EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-23DOI: 10.1016/j.ebiom.2025.105944
Yingzhou Xie, Zu Cao, Yi-Han Shi, Xiyue Shen, Le-Le Wang, Dong Weng, Jianfeng Zhang, Yiting Wang, Gang Li, Jin-Fu Xu
{"title":"Transposition of insertion sequence element from KPC plasmid enhances intracellular survival of Klebsiella pneumoniae.","authors":"Yingzhou Xie, Zu Cao, Yi-Han Shi, Xiyue Shen, Le-Le Wang, Dong Weng, Jianfeng Zhang, Yiting Wang, Gang Li, Jin-Fu Xu","doi":"10.1016/j.ebiom.2025.105944","DOIUrl":"10.1016/j.ebiom.2025.105944","url":null,"abstract":"<p><strong>Background: </strong>The convergence of plasmids encoding Klebsiella pneumoniae carbapenemase (KPC) and virulence determinants is increasingly reported in K. pneumoniae (Kpn). However, how KPC plasmids interfere with the virulence plasmid-mediated pathogen-host interactions, and the significance of this interference in the within-host adaption of hypervirulent carbapenem-resistant K. pneumoniae (Hv-CR-Kpn), remain unclear.</p><p><strong>Methods: </strong>An Hv-CR-Kpn variant based on ST11 CR-Kpn was created to determine the impact of capsular polysaccharide (CPS) in Kpn intracellular proliferation. Whole genome sequencing was conducted to find the cause of CPS loss. The biological significance of spontaneous CPS loss in Hv-CR-Kpn was ascertained with cell lines and murine model.</p><p><strong>Findings: </strong>The acquisition of virulence plasmid resulted in CPS hyperproduction of CR-Kpn, attenuating the bacterial adherence to eukaryotic cells and intracellular proliferation. Spontaneous CPS loss was observed in the Hv-CR-Kpn after phagocytosis by macrophage, as a result from insertion sequence (IS) element transposition from KPC plasmid to chromosomal CPS gene cluster. The loss of capsule hyperproduction enhanced both the in vitro intramacrophage proliferation and evasion of antibiotic killing in vivo of CR-Kpn. The IncF plasmids, the vector for multidrug resistance genes, were characterised as the main reservoir of IS elements in Kpn genomes.</p><p><strong>Interpretation: </strong>Loss of CPS production enhances the Kpn intracellular proliferation, facilitating evasion of antimicrobial killing. In addition to encoding carbapenemase, IS element transposition acts as an auxiliary mechanism by which the KPC plasmid promotes the adaptive evolution of Hv-CR-Kpn, aiding bacterial survival within the host environment.</p><p><strong>Funding: </strong>Noncommunicable Chronic Diseases-National Science and Technology Major Project of China, National Natural Science Foundation of China, Key Scientific Innovation Project of Shanghai Municipal Education Commission and Shanghai Sailing Program.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105944"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-30DOI: 10.1016/j.ebiom.2025.105955
Felix S Bott, Paul Theo Zebhauser, Vanessa D Hohn, Özgün Turgut, Elisabeth S May, Laura Tiemann, Cristina Gil Ávila, Henrik Heitmann, Moritz M Nickel, Melissa A Day, Divya B Adhia, Yoni K Ashar, Tor D Wager, Yelena Granovsky, David Yarnitsky, Mark P Jensen, Joachim Gross, Markus Ploner
{"title":"Exploring electroencephalographic chronic pain biomarkers: a mega-analysis.","authors":"Felix S Bott, Paul Theo Zebhauser, Vanessa D Hohn, Özgün Turgut, Elisabeth S May, Laura Tiemann, Cristina Gil Ávila, Henrik Heitmann, Moritz M Nickel, Melissa A Day, Divya B Adhia, Yoni K Ashar, Tor D Wager, Yelena Granovsky, David Yarnitsky, Mark P Jensen, Joachim Gross, Markus Ploner","doi":"10.1016/j.ebiom.2025.105955","DOIUrl":"10.1016/j.ebiom.2025.105955","url":null,"abstract":"<p><strong>Background: </strong>Chronic pain is associated with alterations in brain function, offering promising avenues for advancing diagnostic and therapeutic strategies. In particular, these alterations may serve as brain-based biomarkers to support diagnosis, guide treatment decisions and monitor clinical courses of chronic pain.