Genome Medicine最新文献

{"title":"Identification of tumor rejection antigens and the immunologic landscape of medulloblastoma.","authors":"Changlin Yang, Vrunda Trivedi, Kyle Dyson, Tongjun Gu, Kate M Candelario, Oleg Yegorov, Duane A Mitchell","doi":"10.1186/s13073-024-01363-y","DOIUrl":"10.1186/s13073-024-01363-y","url":null,"abstract":"<p><strong>Background: </strong>The current standard of care treatments for medulloblastoma are insufficient as these do not take tumor heterogeneity into account. Newer, safer, patient-specific treatment approaches are required to treat high-risk medulloblastoma patients who are not cured by the standard therapies. Immunotherapy is a promising treatment modality that could be key to improving survival and avoiding morbidity. For an effective immune response, appropriate tumor antigens must be targeted. While medulloblastoma patients with subgroup-specific genetic substitutions have been previously reported, the immunogenicity of these genetic alterations remains unknown. The aim of this study is to identify potential tumor rejection antigens for the development of antigen-directed cellular therapies for medulloblastoma.</p><p><strong>Methods: </strong>We developed a cancer immunogenomics pipeline and performed a comprehensive analysis of medulloblastoma subgroup-specific transcription profiles (n = 170, 18 WNT, 46 SHH, 41 Group 3, and 65 Group 4 patient tumors) available through International Cancer Genome Consortium (ICGC) and European Genome-Phenome Archive (EGA). We performed in silico antigen prediction across a broad array of antigen classes including neoantigens, tumor-associated antigens (TAAs), and fusion proteins. Furthermore, we evaluated the antigen processing and presentation pathway in tumor cells and the immune infiltrating cell landscape using the latest computational deconvolution methods.</p><p><strong>Results: </strong>Medulloblastoma patients were found to express multiple private and shared immunogenic antigens. The proportion of predicted TAAs was higher than neoantigens and gene fusions for all molecular subgroups, except for sonic hedgehog (SHH), which had a higher neoantigen burden. Importantly, cancer-testis antigens, as well as previously unappreciated neurodevelopmental antigens, were found to be expressed by most patients across all medulloblastoma subgroups. Despite being immunologically cold, medulloblastoma subgroups were found to have distinct immune cell gene signatures.</p><p><strong>Conclusions: </strong>Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with important implications for the development of immunotherapy for medulloblastoma.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"102"},"PeriodicalIF":10.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolutionary dependency of cancer mutations in gene pairs inferred by nonsynonymous-synonymous mutation ratios.","authors":"Dong-Jin Han, Sunmin Kim, Seo-Young Lee, Youngbeen Moon, Su Jung Kang, Jinseon Yoo, Hye Young Jeong, Hae Jin Cho, Jeong Yang Jeon, Byeong Chang Sim, Jaehoon Kim, Seungho Lee, Ruibin Xi, Tae-Min Kim","doi":"10.1186/s13073-024-01376-7","DOIUrl":"10.1186/s13073-024-01376-7","url":null,"abstract":"<p><strong>Background: </strong>Determining the impact of somatic mutations requires understanding the functional relationship of genes acquiring mutations; however, it is largely unknown how mutations in functionally related genes influence each other.</p><p><strong>Methods: </strong>We employed non-synonymous-to-synonymous or dNdS ratios to evaluate the evolutionary dependency (ED) of gene pairs, assuming a mutation in one gene of a gene pair can affect the evolutionary fitness of mutations in its partner genes as mutation context. We employed PanCancer- and tumor type-specific mutational profiles to infer the ED of gene pairs and evaluated their biological relevance with respect to gene dependency and drug sensitivity.</p><p><strong>Results: </strong>We propose that dNdS ratios of gene pairs and their derived cdNS (context-dependent dNdS) scores as measure of ED distinguishing gene pairs either as synergistic (SYN) or antagonistic (ANT). Mutation contexts can induce substantial changes in the evolutionary fitness of mutations in the paired genes, e.g., IDH1 and IDH2 mutation contexts lead to substantial increase and decrease of dNdS ratios of ATRX indels and IDH1 missense mutations corresponding to SYN and ANT relationship with positive and negative cdNS scores, respectively. The impact of gene silencing or knock-outs on cell viability (genetic dependencies) often depends on ED, suggesting that ED can guide the selection of candidates for synthetic lethality such as TCF7L2-KRAS mutations. Using cell line-based drug sensitivity data, the effects of targeted agents on cell lines are often associated with mutations of genes exhibiting ED with the target genes, informing drug sensitizing or resistant mutations for targeted inhibitors, e.g., PRSS1 and CTCF mutations as resistant mutations to EGFR and BRAF inhibitors for lung adenocarcinomas and melanomas, respectively.