EBioMedicine最新文献

{"title":"Experimental medicine study with stabilised native-like HIV-1 Env immunogens drives long-term antibody responses, but lacks neutralising breadth.","authors":"Katrina M Pollock, Hannah M Cheeseman, Leon R McFarlane, Suzanne Day, Monica Tolazzi, Hannah L Turner, Jennifer Joypooranachandran, Katsiaryna Shramko, Stefania Dispinseri, Philipp Mundsperger, Ilja Bontjer, Nana-Marie Lemm, Sofia Coelho, Maniola Tanaka, Tom Cole, Bette Korber, Dietmar Katinger, Quentin J Sattentau, Andrew B Ward, Gabriella Scarlatti, Rogier W Sanders, Robin J Shattock","doi":"10.1016/j.ebiom.2024.105544","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105544","url":null,"abstract":"<p><strong>Background: </strong>We report findings from an experimental medicine study of rationally designed prefusion stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global circulating strains, delivered by sequential intramuscular injection.</p><p><strong>Methods: </strong>Healthy adult volunteers were enrolled into one of five groups (A to E) each receiving a different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO, either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic Env immunogens (Mos3.1 and Mos3.2). All immunogens were co-formulated with liposomal Monophosphoryl-Lipid A (MPLA) adjuvant, and volunteers were followed up for 28 days post final Mosaic booster injection. Participants gave written informed consent to join the study. The study is registered on ClinicalTrials.gov ID NCT03816137.</p><p><strong>Findings: </strong>Fifty-one participants (men n = 23 and women n = 28) aged 18-55 were enrolled. The seroconversion rate against Env was 100% with all participants having measurable anti-Env IgG antibodies after their second injection and throughout the study. Neutralisation was detected against the ConM pseudovirus in sera of those who had received both ConM and ConS immunogens. However, this activity was limited in breadth and was neither boosted nor broadened in those receiving the Mos3.1 and Mos3.2 immunogens. Neutralising antibody function correlated with binding to V1/V3 and V5 epitopes and peaked after the third injection.</p><p><strong>Interpretation: </strong>Rationally designed prefusion-stabilised native-like Env trimers are robustly immunogenic in a prime-boost schedule. When given alone they are insufficient to induce neutralising antibody titres of significant breadth, but they represent potentially valuable polishing immunogens after germline-targeting.</p><p><strong>Funding: </strong>European Aids Vaccine initiative (EAVI2020) received funding from EU Horizon 2020, grant number 681137. Structural studies were supported by the Bill and Melinda Gates Foundation (INV-002916).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105544"},"PeriodicalIF":9.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926844","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":"Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosis.","authors":"Zeyu Liu, Qi Zheng, Zhoubin Li, Moli Huang, Cheng Zhong, Ruize Yu, Rong Jiang, Haotian Dai, Jingyuan Zhang, Xiaohua Gu, Yongle Xu, Chunwei Li, Shan Shan, Feng Xu, Yue Hong, Tao Ren","doi":"10.1016/j.ebiom.2024.105538","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105538","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia with restrictive ventilation. Recently, the structural and functional defects of small airways have received attention in the early pathogenesis of IPF. This study aimed to elucidate the characteristics of small airway epithelial dysfunction in patients with IPF and explore novel therapeutic interventions to impede IPF progression by targeting the dysfunctional small airways.</p><p><strong>Methods: </strong>Airway trees spanning the proximal-distal axis were harvested from control lungs and explanted lungs with end-stage IPF undergoing transplant. Qualified basal cells (BCs, p63/Krt5/ITGA6/NGFR) were expanded, and their cellular functions, feasibility, safety and efficacy for transplantation therapy in IPF were validated with experiments in vitro and mouse model. Single-cell RNA-sequencing was employed to elucidate the underlying mechanisms governing the BCs based therapy. Based upon these evidences, three patients with advanced IPF and small airway dysfunction received autologous-BCs transplantation. Post-transplantation assessments included lung function, exercise capacity and high resolution computed tomography (HRCT) scans were analyzed to quantify the clinical benefits conferred by the BCs transplantation.