</p><p><strong>Methods: </strong>Motivated by this potential, this study analysed associations between chronic pain and changes of large-scale brain network function using resting-state electroencephalography (EEG) from 614 individuals with chronic pain, collected by research groups from Australia, Germany, Israel, New Zealand, and the US.</p><p><strong>Findings: </strong>Employing a discovery-replication approach, we found limited replicability of associations between pain intensity and brain network connectivity. However, a mega-analysis combining all datasets revealed robust associations between pain intensity and large-scale brain network connectivity at theta frequencies and including the limbic network. Additionally, multivariate analyses identified connectivity patterns spanning theta, alpha, and beta frequencies with strong evidence for associations with pain intensity. Variations and ablations of model features yielded deeper insights into the relative importance of distinct electrophysiological brain features in assessing chronic pain.</p><p><strong>Interpretation: </strong>Our findings highlight challenges and provide guidance for developing EEG-based, scalable, and affordable biomarkers of chronic pain.</p><p><strong>Funding: </strong>This project was funded by the Deutsche Forschungsgemeinschaft and the Technical University of Munich.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105955"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12517086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-30DOI: 10.1016/j.ebiom.2025.105951
Beatriz Guillen-Guio, Eva Suarez-Pajes, Eva Tosco-Herrera, Tamara Hernandez-Beeftink, Jose Miguel Lorenzo-Salazar, Diana Chang, Rafaela González-Montelongo, Luis A Rubio-Rodríguez, Olivia C Leavy, Richard J Allen, Almudena Corrales, Raquel Cruz, Miguel Bardají-Carrillo, Angel Carracedo, Eduardo Tamayo, V Eric Kerchberger, Lorraine B Ware, Brian L Yaspan, Markus Scholz, André Scherag, Jesús Villar, Louise V Wain, Carlos Flores
{"title":"Genome-wide association study of susceptibility to acute respiratory distress syndrome.","authors":"Beatriz Guillen-Guio, Eva Suarez-Pajes, Eva Tosco-Herrera, Tamara Hernandez-Beeftink, Jose Miguel Lorenzo-Salazar, Diana Chang, Rafaela González-Montelongo, Luis A Rubio-Rodríguez, Olivia C Leavy, Richard J Allen, Almudena Corrales, Raquel Cruz, Miguel Bardají-Carrillo, Angel Carracedo, Eduardo Tamayo, V Eric Kerchberger, Lorraine B Ware, Brian L Yaspan, Markus Scholz, André Scherag, Jesús Villar, Louise V Wain, Carlos Flores","doi":"10.1016/j.ebiom.2025.105951","DOIUrl":"10.1016/j.ebiom.2025.105951","url":null,"abstract":"<p><strong>Background: </strong>Acute respiratory distress syndrome (ARDS) is a severe inflammatory process of the lung, often due to sepsis, and poses significant mortality burden in intensive care units. Here we conducted a genome-wide association study (GWAS) of ARDS to identify genetic risk loci that can help guide the development of new therapeutic options.</p><p><strong>Methods: </strong>We performed a case-control GWAS in 716 cases with ARDS, mainly associated with severe infections, and 4399 at-risk controls from three independent studies. Results were meta-analysed across the three studies, with significance set at p < 5 × 10<sup>-8</sup>. Suggestive associations were declared for variants exhibiting consistent direction of effects, likely to replicate and nominal significance (p < 0.05) in all three studies. Prioritised loci were subjected to Bayesian fine mapping, in-silico functional assessments, and gene-based rare variant collapsing analysis using whole-exome sequencing data. Two independent studies with 430 ARDS cases and 1398 at-risk controls served as validation samples.</p><p><strong>Findings: </strong>We identified a variant near HMGCR that showed genome-wide significant association with ARDS and had been previously linked to cholesterol metabolism. This locus was associated with ANKDD1B expression in artery. The rare exonic variant analysis showed associations between HMGCR and ARDS at nominal level (p < 0.05). While no nominal significance was achieved in the two additional validation cohorts, this variant exhibited a consistent direction of effects across all 5 studies.