EBioMedicine最新文献

{"title":"Which experimental factors govern successful animal-to-human translation in multiple sclerosis drug development? A systematic review and meta-analysis.","authors":"Ingrid Berg, Pia Härvelid, Wolfgang Emanuel Zürrer, Marianna Rosso, Daniel S Reich, Benjamin Victor Ineichen","doi":"10.1016/j.ebiom.2024.105434","DOIUrl":"10.1016/j.ebiom.2024.105434","url":null,"abstract":"<p><strong>Background: </strong>Despite successes in multiple sclerosis (MS) drug development, the effectiveness of animal studies in predicting successful bench-to-bedside translation is uncertain. Our goal was to identify predictors of successful animal-to-human translation for MS by systematically comparing animal studies of approved disease-modifying therapies (DMTs) with those that failed in clinical trials due to efficacy or safety concerns.</p><p><strong>Methods: </strong>Systematic review of animal studies testing MS DMTs, identified from searches in PubMed and EMBASE. A random effect meta-analysis was fitted to the data to compare outcome effect sizes for approved versus failed DMTs. Effect sizes and testing under diverse experimental conditions were assessed as potential predictors for successful translation.</p><p><strong>Findings: </strong>We included 497 animal studies, covering 15 approved and 11 failed DMTs, tested in approximately 30'000 animals. DMTs were tested in a small repertoire of experimental parameters: about 86% of studies used experimental autoimmune encephalomyelitis (EAE), 80% used mice, and 76% used female animals. There was no association between animal study outcomes or testing DMTs under varied conditions (e.g., different laboratories or models) and successful approval. Surprisingly, 91% of animal studies were published after first-in-MS trial and 91% after official regulatory approval.</p><p><strong>Interpretation: </strong>Our findings emphasize the complexity in carrying drugs from animals to clinical practice. Specific challenges include limited experimental methods in animal research and a disconnect between preclinical and clinical research. We advocate for efforts to streamline drug development for MS to improve animal research's relevance for patients.</p><p><strong>Funding: </strong>NIH, Swiss National Science Foundation, Universities Federation for Animal Welfare.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105434"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603849","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":"Longitudinal effects of SARS-CoV-2 breakthrough infection on imprinting of neutralizing antibody responses.","authors":"Sebastian Einhauser, Claudia Asam, Manuela Weps, Antonia Senninger, David Peterhoff, Stilla Bauernfeind, Benedikt Asbach, George William Carnell, Jonathan Luke Heeney, Monika Wytopil, André Fuchs, Helmut Messmann, Martina Prelog, Johannes Liese, Samuel D Jeske, Ulrike Protzer, Michael Hoelscher, Christof Geldmacher, Klaus Überla, Philipp Steininger, Ralf Wagner","doi":"10.1016/j.ebiom.2024.105438","DOIUrl":"10.1016/j.ebiom.2024.105438","url":null,"abstract":"<p><strong>Background: </strong>The impact of the infecting SARS-CoV-2 variant of concern (VOC) and the vaccination status was determined on the magnitude, breadth, and durability of the neutralizing antibody (nAb) profile in a longitudinal multicentre cohort study.</p><p><strong>Methods: </strong>173 vaccinated and 56 non-vaccinated individuals were enrolled after SARS-CoV-2 Alpha, Delta, or Omicron infection and visited four times within 6 months and nAbs were measured for D614G, Alpha, Delta, BA.1, BA.2, BA.5, BQ.1.1, XBB.1.5 and JN.1.</p><p><strong>Findings: </strong>Magnitude-breadth-analysis showed enhanced neutralization capacity in vaccinated individuals against multiple VOCs. Longitudinal analysis revealed sustained neutralization magnitude-breadth after antigenically distant Delta or Omicron breakthrough infection (BTI), with triple-vaccinated individuals showing significantly elevated titres and improved breadth. Antigenic mapping and antibody landscaping revealed initial boosting of vaccine-induced WT-specific responses after BTI, a shift in neutralization towards infecting VOCs at peak responses and an immune imprinted bias towards dominating WT immunity in the long-term. Despite that bias, machine-learning models confirmed a sustained shift of the immune-profiles following BTI.</p><p><strong>Interpretation: </strong>In summary, our longitudinal analysis revealed delayed and short lived nAb shifts towards the infecting VOC, but an immune imprinted bias towards long-term vaccine induced immunity after BTI.