</p><p><strong>Findings: </strong>An overall landscape of senescent phenotype in airway epithelial cells and airway stem/progenitor cells along the proximal-distal axis of the airway tree in IPF were outlined. In contrast to the cells situated in distal airways, BCs located in small bronchi in IPF displayed a non-senescent phenotype, with comparable proliferative, differentiative capabilities, and similar transcriptomic profiles to normal controls. In a mouse model of pulmonary fibrosis, BCs exhibited promising protective efficacy and safety for transplantation therapy. Autologous BCs transplantation in three advanced IPF patients with small airway dysfunction yielded significant clinical improvements in pulmonary function, particularly evidence in lung volume and small airway function.</p><p><strong>Interpretation: </strong>Epithelia of small bronchi in IPF contain functional and expandable basal stem cells, which exert therapeutic benefits via bronchoscopic implantation. Our findings offer a potential for IPF treatment by targeting small airways.</p><p><strong>Funding: </strong>National Natural Science Foundation of China (82430001, 81930001, and 81900059), Shanghai Shenkang Hospital Development Center (SHDC2020CR3063B), Department of Science and Technology of Shandong Province (2024HWYQ-058).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105538"},"PeriodicalIF":9.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926838","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":"New questions and avenues for research regarding interpretation of the significance of respiratory viruses adrift in the air.","authors":"John A Lednicky","doi":"10.1016/j.ebiom.2024.105524","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105524","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105524"},"PeriodicalIF":9.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926801","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 comparative cohort study of post-COVID-19 conditions based on physical examination records in China.","authors":"Zhong Liu, Boqiang Hu, Tao Zeng, Cuiping You, Nan Li, Yongjing Liu, Jie Zhang, Chenbing Liu, Piaopiao Jin, Xiaoxi Feng, Jun Chen, Jinyan Huang","doi":"10.1016/j.ebiom.2024.105549","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105549","url":null,"abstract":"<p><strong>Background: </strong>Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2 virus infection, is characterized as a multisystem disease, potentially yielding multifaceted consequences on various organs at multiple levels. At the end of 2022, over 90% of the Chinese population was infected by SARS-CoV-2 within 35 days because of adjustments to epidemic prevention and control policies. This short-term change provides an unprecedented opportunity for comparative studies on COVID-19 infection among large populations.</p><p><strong>Methods: </strong>In this study, the physical examination data of 136,713 people in the past three consecutive years was employed to study the impact of COVID-19. Standard physical examination data, comprising evaluations of nearly a hundred indicators, were investigated for a comprehensive assessment of COVID-19's effect on human health.</p><p><strong>Findings: </strong>The results suggested that most indicators remained stable or changed within a permissible range after the COVID-19 outbreak in December 2022, but several specific indicators presented abnormal patterns of varying durations. There was an observed increase in the fraction of T-wave abnormalities during the outbreak, especially in people with chronic diseases such as hypertension, liver steatosis, and hyperglycemia.</p><p><strong>Interpretation: </strong>These findings highlighted the impact of COVID-19 on cardiovascular health and its potential interaction with chronic diseases.</p><p><strong>Funding: </strong>This work was supported by the National Key Research and Development Program of China (2019YFE0108100), the National Natural Science Foundation of China General Program (82270159, 82070147).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105549"},"PeriodicalIF":9.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926776","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":"Corrigendum for \"Oxidized ATM-mediated glycolysis enhancement in breast cancer-associated fibroblasts contributes to tumor invasion through lactate as metabolic coupling\" [eBioMedicine 41 (2019) 370-383].","authors":"Kexin Sun, Shifu Tang, Yixuan Hou, Lei Xi, Yanlin Chen, Jiali Yin, Meixi Peng, Maojia Zhao, Xiaojiang Cui, Manran Liu","doi":"10.1016/j.ebiom.2024.105542","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105542","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105542"},"PeriodicalIF":9.