter dysfunction.","authors":"Peter Kovermann, Allan Bayat, Christina D Fenger, Lisette Leeuwen, Artem Borovikov, Artem Sharkov, Virginie Levrat, Gaetan Lesca, Laurence Perrin, Jonathan Levy, Christoph Fahlke, Rikke S Møller, Anders A Jensen","doi":"10.1016/j.ebiom.2025.105648","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105648","url":null,"abstract":"<p><strong>Background: </strong>Excitatory amino acid transporter 2 (EAAT2) is the predominant glutamate transporter and a key mediator of excitatory neurotransmission in the human brain. Here we present a cohort of 18 individuals harbouring 13 different SLC1A2 variants, who all present with neurodevelopmental impairment with variable symptoms and disease severities, and we delineate the impact of these variants on EAAT2 function.</p><p><strong>Methods: </strong>The consequences of nine novel missense SLC1A2 variants for expression, transport and anion channel properties of EAAT2 expressed in mammalian cells were characterized by confocal microscopy, enzyme-linked immunosorbent and [³H]-D-aspartate uptake assays, and electrophysiological recordings.</p><p><strong>Findings: </strong>Ten of the 13 SLC1A2 variants mediated significant changes to EAAT2 expression and/or function. These molecular phenotypes were classified into three categories: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. Although specific clinical outcomes in individuals carrying variants within each category varied somewhat, the three categories overall translated into distinct clinical phenotypes in terms of phenotypic traits and severity.</p><p><strong>Interpretation: </strong>The observed associations between functional effects and clinical phenotypes produced by these variants offer valuable insights for future predictions of progression and severity of SLC1A2-associated neurodevelopmental disorders. Furthermore, these associations between variant-induced changes in EAAT2 function and phenotypic traits could assist in tailoring personalized treatments of these disorders.</p><p><strong>Funding: </strong>This work was funded by the German Ministry of Education and Research and by the Lundbeck Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105648"},"PeriodicalIF":9.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational fluid dynamics of small airway disease in chronic obstructive pulmonary disease.","authors":"Yousry K Mohamady, Vincent Geudens, Charlotte De Fays, Marta Zapata, Omar Hagrass, Lucia Aversa, Marie Vermant, Xin Jin, Lynn Willems, Iwein Gyselinck, Charlotte Hooft, Astrid Vermaut, Hanne Beeckmans, Pieterjan Kerckhof, Gitte Aerts, Celine Aelbrecht, Janne Verhaegen, Andrew Higham, Walter Coudyzer, Emanuela E Cortesi, Arno Vanstapel, John E McDonough, Marianne S Carlon, Rozenn Quarck, Matthieu N Boone, Lieven Dupont, Stephanie Everaerts, Dirk E Van Raemdonck, Laurens J Ceulemans, Tillie-Louise Hackett, Robin Vos, Yasser Abuouf, Joseph Jacob, Wim A Wuyts, James C Hogg, Marcel Filoche, Ghislaine Gayan-Ramirez, Wim Janssens, Bart M Vanaudenaerde","doi":"10.1016/j.ebiom.2025.105670","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105670","url":null,"abstract":"<p><strong>Background: </strong>Small airways (<2 mm diameter) are major sites of airflow obstruction in chronic obstructive pulmonary disease (COPD). This study aimed to quantify the impact of small airway disease, characterized by narrowing, occlusion, and obliteration, on airflow parameters in smokers and end-stage patients with COPDs.</p><p><strong>Methods: </strong>We performed computational fluid dynamics (CFD) simulations of inspiratory airflow in three lung groups: control non-used donor lungs (no smoking/emphysema history), non-used donor lungs with a smoking history and emphysema, and explanted end-stage COPD lungs. Each group included four lungs, with two tissue cylinders. Micro-CT-scanned small airways were segmented into 3D models for CFD simulations to quantify pressure, resistance, and shear stress. CFD results were benchmarked against simplified linear and Weibel models.</p><p><strong>Findings: </strong>CFD simulations showed higher pressures in COPD vs. controls (p = 0.0091) and smokers (p = 0.015), along with increased resistance (p = 0.0057 vs. controls; p = 0.0083 vs. smokers) and up to a tenfold rise in shear stress (p = 0.010 vs. controls). Narrowing and occlusion were shown to independently increase pressure, resistance, and shear stress, which were validated through segmentation corrections. Pressures and resistance assessed with simplified models were up to seven-fold higher for smokers and even 72 higher for COPD compared with CFD values.</p><p><strong>Interpretation: </strong>These findings show that increased airflow parameters can explain the association between small airway disease and airflow limitation in COPD, underscoring small airway vulnerability. Additionally, they highlight the limitations of theoretical models in accurately capturing small airway disease.</p><p><strong>Funding: </strong>Supported by the KU Leuven (C16/19/005).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105670"},"PeriodicalIF":9.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the antibody response to Lassa virus vaccination of non-human primates.","authors":"Adrian S Enriquez, Ruben Diaz Avalos, Diptiben Parekh, Christopher L Cooper, Gavin Morrow, Thomas W Geisbert, Christopher L Parks, Kathryn M Hastie, Erica Ollmann Saphire","doi":"10.1016/j.ebiom.2025.105673","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105673","url":null,"abstract":"<p><strong>Background: </strong>Lassa fever, caused by Lassa virus, is a severe disease, endemic in Western Africa, for which no vaccines or therapeutics are yet approved. Understanding the immune responses elicited by candidate vaccines is key for approval, including characterisation of antibody epitopes recognised and capacity for neutralisation.