</p><p><strong>Interpretation: </strong>A common variant near HMGCR was associated with ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed.</p><p><strong>Funding: </strong>Wellcome Trust, National Institute for Health Research Leicester Biomedical Research Centre, National Heart, Lung, and Blood Institute, ATS Research Program, Gobierno de Canarias, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Instituto Tecnológico y de Energías Renovables, Cabildo Insular de Tenerife, Instituto de Salud Carlos III, Agencia Estatal de Investigación, German Ministry of Education and Research, Thuringian Ministry of Education, Science and Culture, the Thuringian Foundation for Technology, Innovation, and Research, German Sepsis Society.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105951"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-29DOI: 10.1016/j.ebiom.2025.105948
Alisa Huber, Albert L Groenendijk, Adriana Navas, Nadira Vadaq, Suzanne D E Ruijten, Vasiliki Matzaraki, Ezio T Fok, Aysel Gurbanova, Wilhelm A J W Vos, Marc J T Blaauw, Louise E van Eekeren, Maartje C P Jacobs-Cleophas, Janneke Stalenhoef, Marvin Berrevoets, Renate van der Molen, Arnold van der Meer, Marien I de Jonge, Joost H A Martens, Casper Rokx, Annelies Verbon, Jan van Lunzen, Hans J P M Koenen, Mihai G Netea, Andre J A M van der Ven, Leo A B Joosten, Jéssica C Dos Santos
{"title":"Phenotypic and epigenetic profiles of circulating NK cells in spontaneous HIV-1 controllers.","authors":"Alisa Huber, Albert L Groenendijk, Adriana Navas, Nadira Vadaq, Suzanne D E Ruijten, Vasiliki Matzaraki, Ezio T Fok, Aysel Gurbanova, Wilhelm A J W Vos, Marc J T Blaauw, Louise E van Eekeren, Maartje C P Jacobs-Cleophas, Janneke Stalenhoef, Marvin Berrevoets, Renate van der Molen, Arnold van der Meer, Marien I de Jonge, Joost H A Martens, Casper Rokx, Annelies Verbon, Jan van Lunzen, Hans J P M Koenen, Mihai G Netea, Andre J A M van der Ven, Leo A B Joosten, Jéssica C Dos Santos","doi":"10.1016/j.ebiom.2025.105948","DOIUrl":"10.1016/j.ebiom.2025.105948","url":null,"abstract":"<p><strong>Background: </strong>NK cells play a key role in eliminating HIV-infected cells, but it is unclear whether there are specific NK cell receptor signatures in spontaneous HIV controllers.</p><p><strong>Methods: </strong>We conducted a cross-sectional analysis of circulating NK cell phenotypes in people living with HIV (PLHIV), divided into spontaneous HIV controllers (HIC), normal progressors on antiretroviral therapy (non-HIC), and first-degree HIV-negative family members. Using supervised and unsupervised flow cytometry, we assessed NK cell markers and receptors. We performed an epigenetic analysis of H3K4me3 chromatin enrichment in NK cells from both HIC and non-HIC and measured IFNγ, Perforin and CD107a expression in NK cells upon stimulation with IL-2/IL-15, K562 cells, and IFNα. Additionally, we conducted a genome-wide association study (GWAS) and quantitative trait locus (QTL) mapping using data from HIC and non-HIC part of the 2000HIV study.</p><p><strong>Findings: </strong>HIV controllers had higher levels of CD56<sup>bright</sup> NK cells and increased expression of NKp46, NKp30, and DNAM-1. The genetic association between protective MHC class I alleles and the NK cell receptor KIR2DL2/3 supports a genetic predisposition to HIV control. Unsupervised clustering identified an HIV-induced NK cell population, separate from CMV-induced NK cells. Epigenetic analysis revealed greater H3K4me3 marks in genes involved in immune response pathways, including IFNα, IL-15, and IL-2. The memory-like NK cell subpopulation was characterised by elevated expression of NKG2C and ILT2, with reduced KIR2DL2/3 in HIC. These memory NK cells were more responsive to stimulation with IFNα, resulting in increased production of IFNγ in HIC.</p><p><strong>Interpretation: </strong>These results suggest that spontaneous HIV control is associated with an NK cell memory phenotype, shaped by HIV infection, epigenetic modifications, and genetic factors.</p><p><strong>Funding: </strong>The authors are part of the 2000HIV study, which is supported by ViiV Healthcare.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105948"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-17DOI: 10.1016/j.ebiom.2025.105905