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926833","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 factors shaping the plasma lipidome and the relations to cardiometabolic risk in children and adolescents.","authors":"Yun Huang, Sara Elizabeth Stinson, Malte Thodberg, Louise Aas Holm, Roman Thielemann, Karolina Sulek, Morten Asp Vonsild Lund, Cilius Esmann Fonvig, Min Kim, Kajetan Trost, Helene Bæk Juel, Trine Nielsen, Peter Rossing, Maja Thiele, Aleksander Krag, Cristina Legido-Quigley, Jens-Christian Holm, Torben Hansen","doi":"10.1016/j.ebiom.2024.105537","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105537","url":null,"abstract":"<p><strong>Background: </strong>Lipid species are emerging as biomarkers for cardiometabolic risk in both adults and children. The genetic regulation of lipid species and their impact on cardiometabolic risk during early life remain unexplored.</p><p><strong>Methods: </strong>Using mass spectrometry-based lipidomics, we measured 227 plasma lipid species in 1149 children and adolescents (44.8% boys) with a median age of 11.2 years. We performed genome-wide association analyses to identify genetic variants influencing lipid species. Colocalisation and Mendelian randomisation (MR) analyses were performed to infer causality between lipid species and cardiometabolic outcomes.</p><p><strong>Findings: </strong>We identified 37 genome-wide significant loci for 52 lipid species, nine of which are previously unreported. Colocalisation analyses revealed that seven lipid loci shared genetic variants associated with adult cardiometabolic outcomes. One-sample MR analysis identified positive causal associations between ceramides and liver enzymes, sphingomyelins and hemoglobin A1c (HbA1c), and phosphatidylethanolamines and high-sensitivity C-reactive protein in children and adolescents. Two-sample MR using adult-based summary statistics showed consistent direction of associations and indicated additional causal links, specifically between ceramides and elevated HbA1c levels, and phosphatidylinositols with elevated liver enzymes.</p><p><strong>Interpretation: </strong>These findings highlight the potential long-term implications of plasma lipid genetic determinants on cardiometabolic risk.</p><p><strong>Funding: </strong>Novo Nordisk Foundation, The Innovation Fund Denmark, The Danish Heart Foundation, EU Horizon, and LundbeckFonden.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105537"},"PeriodicalIF":9.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926797","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":"Evaluation of intestinal biopsy tissue preservation methods to facilitate large-scale mucosal microbiota research.","authors":"Nicola J Wyatt, Hannah Watson, Gregory R Young, Mary Doona, Ned Tilling, Dean Allerton, Andrea C Masi, Tariq Ahmad, Jennifer A Doyle, Katherine Frith, Ailsa Hart, Victoria Hildreth, Peter M Irving, Claire Jones, Nicholas A Kennedy, Sarah Lawrence, Charlie W Lees, Robert Lees, Trevor Liddle, James O Lindsay, Julian R Marchesi, Miles Parkes, Nick Powell, Natalie J Prescott, Tim Raine, Jack Satsangi, Kevin Whelan, Ruth Wood, Andrew King, Luke Jostins-Dean, R Alexander Speight, Naomi McGregor, Christopher J Stewart, Christopher A Lamb","doi":"10.1016/j.ebiom.2024.105550","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105550","url":null,"abstract":"<p><strong>Background: </strong>Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation ('flash freezing') limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions.</p><p><strong>Methods: </strong>We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene).</p><p><strong>Findings: </strong>Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions.</p><p><strong>Interpretation: </strong>Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples.</p><p><strong>Funding: </strong>Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105550"},"PeriodicalIF":9.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913983","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":"Clonal GZMK⁺CD8⁺ T cells are identified as a hallmark of the pathogenesis of cGVHD-induced bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation.","authors":"Yang Gao, Ruixiang Liu, Jiawei Shi, Wei Shan, Hongyu Zhou, Zhi Chen, Xiaoyan Yue, Jie Zhang, Yi Luo, Wenjue Pan, Xiujie Zhao, Xun Zeng, Weiwei Yin, Haowen Xiao","doi":"10.1016/j.ebiom.2024.105535","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105535","url":null,"abstract":"<p><strong>Background: </strong>Bronchiolitis obliterans syndrome (BOS) is one of the most devastating outcomes of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This remains an area of unmet clinical need for optimal therapy for BOS patients partly due to the limited understanding of pathogenic mechanisms.</p><p><strong>Methods: </strong>We collected blood samples from 22 patients with cGVHD and 11 patients without cGVHD following allo-HSCT. By applying a combination of mass cytometry (CyTOF), RNA-sequencing and the quantitative cytokine array, we discovered a new cellular hallmarker of patients with cGVHD-BOS. This finding was further validated in cGVHD-BOS murine models by using single-cell RNA sequencing (scRNA-seq) and paired single-cell V(D)J sequencing analyses.