</p><p><strong>Funding: </strong>This work was funded by the Bavarian State Ministry of Science and the Arts for the CoVaKo study and the ForCovid project. The funders had no influence on the study design, data analysis or data interpretation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105438"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11585733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616646","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":"Development and evaluation of an antigen targeting lateral flow test for Crimean-Congo Haemorrhagic Fever.","authors":"Caitlin R Thompson, Ilkay Bozkurt, Yasemin Cosgun, Patricia Blundell, Annelyse Duvoix, Michael Johnson, Hakan Hedef, Fatma Gonca Arslan, Busra Ayyildiz Umudum, Heval Can Bilek, Esra Tanyel, Ayşe Nur Pektaş, Tuba Nur Taşseten, Mehmet Bakir, Seyit Ali Büyüktuna, Yildiz Olçar, Feray Aycan Yilmaz, Mustafa Arslan, Riyadh A Al-Hilfi, Hussein Alwan Hasan, Raghad Ibrahim Khaleel, Iman M Aufi, Sinan Ghazi Mahdi, Ihab R Aakef, Hawraa A Shakir, Ahmed A Hussein, Noora A Abdulhadi, Zainb A Mohsin, Gulay Korukluoglu, Ana I Cubas Atienzar, Tom E Fletcher, Emily Adams","doi":"10.1016/j.ebiom.2024.105460","DOIUrl":"10.1016/j.ebiom.2024.105460","url":null,"abstract":"<p><strong>Background: </strong>Crimean-Congo Haemorrhagic Fever (CCHF) is a viral haemorrhagic fever with a case fatality rate of 5-25% that has been prioritised for research and development by the World Health Organisation. There are no CCHF rapid diagnostic tests (RDTs) commercially available. We describe the development and evaluation of an antigen-targeting lateral flow immunoassay RDT for CCHF.</p><p><strong>Methods: </strong>Prospective clinical samples were collected and tested between July and October 2023 in Türkiye. Retrospective stored samples were obtained from the Central Public Health Laboratory, Baghdad, Iraq. The sensitivity and specificity of the CCHF RDT was compared to reverse transcription quantitative polymerase chain reaction assays.</p><p><strong>Findings: </strong>On prospective clinical samples in Türkiye, the sensitivity and specificity of the CCHF RDT was 90.4% [95% CI 81.5-95.3%] (n = 73) and 96.2% [95% CI 87.0-99.3%] (n = 52), respectively with a sensitivity of 92.9% [95% CI 84.3-96.9%] (n = 70) in samples with a cycle threshold (Ct) ≤30. On retrospective stored samples in Iraq, sensitivity and specificity of the RDT was 71.7% [95% CI 59.2-81.5%] (n = 60) and 92.5% [95% CI 80.1-97.8%] (n = 40), respectively with a sensitivity of 82.2% [95% CI 68.7-90.7%] (n = 45) in samples of Ct ≤30.</p><p><strong>Interpretation: </strong>The CCHF RDT was an effective rapid diagnostic test in this preliminary clinical evaluation, showing this RDT has the potential diagnostic capability for use at the point-of-care. Definitive evaluation is now required to ensure the RDT meets the regulatory requirements for commercialisation.</p><p><strong>Funding: </strong>The Liverpool School of Tropical Medicine, National Institute for Health Research Health Protection Research Unit in Emerging Zoonotic Infections, The Medical Research Council and The Pandemic Institute.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105460"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11617902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686373","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":"Exposure to air pollution increases susceptibility to ulcerative colitis through epigenetic alterations in CXCR2 and MHC class III region.","authors":"Jie Chen, Han Zhang, Tian Fu, Jianhui Zhao, Jan Krzysztof Nowak, Rahul Kalla, Judith Wellens, Shuai Yuan, Alexandra Noble, Nicholas T Ventham, Malcolm G Dunlop, Jonas Halfvarson, Ren Mao, Evropi Theodoratou, Jack Satsangi, Xue Li","doi":"10.1016/j.ebiom.2024.105443","DOIUrl":"10.1016/j.ebiom.2024.105443","url":null,"abstract":"<p><strong>Background: </strong>This study aims to confirm the associations of air pollution with ulcerative colitis (UC) and Crohn's disease (CD); to explore interactions with genetics and lifestyle; and to characterize potential epigenetic mechanisms.