</p><p><strong>Conclusions: </strong>We propose that the ED of gene pairs evaluated by dNdS ratios can advance our understanding of the functional relationship of genes with potential biological and clinical implications.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"103"},"PeriodicalIF":10.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.","authors":"Jonathan E Knikman, Qinglian Zhai, Carin A T C Lunenburg, Linda M Henricks, Stefan Böhringer, Maaike van der Lee, Femke M de Man, Steven M Offer, Shikshya Shrestha, Geert-Jan Creemers, Arnold Baars, Vincent O Dezentjé, Alexander L T Imholz, Frank J F Jeurissen, Johanna E A Portielje, Rob L H Jansen, Paul Hamberg, Helga J Droogendijk, Miriam Koopman, Peter Nieboer, Marlène H W van de Poel, Caroline M P W Mandigers, Ron H N van Schaik, Hans Gelderblom, Ron H J Mathijssen, Jan H M Schellens, Annemieke Cats, Henk-Jan Guchelaar, Jesse J Swen","doi":"10.1186/s13073-024-01354-z","DOIUrl":"10.1186/s13073-024-01354-z","url":null,"abstract":"<p><strong>Background: </strong>The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity.</p><p><strong>Methods: </strong>Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS.</p><p><strong>Results: </strong>Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 - 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41-11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10^-8), however, five variants were suggestive of association (P < 5 × 10^-6) with severe toxicity.</p><p><strong>Conclusions: </strong>Results from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"101"},"PeriodicalIF":10.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of genetic ancestry with molecular tumor profiles in colorectal cancer.","authors":"Brooke Rhead, David M Hein, Yannick Pouliot, Justin Guinney, Francisco M De La Vega, Nina N Sanford","doi":"10.1186/s13073-024-01373-w","DOIUrl":"10.1186/s13073-024-01373-w","url":null,"abstract":"<p><strong>Background: </strong>There are known disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity. Some of these disparities may be mediated by molecular changes in tumors that occur at different rates across populations. Genetic ancestry is a measure complementary to race and ethnicity that can overcome missing data issues and better capture genetic similarity in admixed populations. We aimed to identify somatic mutations and tumor gene expression differences associated with both genetic ancestry and imputed race and ethnicity.</p><p><strong>Methods: </strong>Sequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8454 primarily late-stage CRC patients. Genetic ancestry proportions for five continental groups-Africa (AFR), American indigenous (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS)-were estimated using ancestry informative markers. To address data gaps, race and ethnicity categories were imputed, resulting in assignments for 952 Hispanic/Latino, 420 non-Hispanic (NH) Asian, 1061 NH Black, and 5763 NH White individuals. We assessed association of genetic ancestry proportions and imputed race and ethnicity categories with somatic mutations in relevant CRC genes and in 2608 expression profiles, as well as 1957 consensus molecular subtypes (CMS).</p><p><strong>Results: </strong>Increased AFR ancestry was associated with higher odds of somatic mutations in APC, KRAS, and PIK3CA and lower odds of BRAF mutations. Additionally, increased EAS ancestry was associated with lower odds of mutations in KRAS, EUR with higher odds in BRAF, and the Hispanic/Latino category with lower odds in BRAF. Greater AFR ancestry and the NH Black category were associated with higher rates of CMS3, while a higher proportion of Hispanic/Latino patients exhibited indeterminate CMS classifications.</p><p><strong>Conclusions: </strong>Molecular differences in CRC tumor mutation frequencies and gene expression that may underlie observed differences by race and ethnicity were identified. The association of AFR ancestry with increased KRAS mutations aligns with higher CMS3 subtype rates in NH Black patients. The increase of indeterminate CMS in Hispanic/Latino patients suggests that subtype classification methods could benefit from enhanced patient diversity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"99"},"PeriodicalIF":10.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11321170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Laterality, heterotaxy, and isolated congenital heart defects : The genetic basis of the segmental nature of the heart.","authors":"Carolina Putotto, Flaminia Pugnaloni, Marta Unolt, Giulio Calcagni, Paolo Versacci, Bruno Marino","doi":"10.1186/s13073-024-01375-8","DOIUrl":"10.1186/s13073-024-01375-8","url":null,"abstract":"<p><p>To date, the role of NODAL in normal and abnormal L-R asymmetry has been well established. In a recent paper, mutations of this gene have been reported in heterotaxy but also in transposition with D- or L-ventricular loop. The effects of NODAL and other laterality genes can be recognized separately in all three cardiac segments: for topology and septation of the atria, for ventricular looping, and for spiralization and alignment of the great arteries.