Florian Deisenhammer, Harald Hegen, Georgina Arrambide, Brenda L Banwell, Tim Coetzee, Sharmilee Gnanapavan, Xavier Montalban, Hayrettin Tumani, Maria A Willrich, Mark S Freedman
{"title":"Positive cerebrospinal fluid in the 2024 McDonald criteria for multiple sclerosis.","authors":"Florian Deisenhammer, Harald Hegen, Georgina Arrambide, Brenda L Banwell, Tim Coetzee, Sharmilee Gnanapavan, Xavier Montalban, Hayrettin Tumani, Maria A Willrich, Mark S Freedman","doi":"10.1016/j.ebiom.2025.105905","DOIUrl":"10.1016/j.ebiom.2025.105905","url":null,"abstract":"<p><p>The 2024 McDonald diagnostic criteria for Multiple Sclerosis (MS) introduce kappa free light chains (κ-FLC) detection in cerebrospinal fluid (CSF) which can be used interchangeably with oligoclonal IgG bands (OCB) to demonstrate intrathecal immunoglobulin synthesis. Diagnostic sensitivity and specificity of κ-FLC is equal to OCB on a 95% confidence level. In rare cases determination of both, κ-FLC and OCB should be considered as the concordance rate is around 90%. We recommend calculating the κ-FLC index with values of ≥6.1 performing best for diagnosing MS. Validated turbidimetric or nephelometric assays should be applied for which proficiency testing programs are available. There is some prognostic use of the κ-FLC index with higher values predicting higher disease activity. Neurofilament light (NfL) should not be used for diagnostic purposes although it might be useful for prognosis and disease monitoring. All recommendations apply to paediatric and adult relapsing as well as progressive onset MS.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105905"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085364","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}
EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-25DOI: 10.1016/j.ebiom.2025.105950
Cyprian M Mostert, Chinedu Udeh-Momoh, Andrea Sylvia Winkler, Connor McLaughlin, Harris Eyre, Mohamed Salama, Kirti Ranchod, Dominic Trepel, George Vradenburg, William Hynes, Graham Fieggen, Shehzad Ali, Najat E L Mekkaoui, Alan Landay, Kirsten Bobrow, Levi Muyela, Kelly Atkins, Antonella Santuccione Chadha, Roberta Marongiu, Mariapaola Barbato, Sam Nightingale, John Joska, Alfred K Njamnshi, Mie Rizig, James G Kahn, Karen Blackmon, Zul Merali, Agustin Ibanez
{"title":"Broadening dementia risk models: building on the 2024 Lancet Commission report for a more inclusive global framework.","authors":"Cyprian M Mostert, Chinedu Udeh-Momoh, Andrea Sylvia Winkler, Connor McLaughlin, Harris Eyre, Mohamed Salama, Kirti Ranchod, Dominic Trepel, George Vradenburg, William Hynes, Graham Fieggen, Shehzad Ali, Najat E L Mekkaoui, Alan Landay, Kirsten Bobrow, Levi Muyela, Kelly Atkins, Antonella Santuccione Chadha, Roberta Marongiu, Mariapaola Barbato, Sam Nightingale, John Joska, Alfred K Njamnshi, Mie Rizig, James G Kahn, Karen Blackmon, Zul Merali, Agustin Ibanez","doi":"10.1016/j.ebiom.2025.105950","DOIUrl":"10.1016/j.ebiom.2025.105950","url":null,"abstract":"<p><p>The 2024 Lancet Commission Report on dementia prevention has identified 14 modifiable risk factors that account for approximately 45% of global dementia cases. We used a global multidimensional approach that integrates gender equity considerations, poverty, wealth shocks, income inequality and HIV infection rates to identify additional risk factors beyond those reported in 2024 report. This methodological framework aims to enhance equitable prevention strategies to mitigate the global burden of dementia. We demonstrate that adding four additional risk factors: poverty, wealth shocks, income inequality, and HIV, while also considering the influences of sex and gender will improve the global applicability of the 