</p><p><strong>Methods: </strong>We identified over 450,000 individuals from the UK Biobank and investigated the relationship between air pollution and incident inflammatory bowel disease (IBD). Cox regression was utilized to calculate hazard ratios (HRs), while also exploring potential interactions with genetics and lifestyle factors. Additionally, we conducted epigenetic Mendelian randomization (MR) analyses to examine the association between air pollution-related DNA methylation and UC. Finally, our findings were validated through genome-wide DNA methylation analysis of UC, as well as co-localization and gene expression analyses.</p><p><strong>Findings: </strong>Higher exposures to NO_x (HR = 1.20, 95% CI 1.05-1.38), NO₂ (HR = 1.19, 95% CI = 1.03-1.36), PM_2.5 (HR = 1.19, 95% CI = 1.05-1.36) and combined air pollution score (HR = 1.26, 95% CI = 1.11-1.45) were associated with incident UC but not CD. Interactions with genetic risk score and lifestyle were observed. In MR analysis, we found five and 22 methylated CpG sites related to PM_2.5 and NO₂ exposure to be significantly associated with UC. DNA methylation alterations at CXCR2 and sites within the MHC class III region, were validated in genome-wide DNA methylation analysis, co-localization analysis and analysis of colonic tissue.</p><p><strong>Interpretation: </strong>We report a potential causal association between air pollution and UC, modified by lifestyle and genetic influences. Biological pathways implicated include epigenetic alterations in key genetic loci, including CXCR2 and susceptible loci within MHC class III region.</p><p><strong>Funding: </strong>Xue Li was supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (No. 82204019). ET was supported by the CRUK Career Development Fellowship (C31250/A22804) and the Research Foundation Flanders (FWO). JW was supported by Belgium by a PhD Fellowship strategic basic research (SB) grant (1S06023N). JKN was supported by the National Science Center, Poland (No. 2020/39/D/NZ5/02720). The IBD Character was supported by the European Union's Seventh Framework Programme [FP7] grant IBD Character (No. 2858546).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105443"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11605448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616642","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":"A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicity.","authors":"Yuhan Li, Xianwen Zhang, Wanbo Tai, Xinyu Zhuang, Huicheng Shi, Shumin Liao, Xinyang Yu, Rui Mei, Xingzhao Chen, Yanhong Huang, Yubin Liu, Jianying Liu, Yang Liu, Yibin Zhu, Penghua Wang, Mingyao Tian, Guocan Yu, Liang Li, Gong Cheng","doi":"10.1016/j.ebiom.2024.105437","DOIUrl":"10.1016/j.ebiom.2024.105437","url":null,"abstract":"<p><strong>Background: </strong>Global dissemination of SARS-CoV-2 Omicron sublineages has provided a sufficient opportunity for natural selection, thus enabling beneficial mutations to emerge. Characterisation of these mutations uncovers the underlying machinery responsible for the fast transmission of Omicron variants and guides vaccine development for combating the COVID-19 pandemic.</p><p><strong>Methods: </strong>Through systematic bioinformatics analysis of 496,606 sequences of Omicron variants, we obtained 40 amino acid substitutions that occurred with high frequency in the S protein. Utilising pseudoviruses and a trans-complementation system of SARS-CoV-2, we identified the effect of high-frequency mutations on viral infectivity and elucidated the molecular mechanisms. Finally, we evaluated the impact of a key emerging mutation on the immune protection induced by the SARS-CoV-2 VLP mRNA vaccine in a murine model.</p><p><strong>Findings: </strong>We identified a proline-to-leucine substitution at the 1263rd residue of the Spike protein, and upon investigating the relative frequencies across multiple Omicron sublineages, we found a trend of increasing frequency for P1263L. The substitution significantly enhances the capacity for S-mediated viral entry and improves the immunogenicity of a virus-like particle mRNA vaccine. Mechanistic studies showed that this mutation is located in the FERM binding motif of the cytoplasmic tail and impairs the interaction between the S protein and the Ezrin/Radixin/Moesin proteins. Additionally, this mutation facilitates the incorporation of S proteins into SARS-CoV-2 virions.</p><p><strong>Interpretation: </strong>This study offers mechanistic insight into the constantly increasing transmissibility of SARS-CoV-2 Omicron variants and provides a meaningful optimisation strategy for vaccine development against SARS-CoV-2.