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"100"},"PeriodicalIF":10.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial multiomics reveals a subpopulation of fibroblasts associated with cancer stemness in human hepatocellular carcinoma.","authors":"Si-Yu Jing, Dan Liu, Na Feng, Hui Dong, He-Qi Wang, Xi Yan, Xu-Feng Chen, Min-Cheng Qu, Ping Lin, Bin Yi, Feiling Feng, Lei Chen, Hong-Yang Wang, Hong Li, Yu-Fei He","doi":"10.1186/s13073-024-01367-8","DOIUrl":"10.1186/s13073-024-01367-8","url":null,"abstract":"<p><strong>Background: </strong>Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear.</p><p><strong>Methods: </strong>We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays.</p><p><strong>Results: </strong>We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells.</p><p><strong>Conclusions: </strong>We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"98"},"PeriodicalIF":10.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ENU-based dominant genetic screen identifies contractile and neuronal gene mutations in congenital heart disease","authors":"Xiaoxi Luo, Lifeng Liu, Haowei Rong, Xiangyang Liu, Ling Yang, Nan Li, Hongjun Shi","doi":"10.1186/s13073-024-01372-x","DOIUrl":"https://doi.org/10.1186/s13073-024-01372-x","url":null,"abstract":"Congenital heart disease (CHD) is the most prevalent congenital anomaly, but its underlying causes are still not fully understood. It is believed that multiple rare genetic mutations may contribute to the development of CHD. In this study, we aimed to identify novel genetic risk factors for CHD using an ENU-based dominant genetic screen in mice. We analyzed fetuses with malformed hearts and compared them to control littermates by whole exome or whole genome sequencing (WES/WGS). The differences in mutation rates between observed and expected values were tested using the Poisson and Binomial distribution. Additionally, we compared WES data from human CHD probands obtained from the Pediatric Cardiac Genomics Consortium with control subjects from the 1000 Genomes Project using Fisher’s exact test to evaluate the burden of rare inherited damaging mutations in patients. By screening 10,285 fetuses, we identified 1109 cases with various heart defects, with ventricular septal defects and bicuspid aortic valves being the most common types. WES/WGS analysis of 598 cases and 532 control littermates revealed a higher number of ENU-induced damaging mutations in cases compared to controls. GO term and KEGG pathway enrichment analysis showed that pathways related to cardiac contraction and neuronal development and functions were enriched in cases. Further analysis of 1457 human CHD probands and 2675 control subjects also revealed an enrichment of genes associated with muscle and nervous system development in patients. By combining the mice and human data, we identified a list of 101 candidate digenic genesets, from which each geneset was co-mutated in at least one mouse and two human probands with CHD but not in control mouse and control human subjects. Our findings suggest that gene mutations affecting early hemodynamic perturbations in the developing heart may play a significant role as a genetic risk factor for CHD. Further validation of the candidate gene set identified in this study could enhance our understanding of the complex genetics underlying CHD and potentially lead to the development of new diagnostic and therapeutic approaches.","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"69 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141940261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genetics and epidemiology of N- and O-immunoglobulin A glycomics.","authors":"Alessia Visconti, Niccolò Rossi, Albert Bondt, Agnes Hipgrave Ederveen, Gaurav Thareja, Carolien A M Koeleman, Nisha Stephan, Anna Halama, Hannah J Lomax-Browne, Matthew C Pickering, Xu-Jie Zhou, Manfred Wuhrer, Karsten Suhre, Mario Falchi","doi":"10.1186/s13073-024-01369-6","DOIUrl":"10.1186/s13073-024-01369-6","url":null,"abstract":"<p><strong>Background: </strong>Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation.</p><p><strong>Methods: </strong>We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species.</p><p><strong>Results: </strong>We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries.</p><p><strong>Conclusions: </strong>Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"96"},"PeriodicalIF":10.4,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11312925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial heterogeneity in the ischemic stroke mouse brain of both sexes.","authors":"Ángela Del Águila, Ran Zhang, Xinyuan Yu, Lihong Dang, Feng Xu, Jin Zhang, Vaibhav Jain, Jilin Tian, Xiao-Ping Zhong, Huaxin Sheng, Wei Yang","doi":"10.1186/s13073-024-01368-7","DOIUrl":"10.1186/s13073-024-01368-7","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke elicits a complex and sustained immune response in the brain. Immunomodulatory treatments have long held promise for improving stroke outcomes, yet none have succeeded in the clinical setting. This lack of success is largely due to our incomplete understanding of how immune cells respond to stroke. The objective of the current study was to dissect the effect of permanent stroke on microglia, the resident immune cells within the brain parenchyma.</p><p><strong>Methods: </strong>A permanent middle cerebral artery occlusion (pMCAO) model was used to induce ischemic stroke in young male and female mice. Microglia were sorted from fluorescence reporter mice after pMCAO or sham surgery and then subjected to single-cell RNA sequencing analysis. Various methods, including flow cytometry, RNA in situ hybridization, immunohistochemistry, whole-brain imaging, and bone marrow transplantation, were also employed to dissect the microglial response to stroke. Stroke outcomes were evaluated by infarct size and behavioral tests.</p><p><strong>Results: </strong>First, we showed the morphologic and spatial changes in microglia after stroke. We then performed single-cell RNA sequencing analysis on microglia isolated from sham and stroke mice of both sexes. The data indicate no major sexual dimorphism in the microglial response to permanent stroke. Notably, we identified seven potential stroke-associated microglial clusters, including four major clusters characterized by a disease-associated microglia-like signature, a highly proliferative state, a macrophage-like profile, and an interferon (IFN) response signature, respectively. Importantly, we provided evidence that the macrophage-like cluster may represent the long-sought stroke-induced microglia subpopulation with increased CD45 expression. Lastly, given that the IFN-responsive subset constitutes the most prominent microglial population in the stroke brain, we used fludarabine to pharmacologically target STAT1 signaling and found that fludarabine treatment improved long-term stroke outcome.</p><p><strong>Conclusions: </strong>Our findings shed new light on microglia heterogeneity in stroke pathology and underscore the potential of targeting specific microglial populations for effective stroke therapies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"95"},"PeriodicalIF":10.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-analysis identifies common gut microbiota associated with multiple sclerosis.","authors":"Qingqi Lin, Yair Dorsett, Ali Mirza, Helen Tremlett, Laura Piccio, Erin E Longbrake, Siobhan Ni Choileain, David A Hafler, Laura M Cox, Howard L Weiner, Takashi Yamamura, Kun Chen, Yufeng Wu, Yanjiao Zhou","doi":"10.1186/s13073-024-01364-x","DOIUrl":"10.1186/s13073-024-01364-x","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have identified a diverse group of microbial taxa that differ between patients with multiple sclerosis (MS) and the healthy population. However, interpreting findings on MS-associated microbiota is challenging, as there is no true consensus. It is unclear whether there is gut microbiota commonly altered in MS across studies.</p><p><strong>Methods: </strong>To answer this, we performed a meta-analysis based on the 16S rRNA gene sequencing data from seven geographically and technically diverse studies comprising a total of 524 adult subjects (257 MS and 267 healthy controls). Analysis was conducted for each individual study after reprocessing the data and also by combining all data together. The blocked Wilcoxon rank-sum test and linear mixed-effects regression were used to identify differences in microbial composition and diversity between MS and healthy controls. Network analysis was conducted to identify bacterial correlations. A leave-one-out sensitivity analysis was performed to ensure the robustness of the findings.</p><p><strong>Results: </strong>The microbiome community structure was significantly different between studies. Re-analysis of data from individual studies revealed a lower relative abundance of Prevotella in MS across studies, compared to controls. Meta-analysis found that although alpha and beta diversity did not differ between MS and controls, a higher abundance of Actinomyces and a lower abundance of Faecalibacterium were reproducibly associated with MS. Additionally, network analysis revealed that the recognized negative Bacteroides-Prevotella correlation in controls was disrupted in patients with MS.</p><p><strong>Conclusions: </strong>Our meta-analysis identified common gut microbiota associated with MS across geographically and technically diverse studies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"94"},"PeriodicalIF":10.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}