2024 report. This is important because, despite dementia primarily affecting women, 57% of the risk factors identified in the 2024 report are more prevalent in men. Our analysis suggests that incorporating these four additional factors could potentially increase the proportion of preventable dementia cases to about 65%. This approach would also reshape the understanding of dementia risk, indicating that around 56% of modifiable risks disproportionately impact women. Expanding risk models in this manner is crucial for developing equitable and effective global dementia prevention strategies, particularly in underrepresented regions. We present these considerations as enhancements to the Commission's significant work.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105950"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Brain-clinical signatures of basal ganglia-related dysfunctional reorganisation in Parkinson's disease.","authors":"Lili Chen, Lianglong Sun, Junyan Sun, Junling Wang, Dongling Zhang, Mingrui Xia, Tao Wu","doi":"10.1016/j.ebiom.2025.105917","DOIUrl":"10.1016/j.ebiom.2025.105917","url":null,"abstract":"<p><strong>Background: </strong>The hierarchical organisation of functional networks is crucial for integration and segregation, and its dysregulation is implicated in neurodegenerative progression. The basal ganglia (BG) is the communication hub of the BG-thalamo-cortical circuit, and its dysfunction drives the progression of clinical symptoms in Parkinson's disease (PD). However, network-level functional reorganisation of BG disruption remains unclear.</p><p><strong>Methods: </strong>In this cross-sectional study, we applied functional gradient analysis based on a diffusion map embedding algorithm to delineate macroscale functional architectures of BG in 102 PD patients and 88 healthy controls (HCs). Partial least squares correlation analysis was employed to investigate the relationship between gradient alterations and clinical symptoms in PD.</p><p><strong>Findings: </strong>The first functional gradient of BG extended from caudate nucleus to putamen, whereas second gradient was anchored at dorsal and ventral caudate nucleus. In PD patients, the first gradient showed significant global compression with the progression from unilateral to bilateral motor symptoms. The second gradient exhibited local disruptions in nucleus accumbens and putamen, driven by reduced connectivity with multiple functional systems. Gradient scores of these two nuclei displayed significant lateralisation in PD, regardless of motor deficit dominance. Dysfunctional gradients in PD are associated with motor deficits and emotional symptoms.</p><p><strong>Interpretation: </strong>Our findings reveal that functional gradient reorganisation is a network-level signature of early-stage PD, linking functional reorganisation in BG circuit to clinical symptoms. The hemispheric asymmetry of gradient patterns may inform ongoing research on PD lateralisation.</p><p><strong>Funding: </strong>National Natural Science Foundation of China (Nos. 82071423 and 82021004) and Beijing Natural Science Foundation (No. JQ23033).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105917"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052392","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}
EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-17DOI: 10.1016/j.ebiom.2025.105932
Arturo Roca-Rivada, Junior Garcia Oliveira, Eugenia Martin-Vazquez, Alexandra Coomans de Brachène, Xiaoyan Yi, Jose Maria Costa-Júnior, Priscila L Zimath, Flore Van Goethem, François Pattou, Julie Kerr-Conte, Antoine Buemi, Nizar I Mourad, Decio L Eizirik