</p><p><strong>Funding: </strong>This study was supported by grants from the National Key Research and Development Plan of China (2021YFC2302405, 2022YFC2303200, 2021YFC2300200 and 2022YFC2303400), the National Natural Science Foundation of China (32188101, 32200772, 82422049, 82241082, 32270182, 82372254, 82271872, 82341046, 32100755 and 82102389), Shenzhen Medical Research Fund (B2404002, A2303036), the Shenzhen Bay Laboratory Startup Fund (21330111), Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases (SZSM202211023), Yunnan Provincial Science and Technology Project at Southwest United Graduate School (202302AO370010). The New Cornerstone Science Foundation through the New Cornerstone Investigator Program, and the Xplorer Prize from Tencent Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105437"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616739","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":"Screening for depression in the general population through lipid biomarkers.","authors":"Anna Tkachev, Elena Stekolshchikova, Anastasia Golubova, Anna Serkina, Anna Morozova, Yana Zorkina, Daria Riabinina, Elizaveta Golubeva, Aleksandra Ochneva, Valeria Savenkova, Daria Petrova, Denis Andreyuk, Anna Goncharova, Irina Alekseenko, Georgiy Kostyuk, Philipp Khaitovich","doi":"10.1016/j.ebiom.2024.105455","DOIUrl":"10.1016/j.ebiom.2024.105455","url":null,"abstract":"<p><strong>Background: </strong>Anxiety and depression significantly contribute to the overall burden of mental disorders, with depression being one of the leading causes of disability. Despite this, no biochemical test has been implemented for the diagnosis of these mental disorders, while recent studies have highlighted lipids as potential biomarkers.</p><p><strong>Methods: </strong>Using a streamlined high-throughput lipidome analysis method, direct-infusion mass spectrometry, we evaluated blood plasma lipid levels in 604 individuals from a general urban population and analysed their association with self-reported anxiety and depression symptoms. We also assessed lipidome profiles in 32 patients with clinical depression, matched to 21 healthy controls.</p><p><strong>Findings: </strong>We found a significant correlation between lipid abundances and the severity of self-reported depression symptoms. Moreover, lipid alterations detected in high scoring volunteers mirrored the lipidome profiles identified in patients with clinical depression included in our study. Based on these findings, we developed a lipid-based predictive model distinguishing individuals reporting severe depressive symptoms from non-depressed subjects with high accuracy.</p><p><strong>Interpretation: </strong>This study demonstrates the possibility of generalizing lipid alterations from a clinical cohort to the general population and underscores the potential of lipid-based biomarkers in assessing depressive states.</p><p><strong>Funding: </strong>This study was sponsored by the Moscow Center for Innovative Technologies in Healthcare, №2707-2, №2102-11.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105455"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11617895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686375","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":"Genomic insights for personalised care in lung cancer and smoking cessation: motivating at-risk individuals toward evidence-based health practices.","authors":"Tony Chen, Giang Pham, Louis Fox, Nina Adler, Xiaoyu Wang, Jingning Zhang, Jinyoung Byun, Younghun Han, Gretchen R B Saunders, Dajiang Liu, Michael J Bray, Alex T Ramsey, James McKay, Laura J Bierut, Christopher I Amos, Rayjean J Hung, Xihong Lin, Haoyu Zhang, Li-Shiun Chen","doi":"10.1016/j.ebiom.2024.105441","DOIUrl":"10.1016/j.ebiom.2024.105441","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer and tobacco use pose significant global health challenges, necessitating a comprehensive translational roadmap for improved prevention strategies such as cancer screening and tobacco treatment, which are currently under-utilised. Polygenic risk scores (PRSs) may further motivate health behaviour change in primary care for lung cancer in diverse populations. In this work, we introduce the GREAT care paradigm, which integrates PRSs within comprehensive patient risk profiles to motivate positive health behaviour changes.</p><p><strong>Methods: </strong>We developed PRSs using large-scale multi-ancestry genome-wide association studies and standardised PRS distributions across all ancestries. We validated our PRSs in 561,776 individuals of diverse ancestry from the GISC Trial, UK Biobank (UKBB), and All of Us Research Program (AoU).