</p><p><strong>Methods: </strong>Here we used negative-stain electron microscopy polyclonal antibody epitope mapping (EMPEM), in-vitro pseudovirus neutralisation assays, and biophysical antibody competition assays to uncover components of polyclonal antibody responses elicited in nonhuman primates 26 days after receipt of a single immunisation with a fully protective, recombinant, replication-competent vesicular stomatitis virus-based vaccine bearing the Lassa virus glycoprotein GPC.</p><p><strong>Findings: </strong>Although the vaccinee sera are overall poorly-neutralising, we do directly visualise, within the polyclonal pool, antibodies targeting epitopes on GPC that are consistent with neutralisation, as well as competition with known neutralising mAbs. Nearly every animal, for example, produced antibodies that compete with mAbs against GP1-A and GPC-A neutralising epitopes. The most abundant classes of antibodies, however, are directed against interior interfaces of GPC, while other antibodies recognise post-fusion GPC epitopes not consistent with neutralisation.</p><p><strong>Interpretation: </strong>It may be that some individual antibodies in the pool are neutralising, but that the abundance of non-neutralising epitopes reduces potency as measured at the polyclonal level. The finding, however, neutralisation-consistent sites and competition with known neutralising antibodies are important steps in vaccine design toward eliciting more potent neutralisation.</p><p><strong>Funding: </strong>A complete list of funding bodies that supported this study is presented in the Funding section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105673"},"PeriodicalIF":9.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic association studies in critically ill patients: a systematic review.","authors":"Wenbo Zhang, Nam Nguyen-Hoang, Sean C S Rivrud, Anne-Fleur Zandbergen, Yalan Yan, Eline G M Cox, Eva Suarez-Pajes, Amanda Y Chong, Alexander J Mentzer, Carlos Flores, Gerton Lunter, Frederik Keus, Harold Snieder","doi":"10.1016/j.ebiom.2025.105678","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105678","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Critical illness is complex, and genetic research holds the potential to uncover underlying disease mechanisms. However, existing research results have not been systematically summarized. This study aims to compile all genetic association studies in critically ill patients and assess their risks of bias.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We systematically reviewed PubMed, EMBASE, and the Cochrane Library (PROSPERO protocol: CRD42021209744) and conducted a bias risk assessment of identified studies using a newly developed risk-of-bias assessment tool for genetic association studies. We compiled all significant single nucleotide polymorphisms (SNPs) from the studies identified in our systematic review and conducted a lookup in the results of two genome-wide association studies (GWASs) in critically ill patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;We identified a total of 61 studies that evaluated genetic variants with various traits in adult intensive care patients, encompassing a total of 126 genetic loci and focussing on six clustered critical care-related traits. Assessment of the risk of bias across these studies revealed that 97% of the studies demonstrated some concerns or high risk of bias and only two studies (3%, both GWAS), had an overall low risk of bias. Only two significantly associated SNPs emerged from the two studies assessed to have a low risk of bias. One SNP (rs4957796) in FER was associated with 28-day survival (p = 3.4 × 10&lt;sup&gt;-9&lt;/sup&gt;) and mortality (p = 5.6 × 10&lt;sup&gt;-8&lt;/sup&gt;), and rs9508032 in FLT1 was associated with respiratory failure (p = 5.2 × 10&lt;sup&gt;-8&lt;/sup&gt;). Fifty-four significant associations were replicated in the candidate gene studies, but most had an overall high risk of bias. Only one association, of rs2569190 in CD14 with mortality, remained significant after multiple testing correction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;Our systematic review underscored a deficiency in high-quality genetic research in critical care medicine. The detected gaps emphasize an urgent need for additional rigorous genetic association studies that are preferably genome-wide, to enhance our understanding of the underlying mechanisms of critical illness.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;Wenbo Zhang was financially supported by a grant from the China Scholarship Council (File no. 202006210041). Carlos Flores was funded by Instituto de Salud Carlos III (PI23/00980 and CB06/06/1088) and co-financed by the European Regional Development Fund, \"A way of making Europe\" from the European Union; and the agreement OA23/043 with Instituto Tecnológico y de Energías Renovables (ITER) to strengthen scientific and technological education, training, research, development and scientific innovation in genomics, epidemiological surveillance based on massive sequencing, personalized medicine, and biotechnology. Eva Suarez-Pajes was financially supported by Agencia Canaria de Investigación, Innovación y Sociedad de la Inform","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105678"},"PeriodicalIF":9.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}