</p><p><strong>Findings: </strong>We revealed that circulating Granzyme K (GZMK)-expressing CD8⁺ T cells with increased expression of CCR5 were accumulated in cGVHD-BOS patients, and GZMK can induce the expression of fibrosis-essential proteins, collagen type I alpha 1 chain (COL1A1) and fibronectin (FN1), in human fibroblasts. As compared to those of control mice, GZMK⁺CD8⁺ T cells in the lungs of cGVHD-BOS mice were undergoing significant infiltration and clonal hyperexpansion, with more cytotoxic, pro-inflammatory, migratory and exhausted phenotypes. Moreover, we screened small-molecule drugs and revealed that Bosutinib, the second-generation BCR-ABL1-targeting tyrosine kinase inhibitor (TKI), could inhibit GZMK expression in CD8⁺ T cells and reduce lung stiffness and pulmonary fibrosis in cGVHD-BOS mice.</p><p><strong>Interpretation: </strong>This study provides proof-of-principle evidence for clonal GZMK⁺CD8⁺ T cells as an unexplored contributor to the pathogenesis of cGVHD-BOS, which can be an underlying biomarker for treatment.</p><p><strong>Funding: </strong>This work was supported by the National Natural Science Foundation of China (No. 82170141, 82100123, 81870136), and \"Pioneer\" and \"Leading Goose\" R&D Program of Zhejiang (grant No. 2022C03012).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105535"},"PeriodicalIF":9.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909317","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":"Assessing the outcomes of malaria intermittent preventive treatment during pregnancy on child growth trajectories.","authors":"Wei-Zhen Tang, Qin-Yu Cai, Tai-Hang Liu","doi":"10.1016/j.ebiom.2024.105547","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105547","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105547"},"PeriodicalIF":9.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909314","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":"miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthma.","authors":"Rinku Sharma, Kevin Mendez, Sofina Begum, Su Chu, Nicole Prince, Julian Hecker, Rachel S Kelly, Qingwen Chen, Craig E Wheelock, Juan C Celedón, Clary Clish, Robert Gertszen, Kelan G Tantisira, Scott T Weiss, Jessica Lasky-Su, Michael McGeachie","doi":"10.1016/j.ebiom.2024.105534","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105534","url":null,"abstract":"<p><strong>Background: </strong>There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma.</p><p><strong>Methods: </strong>We performed miRNAome-metabolome-wide association studies ('miR-metabo-WAS') in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (N_Baseline = 312 and N_{End of trial} = 454). We conducted a meta-analysis of the two cohorts to identify common contemporaneous associations between CAMP and GACRS (false-discovery rate (FDR) = 0.05). We assessed persistent miRNA-metabolome associations using baseline miRNAs and metabolomic profiling in CAMP at the end of the trial. The relation between miRNAs, metabolites and clinical phenotypes, including airway hyper-responsiveness (AHR), peripheral blood eosinophilia, and airflow obstruction, were then assessed via. Mediation analysis with 1000 bootstraps at an FDR significance level of 0.05.</p><p><strong>Findings: </strong>The meta-analysis yielded a total of 369 significant contemporaneous associations, involving 133 miRNAs and 60 metabolites. We identified 13 central hub metabolites (taurine, 12,13-diHOME, sebacate, 9-cis-retinoic acid, azelate, asparagine, C5:1 carnitine, cortisol, 3-methyladipate, inosine, NMMA, glycine, and Pyroglutamic acid) and four hub miRNAs (hsa-miR-186-5p, hsa-miR-143-3p, hsa-miR-192-5p, and hsa-miR-223-3p). Nine of these associations, between eight miRNAs and eight metabolites, were persistent in CAMP from baseline to the end of trial. Finally, five central hub metabolites (9-cis-retinoic acid, taurine, sebacate, azelate, and 12,13-diHOME) were identified as primary mediators in over 100 significant indirect miRNA-metabolite associations, with a collective influence on peripheral blood eosinophilia, AHR, and airflow obstruction.</p><p><strong>Interpretation: </strong>The robust association between miRNAs and metabolites, along with the substantial indirect impact of miRNAs via 5 hub metabolites on multiple clinical asthma metrics, suggests important integrated effects of miRNAs and metabolites on asthma. These findings imply that the indirect regulation of metabolism and cellular functions by miRNA influences Th2 inflammation, AHR, and airflow obstruction in childhood asthma.</p><p><strong>Funding: </strong>Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105534"},"PeriodicalIF":9.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909320","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}