</p><p><strong>Findings: </strong>Significant odds ratios (ORs) for lung cancer and difficulty quitting smoking were observed in both UKBB and AoU. For lung cancer, the ORs for individuals in the highest risk group (top 20% versus bottom 20%) were 1.85 (95% CI: 1.58-2.18) in UKBB and 2.39 (95% CI: 1.93-2.97) in AoU. For difficulty quitting smoking, the ORs (top 33% versus bottom 33%) were 1.36 (95% CI: 1.32-1.41) in UKBB and 1.32 (95% CI: 1.28-1.36) in AoU.</p><p><strong>Interpretation: </strong>Our PRS-based intervention model leverages large-scale genetic data for robust risk assessment across populations, which will be evaluated in two cluster-randomised clinical trials. This approach integrates genomic insights into primary care, promising improved outcomes in cancer prevention and tobacco treatment.</p><p><strong>Funding: </strong>National Institutes of Health, NIH Intramural Research Program, National Science Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105441"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616645","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":"Circadian clock disruption impairs immune oscillation in chronic endogenous hypercortisolism: a multi-level analysis from a multicentre clinical trial.","authors":"Valeria Hasenmajer, Emilia Sbardella, Francesca Sciarra, Chiara Simeoli, Claudia Pivonello, Filippo Ceccato, Riccardo Pofi, Marianna Minnetti, Flavio Rizzo, Davide Ferrari, Ilaria Bonaventura, Federica Barbagallo, Elisa Giannetta, Danilo Alunni Fegatelli, Simone Conia, Roberto Navigli, Giorgio Arnaldi, Carla Scaroni, Rosario Pivonello, Daniele Gianfrilli, Mary Anna Venneri, Andrea M Isidori","doi":"10.1016/j.ebiom.2024.105462","DOIUrl":"10.1016/j.ebiom.2024.105462","url":null,"abstract":"<p><strong>Background: </strong>Glucocorticoids (GC) are potent entrainers of the circadian clock. However, their effects on biological rhythms in chronic human exposure have yet to be studied. Endogenous hypercortisolism (Cushing's Syndrome, CS) is a rare condition in which circadian disruption is sustained by a tumorous source of GC excess, offering the unique opportunity to investigate GC's chronic effects in vivo.</p><p><strong>Methods: </strong>In a 12-month prospective case-control multicentre trial, the daily fluctuations in the number of circulating peripheral blood mononuclear cells (PBMCs) and the time-specific expression of clock-related genes were analysed in a cohort of 68 subjects, 34 affected by CS and 34 matched controls. Cosinor mixed effects model, rhythmicity algorithms and machine learning techniques were applied to the multi-level dataset.</p><p><strong>Findings: </strong>Multiple, 5-point daily sampling revealed profound changes in the levels, amplitude, and rhythmicity of several PBMC populations during active CS, only partially restored after remission. Clock gene analyses in isolated PBMCs showed a significant flattening of circadian oscillation of CLOCK, PER1, PER2, PER3, and TIMELESS expression. In active CS, all methods confirmed a loss of rhythmicity of those genes which were circadian in the PBMCs of controls. Most, but not all, genes regained physiological oscillation after remission. Machine learning revealed that while combined time-course sets of clock genes were highly effective in separating patients from controls, immune profiling was efficient even as single time points.</p><p><strong>Interpretation: </strong>In conclusion, the oscillation of circulating immune cells is profoundly altered in patients with CS, representing a convergence point of circadian rhythm disruption and metabolic and steroid hormone imbalances. Machine learning techniques proved the superiority of immune profiling over parameters such as cortisol, anthropometric and metabolic variables, and circadian gene expression analysis to identify CS activity.</p><p><strong>Funding: </strong>The research leading to these results has received funding from the European Union in the context of the National Recovery and Resilience Plan, Investment PE8 - Project Age-It: \"Ageing Well in an Ageing Society\". This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022], the PRecisiOn Medicine to Target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Italian Ministry of Health, and through internal funding to Sapienza University of Rome.