{"title":"The type 1 diabetes candidate genes PTPN2 and BACH2 regulate the IFN-α-induced crosstalk between JAK/STAT and MAPKs pathways in human beta cells.","authors":"Arturo Roca-Rivada, Junior Garcia Oliveira, Eugenia Martin-Vazquez, Alexandra Coomans de Brachène, Xiaoyan Yi, Jose Maria Costa-Júnior, Priscila L Zimath, Flore Van Goethem, François Pattou, Julie Kerr-Conte, Antoine Buemi, Nizar I Mourad, Decio L Eizirik","doi":"10.1016/j.ebiom.2025.105932","DOIUrl":"10.1016/j.ebiom.2025.105932","url":null,"abstract":"<p><strong>Background: </strong>Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the progressive loss of pancreatic beta cells. Interferons (IFNs) contribute to the initiation and amplification of beta cell autoimmunity. STAT1 is the main mediator of IFN signalling but little is known about its complex activation processes and role in the progression of beta cell failure.</p><p><strong>Methods: </strong>We investigated the IFN-α-stimulated STAT1 pathway from three human beta cell models: EndoC-βH1 cells, iPSC-derived islet-like cells and human islets by directly targeting two T1D candidate genes, namely PTPN2 and BACH2.</p><p><strong>Findings: </strong>We presently show that PTPN2 and BACH2 modulate STAT1 activation via two different pathways, namely the JAK/STAT, involved in the phosphorylation of its tyrosine residue (Y701), and the MAPKs pathway, involved in the phosphorylation of its serine residue (S727). Each STAT1 phosphorylation type can independently induce expression of CXCL10, but both residues are necessary for the expression of MHC class I molecules. IFN-α-induced STAT1 activation is dynamic and residue-dependent, being STAT1-Y701 fast but transitory, while STAT1-S727 increases slowly and is associated with the long-term effects of IFN-α exposure.</p><p><strong>Interpretation: </strong>The present findings provide a better understanding of the dynamics of STAT1 activation in human beta cells and will be useful to develop new and targeted (i.e. favouring individuals with particular polymorphisms) therapies for T1D and other autoimmune diseases.</p><p><strong>Funding: </strong>EFSD and Sanofi European Diabetes Research Programme on autoimmunity in type 1 diabetes; Breakthrough T1D, HIRN-CBDS, NIDDK, Fondation Saint-Luc, Programme d'Investissement d'Avenir' to European Genomic Institute for Diabetes, and Fondation de la Recherche Médicale.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105932"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-17DOI: 10.1016/j.ebiom.2025.105939
Dong June Lee, Minku Song, Soohyun Lim, Sanghyeon Park, Hyejin Kim, Yeeun Ahn, Faith Choi, Woojae Myung, Hong-Hee Won
{"title":"Identification of potential therapeutic targets for problematic alcohol use using multi-omics data.","authors":"Dong June Lee, Minku Song, Soohyun Lim, Sanghyeon Park, Hyejin Kim, Yeeun Ahn, Faith Choi, Woojae Myung, Hong-Hee Won","doi":"10.1016/j.ebiom.2025.105939","DOIUrl":"10.1016/j.ebiom.2025.105939","url":null,"abstract":"<p><strong>Background: </strong>Problematic alcohol use (PAU) is a serious global health issue with limited treatment options. Although genetic studies have identified genomic regions associated with PAU, the specific causal genes and proteins remain unclear. This study aimed to identify these causal genes by integrating diverse genetic and molecular data to inform better treatment strategies.</p><p><strong>Methods: </strong>We used Mendelian randomisation (MR) to identify genes and proteins that may cause PAU by combining genetic data with gene activity in brain and blood tissues. Multiple statistical tests confirmed shared genetic signals between expression and PAU. We also examined their effects on other traits and potential interactions with existing drugs.</p><p><strong>Findings: </strong>We identified 97 genes and 13 proteins that are likely to play a causal role in PAU through MR, with strong enrichment in brain tissues. These associations remained significant after Bonferroni correction and were further supported by colocalisation analyses (posterior probability of hypothesis 4 > 0.75) and consistency across multiple datasets. Some targets also showed concordant effects with PAU on other health outcomes, supported by Bonferroni-significant associations in phenome-wide analyses, suggesting potential for drug repurposing.</p><p><strong>Interpretation: </strong>This study highlights molecular signatures in both brain and blood tissues that may contribute to the development of PAU. Integrative multi-omics analyses revealed shared biological pathways across neural and peripheral systems, suggesting the potential for developing multi-systemic interventions with favourable safety profiles.</p><p><strong>Funding: </strong>This study was supported by Samsung Research Fund, Sungkyunkwan University, 2023.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105939"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EBioMedicinePub Date : 2025-10-01Epub Date: 2025-09-19DOI: 10.1016/j.ebiom.2025.105930
