Genome Medicine最新文献

{"title":"Genomic surveillance of multidrug-resistant organisms based on long-read sequencing.","authors":"Fabian Landman, Casper Jamin, Angela de Haan, Sandra Witteveen, Jeroen Bos, Han G J van der Heide, Leo M Schouls, Antoni P A Hendrickx","doi":"10.1186/s13073-024-01412-6","DOIUrl":"10.1186/s13073-024-01412-6","url":null,"abstract":"<p><strong>Background: </strong>Multidrug-resistant organisms (MDRO) pose a significant threat to public health worldwide. The ability to identify antimicrobial resistance determinants, to assess changes in molecular types, and to detect transmission are essential for surveillance and infection prevention of MDRO. Molecular characterization based on long-read sequencing has emerged as a promising alternative to short-read sequencing. The aim of this study was to characterize MDRO for surveillance and transmission studies based on long-read sequencing only.</p><p><strong>Methods: </strong>Genomic DNA of 356 MDRO was automatically extracted using the Maxwell-RSC48. The MDRO included 106 Klebsiella pneumoniae isolates, 85 Escherichia coli, 15 Enterobacter cloacae complex, 10 Citrobacter freundii, 34 Pseudomonas aeruginosa, 16 Acinetobacter baumannii, and 69 methicillin-resistant Staphylococcus aureus (MRSA), of which 24 were from an outbreak. MDRO were sequenced using both short-read (Illumina NextSeq 550) and long-read (Nanopore Rapid Barcoding Kit-24-V14, R10.4.1) whole-genome sequencing (WGS). Basecalling was performed for two distinct models using Dorado-0.3.2 duplex mode. Long-read data was assembled using Flye, Canu, Miniasm, Unicycler, Necat, Raven, and Redbean assemblers. Long-read WGS data with > 40 × coverage was used for multi-locus sequence typing (MLST), whole-genome MLST (wgMLST), whole-genome single-nucleotide polymorphisms (wgSNP), in silico multiple locus variable-number of tandem repeat analysis (iMLVA) for MRSA, and identification of resistance genes (ABRicate).</p><p><strong>Results: </strong>Comparison of wgMLST profiles based on long-read and short-read WGS data revealed > 95% of wgMLST profiles within the species-specific cluster cut-off, except for P. aeruginosa. The wgMLST profiles obtained by long-read and short-read WGS differed only one to nine wgMLST alleles or SNPs for K. pneumoniae, E. coli, E. cloacae complex, C. freundii, A. baumannii complex, and MRSA. For P. aeruginosa, differences were up to 27 wgMLST alleles between long-read and short-read wgMLST and 0-10 SNPs. MLST sequence types and iMLVA types were concordant between long-read and short-read WGS data and conventional MLVA typing. Antimicrobial resistance genes were detected in long-read sequencing data with high sensitivity/specificity (92-100%/99-100%). Long-read sequencing enabled analysis of an MRSA outbreak.</p><p><strong>Conclusions: </strong>We demonstrate that molecular characterization of automatically extracted DNA followed by long-read sequencing is as accurate compared to short-read sequencing and suitable for typing and outbreak analysis as part of genomic surveillance of MDRO. However, the analysis of P. aeruginosa requires further improvement which may be obtained by other basecalling algorithms. The low implementation costs and rapid library preparation for long-read sequencing of MDRO extends its applicability to resource-constrained settings ","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"137"},"PeriodicalIF":10.4,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715904","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":"Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities.","authors":"Yuka Takemon, Erin D Pleasance, Alessia Gagliardi, Christopher S Hughes, Veronika Csizmok, Kathleen Wee, Diane L Trinh, Ryan D Huff, Andrew J Mungall, Richard A Moore, Eric Chuah, Karen L Mungall, Eleanor Lewis, Jessica Nelson, Howard J Lim, Daniel J Renouf, Steven Jm Jones, Janessa Laskin, Marco A Marra","doi":"10.1186/s13073-024-01401-9","DOIUrl":"10.1186/s13073-024-01401-9","url":null,"abstract":"<p><strong>Background: </strong>Loss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required.</p><p><strong>Methods: </strong>Here, we computationally map genetic networks of KMT2D, a tumour suppressor gene frequently mutated in several cancer types. Using KMT2D loss-of-function (KMT2D^LOF) mutations as a model, we illustrate the utility of in silico genetic networks in uncovering novel functional associations and vulnerabilities in cancer cells with LOF alterations affecting tumour suppressor genes.