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105462"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754747","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":"The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome.","authors":"Laura Xicota, Lam-Ha T Dang, Alice Lee, Sharon Krinsky-McHale, Deborah Pang, Lisa Melilli, Sid O'Bryant, Rachel L Henson, Charles Laymon, Florence Lai, H Diana Rosas, Beau Ances, Ira Lott, Christy Hom, Bradley Christian, Sigan Hartley, Shahid Zaman, Elizabeth Head, Mark Mapstone, Zhezhen Jin, Wayne Silverman, Nicole Schupf, Benjamin Handen, Joseph H Lee","doi":"10.1016/j.ebiom.2024.105433","DOIUrl":"10.1016/j.ebiom.2024.105433","url":null,"abstract":"<p><strong>Background: </strong>Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.</p><p><strong>Methods: </strong>We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ₄₀, Aβ₄₂, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ₄₀, Aβ₄₂, tau, ptau181, and NfL) and amyloid and tau PET data.</p><p><strong>Findings: </strong>For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ₄₀ and Aβ₄₂ concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia.</p><p><strong>Interpretation: </strong>Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted.</p><p><strong>Funding: </strong>National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105433"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11570228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582456","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":"Physical inactivity exacerbates pathologic inflammatory signalling at the single cell level in patients with systemic lupus.","authors":"Sarah L Patterson, Hoang Van Phan, Chun Jimmie Ye, Cristina Lanata, Sebastián Cruz González, Joonsuk Park, Lindsey A Criswell, Kamil E Barbour, Jinoos Yazdany, Maria Dall'Era, Marina Sirota, Patricia Katz, Charles R Langelier","doi":"10.1016/j.ebiom.2024.105432","DOIUrl":"10.1016/j.ebiom.2024.105432","url":null,"abstract":"<p><strong>Background: </strong>Physical activity is an adjunctive therapy that improves symptoms in people living with systemic lupus erythematosus (SLE), yet the mechanisms underlying this benefit remain unclear.</p><p><strong>Methods: </strong>We carried out a cohort study of 123 patients with SLE enrolled in the California Lupus Epidemiology Study (CLUES). The primary predictor variable was self-reported physical activity, which was measured using a previously validated instrument. We analyzed peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data available from the cohort. From the scRNA-seq data, we compared immune cell frequencies, cell-specific gene expression, biological signalling pathways, and upstream cytokine activation states between physically active and inactive patients, adjusting for age, sex and race.</p><p><strong>Findings: </strong>We found that physical activity influenced immune cell frequencies, with sedentary patients most notably demonstrating greater CD4+ T cell lymphopenia (P_adj = 0.028). Differential gene expression analysis identified a transcriptional signature of physical inactivity across five cell types. In CD4+ and CD8+ T cells, this signature was characterized by 686 and 445 differentially expressed genes (P_adj < 0.1). Gene set enrichment analysis demonstrated enrichment of proinflammatory genes in the TNF-α signalling through NF-kB, interferon-γ (IFN-γ), IL2/STAT5, and IL6/JAK/STAT3 signalling pathways. Computational prediction of upstream cytokine activation states suggested CD4+ T cells from physically inactive patients exhibited increased activation of TNF-α, IFN-γ, IL1Β, and other proinflammatory cytokines. Network analysis demonstrated interconnectivity of genes driving the proinflammatory state of sedentary patients. Findings were consistent in sensitivity analyses adjusting for corticosteroid treatment and physical function.</p><p><strong>Interpretation: </strong>Taken together, our findings suggest a mechanistic explanation for the observed benefits of physical activity in patients with SLE. Specifically, we find that physical inactivity is associated with altered frequencies and transcriptional profiles of immune cell populations and may exacerbate pathologic inflammatory signalling via CD4+ and CD8+ T cells.</p><p><strong>Funding: </strong>This work was supported by the US National Institutes of Health (NIH) (R01 AR069616, K23HL138461-01A1, K23AT011768) the US CDC (U01DP0670), and the CZ Biohub.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"110 ","pages":"105432"},"PeriodicalIF":9.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616659","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}