Badrieh Fazeli, Sara Botzenhardt, Franziska Bachhuber, Paula Klassen, Veronika Klose, Johannes Dorst, Maximilian Wiesenfarth, Zeljko Uzelac, Sarah Jesse, David Brenner, Sarah Anderl-Straub, Albert C Ludolph, Markus Otto, Jochen Weishaupt, Hayrettin Tumani, Steffen Halbgebauer
{"title":"Comparative analysis of cerebrospinal fluid neurofilament medium, light and heavy chain in neurodegenerative diseases using an in-house assay for the detection of neurofilament medium chain.","authors":"Badrieh Fazeli, Sara Botzenhardt, Franziska Bachhuber, Paula Klassen, Veronika Klose, Johannes Dorst, Maximilian Wiesenfarth, Zeljko Uzelac, Sarah Jesse, David Brenner, Sarah Anderl-Straub, Albert C Ludolph, Markus Otto, Jochen Weishaupt, Hayrettin Tumani, Steffen Halbgebauer","doi":"10.1016/j.ebiom.2025.105930","DOIUrl":"10.1016/j.ebiom.2025.105930","url":null,"abstract":"<p><strong>Background: </strong>Neurofilaments are key axonal proteins, with neurofilament light (NfL) and heavy (NfH) chain recognised as promising biomarkers for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, neurofilament medium chain (NfM) remained previously underexplored due to a lack of quantitative assays. In this study, we developed a sensitive immunoassay to measure NfM in cerebrospinal fluid (CSF) and analysed its levels in ALS, Alzheimer's disease (AD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Correlations among neurofilaments and their diagnostic performance were also evaluated.</p><p><strong>Methods: </strong>In this study CSF levels of three neurofilament proteins were measured in 305 participants, including patients with ALS (n = 91), AD (n = 59), FTD (n = 38), LBD (n = 18), non-neurodegenerative controls (CTRL, n = 51), and 48 individuals initially evaluated for ALS but ultimately diagnosed with other conditions (CTRL.DD). NfM levels were quantified using a homemade sandwich ELISA, while NfL and NfH were measured using commercialised Ella cartridges.</p><p><strong>Findings: </strong>All three neurofilaments were significantly elevated in ALS compared to CTRL and CTRL.DD groups (p < 0.0001 for both), with NfM and NfL also increased in FTD (p < 0.0001 for both) and AD (NfM, p < 0.0001; NfL, p = 0.0001) compared to CTRL. NfH demonstrated the greatest distinction between ALS and FTD (p < 0.0001). Strong correlations were observed among neurofilament subunits, particularly between NfM and NfL (r = 0.93, 95% CI: 0.91-0.94, p < 0.0001). All neurofilaments effectively distinguished ALS from CTRL and CTRL.DD, with AUC values ranging from 0.92 to 0.99. NfM and NfL showed high accuracy in differentiating AD (NfM, AUC: 0.91; NfL, AUC: 0.89) and FTD (NfM, AUC: 0.91; NfL, AUC: 0.92) from CTRL, while NfH best separated ALS from FTD (AUC: 0.96).</p><p><strong>Interpretation: </strong>This study provides a quantitative comparison of NfM with NfL and NfH in a neurodegenerative cohort, highlighting its potential diagnostic value. Further research with larger cohorts, longitudinal studies, and investigations into neurofilament distribution in different compartments is needed to clarify the distinct roles of NfM, NfL, and NfH in the diagnosis and treatment of neurological diseases.</p><p><strong>Funding: </strong>The present study was supported by the Else Kroener-Fresenius Foundation (2024-EKEA.126) and Chemische Fabrik Karl Bucher GmbH.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105930"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}