</p><p><strong>Results: </strong>We revealed genetic interactors with functions in histone modification, metabolism, and immune response and synthetic lethal (SL) candidates, including some encoding existing therapeutic targets. Notably, we predicted WRN as a novel SL interactor and, using recently available WRN inhibitor (HRO761 and VVD-133214) treatment response data, we observed that KMT2D mutational status significantly distinguishes treatment-sensitive MSI cell lines from treatment-insensitive MSI cell lines.</p><p><strong>Conclusions: </strong>Our study thus illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"136"},"PeriodicalIF":10.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692865","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":"Epigenetic age and long-term cancer risk following a stroke.","authors":"Antoni Suárez-Pérez, Adrià Macias-Gómez, Isabel Fernández-Pérez, Marta Vallverdú-Prats, Elisa Cuadrado-Godia, Eva Giralt-Steinhauer, Maia Campanale, Daniel Guisado-Alonso, Ana Rodríguez-Campello, Joan Jiménez-Balado, Jordi Jiménez-Conde, Angel Ois","doi":"10.1186/s13073-024-01408-2","DOIUrl":"10.1186/s13073-024-01408-2","url":null,"abstract":"<p><strong>Background: </strong>The association between increased cancer risk following a cerebrovascular event (CVE) has been previously reported. We hypothesize that biological age (B-age) acceleration is involved in this association. Our study aims to examine B-age as a novel contributing factor to cancer development post-CVE.</p><p><strong>Methods: </strong>From our prospective stroke registry (BasicMar), we selected 940 cases with epigenetic data. For this study, we specifically analyzed 648 of these patients who had available data, no prior history of cancer, and a minimum follow-up of 3 months. The primary outcome was cancer incidence. B-age was estimated using DNA methylation data derived from whole blood samples obtained within 24 h of stroke onset, employing various epigenetic clocks (including Hannum, Horvath, PhenoAge, Zhang_BLUP, Zhang_EN, and the mitotic epiTOC). Extrinsic epigenetic age acceleration (EEAA) was calculated as the residuals from the regression of B-age against chronological age (C-age). For epiTOC, the age-adjusted values were obtained by regressing out the effect of age from the raw epiTOC measurements. Estimated white cell counts were derived from DNA methylation data, and these cell fractions were used to compute the intrinsic epigenetic age acceleration (IEAA). Subsequently, we evaluated the independent association between EEAA, IEAA, and cancer incidence while controlling for potential confounding variables.</p><p><strong>Results: </strong>Among 648 patients with a median follow-up of 8.15 years, 83 (12.8%) developed cancer. Cox multivariable analyses indicated significant associations between Hannum, Zhang, and epiTOC EEAA and the risk of cancer after CVE. After adjusting for multiple testing and competing risks, EEAA measured by Hannum clock maintained an independent association with cancer risk. Specifically, for each year increase in Hannum's EEAA, we observed a 6.0% increased incidence of cancer (HR 1.06 [1.02-1.10], p value = 0.002).</p><p><strong>Conclusions: </strong>Our findings suggest that epigenetic accelerated aging, as indicated by Hannum's EEAA, may play a significant role in the increased cancer risk observed in CVE survivors.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"135"},"PeriodicalIF":10.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692863","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":"Integrated single-cell analysis reveals distinct epigenetic-regulated cancer cell states and a heterogeneity-guided core signature in tamoxifen-resistant breast cancer.","authors":"Kun Fang, Aigbe G Ohihoin, Tianxiang Liu, Lavanya Choppavarapu, Bakhtiyor Nosirov, Qianben Wang, Xue-Zhong Yu, Sailaja Kamaraju, Gustavo Leone, Victor X Jin","doi":"10.1186/s13073-024-01407-3","DOIUrl":"10.1186/s13073-024-01407-3","url":null,"abstract":"<p><strong>Background: </strong>Inter- and intra-tumor heterogeneity is considered a significant factor contributing to the development of endocrine resistance in breast cancer. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) allow us to explore inter- and intra-tumor heterogeneity at single-cell resolution. However, such integrated single-cell analysis has not yet been demonstrated to characterize the transcriptome and chromatin accessibility in breast cancer endocrine resistance.</p><p><strong>Methods: </strong>In this study, we conducted an integrated analysis combining scRNA-seq and scATAC-seq on more than 80,000 breast tissue cells from two normal tissues (NTs), three primary tumors (PTs), and three tamoxifen-treated recurrent tumors (RTs). A variety of cell types among breast tumor tissues were identified, PT- and RT-specific cancer cell states (CSs) were defined, and a heterogeneity-guided core signature (HCS) was derived through such integrated analysis. Functional experiments were performed to validate the oncogenic role of BMP7, a key gene within the core signature.</p><p><strong>Results: </strong>We observed a striking level of cell-to-cell heterogeneity among six tumor tissues and delineated the primary to recurrent tumor progression, underscoring the significance of these single-cell level tumor cell clusters classified from scRNA-seq data. We defined nine CSs, including five PT-specific, three RT-specific, and one PT-RT-shared CSs, and identified distinct open chromatin regions of CSs, as well as a HCS of 137 genes. In addition, we predicted specific transcription factors (TFs) associated with the core signature and novel biological/metabolism pathways that mediate the communications between CSs and the tumor microenvironment (TME). We finally demonstrated that BMP7 plays an oncogenic role in tamoxifen-resistant breast cancer cells through modulating MAPK signaling pathways.</p><p><strong>Conclusions: </strong>Our integrated single-cell analysis provides a comprehensive understanding of the tumor heterogeneity in tamoxifen resistance. We envision this integrated single-cell epigenomic and transcriptomic measure will become a powerful approach to unravel how epigenetic factors and the tumor microenvironment govern the development of tumor heterogeneity and to uncover potential therapeutic targets that circumvent heterogeneity-related failures.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"134"},"PeriodicalIF":10.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11572372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666970","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":"Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study.","authors":"Tongpeng Xu, Tian Tian, Chen Wang, Xiaofeng Chen, Xiangrong Zuo, Hanyu Zhou, Jianan Bai, Chenhui Zhao, Sujie Fu, Chongqi Sun, Ting Wang, Ling Zhu, Jingzhi Zhang, Enxiu Wang, Ming Sun, Yongqian Shu","doi":"10.1186/s13073-024-01405-5","DOIUrl":"10.1186/s13073-024-01405-5","url":null,"abstract":"<p><strong>Background: </strong>Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma.</p><p><strong>Methods: </strong>In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity.</p><p><strong>Results: </strong>We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME.</p><p><strong>Conclusions: </strong>Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma.</p><p><strong>Trial registration: </strong>ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"133"},"PeriodicalIF":10.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643755","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":"Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients.","authors":"Xiuli Zhang, S Peter Goedegebuure, Michael Y Chen, Rashmi Mishra, Felicia Zhang, Yik Yeung Yu, Kartik Singhal, Lijin Li, Feng Gao, Nancy B Myers, Tammi Vickery, Jasreet Hundal, Michael D McLellan, Mark A Sturmoski, Samuel W Kim, Ina Chen, Jesse T Davidson, Narendra V Sankpal, Stephanie Myles, Rama Suresh, Cynthia X Ma, Ademuyiwa Foluso, Andrea Wang-Gillam, Sherri Davies, Ian S Hagemann, Elaine R Mardis, Obi Griffith, Malachi Griffith, Christopher A Miller, Ted H Hansen, Timothy P Fleming, Robert D Schreiber, William E Gillanders","doi":"10.1186/s13073-024-01388-3","DOIUrl":"10.1186/s13073-024-01388-3","url":null,"abstract":"<p><strong>Background: </strong>Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence.</p><p><strong>Methods: </strong>Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing.</p><p><strong>Results: </strong>Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4-20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7-100%) in the cohort of vaccinated patients.</p><p><strong>Conclusion: </strong>Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses.</p><p><strong>Clinical trial registration number: </strong>NCT02348320.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"131"},"PeriodicalIF":10.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618566","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":"pVACview: an interactive visualization tool for efficient neoantigen prioritization and selection.","authors":"Huiming Xia, My H Hoang, Evelyn Schmidt, Susanna Kiwala, Joshua McMichael, Zachary L Skidmore, Bryan Fisk, Jonathan J Song, Jasreet Hundal, Thomas Mooney, Jason R Walker, S Peter Goedegebuure, Christopher A Miller, William E Gillanders, Obi L Griffith, Malachi Griffith","doi":"10.1186/s13073-024-01384-7","DOIUrl":"10.1186/s13073-024-01384-7","url":null,"abstract":"<p><strong>Background: </strong>Neoantigen-targeting therapies including personalized vaccines have shown promise in the treatment of cancers, particularly when used in combination with checkpoint blockade therapy. At least 100 clinical trials involving these therapies have been initiated globally. Accurate identification and prioritization of neoantigens is crucial for designing these trials, predicting treatment response, and understanding mechanisms of resistance. With the advent of massively parallel DNA and RNA sequencing technologies, it is now possible to computationally predict neoantigens based on patient-specific variant information. However, numerous factors must be considered when prioritizing neoantigens for use in personalized therapies. Complexities such as alternative transcript annotations, various binding, presentation and immunogenicity prediction algorithms, and variable peptide lengths/registers all potentially impact the neoantigen selection process. There has been a rapid development of computational tools that attempt to account for these complexities. While these tools generate numerous algorithmic predictions for neoantigen characterization, results from these pipelines are difficult to navigate and require extensive knowledge of the underlying tools for accurate interpretation. This often leads to over-simplification of pipeline outputs to make them tractable, for example, limiting prediction to a single RNA isoform or only summarizing the top ranked of many possible peptide candidates. In addition to variant detection, gene expression, and predicted peptide binding affinities, recent studies have also demonstrated the importance of mutation location, allele-specific anchor locations, and variation of T-cell response to long versus short peptides. Due to the intricate nature and number of salient neoantigen features, presenting all relevant information to facilitate candidate selection for downstream applications is a difficult challenge that current tools fail to address.</p><p><strong>Results: </strong>We have created pVACview, the first interactive tool designed to aid in the prioritization and selection of neoantigen candidates for personalized neoantigen therapies including cancer vaccines. pVACview has a user-friendly and intuitive interface where users can upload, explore, select, and export their neoantigen candidates. The tool allows users to visualize candidates at multiple levels of detail including variant, transcript, peptide, and algorithm prediction information.</p><p><strong>Conclusions: </strong>pVACview will allow researchers to analyze and prioritize neoantigen candidates with greater efficiency and accuracy in basic and translational settings. The application is available as part of the pVACtools software at pvactools.org and as an online server at pvacview.org.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"132"},"PeriodicalIF":10.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618568","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":"Identification of pathological pathways centered on circRNA dysregulation in association with irreversible progression of Alzheimer's disease.","authors":"Feng Wang, Yangping Li, Huifeng Shen, Paula Martinez-Feduchi, Xingyu Ji, Peng Teng, Siddharth Krishnakumar, Jian Hu, Li Chen, Yue Feng, Bing Yao","doi":"10.1186/s13073-024-01404-6","DOIUrl":"10.1186/s13073-024-01404-6","url":null,"abstract":"<p><strong>Background: </strong>Circular RNAs (circRNAs) are highly stable regulators, often accumulated in mammalian brains and thought to serve as \"memory molecules\" that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the brains of Alzheimer's disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored.</p><p><strong>Methods: </strong>We combined Poly(A)-tailing/RNase R digestion experimental approach with CARP, our published computational framework using pseudo-reference alignment for more sensitive and accurate circRNA detection to identify genome-wide circRNA dysregulation and their downstream pathways in the 5xFAD mouse cerebral cortex between 5 and 7 months of age, a critical window marks the transition from reversible to irreversible pathogenic progression. Dysregulated circRNAs and pathways associated with disease progression in 5xFAD cortex were systematically compared with circRNAs affected in postmortem subcortical areas of a large human AD cohort. A top-ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to examine AD-relevant molecular and cellular changes.</p><p><strong>Results: </strong>We discovered genome-wide circRNA alterations specifically in 5xFAD cortex associated with AD progression, many of which are commonly dysregulated in the subcortical areas of AD patients. Among these circRNAs, circGigyf2 is highly conserved and showed the highest net reduction specifically in the 7-month 5xFAD cortex. CircGIGYF2 level in AD patients' cortices negatively correlated with dementia severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs), including the cleavage and polyadenylation factor 6 (CPSF6). Moreover, circGigyf2 downregulation in AD promoted silencing activities of its sponged miRNAs and enhanced polyadenylation site processing efficiency of CPSF6 targets. Furthermore, circGigyf2 depletion in a mouse neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated apoptotic responses upon insults, which strongly support the causative roles of circGigyf2 deficiency in AD neurodegeneration.</p><p><strong>Conclusions: </strong>Together, our results unveiled brain circRNAs associated with irreversible disease progression in an AD mouse model that is also affected in AD patients and identified novel molecular mechanisms underlying the dysregulation of conserved circRNA pathways contributing to AD pathogenesis.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"129"},"PeriodicalIF":10.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618548","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":"KleTy: integrated typing scheme for core genome and plasmids reveals repeated emergence of multi-drug resistant epidemic lineages in Klebsiella worldwide.","authors":"Heng Li, Xiao Liu, Shengkai Li, Jie Rong, Shichang Xie, Yuan Gao, Ling Zhong, Quangui Jiang, Guilai Jiang, Yi Ren, Wanping Sun, Yuzhi Hong, Zhemin Zhou","doi":"10.1186/s13073-024-01399-0","DOIUrl":"10.1186/s13073-024-01399-0","url":null,"abstract":"<p><strong>Background: </strong>Clinically important lineages in Klebsiella, especially those expressing multi-drug resistance (MDR), pose severe threats to public health worldwide. They arose from the co-evolution of the vertically inherited core genome and horizontal gene transfers by plasmids, which has not been systematically explored.</p><p><strong>Methods: </strong>We designed KleTy, which consists of dedicated typing schemes for both the core genome and plasmids in Klebsiella. We compared the performance of KleTy with many state-of-the-art pipelines using both simulated and real data.</p><p><strong>Results: </strong>Employing KleTy, we genotyped 33,272 Klebsiella genomes, categorizing them into 1773 distinct populations and predicting the presence of 87,410 plasmids from 837 clusters (PCs). Notably, Klebsiella is the center of the plasmid-exchange network within Enterobacteriaceae. Our results associated the international emergence of prevalent Klebsiella populations with only four carbapenem-resistance (CR) PCs, two hypervirulent PCs, and two hvCR-PCs encoding both carbapenemase and hypervirulence. Furthermore, we observed the ongoing international emergence of bla_NDM, accompanied by the replacement of the previously dominant population, bla_KPC-encoding HC1360_8 (CC258), during 2003-2018, with the emerging bla_NDM-encoding HC1360_3 (CC147) thereafter. Additionally, expansions of hypervirulent carbapenem-resistant Klebsiella pneumoniae (hvCRKP) were evidenced in both populations, driven by plasmids of MDR-hypervirulence convergences.</p><p><strong>Conclusions: </strong>The study illuminates how the global genetic landscape of Klebsiella has been shaped by the co-evolution of both the core genome and the plasmids, underscoring the importance of surveillance and control of the dissemination of plasmids for curtailing the emergence of hvCRKPs.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"130"},"PeriodicalIF":10.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11556198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618562","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":"Exploring multi-omics and clinical characteristics linked to accelerated biological aging in Asian women of reproductive age: insights from the S-PRESTO study.","authors":"Li Chen, Karen Mei-Ling Tan, Jia Xu, Priti Mishra, Sartaj Ahmad Mir, Min Gong, Kothandaraman Narasimhan, Bryan Ng, Jun Shi Lai, Mya Thway Tint, Shirong Cai, Suresh Anand Sadananthan, Navin Michael, Jadegoud Yaligar, Sambasivam Sendhil Velan, Melvin Khee Shing Leow, Kok Hian Tan, Jerry Chan, Michael J Meaney, Shiao-Yng Chan, Yap Seng Chong, Johan G Eriksson","doi":"10.1186/s13073-024-01403-7","DOIUrl":"10.1186/s13073-024-01403-7","url":null,"abstract":"<p><strong>Background: </strong>Phenotypic age (PhenoAge), a widely used marker of biological aging, has been shown to be a robust predictor of all-cause mortality and morbidity in different populations. Existing studies on biological aging have primarily focused on individual domains, resulting in a lack of a comprehensive understanding of the multi-systemic dysregulation that occurs in aging.</p><p><strong>Methods: </strong>PhenoAge was evaluated based on a linear combination of chronological age (CA) and 9 clinical biomarkers in 952 multi-ethnic Asian women of reproductive age. Phenotypic age acceleration (PhenoAgeAccel), an aging biomarker, represents PhenoAge after adjusting for CA. This study conducts an in-depth association analysis of PhenoAgeAccel with clinical, nutritional, lipidomic, gut microbiome, and genetic factors.</p><p><strong>Results: </strong>Higher adiposity, glycaemia, plasma saturated fatty acids, kynurenine pathway metabolites, GlycA, riboflavin, nicotinamide, and insulin-like growth factor binding proteins were positively associated with PhenoAgeAccel. Conversely, a healthier diet and higher levels of pyridoxal phosphate, all-trans retinol, betaine, tryptophan, glutamine, histidine, apolipoprotein B, and insulin-like growth factors were inversely associated with PhenoAgeAccel. Lipidomic analysis found 132 lipid species linked to PhenoAgeAccel, with PC(O-36:0) showing the strongest positive association and CE(24:5) demonstrating the strongest inverse association. A genome-wide association study identified rs9864994 as the top genetic variant (P = 5.69E-07) from the ZDHHC19 gene. Gut microbiome analysis revealed that Erysipelotrichaceae UCG-003 and Bacteroides vulgatus were inversely associated with PhenoAgeAccel. Integrative network analysis of aging-related factors underscored the intricate links among clinical, nutritional and lipidomic variables, such as positive associations between kynurenine pathway metabolites, amino acids, adiposity, and insulin resistance. Furthermore, potential mediation effects of blood biomarkers related to inflammation, immune response, and nutritional and energy metabolism were observed in the associations of diet, adiposity, genetic variants, and gut microbial species with PhenoAgeAccel.</p><p><strong>Conclusions: </strong>Our findings provide a comprehensive analysis of aging-related factors across multiple platforms, delineating their complex interconnections. This study is the first to report novel signatures in lipidomics, gut microbiome and blood biomarkers specifically associated with PhenoAgeAccel. These insights are invaluable in understanding the molecular and metabolic mechanisms underlying biological aging and shed light on potential interventions to mitigate accelerated biological aging by targeting modifiable factors.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"128"},"PeriodicalIF":10.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618544","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}